610 results
Search Results
2. Oxytocic polypeptides in human urine.
- Author
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WALASZEK EJ
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- Animals, Female, Rats, Bradykinin, Dental Pulp, Furans, Muscles physiology, Oxytocics, Paper, Peptides, Serum Globulins, Work
- Abstract
The work of Gomes on the polypeptide in human urine which causes contraction of the rat uterus has been extended. Concentrates were prepared by means of paper pulp columns similar to those used by Rocha e Silva and his colleagues for the purification of bradykinin, and evidence was obtained for the presence of two different active substances not only in human urine but also in a preparation of bradykinin. The effect of human urine on the rat uterus is probably due to bradykinin itself or a mixture of similar substances.
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- 1957
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3. Kininogenase of the guinea-pig's coagulating gland and the release of bradykinin.
- Author
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Moriwaki C and Schachte M
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- Animals, Arginine, Chromatography, Chromatography, Gel, Chromatography, Paper, Chromatography, Thin Layer, Esters, Guinea Pigs, Male, Methylcellulose, Protease Inhibitors, Serum Globulins, Tosyl Compounds, Bradykinin, Endopeptidases isolation & purification, Genitalia, Male enzymology
- Abstract
A kininogenase (CGK) in the coagulating gland of the guinea-pig was partially purified, characterized and separated from a kininase also present in the gland. This kininogenase is not inhibited by the usual kininogenase and protease inhibitors. Our results indicate that it is identical with the esterolytic enzyme in the gland which hydrolyses the synthetic ester TAME. The kinin released by CGK from dog's crude pseudoglobulin was purified more than 1500 times and identified as bradykinin by chromatography on paper, on carboxymethyl-cellulose columns, and on silica gel.
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- 1971
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4. Radiommunoassay of bradykinin.
- Author
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Rinderknecht H, Haverback BJ, and Aladjem F
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- Animals, Antibody Formation, Carbon metabolism, Carbon Isotopes, Chromatography, Paper, Goats, Hemocyanins, Immune Sera, Immunization, Protein Binding, Tritium, Bradykinin analysis, Immunoassay
- Published
- 1967
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5. All-D-bradykinin and the problem of peptide antimetabolites.
- Author
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Stewart JM and Woolley DW
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- Animals, Biological Assay, Chemical Phenomena, Chemistry, Chemistry Techniques, Analytical, Chromatography, Paper, Countercurrent Distribution, Duodenum drug effects, Electrophoresis, Female, In Vitro Techniques, Muscle, Smooth drug effects, Rats, Stomach drug effects, Uterus drug effects, Antimetabolites, Bradykinin
- Published
- 1965
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6. Formation of bradykinin from kallidin-10 by aminopeptidase B.
- Author
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Hopsu-Havu VK, Mäkinen KK, and Glenner GG
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- Chromatography, Paper, Aminopeptidases metabolism, Bradykinin biosynthesis, Kallidin metabolism
- Published
- 1966
- Full Text
- View/download PDF
7. Evidence for the release of bradykinin in carcinoid syndrome.
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Oates JA, Pettinger WA, and Doctor RB
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- Animals, Chromatography, Paper, Electrophoresis, Female, Humans, Rats, Uterus drug effects, Bradykinin metabolism, Bradykinin pharmacology, Malignant Carcinoid Syndrome metabolism
- Published
- 1966
- Full Text
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8. A historic overview of the paper An excitatory nociceptive cardiac reflex elicited by bradykinin and potentiated by prostaglandins and myocardial ischaemia (1976)
- Author
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Janina Staszewska-Woolley
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Myocardial ischaemia ,Physiology ,Heart Ventricles ,Myocardial Ischemia ,Pain ,Bradykinin ,Cardiac reflex ,chemistry.chemical_compound ,Dogs ,Physiology (medical) ,Reflex ,medicine ,Animals ,Myocardial infarction ,Publishing ,business.industry ,Adrenergic response ,Heart ,History, 20th Century ,medicine.disease ,Nociception ,chemistry ,Bibliometrics ,Anesthesia ,Prostaglandins ,Excitatory postsynaptic potential ,Cardiology and Cardiovascular Medicine ,business ,Histamine - Abstract
The work described in this paper has a long and complex history. Its origin can be traced back to 1964 when, after receiving my M.D. degree, I was offered by Dr. John Vane (whom I had met in Poland in 1963) a postdoctoral fellowship in his laboratory in the Deptartment of Pharmacology, Royal College of Surgeons of England in London. My work there made use of the original blood-bathed organ (BBO) bioassay technique of Vane [1] to study the release of catecholamines by histamine and by peptides, including bradykinin. This was my first introduction into the pharmacology of bradykinin, which turned out to be of great value for its subsequent use in studies of cardiac reflexes. My interest in cardiac reflexes had been stimulated by studies of the adrenergic response associated with acute myocardial infarction in dogs, which were carried out in collaboration with Dr. L. Ceremuzynski during 1967–1970 in the Medical Research Centre of the Polish Academy of Sciences …
- Published
- 2000
9. Understanding COVID-19 outcome: Exploring the prognostic value of soluble biomarkers indicative of endothelial impairment.
- Author
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Mariappan V, Adla D, Jangili S, Ranganadin P, Green SR, Mohammed S, Mutheneni SR, and Pillai AB
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- Humans, Female, Male, Middle Aged, Prognosis, Adult, Aged, Fibrin Fibrinogen Degradation Products metabolism, Fibrin Fibrinogen Degradation Products analysis, Severity of Illness Index, Endothelium, Vascular metabolism, Kallikreins blood, alpha 1-Antitrypsin blood, COVID-19 blood, COVID-19 diagnosis, Biomarkers blood, Interleukin-18 blood, SARS-CoV-2, Bradykinin blood
- Abstract
Host proteins released by the activated endothelial cells during SARS-CoV-2 infection are implicated to be involved in coagulation and endothelial dysfunction. However, the underlying mechanism that governs the vascular dysfunction and disease severity in COVID-19 remains obscure. The study evaluated the serum levels of Bradykinin, Kallikrein, SERPIN A, and IL-18 in COVID-19 (N-42 with 20 moderate and 22 severe) patients compared to healthy controls (HC: N-10) using ELISA at the day of admission (DOA) and day 7 post-admission. The efficacy of the protein levels in predicting disease severity was further determined using machine learning models. The levels of bradykinins and SERPIN A were higher (P ≤ 0.001) in both severe and moderate cases on day 7 post-admission compared to DOA. All the soluble proteins studied were found to elevated (P ≤ 0.01) in severe compared to moderate in day 7 and were positively correlated (P ≤ 0.001) with D-dimer, a marker for coagulation. ROC analysis identified that SERPIN A, IL-18, and bradykinin could predict the clinical condition of COVID-19 with AUC values of 1, 0.979, and 1, respectively. Among the models trained using univariate model analysis, SERPIN A emerged as a strong prognostic biomarker for COVID-19 disease severity. The serum levels of SERPIN A in conjunction with the coagulation marker D-dimer, serve as a predictive indicator for COVID-19 clinical outcomes. However, studies are required to ascertain the role of these markers in disease virulence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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10. Mast cell degranulation and bradykinin-induced angioedema - searching for the missing link.
- Author
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Porebski G, Dziadowiec A, Rybka H, Kitel R, and Kwitniewski M
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- Humans, Animals, Angioedema metabolism, Angioedema immunology, Angioedema etiology, Nerve Tissue Proteins metabolism, Kallikrein-Kinin System physiology, Mast Cells immunology, Mast Cells metabolism, Cell Degranulation, Bradykinin metabolism, Receptors, G-Protein-Coupled metabolism, Receptors, Neuropeptide metabolism
- Abstract
Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor MR declared a past co-authorship with the author GP., (Copyright © 2024 Porebski, Dziadowiec, Rybka, Kitel and Kwitniewski.)
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- 2024
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11. The virtually mature B‐type natriuretic peptide (BNP1‐32) is a precursor for the more effective BNP1‐30
- Author
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Xudong Zhu, Andrew M. Moore, Yong Wang, Anja Schwiebs, Kristin Pankow, Thomas Walther, and Wolf-Eberhard Siems
- Subjects
0301 basic medicine ,medicine.drug_class ,Vasodilator Agents ,Metabolite ,Bradykinin ,Pharmacology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Natriuretic Peptide, Brain ,Natriuretic peptide ,Animals ,Medicine ,Natriuretic Peptides ,Receptor ,Heart Failure ,Peptide Metabolism ,business.industry ,Biological activity ,Research Papers ,Angiotensin II ,030104 developmental biology ,chemistry ,Guanylate Cyclase ,business ,Atrial Natriuretic Factor ,030217 neurology & neurosurgery ,Research Paper - Abstract
Background and purpose The B-type natriuretic peptide (BNP1-32) exerts vasorelaxing and cardioprotective activity. BNP is used as a biomarker for the diagnosis of cardiopathological conditions and recombinant BNP1-32 as a drug for the treatment of such. BNP1-32 has a short half-life and thus, similar to other vasoactive peptides like angiotensin II and bradykinin, can be enzymatically truncated forming bioactive metabolites. We aimed to investigate the metabolism of BNP1-32 in the mouse lung, to identify potential new BNP metabolites and to disclose their biological activity compared to the BNP1-32, in vitro and in vivo. Experimental approach Using HPLC and MS, we identified a new BNP metabolite, BNP1-30, in the lung being generated by endothelin-converting enzyme-1. Key results BNP1-30 is more efficient in stimulating the guanylyl cyclase (GC) receptor A and, in contrast to BNP1-32, is also able to profoundly stimulate the GC-B. In vivo, BNP1-30 reduced the mean arterial BP of normotensive mice after acute infusion significantly more than BNP1-32. In a model of severe hypertension, a 3-day infusion of BNP1-30 was able to reduce systolic BP by 30 mmHg and to improve markers of heart failure, while BNP1-32 was without significant effect. Conclusions and implications Our results suggest that BNP1-32 is the precursor for the biologically more active BNP1-30 leading to a fundamental extension of the natriuretic peptide system. Due to expanded activity, BNP1-30 might be a promising treatment option for cardiovascular diseases. Furthermore, its potency as a new diagnostic marker of specific cardiac diseases should be evaluated.
- Published
- 2020
12. Targeted LC-MS/MS platform for the comprehensive determination of peptides in the kallikrein-kinin system
- Author
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Bjoern B. Burckhardt and Tanja Gangnus
- Subjects
Bioanalysis ,Kallikrein-Kinin System ,Bradykinin ,Endogeny ,Pharmacology ,01 natural sciences ,Biochemistry ,Analytical Chemistry ,Plasma ,03 medical and health sciences ,chemistry.chemical_compound ,Limit of Detection ,Tandem Mass Spectrometry ,In vivo ,Lc ms ms ,medicine ,Humans ,cardiovascular diseases ,LC-MS/MS ,Angioedema ,030304 developmental biology ,0303 health sciences ,Kallidin ,010401 analytical chemistry ,COVID-19 ,Kinin ,Peptide Fragments ,0104 chemical sciences ,chemistry ,medicine.symptom ,circulatory and respiratory physiology ,Research Paper ,Chromatography, Liquid - Abstract
The kallikrein-kinin system (KKS) is involved in many physiological and pathophysiological processes and is assumed to be connected to the development of clinical symptoms of angioedema or COVID-19, among other diseases. However, despite its diverse role in the regulation of physiological and pathophysiological functions, knowledge about the KKS in vivo remains limited. The short half-lives of kinins, their low abundance and structural similarities and the artificial generation of the kinin bradykinin greatly hinder reliable and accurate determination of kinin levels in plasma. To address these issues, a sensitive LC-MS/MS platform for the comprehensive and simultaneous determination of the four active kinins bradykinin, kallidin, des-Arg(9)-bradykinin and des-Arg(10)-kallidin and their major metabolites bradykinin 2-9, bradykinin 1-7 and bradykinin 1-5 was developed. This platform was validated according to the bioanalytical guideline of the US Food and Drug Administration regarding linearity, accuracy, precision, sensitivity, carry-over, recovery, parallelism, matrix effects and stability in plasma of healthy volunteers. The validated platform encompassed a broad calibration curve range from 2.0–15.3 pg/mL (depending on the kinin) up to 1000 pg/mL, covering the expected concentrations in disease states. No source-dependent matrix effects were identified, and suitable stability of the analytes in plasma was observed. The applicability of the developed platform was proven by the determination of endogenous levels in healthy volunteers, whose plasma kinin levels were successfully detected in the low pg/mL range. The established platform facilitates the investigation of kinin-mediated diseases (e.g. angioedema, COVID-19) and enables the assessment of the impact of altered enzyme activities on the formation or degradation of kinins. Graphical abstract
- Published
- 2021
13. Vasomotor effects of 5-hydroxytryptamine, histamine, angiotensin II, acetylcholine, noradrenaline, and bradykinin on the cerebral artery of bottlenose dolphin (Tursiops truncatus)
- Author
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Yuji Sawatari, Mitsuya Shiraishi, Moe Nakamura, Mika Otsuka, Takeshi Obi, Atsushi Miyamoto, Shusuke Kojima, Md. Zahorul Islam, Kyouko Sasaki, and Yusuke Kiyama
- Subjects
Serotonin ,medicine.medical_specialty ,Ketanserin ,Swine ,040301 veterinary sciences ,receptor ,medicine.medical_treatment ,Cerebral arteries ,Bradykinin ,H2 antagonist ,0403 veterinary science ,Norepinephrine ,03 medical and health sciences ,chemistry.chemical_compound ,Phentolamine ,Internal medicine ,medicine ,Animals ,Cimetidine ,vasodilator ,Phylogeny ,030304 developmental biology ,Pharmacology ,cerebral artery ,0303 health sciences ,Full Paper ,General Veterinary ,dolphin ,Chemistry ,Angiotensin II ,Antagonist ,04 agricultural and veterinary sciences ,Cerebral Arteries ,Acetylcholine ,Bottle-Nosed Dolphin ,Endocrinology ,Basilar Artery ,vasoconstrictor ,Histamine ,medicine.drug - Abstract
From an evolutionary aspect, dolphins share a very close phylogenetic relationship with pigs. Previously, we characterized porcine cerebral artery responsiveness to intrinsic vasoactive substances. Therefore, here, we investigated dolphin (Tursiops truncatus) cerebral artery responsiveness to 5-hydroxytryptamine (5-HT), histamine (His), angiotensin (Ang) II, acetylcholine (ACh), noradrenaline (NA), and bradykinin (BK) to characterize their related receptor subtypes. We also compared dolphin cerebral artery responsiveness with porcine cerebral artery responsiveness. We found that 5-HT and His induced concentration-dependent contraction of the dolphin cerebral artery. Ketanserin (a 5-HT2 antagonist) and methiothepin (a 5-HT1 and 5-HT2 antagonist) shifted the concentration-response curve for 5-HT to the right. Although diphenhydramine (an H1 antagonist) shifted the concentration-response curve for His to the right, cimetidine (an H2 antagonist) had no such effect. Ang II and ACh did not produce any vasomotor actions. NA induced concentration-dependent relaxation. Propranolol (a β antagonist) shifted the concentration-response curve for NA to the right, whereas phentolamine (an α antagonist) had no significant effect. BK induced relaxation followed by contraction in pre-contracted arteries with intact endothelium. HOE140 (a B2 antagonist) shifted the concentration-response curve for BK to the right, whereas des-Arg9-[Leu8]-BK (a B1 antagonist) had no significant effect. These results suggest that 5-HT1, 5-HT2, and H1 receptor subtypes are important in arterial contraction and that β and B2 receptor subtypes modify these contractions to relaxations. The responsiveness of the dolphin cerebral artery is very similar to that of porcine cerebral artery, supporting their evolutionary linkage.
- Published
- 2020
14. Effects of Root Extracts of Eurycoma longifolia Jack on Corpus Cavernosum of Rat
- Author
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S.-K. Lam, Swee Hung Cheah, See Ziau Hoe, and Bae Huey Tee
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Male ,endocrine system ,medicine.medical_specialty ,genetic structures ,Muscle Relaxation ,Bradykinin ,In Vitro Techniques ,Peptidyl-Dipeptidase A ,030204 cardiovascular system & hematology ,Pharmacology ,Plant Roots ,Rats, Sprague-Dawley ,Phenylephrine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Eurycoma ,Original Paper ,biology ,Plant Extracts ,urogenital system ,business.industry ,Angiotensin II ,Angiotensin-converting enzyme ,General Medicine ,biology.organism_classification ,Rats ,Endocrinology ,chemistry ,030221 ophthalmology & optometry ,biology.protein ,Eurycoma longifolia ,Angiotensin I ,business ,Muscle Contraction ,Penis - Abstract
Objective: This study was conducted to investigate the mechanisms of action of Eurycoma longifolia in rat corpus cavernosum. Materials and Methods: Tincture of the roots was concentrated to dryness by evaporating the ethanol in vacuo. This ethanolic extract was partitioned into 5 fractions sequentially with hexane, dichloromethane (DCM), ethyl acetate, butanol, and water. The corpus cavernosum relaxant activity of each fraction was investigated. The DCM fraction which showed the highest potency in relaxing phenylephrine-precontracted corpora cavernosa was purified by column chromatography. The effects of the most potent DCM subfraction in relaxing phenylephrine-precontracted corpora cavernosa, DCM-I, on angiotensin I- or angiotensin II-induced contractions in corpora cavernosa were investigated. The effects of DCM-I pretreatment on the responses of phenylephrine-precontracted corpora cavernosa to angiotensin II or bradykinin were also studied. An in vitro assay was conducted to evaluate the effect of DCM-I on angiotensin-converting enzyme activity. Results: Fraction DCM-I decreased the maximal contractions (100%) evoked by angiotensin I and angiotensin II to 30 ± 14% and 26 ± 16% (p < 0.001), respectively. In phenylephrine-precontracted corpora cavernosa, DCM-I pretreatment caused angiotensin II to induce 82 ± 27% relaxation of maximal contraction (p < 0.01) and enhanced (p < 0.001) bradykinin-induced relaxations from 47 ± 8% to 100 ± 5%. In vitro, DCM-I was able to reduce (p < 0.001) the maximal angiotensin-converting enzyme activity to 78 ± 0.24%. Conclusion: Fraction DCM-I was able to antagonize angiotensin II-induced contraction to cause corpus cavernosum relaxation via inhibition of angiotensin II type 1 receptor and enhance bradykinin-induced relaxation through inhibition of angiotensin-converting enzyme.
- Published
- 2017
15. Bradykinin regulates cell growth and migration in cultured human cardiac c-Kit+ progenitor cells
- Author
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Gui-Rong Li, Gang Li, and Yan Wang
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,medicine.medical_specialty ,Receptor, Bradykinin B2 ,proliferation ,Blotting, Western ,Bradykinin ,Gene Expression ,bradykinin receptor 2 ,migration ,Receptor, Bradykinin B1 ,03 medical and health sciences ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,Cyclin D1 ,Cell Movement ,Internal medicine ,Pathology Section ,medicine ,Humans ,Heart Atria ,Progenitor cell ,Bradykinin receptor ,Receptor ,Extracellular Signal-Regulated MAP Kinases ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Protein Kinase C ,Cell Proliferation ,human cardiac c-Kit+ ,Dose-Response Relationship, Drug ,Cell growth ,Reverse Transcriptase Polymerase Chain Reaction ,Stem Cells ,Cell Cycle ,progenitor cells ,Molecular biology ,Research Paper: Pathology ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Endocrinology ,Oncology ,chemistry ,Type C Phospholipases ,RNA Interference ,Proto-Oncogene Proteins c-akt - Abstract
// Gang Li 1,2 , Yan Wang 1 and Gui-Rong Li 1,2 1 Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, China 2 Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Correspondence to: Yan Wang, email: // Gui-Rong Li, email: // Keywords : Bradykinin; bradykinin receptor 2; human cardiac c-Kit+ progenitor cells; proliferation; migration; Pathology Section Received : June 27, 2016 Accepted : January 06, 2017 Published : January 12, 2017 Abstract Bradykinin is a well-known endogenous vasoactive peptide. The present study investigated the bradykinin receptor expression in human cardiac c-Kit + progenitor cells and the potential role of bradykinin in regulating cell cycling progression and mobility. It was found that mRNA and protein of bradykinin type 2 receptors, but not bradykinin type 1 receptors, were abundant in cultured human cardiac c-Kit + progenitor cells. Bradykinin (1-10 nM) stimulated cell growth and migration in a concentration-dependent manner. The increase of cell proliferation was related to promoting G0/G1 transition into G2/M and S phase. Western blots revealed that bradykinin significantly increased pAkt and pERK1/2 as well as cyclin D1, which were countered by HOE140 (an antagonist of bradykinin type 2 receptors) or by silencing bradykinin type 2 receptors. The increase of pAkt, pERK1/2 and cyclin D1 by bradykinin was prevented by the PI3K inhibitor Ly294002, the PLC inhibitors U73122 and neomycin, and/or the PKC inhibitor chelerythrine and the MAPK inhibitor PD98059. Our results demonstrate the novel information that bradykinin promotes cell cycling progression and migration in human cardiac c-Kit + progenitor cells via activating PI3K, PLC, PKC, cyclin D1, pERK1/2, and pAkt.
- Published
- 2017
16. Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation
- Author
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Davalieva, Katarina, Makridakis, Manousos, Vlahou, Antonia, Frantzi, Maria, Boizard, Franck, Moussaoui, Nabila, Lescat, Ophélie, Fedou, Camille, Feuillet, Guylène, Casemayou, Audrey, Neau, Eric, Decatte, Luc, Raaijmakers, Anke, Vayssière, Christophe, Goua, Valérie, Lucas, Charlotte, Benachi, Alexandra, Delmas, Hélène Laurichesse, Allain-Launay, Emma, Boudailliez, Bernard, Simon, Elisabeth, Noel, Catherine, Floch, Corinne, Bourdat-Michel, Guylène, Weingertner, Anne-Sophie, Oury, Jean-François, Baudouin, Véronique, Bory, Jean-Paul, Pietrement, Christine, Fiorenza, Maryse, Kessler, Sylvie, Auriol, Françoise Conte, Marcorelles, Pascale, Collardeau-Frachon, Sophie, Magalhães, Pedro, Batut, Julie, Blader, Patrick, Saulnier Blache, Jean-Sebastien, Allegaert, Karel, Aubard, Yves, Basmaison, Odile, Benevent, Jean-Baptiste, Biquard, Florence, Champion, Gérard, Delbosc, Jean-Marie, Eckart, Philippe, Gaucherand, Pascal, Guigonis, Vincent, Hougas, Blandine, Martin, Alain, Martin, Sophie, Maupin-Hyvonnet, Mariannick, Merveille, Marina, Mousty, Eve, Nobili, François, Taque, Sophie, Latosinska, Agnieszka, Faguer, Stanislas, Beige, Joachim, van der Zanden, Loes, Levtchenko, Elena, Moulos, Panogiotis, Lounis, Nadia, Conte-Auriol, Françoise, Olsen, Henning, Hindryckx, An, De Catte, Luc, Vayssieres, Christophe, Sartor, Agnes, Groussolles, Marion, Plard, Christelle, Guerby, Paul, Connan, Laure, Morin, Mathieu, Simon, Elizabeth, Breaud, Jean, Saliou, Anne-Hélène, De Parscau, Loic, Jay, Nadine, Germouty, Isabelle, Le Bouar, Gwenaelle, Ryckewaert, Amelie, Manca-Pellissier, Marie-Christine, Merrot, Thierry, Laurichesse, Helene, Gallot, Denis, Bessenay, Lucie, Bidat, Laurent, Boize, Philippe, Winer, Norbert, Allain-Launey, Emma, Le Vaillant, Claudine, Prieur, Fabienne, Lavocat, Marie-Pierre, Coatleven, Frederic, Debromez, Eric, Harembat, Jérôme, Llanas, Brigitte, Favre, Romain, Moog, Raphael, Zaloszyc, Ariane, Massardier, Jérôme, DEMEDE, Delphine, Perrotin, Franck, Cloarec, Sylvie, Vequeau-Goua, Valérie, Descombes, Emmanuelle, Boulot, Pierre, Morin, Denis, Fuchs, Florent, Tenenbaum, Julie, Ville, Yves, Blanc, Thomas, Heidet, Laurence, Paris, Anne, Dobremez, Eric, Froute, Marie-Françoise, Gondry, Jean, Muszynski, Charles, Haraux, Elodie, Lobelle, Fabienne, Chevreau, Julien, Rosenblatt, Jonathan, Baudoin, Véronique, Deschenes, Georges, Guigue, Virginie, Amblard, Florence, Bourdat-Michel, Guylhène, Wühl, Elke, Schaefer, Franz, Elsässer, Michael, Persico, Nicola, Rossi, Federica, Manzoni, Gianantonio, De Marco, Erika, Montini, Giovanni, Capone, Valentina, Caforio, Leonardo, Zaccara, Antonio, Innocenzi, Michele, Bagolan, Pietro, Capozza, Nicola, Castagnetti, Marco, Mancini, Mariangela, Oepkes, Dick, van Scheltema, Phebe Adama, Feitz, Wout, Kortmann, Barbara, Schreuder, Michiel, Pawłowska, Barbara, Fortecka-Piestrzeniewicz, Katarzyna, Olejniczak, Dariusz, Ariceta, Gema, Arevalo, Silvia, RODO, Carlota, Fossum, Magdalena, Lindgren, Peter, Parvex, Paloma, Chehade, Hassib, He, Tianlin, Metzger, Jochen, Mullen, William, Mischak, Harald, Zürbig, Petra, Jankowski, Vera, Buffin-Meyer, Bénédicte, Tkaczyk, Marcin, Stańczyk, Małgorzata, Breuil, Benjamin, Siwy, Justyna, Szaflik, Krzysztof, Talar, Tomasz, Wojtera, Justyna, Krzeszowski, Waldemar, Decramer, Stéphane, Lopatko Fagerström, Ingrid, Ståhl, Anne-lie, Mossberg, Maria, Tati, Ramesh, Kristoffersson, Ann-Charlotte, Kahn, Robin, Bascands, Jean-Loup, Klein, Julie, Schanstra, Joost, Segelmark, Mårten, Karpman, Diana, Department of Pediatrics [Lund, Sweden] (Clinical Sciences), Lund University [Lund], Wallenberg Center for Molecular Medicine [Lund, Sweden], Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Nephrology [Lund, Sweden] (Clinical Sciences Lund), Department of Medical and Health Sciences [Lund, Sweden], Linköping University (LIU), The study was supported by The Swedish Research Council (K2015-99X-22877-01-6 and 2017-01920), The Knut and Alice Wallenberg Foundation (Wallenberg Clinical Scholar 2015.0320), The Torsten Söderberg Foundation, Skåne Centre of Excellence in Health, IngaBritt och Arne Lundberg's Research Foundation, Crown Princess Lovisa's Society for Child Care, Region Skåne and The Konung Gustaf V:s 80-årsfond (all to DK). Alfred Österlund Foundation (to LMFLL and RK). TheWallenberg Center forMolecular Medicine, The Swedish RheumatismAssociation, The Anna-Greta Crafoord Foundation, Greta and Johan Kock's Foundation, the Samariten Foundation, Fanny Ekdahl foundation, the Jerring foundation and the Thelma Zoegas Foundation (to RK). JPS and JK were partially funded by a grant from the 'Fondation pour la Recherche Médicale' (grant number DEQ20170336759). MS was funded by The Swedish Rheumatism Association and the Ingrid Asp Foundation., Schanstra, Joost, Macedonian Academy of Sciences and Arts [Skopje, North Macedonia] (MASA), Biomedical Research Foundation of the Academy of Athens (BRFAA), Mosaiques Diagnostics & Therapeutics (MOSAIQUES DIAGNOSTICS & THERAPEUTICS), Mosaiques Diagnostics & Therapeutics AG, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], KfH-Nierenzentrum und Klinikum St. Georg, Nephrologie, Leipzig, Radboud University Medical Center [Nijmegen], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), HybridStat Predictive Analytics [Athens, Greece], Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospitals Leuven [Leuven], Heidelberg University Hospital [Heidelberg], University of Milan, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, Polish Mother’s Memorial Hospital Research Institute [Lodz] (ICZMP), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), and Université Fédérale Toulouse Midi-Pyrénées
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0301 basic medicine ,Male ,Research paper ,Mouse ,Kallikrein-Kinin System ,[SDV]Life Sciences [q-bio] ,Pharmacology ,Kidney ,Mice ,0302 clinical medicine ,Glomerular C3 deposition ,Cell-Derived Microparticles ,Complement Activation ,Cells, Cultured ,Chemistry ,General Medicine ,Kinin ,Middle Aged ,Receptor antagonist ,3. Good health ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Endothelial microvesicles ,Complement C1 Inhibitor Protein ,Protein Binding ,Vasculitis ,Complement ,Radiology, Nuclear Medicine and Medical Imaging ,Adult ,Endothelium ,medicine.drug_class ,Inflammation ,Bradykinin ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Classical complement pathway ,medicine ,Animals ,Humans ,Aged ,Endothelial Cells ,Biological Transport ,Complement System Proteins ,Microvesicles ,Complement system ,Disease Models, Animal ,030104 developmental biology ,Immunoglobulin G ,Endothelium, Vascular ,Radiologi och bildbehandling - Abstract
Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation. Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist. Findings: Vasculitis patient plasma had significantly more C3- and C9-positive endothelial microvesicles than controls. Perfusion of patient acute-phase plasma samples over glomerular endothelial cells induced the release of significantly more complement-positive microvesicles, in comparison to remission or control plasma. Complement activation on endothelial microvesicles was reduced by kinin B1- and B2-receptor antagonists or by C1-inhibitor (the main inhibitor of the classical pathway and the KKS). Likewise, perfusion of glomerular endothelial cells with C1-inhibitor-depleted plasma induced the release of complement-positive microvesicles, which was significantly reduced by kinin-receptor antagonists or C1-inhibitor. Mice with nephrotoxic serum-induced glomerulonephritis exhibited significantly reduced glomerular C3 deposition when treated with a B1-receptor antagonist. Interpretation: Excessive complement deposition on the endothelium will promote endothelial injury and the release of endothelial microvesicles. This study demonstrates that blockade of the KKS can reduce complement activation and thereby the inflammatory response on the endothelium. (C) 2019 The Authors. Published by Elsevier B.V. Funding Agencies|Swedish Research CouncilSwedish Research Council [K2015-99X-22877-01-6, 2017-01920]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [2015.0320]; Torsten Soderberg Foundation; Skane Centre of Excellence in Health; Crown Princess Lovisas Society for Child Care; Konung Gustaf V:s 80-arsfond; Alfred Osterlund Foundation; Wallenberg Center for Molecular Medicine; Swedish Rheumatism Association; Anna-Greta Crafoord Foundation; Greta and Johan Kocks Foundation; Samariten Foundation; Fanny Ekdahl foundation; Jerring foundation; Fondation pour la Recherche MedicaleFondation pour la Recherche Medicale [DEQ20170336759]; Ingrid Asp Foundation; IngaBritt och Arne Lundbergs Research Foundation; Region Skane; Thelma Zoegas Foundation
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- 2019
17. Bradykinin and noradrenaline preconditioning influences level of antioxidant enzymes SOD, CuZn-SOD, Mn-SOD and catalase in the white matter of spinal cord in rabbits after ischemia/reperfusion
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Alexandra Kunová, Zuzana Fagová, Marianna Danková, Iveta Domoráková, Eva Mechírová, and Milan Stebnický
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0301 basic medicine ,Male ,medicine.medical_specialty ,Histology ,Antioxidant ,medicine.medical_treatment ,Biophysics ,Ischemia ,rabbit ,Bradykinin ,ischemia ,medicine.disease_cause ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,Norepinephrine ,0302 clinical medicine ,Superoxide Dismutase-1 ,preconditioning ,antioxidant enzymes ,Internal medicine ,medicine ,Animals ,lcsh:QH301-705.5 ,Enzyme Assays ,Original Paper ,Glial fibrillary acidic protein ,biology ,Ubiquitin ,spinal cord ,Cell Biology ,medicine.disease ,Catalase ,Immunohistochemistry ,White Matter ,Enzyme assay ,030104 developmental biology ,Endocrinology ,chemistry ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Reperfusion Injury ,biology.protein ,noradrenaline ,Rabbits ,Neuroglia ,Oxidative stress - Abstract
The aim of present work is to assess the effects of bradykinin (Br) or noradrenaline (Nor) preconditioning to the levels of antioxidant enzymes: superoxide dismutase (SOD), copper, zinc superoxide dismutase (CuZn-SOD), manganese superoxide dismutase (Mn-SOD) and catalase in ischemia/reperfusion (I/R) model in the rabbit spinal cord white matter as well as effect on glial fibrillary acidic protein (GFAP) and ubiquitin immunoreaction in glial cells. Rabbits were preconditioned by intraperitoneal single dose of Br or Nor 48 h prior to 20 min of ischemia followed by 24 or 48 h of reperfusion. White matter of L3-L6 spinal cord segments was used for comparison of antioxidant enzyme levels in sham control, ischemic groups and four preconditioned groups. The total SOD level in the Br or Nor preconditioned groups after 48 h of reperfusion was increased vs Br or Nor preconditioned groups after 24 h of reperfusion. The comparison among the ischemic group vs Br preconditioned (P
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- 2019
18. Different mechanisms involved in liraglutide and glucagon‐like peptide‐1 vasodilatation in rat mesenteric small arteries
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Daniel Dias Rufino Arcanjo, Michael Gejl, Khiem Dinh Huynh, Jakob S. Knudsen, Alejandro Gutierrez, Ulf Simonsen, Asbjørn Graver Petersen, Jørgen Rungby, and Maj Bangshaab
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Male ,0301 basic medicine ,PHARMACOKINETICS ,endocrine system ,medicine.medical_specialty ,EXENATIDE ,medicine.drug_class ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,Bradykinin ,BLOOD-PRESSURE ,Vasodilation ,ENDOTHELIUM-DEPENDENT RELAXATION ,Glucagon-Like Peptide-1 Receptor ,GLUCOSE ,ACTIVATION ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Glucagon-Like Peptide 1 ,Superoxides ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Receptor ,Mesenteric arteries ,Pharmacology ,Dose-Response Relationship, Drug ,Liraglutide ,Insulin ,digestive, oral, and skin physiology ,Receptor antagonist ,CONCISE GUIDE ,RECEPTOR AGONISTS ,Research Papers ,Glucagon-like peptide-1 ,Mesenteric Arteries ,Rats ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,GLP-1 ,RESISTANCE ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner, and has been reported to induce vasodilatation. Here, the aim was to examine the possible vasorelaxant effect of GLP-1 and the underlying mechanisms.EXPERIMENTAL APPROACH: Rat mesenteric arteries (diameter ≈ 200-400 μm) and human subcutaneous arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined at normoglycemic conditions and at high glucose.KEY RESULTS: In rat mesenteric arteries and human subcutaneous arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation, or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39) in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted concentration relaxation curves for bradykinin in subcutaneous arteries from patients with peripheral arterial disesase, an effect insensitive to exendin-(9-39). In normoglycemic conditions neither GLP-1 nor liraglutide changed acetylcholine relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated acetylcholine-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose.CONCLUSION AND IMPLICATIONS: Our findings suggest that a GLP-1 receptor-dependent mechanism is involved in liraglutide relaxation in branched arteries in normoglycemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycemia.
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- 2018
19. Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT
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Elaine Leocádia, Anton, Daniel, Fernandes, Jamil, Assreuy, and José Eduardo, da Silva-Santos
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Lipopolysaccharides ,Male ,Receptor, Bradykinin B2 ,Angiotensin II ,Vasodilator Agents ,Blood Pressure ,Bradykinin ,Research Papers ,Receptor, Angiotensin, Type 1 ,Rats ,Injections, Intravenous ,Animals ,Female ,Rats, Wistar ,Dimerization ,Injections, Intraperitoneal - Abstract
BACKGROUND AND PURPOSE: Bradykinin may induce vasoconstriction in selected vessels or under specific experimental conditions. We hypothesized that inflammatory stimuli, such as endotoxin challenge, may induce the dimerization of AT(1)/B(2) receptors, altering the vascular effects of bradykinin. EXPERIMENTAL APPROACH: Wistar rats received LPS (1 mg·kg(−1), i.p.) and were anaesthetized for assessment of BP. Mesenteric resistance arteries were used in organ baths and subjected to co‐immunoprecipitation and Western blot analyses. KEY RESULTS: At 24 and 48 hr after LPS, bradykinin‐induced hypotension was followed by a sustained increase in BP, which was not found in non‐endotoxemic animals. The B(2) receptor antagonist Hoe‐140 fully blocked the responses to bradykinin. The pressor effect of bradykinin was not prevented by prazosin, an α(1)‐adrenoceptor antagonist, but it was inhibited by the AT(1) receptor antagonist losartan or the Rho‐kinase inhibitor Y‐27632. Endotoxemic rats also displayed enhanced pressor responses to angiotensin II, which were blocked by Hoe‐140. Co‐immunoprecipitation isolated using anti‐B(2) or anti‐AT(1) receptor antibodies showed that resistance arteries presented augmented levels of the AT(1)/B(2) receptor complexes at 24 hr after LPS injection. The presence of AT(1)/B(2) receptor heterodimers did correlate with the development of losartan‐sensitive contractile responses to bradykinin and potentiation of angiotensin II‐induced contraction, which was prevented by Hoe‐140. CONCLUSIONS AND IMPLICATIONS: Endotoxin challenge is a stimulus for AT(1)/B(2) receptor heterodimerization in native vessels and shifts the B(2) receptor‐dependent vascular effect of bradykinin to a more complex pathway, which also depends on AT(1) receptors and their intracellular signalling pathways.
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- 2018
20. KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine
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Adam G. Goodwill, Eli D. Casalini, Daniel J. Sassoon, Zachary C. Berwick, Gregory M. Dick, Lijuan Fu, Ghassan S. Kassab, Jillian N. Noblet, and Johnathan D. Tune
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0301 basic medicine ,Indoles ,Pyridines ,Swine ,Physiology ,Vasodilator Agents ,Aminopyridines ,Vasodilation ,030204 cardiovascular system & hematology ,Pharmacology ,Linopirdine ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,KCNQ Potassium Channels ,Coronary Vessels ,medicine.anatomical_structure ,KCNQ1 Potassium Channel ,Call for Papers ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Adventitia ,medicine.medical_specialty ,Blotting, Western ,Ischemia ,Bradykinin ,Real-Time Polymerase Chain Reaction ,KCNQ3 Potassium Channel ,03 medical and health sciences ,Coronary circulation ,Coronary Circulation ,Physiology (medical) ,Internal medicine ,Paracrine Communication ,Potassium Channel Blockers ,Animals ,KCNQ2 Potassium Channel ,business.industry ,medicine.disease ,Coronary arteries ,030104 developmental biology ,chemistry ,Vasoconstriction ,Endothelium, Vascular ,business ,Ex vivo - Abstract
Hydrogen peroxide (H2O2) and voltage-dependent K+ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli.
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- 2016
21. Specific immunotherapy with mugwort pollen allergoid reduce bradykinin release into the nasal fluid
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Radosław Gawlik, Barbara Jawor, Eugeniusz Czecior, and A. Grzanka
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lcsh:Internal medicine ,Allergen immunotherapy ,seasonal allergic rhinitis ,Mugwort pollen ,Bradykinin ,Dermatology ,chemistry.chemical_compound ,Mugwort ,mugwort ,lcsh:Dermatology ,otorhinolaryngologic diseases ,Immunology and Allergy ,Medicine ,lcsh:RC31-1245 ,Nasal fluid ,Original Paper ,business.industry ,nasal lavage ,Specific immunotherapy ,lcsh:RL1-803 ,Allergoid ,chemistry ,Immunology ,allergen immunotherapy ,Nasal Lavage ,bradykinin ,business - Abstract
Introduction: A pathomechanism of allergic rhinitis is complex. A neurogenic mechanism seems to play a significant role in this phenomenon. Aim: The evaluation of influence of specific immunotherapy of mugwort pollen allergic patients on the bradykinin concentration in the nasal lavage fluid. Material and methods : The study included 22 seasonal allergic rhinitis patients. Thirty persons with monovalent allergy to mugwort pollen, confirmed with skin prick tests and allergen-specific immunoglobulin E, underwent a 3-year-long allergen immunotherapy with the mugwort extract (Allergovit, Allergopharma, Germany). The control group was composed of 9 persons with polyvalent sensitivity to pollen, who were treated with pharmacotherapy. Before the allergen-specific immunotherapy (AIT) and in subsequent years before the pollen seasons, a provocation allergen test with the mugwort extract was performed, together with collection of nasal fluids, where bradykinin concentration was determined according to Proud method. Results : There were similar levels of bradykinin in both groups at baseline prior to therapy (AIT group: 584.0 ±87.2 vs. controls 606.3 ±106.5 pg/ml) and changes after allergen challenge 1112.4 ±334.8 vs. 1013.3 ±305.9 pg/ml as well. The bradykinin concentration in nasal lavage fluid after mugwort challenge in 1 year was lower in the AIT group (824.1 ±184.2 pg/ml vs. 1000.4 ±411.5 pg/l; p < 005) with a further significant decrease after the 2nd and 3rd year of specific immunotherapy. Significant reduction of symptoms and medications use was observed in hyposensitized patients. Conclusions : A decreased level of bradykinin as a result of AIT suggests that some of the symptomatic benefits of AIT may be related to the reduced release of bradykinin into nasal secretions. These values correlate with clinical improvement within the course of treatment.
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- 2016
22. The role of bradykinin receptor type 2 in spontaneous extravasation in mice skin: implications for non‐allergic angio‐oedema
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Bisha, Marion, Dao, Vu Thao‐Vi, Gholamreza‐Fahimi, Ehsan, Vogt, Michael, van Zandvoort, Marc, Weber, Sarah, Bas, Murat, Khosravani, Farbod, Kojda, Georg, and Suvorava, Tatsiana
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Male ,Mice, Inbred C57BL ,Kinetics ,Mice ,Receptor, Bradykinin B2 ,Animals ,Edema ,Mice, Transgenic ,Bradykinin ,Research Papers ,Skin - Abstract
BACKGROUND AND PURPOSE: Non‐allergic angio‐oedema is a life‐threatening disease mediated by activation of bradykinin type 2 receptors (B(2) receptors). The aim of this study was to investigate whether activation of B(2) receptors by endogenous bradykinin contributes to physiological extravasation. This may shed new light on the assumption that treatment with an angiotensin converting enzyme inhibitor (ACEi) results in an alteration in the vascular barrier function predisposing to non‐allergic angio‐oedema. EXPERIMENTAL APPROACH: We generated a new transgenic mouse model characterized by endothelium‐specific overexpression of the B(2) receptor (B2(tg)) and established a non‐invasive two‐photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2(tg) mice showed normal morphology and litter size as compared with their transgene‐negative littermates (B2(n)). KEY RESULTS: Overexpression of B(2) receptors was functional in conductance vessels and resistance vessels as evidenced by B(2) receptor‐mediated aortic dilation to bradykinin in presence of non‐specific COX inhibitor diclofenac and by significant hypotension in B2(tg) respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2(tg) as compared with B2(n). However, neither endothelial overexpression of B(2) receptors nor treatment with the ACEi moexipril or B(2) antagonist icatibant had any effect on spontaneous extravasation measured by two‐photon laser microscopy. CONCLUSIONS AND IMPLICATIONS: Activation of B(2) receptors does not appear to be involved in spontaneous extravasation. Therefore, the assumption that treatment with an ACEi results in an alteration in the physiological vascular barrier function predisposing to non‐allergic angio‐oedema is not supported by our findings.
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- 2018
23. Acute activation of endothelial AMPK surprisingly inhibits endothelium-dependent hyperpolarization-like relaxations in rat mesenteric arteries
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Hui Chen, Paul M. Vanhoutte, and Susan W.S. Leung
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0301 basic medicine ,Male ,medicine.medical_specialty ,Endothelium ,Swine ,Thiophenes ,AMP-Activated Protein Kinases ,In Vitro Techniques ,Bradykinin ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Endothelial dysfunction ,Mesenteric arteries ,Pharmacology ,Activator (genetics) ,Chemistry ,Biphenyl Compounds ,AMPK ,Hyperpolarization (biology) ,Ribonucleotides ,medicine.disease ,Aminoimidazole Carboxamide ,Coronary Vessels ,Research Papers ,Potassium channel ,Acetylcholine ,Mesenteric Arteries ,Blot ,Mice, Inbred C57BL ,Vasodilation ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Pyrones ,Endothelium, Vascular ,030217 neurology & neurosurgery - Abstract
Background and purpose Endothelium-dependent hyperpolarizations (EDHs) contribute to the regulation of peripheral resistance. They are initiated through opening of endothelial calcium-activated potassium channels (KCa ); the potassium ions released then diffuse to the underlying smooth muscle cells, causing hyperpolarization and thus relaxation. The present study aimed to examine whether or not AMPK modulates EDH-like relaxations in rat mesenteric arteries. Experimental approach Arterial rings were isolated for isometric tension recording. AMPK activity and protein level were measured by ELISA and western blotting respectively. Key results The AMPK activator, AICAR, reduced ACh-induced EDH-like relaxations and increased AMPK activity in preparations with endothelium; these responses were prevented by compound C, an AMPK inhibitor. AICAR inhibited relaxations induced by SKA-31 (opener of endothelial KCa ) but did not affect potassium-induced, hyperpolarization-attributable relaxations or increase AMPK activity in preparations without endothelium. A769662, another AMPK activator, not only caused a similar inhibition of relaxations to ACh and SKA-31 in preparations with endothelium but also inhibited hyperpolarization-attributable relaxations and augmented AMPK activity in rings without endothelium. Protein levels of total AMPKα, AMPKα1, or AMPKβ1/2 were comparable between preparations with and without endothelium. Conclusions and implications Activation of endothelial AMPK, by either AICAR or A769662, acutely inhibits EDH-like relaxations of rat mesenteric arteries. Furthermore, A769662 inhibits signalling downstream of smooth muscle hyperpolarization. In view of the major blunting effect of AMPK activation on EDH-like relaxations, caution should be applied when administering therapeutic agents that activate AMPK in patients with endothelial dysfunction characterized by reduced production and/or bioavailability of NO.
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- 2018
24. Genetic associations of bradykinin type 2 receptor, alpha-adrenoceptors and endothelial nitric oxide synthase with blood pressure and left ventricular mass in outpatients without overt heart disease
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José Eduardo Krieger, Rafael Amorim Belo Nunes, Alfredo José Mansur, Larissa Barbosa Lima, Alexandre C. Pereira, and Nelson I. Tanaka
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lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,Heart disease ,Diastole ,ESTATÍSTICA APLICADA ,Bradykinin ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Left ventricular mass ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Enos ,Polymorphism (computer science) ,Internal medicine ,Genotype ,medicine ,Genetics ,Bradykinin receptor ,Original Paper ,Bradykinin B2-receptors ,biology ,business.industry ,medicine.disease ,biology.organism_classification ,Endocrinology ,Blood pressure ,Alpha-adrenergic receptors ,chemistry ,lcsh:RC666-701 ,Endothelial nitric oxide synthase ,Cardiology and Cardiovascular Medicine ,business ,Polymorphisms - Abstract
Background: Physiological pathways such as bradykinin, renin-angiotensin, neurohormones and nitric oxide have been shown to play an important role in the regulation of cardiovascular function. Genetic variants of these pathways may impact blood pressure and left ventricular (LV) mass in different populations. To evaluate associations of genetic polymorphisms of bradykinin B2 receptor (BDKRB2), alpha-adrenergic receptors (ADRA) and endothelial nitric oxide synthase (eNOS) on the modulation of the blood pressure and the left ventricular mass. Methods: We enrolled 758 individuals without overt heart disease. Blood pressure was estimated by auscultatory method during the clinical examination. Left ventricular (LV) mass was assessed by echocardiography. Genotypes for ADRA1A rs1048101, ADRA2A rs553668, ADRA2B rs28365031, eNOS rs2070744, eNOS rs1799983, and BDKRB2 rs5810761 polymorphisms were assessed by high-resolution melting analysis. Results: BDKRB2 polymorphism rs5810761 was associated with blood pressure. Carriers of DD genotype had higher levels of SBP and DBP than carrier of II genotype (p = 0.013 and p = 0.007, respectively). eNOS polymorphism rs1799983 was associated with DBP. Carriers of GT genotype had lower levels of DBP than carriers of GG genotype (p = 0.018). eNOS polymorphism rs2070744 was associated with LV mass. Carriers of TC genotype had higher LV mass than carriers of TT genotype (p = 0.028). Conclusions: In a cohort of individuals without overt heart disease, the BDKRB2 rs5810761 polymorphism (DD genotype carriers) were associated higher systolic and diastolic blood pressures, and the eNOS rs1799983 polymorphism (T allele carriers) were associated with lower diastolic blood pressure. The eNOS rs2070744 polymorphism (C allele carriers) was associated with higher left ventricular mass. These data suggest that eNOS and bradykinin receptor genetic variants may be potential markers of common cardiovascular phenotypes. Keywords: Genetics, Polymorphisms, Left ventricular mass, Blood pressure, Alpha-adrenergic receptors, Bradykinin B2-receptors, Endothelial nitric oxide synthase
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- 2018
25. Streptococcus gallolyticus subsp gallolyticus endocarditis isolate interferes with coagulation and activates the contact system
- Author
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Shaynoor Dramsi, Juliane Köhler, Sonja Oehmcke-Hecht, Bernd Kreikemeyer, Julia Isenring, Marcus Frank, Camille Danne, Masanobu Nakata, Pierre Renault, Christoph Jans, Oehmcke-Hecht, Sonja, University of Rostock, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Osaka University, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), Institut Pasteur [Paris] (IP), Biologie des Bactéries pathogènes à Gram-positif - Biology of Gram-Positive Pathogens (BBPG+), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Deutsche Forschungsgemeinschaft (DFG) [OE 547/4-1], EU ERAfrica, Swiss Walter Hochstrasser Stiftung, Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Microbiology (medical) ,Streptococcus gallolyticus ,030106 microbiology ,Immunology ,Contact system ,Virulence ,Streptococcus gallolyticus subsp. gallolyticus ,Biology ,Microbiology ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,Streptococcal Infections ,parasitic diseases ,medicine ,Endocarditis ,lcsh:RC109-216 ,Streptococcus gallolyticus subspecies gallolyticus ,Microbiology and Parasitology ,Streptococcus ,contact system ,medicine.disease ,Microbiologie et Parasitologie ,3. Good health ,Streptococcus bovis ,030104 developmental biology ,Infectious Diseases ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Coagulation ,Infective endocarditis ,Bacteremia ,bradykinin ,endocarditis ,pili ,Parasitology ,Research Paper - Abstract
International audience; Streptococcus gallolyticus subsp. gallolyticus, formerly classified as S. bovis biotype I, is an increasing cause of bacteremia and infective endocarditis in the elderly. The physiopathology of infective endocarditis is poorly understood and involves immune and coagulation systems. In this study, we found that S. gallolyticus subsp. gallolyticus activates the human contact system, which in turn has two consequences: cleavage of high-molecular-weight kininogen (HK) resulting in release of the potent pro-inflammatory peptide bradykinin, and initiation of the intrinsic pathway of coagulation. S. gallolyticus subsp. gallolyticus was found to bind and activate factors of the human contact system at its surface, leading to a significant prolongation of the intrinsic coagulation time and to the release of bradykinin. High-affinity binding of factor XII to the bacterial Pil1 collagen binding protein was demonstrated with a K-D of 13 nM. Of note, Pil1 expression was exclusively found in S. gallolyticus subsp. gallolyticus, further supporting an essential contribution of this pilus in virulence.
- Published
- 2018
26. Bradykinin inhibits oxidative stress-induced senescence of endothelial progenitor cells through the B2R/AKT/RB and B2R/EGFR/RB signal pathways
- Author
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Bing Li, Yuning Sun, Yuyu Yao, Genshan Ma, and Cong Fu
- Subjects
Senescence ,senescence ,Receptor, Bradykinin B2 ,Antigens, CD34 ,Biology ,Bradykinin ,Transfection ,medicine.disease_cause ,Retinoblastoma Protein ,Antioxidants ,Research Paper: Gerotarget (Focus on Aging) ,Cyclin D1 ,Downregulation and upregulation ,Bradykinin B2 Receptor Antagonists ,Diabetes Mellitus ,medicine ,Humans ,Progenitor cell ,Protein Kinase Inhibitors ,Protein kinase B ,Cells, Cultured ,Cellular Senescence ,PI3K/AKT/mTOR pathway ,endothelial progenitor cells ,B2 receptor ,Oxidants ,ErbB Receptors ,Oxidative Stress ,Oncology ,Cytoprotection ,Case-Control Studies ,Cancer research ,RNA Interference ,Proto-Oncogene Proteins c-akt ,Cell aging ,Oxidative stress ,Signal Transduction - Abstract
Circulating endothelial progenitor cells (EPCs) have multiple protective effects that facilitate repair of damage to tissues and organs. However, while various stressors are known to impair EPC function, the mechanisms of oxidative stress-induced EPC senescence remains unknown. We demonstrated that B2 receptor (B2R) expression on circulating CD34(+) cells was significantly reduced in patients with diabetes mellitus (DM) as compared to healthy controls. Furthermore, CD34(+) cell B2R expression in patients with DM was inversely correlated with plasma myeloperoxidase concentrations. Bradykinin (BK) treatment decreased human EPC (hEPC) senescence and intracellular oxygen radical production, resulting in reduced retinoblastoma 1 (RB) RNA expression in H2O2-induced senescent hEPCs and a reversal of the B2R downregulation that is normally observed in senescent cells. Furthermore, BK treatment of H2O2-exposed cells leads to elevated phosphorylation of RB, AKT, and cyclin D1 compared with H2O2-treatment alone. Antagonists of B2R, PI3K, and EGFR signaling pathways and B2R siRNA blocked BK protective effects. In summary, this study demonstrates that BK significantly inhibits oxidative stress-induced hEPC senescence though B2R-mediated activation of PI3K and EGFR signaling pathways.
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- 2015
27. Effect of Bradykinin Postconditioning on Ischemic and Toxic Brain Damage
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Maria Lalkovicova, Jozef Burda, Viera Danielisová, and Petra Bonova
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Male ,Post-conditioning ,Ischemia ,Intoxication ,Hippocampus ,Brain damage ,Pharmacology ,Bradykinin ,Neuroprotection ,Biochemistry ,Brain Ischemia ,Brain ischemia ,Cellular and Molecular Neuroscience ,Medicine ,Animals ,Rats, Wistar ,Hypoxia, Brain ,Ischemic Postconditioning ,Maze Learning ,Original Paper ,business.industry ,Dentate gyrus ,General Medicine ,medicine.disease ,Barnes maze ,Rats ,Neuroprotective Agents ,Toxic injury ,Anesthesia ,medicine.symptom ,Glutamate ,business - Abstract
Brain damage caused by ischemia or toxic agents leads in selectively vulnerable regions to apoptosis-like delayed neuronal death and can result in irreversible damage. Selectively vulnerable neurons of the CA1 area of hippocampus are particularly sensitive to ischemic damage. We investigated the effects of bradykinin (BR) postconditioning on cerebral ischemic and toxic injury. Transient forebrain ischemia was induced by four-vessel occlusion for 10 min and toxic injury was induced by trimethyltin (TMT, 8 µg/kg i.p.). BR as a postconditioner at a dose of 150 µg/kg was applied intraperitoneally 48 h after ischemia or TMT intoxication. Experimental animals were divided into groups according to the length of survival (short—3 and 7 days, and long—28 days survival) and according to the applied ischemic or toxic injury. Glutamate concentration was lowered in both CA1 and dentate gyrus areas of hippocampus after the application of BR postconditioning in both ischemic and toxic brain damage. The number of degenerated neurons in the hippocampal CA1 region was significantly lower in BR-treated ischemic and toxic groups compared to vehicle group. The behavioral test used in our experiments confirms also the memory improvement in conditioned animals. The rats’ ability to form spatial maps and learn was preserved, which is visible from our Barnes maze results. By using the methods of delayed postconditioning is possible to stimulate the endogenous protective mechanisms of the organism and induce the neuroprotective effect. In this study we demonstrated that BR postconditioning, if applied before the onset of irreversible neurodegenerative changes, induced neuroprotection against ischemic or toxic injury.
- Published
- 2015
28. Activation of peripheral KCNQ channels relieves gout pain
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Haiyan Xu, Yueming Zheng, Xindi Zhou, Zhaobing Gao, Li Zhan, and Xueqin Chen
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Male ,Gout ,Analgesic ,Pain ,Action Potentials ,Bradykinin ,Mice, Inbred Strains ,Inflammation ,CHO Cells ,Pharmacology ,Hippocampus ,Rats, Sprague-Dawley ,KCNQ ,Mice ,chemistry.chemical_compound ,Benzbromarone ,Cricetulus ,Dorsal root ganglion ,In vivo ,Formaldehyde ,Ganglia, Spinal ,medicine ,Animals ,KCNQ2 Potassium Channel ,Cells, Cultured ,Neurons ,Arthritis ,Long-term potentiation ,Uricosuric Agents ,medicine.disease ,Rats ,Uric Acid ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Animals, Newborn ,Neurology ,chemistry ,Neurology (clinical) ,Peripheral nervous system ,medicine.symptom ,Research Paper - Abstract
Supplemental Digital Content is Available in the Text. Combining electrophysiology and in vivo pain models, the concept that activation of peripheral KCNQ channels relieves the gout pain is demonstrated., Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK). Benzbromarone consistently attenuates BK-, formalin-, or monosodium urate–induced inflammatory pain in rat and mouse models. Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout.
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- 2015
29. Endostatin inhibits bradykinin-induced cardiac contraction
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Yuka Kajiwara, Hideyuki Yamawaki, Muneyosi Okada, Lila Takada, and Jumpei Yasuda
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Male ,medicine.medical_specialty ,Patch-Clamp Techniques ,Contraction (grammar) ,endostatin ,Adrenergic beta-Antagonists ,Guinea Pigs ,Bradykinin ,chemistry.chemical_element ,macromolecular substances ,Calcium ,Mice ,chemistry.chemical_compound ,Internal medicine ,Collagen Type XVIII ,medicine ,Animals ,Pharmacology ,voltage-dependent calcium channel ,Dose-Response Relationship, Drug ,Full Paper ,General Veterinary ,Cardiac cycle ,Voltage-dependent calcium channel ,bradykinin type 2 receptor ,Calcium channel ,Myocardial Contraction ,Propranolol ,Endostatins ,Endocrinology ,chemistry ,cardiovascular system ,Atrial Function, Left ,Calcium Channels ,Endostatin - Abstract
Endogenous fragments of extracellular matrix are known to possess various biological effects. Levels of endostatin, a fragment of collagen type XVIII, increase in certain cardiac diseases, such as cardiac hypertrophy and myocardial infarction. However, the influence of endostatin on cardiac contraction has not been clarified. In the present study, we investigated the effects of endostatin on bradykinin-induced atrial contraction. Isometric contractile force of mouse isolated left atria induced by electrical current pulse was measured. Voltage-dependent calcium current of guinea pig ventricular myocytes was measured by a whole-cell patch-clamp technique. Endostatin (100–1,000 ng/ml) alone treatment had no influence on left atrial contraction. On the other hand, pretreatment with endostatin (300 ng/ml) significantly inhibited bradykinin (1 µM)-induced contraction and voltage-dependent calcium current. These data suggest that endostatin may decrease bradykinin-induced cardiac contraction perhaps through the inhibition of voltage-dependent calcium channel.
- Published
- 2015
30. Expression, distribution and function of kinin B
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Soumaya, Hachana, Menakshi, Bhat, Jacques, Sénécal, Frédéric, Huppé-Gourgues, Réjean, Couture, and Elvire, Vaucher
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Male ,Diabetic Retinopathy ,Administration, Ophthalmic ,Bradykinin ,Receptor, Bradykinin B1 ,Research Papers ,Leukostasis ,Retina ,Streptozocin ,Diabetes Mellitus, Experimental ,Rats ,Capillary Permeability ,Gene Expression Regulation ,Animals ,RNA, Messenger ,RNA, Small Interfering ,Rats, Wistar - Abstract
BACKGROUND AND PURPOSE: The kinin B(1) receptor contributes to vascular inflammation and blood‐retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression, cellular localization and vascular inflammatory effect of B(1) receptors in retina of streptozotocin diabetic rats. EXPERIMENTAL APPROACH: The distribution of B(1) receptors on retinal cell types was investigated by immunocytochemistry. Effects of B(1) receptor agonist, R‐838, and antagonist, R‐954, on retinal leukocyte adhesion, gene expression of kinin and VEGF systems, B(1) receptor immunoreactivity, microgliosis and capillary leakage were measured. Effect of B(1) receptor siRNA on gene expression was also assessed. KEY RESULTS: mRNA levels of the kinin and VEGF systems were significantly enhanced at 2 weeks in streptozotocin (STZ)‐retina compared to control‐retina and were further increased at 6 weeks. B(1) receptor mRNA levels remained increased at 6 months. B(1) receptor immunolabelling was detected in vascular layers of the retina, on glial and ganglion cells. Intravitreal R‐838 amplified B(1) and B(2) receptor gene expression, B(1) receptor levels (immunodetection), leukostasis and vascular permeability at 2 weeks in STZ‐retina. Topical application (eye drops) of R‐954 reversed these increases in B(1) receptors, leukostasis and vascular permeability. Intravitreal B(1) receptor siRNA inhibited gene expression of kinin and VEGF systems in STZ‐retina. Microgliosis was unaffected by R‐838 or R‐954 in STZ‐retina. CONCLUSION AND IMPLICATIONS: Our results support the detrimental role of B(1) receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B(1) receptor antagonist R‐954 seems a feasible therapeutic approach for the treatment of DR.
- Published
- 2017
31. Age-related impairment of conducted dilation in human coronary arterioles
- Author
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Attila Feher, Zuzana Broskova, and Zsolt Bagi
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Male ,Aging ,Physiology ,Vasodilator Agents ,Bradykinin ,Vasodilation ,Nitric Oxide ,Nitric oxide ,Potassium Channels, Calcium-Activated ,chemistry.chemical_compound ,Physiology (medical) ,Age related ,medicine ,Humans ,Aged ,Aged, 80 and over ,Microscopy, Video ,Electrical impedance myography ,business.industry ,Myography ,Middle Aged ,Coronary Vessels ,Arterioles ,medicine.anatomical_structure ,chemistry ,Anesthesia ,Call for Papers ,Vascular resistance ,Dilation (morphology) ,Female ,Vascular Resistance ,Cardiology and Cardiovascular Medicine ,business ,Perfusion - Abstract
Conducted vasodilation is essential to coordinate vascular resistance along distances to ensure adequate tissue perfusion. We hypothesized that conducted vasodilation of coronary resistance arteries declines with age. Coronary arterioles were dissected from right atrial appendage of patients ( n = 27) undergoing cardiac surgery. Arterioles (∼100 μm) were cannulated and pressurized (80 mmHg), and developed spontaneous myogenic tone. Conducted vasodilation was initiated by locally administering the endothelium-dependent agonist bradykinin (BK; 100 μM) ejected from a glass micropipette (∼3 μm tip opening, positioned in close proximity to the vessel wall). Diameter changes were measured at local and upstream sites (500 and 1,000 μm from the stimulus) with videomicroscopy. Local administration of BK elicited vasodilation, the magnitude of which increased with the duration of stimulus (69 ± 6, 81 ± 6, 90 ± 2%, after 1, 3, and 5 × 100 ms, respectively). BK-induced dilation remained substantial at upstream sites (500 μm: 53 ± 7%; 1,000 μm: 46 ± 9%). The gap junction uncoupler carbenoxolone or 18-α-glycyrrhetinic acid did not affect local responses, but diminished conducted vasodilation. Inhibitors of small/intermediate conductance calcium-activated potassium channels (SKCa/IKCa), apamin and TRAM34, reduced dilations both at local and remote sites. We found that conducted dilation, but not the local response, was significantly reduced in older (≥64 yr) patients. The nitric oxide (NO) synthesis inhibitor Nω-nitro-l-arginine methyl ester did not affect local responses, but markedly reduced conducted dilation in younger (Ca/IKCa-mediated hyperpolarization spread through gap junctions, which contributes to conducted vasodilation initiated by focal application of BK. We demonstrate that conducted dilation declines with age, likely due to reduced NO availability, which plays a permissive role in propagating longitudinal vasomotor signaling.
- Published
- 2014
32. Vasomotor Effects of Acetylcholine, Bradykinin, Noradrenaline, 5-Hydroxytryptamine, Histamine and Angiotensin II on the Mouse Basilar Artery
- Author
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Yutaka Watanabe, Takeshi Obi, Mitsuya Shiraishi, Atsushi Miyamoto, Emi Yamazaki-Himeno, Ha Thi Thanh Nguyen, and Md. Zahorul Islam
- Subjects
Male ,medicine.medical_specialty ,Serotonin ,Vasodilator Agents ,Cerebral arteries ,Bradykinin ,Vasodilation ,Pharmacology ,receptor subtype ,Tissue Culture Techniques ,chemistry.chemical_compound ,Mice ,Norepinephrine ,Internal medicine ,medicine.artery ,medicine ,Basilar artery ,Animals ,Vasoconstrictor Agents ,vasodilator ,cerebral artery ,General Veterinary ,Full Paper ,business.industry ,Angiotensin II ,Acetylcholine ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Vasoconstriction ,Basilar Artery ,Circulatory system ,vasoconstrictor ,business ,pA2 ,medicine.drug ,Artery - Abstract
Because of the very small internal diameter (0.09–0.14 mm) and length (4–5 mm) of the mouse basilar artery, little information has been available regarding its reactivity to intrinsic vasoactive substances, such as acetylcholine (ACh), bradykinin (BK), noradrenaline (NA), 5-hydroxytryptamine (5-HT), histamine (His) and angiotensin (Ang) II in vitro and the receptor subtypes involved. The basilar artery runs along the ventral aspect of the medulla oblongata and supplies the brain with blood in reptiles [33], birds [20] and mammals. The responsiveness of this artery seems to reflect changes in cerebral blood flow and local microvascular pressure. Species differences in the responsiveness of this artery to intrinsic vasoactive substances have been reported, and some are very unique and characteristic. For example, NA, a well-known vasoconstrictor, induces contraction of the basilar artery in dogs [26], monkeys [24], guinea pigs [7] and rabbits [8], whereas it induces relaxation in that of cattle [3] and pigs [16]. The intensity of relaxation in pigs is much greater than that in cattle, and this larger relaxation induced by NA is one of the characteristics of porcine basilar artery. In other case, BK, which is a well-known vasorelaxing factor, induces relaxation in human basilar artery, but induces very strong contraction in equine basilar artery [25]. The contraction induced by BK is greater than that induced by NA, His or 5-HT, and this is also one of the characteristics of the equine basilar artery. Differences in responsiveness to these vasoactive substances might be dependent on differences in the distribution of their receptor subtypes on smooth muscle or endothelial cells. To our knowledge, basilar arterial responsiveness to these vasoactive substances in one species of animal has never been similar to that of other species. Therefore, characterization of basilar arterial reactivity in different species of animal would appear to be useful for investigating evolutionary relationships among animals. Mice are widely considered to be a prime model of inherited human disease and share 99% of their genes with humans [28]. They are the most commonly used vertebrate species, because of their availability, size, low cost, ease of handling and high reproduction rate. The routine availability of mouse models of various cerebral circulatory disorders like Alzheimer’s disease, migraine and stroke (4) requires characterization of the regulation of basilar arterial tone. A study of basilar artery is important, because it is one of the major resistance vessels in the brain. In the present study, therefore, we attempted to clarify in detail the responsiveness of isolated mouse basilar arteries to ACh, BK, NA, 5-HT, His and Ang II and the receptor subtypes involved.
- Published
- 2014
33. Bile as a key aetiological factor of acute but not chronic pancreatitis: a possible theory revealed
- Author
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Hegyi, Péter
- Subjects
Male ,stellate cells ,Molecular and cellular ,pancreatitis ,bile ,Acinar Cells ,Bradykinin ,digestive system ,necrosis ,Mice ,Animals ,Humans ,Calcium Signaling ,Pancreas ,Cells, Cultured ,calcium ,Pancreatitis, Acute Necrotizing ,Pancreatic Stellate Cells ,Sodium ,Mice, Inbred C57BL ,Cellular and Molecular Physiology ,Editor's Choice ,inflammation ,Acute Disease ,Perspectives ,Taurolithocholic Acid ,Research Paper - Abstract
Key points Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas.Bile acids are known to induce Ca2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored.Here we show that cholate and taurocholate elicit more dramatic Ca2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells.Ca2+ signals and necrosis are strongly dependent on extracellular Ca2+ as well as Na+; and Na+‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells.Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. Abstract Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid‐elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3‐sulfate (TLC‐S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium–taurocholate cotransporting polypeptide (NTCP) indicate a Na+‐dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca2+ and significantly reduced in the absence of Na+, showing that bile‐dependent cell death was a downstream event of Ca2+ signals. Finally, combined application of TLC‐S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC‐S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells., Key points Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas.Bile acids are known to induce Ca2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored.Here we show that cholate and taurocholate elicit more dramatic Ca2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells.Ca2+ signals and necrosis are strongly dependent on extracellular Ca2+ as well as Na+; and Na+‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells.Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis.
- Published
- 2016
34. Necrotic amplification loop in acute pancreatitis: pancreatic stellate cells and nitric oxide are important players in the development of the disease
- Author
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Péter Hegyi
- Subjects
0301 basic medicine ,calcium signalling ,Pathology ,medicine.medical_specialty ,Physiology ,Vasodilator Agents ,Acinar Cells ,Disease ,Nitric Oxide ,Bradykinin ,Nitric oxide ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Acinar cell ,Humans ,Animals ,Calcium Signaling ,03.02. Klinikai orvostan ,Cells, Cultured ,030102 biochemistry & molecular biology ,business.industry ,Pancreatic Stellate Cells ,Special section: Intracellular calcium signalling ,medicine.disease ,Trypsin ,Pancreas, Exocrine ,Mice, Inbred C57BL ,Editor's Choice ,030104 developmental biology ,Pancreatitis ,chemistry ,Alcohols ,exocrine pancreas ,Hepatic stellate cell ,Acute pancreatitis ,Calcium ,business ,Research Paper ,medicine.drug - Abstract
Key points Ca2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared.Ca2+ signals evoked by K+‐induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca2+ signals in acinar but not in stellate cells.Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca2+ signals in response to membrane depolarization.The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol‐related acute pancreatitis, but they became sensitive to stimulation with trypsin.Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. Abstract Physiological Ca2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca2+ signals in the peri‐acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization‐evoked Ca2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca2+ signals in response to membrane depolarization. The principal agent evoking Ca2+ signals in the stellate cells is bradykinin, but in experimental alcohol‐related acute pancreatitis, these cells become much less responsive to bradykinin and then acquire sensitivity to trypsin. Our new findings have implications for our understanding of the development of acute pancreatitis and we propose a scheme in which Ca2+ signals in stellate cells provide an amplification loop promoting acinar cell death. Initial release of the proteases kallikrein and trypsin from dying acinar cells can, via bradykinin generation and protease‐activated receptors, induce Ca2+ signals in stellate cells which can then, possibly via nitric oxide generation, damage more acinar cells and thereby cause additional release of proteases, generating a vicious circle., Key points Ca2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared.Ca2+ signals evoked by K+‐induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca2+ signals in acinar but not in stellate cells.Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca2+ signals in response to membrane depolarization.The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol‐related acute pancreatitis, but they became sensitive to stimulation with trypsin.Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation.
- Published
- 2018
35. Endothelin‐1 shifts the mediator of bradykinin‐induced relaxation from NO to H2O2 in resistance arteries from patients with cardiovascular disease
- Author
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Leurgans, Thomas M, Bloksgaard, Maria, Brewer, Jonathan R, Bagatolli, Luis A, Fredgart, Maise H, Rosenstand, Kristoffer, Hansen, Maria L, Rasmussen, Lars M, Irmukhamedov, Akhmadjon, and De Mey, Jo G R
- Subjects
Male ,Endothelin-1 ,Arteries ,Hydrogen Peroxide ,In Vitro Techniques ,Bradykinin ,Nitric Oxide ,Research Papers ,Bradykinin/pharmacology ,Cardiovascular Diseases/metabolism ,Arteries/drug effects ,Cardiovascular Diseases ,Nitric Oxide/metabolism ,Humans ,Female ,Endothelin-1/pharmacology ,Hydrogen Peroxide/metabolism ,Aged - Abstract
Background and Purpose We tested the hypothesis that in resistance arteries from cardiovascular disease (CVD) patients, effects of an endothelium-dependent vasodilator depend on the contractile stimulus. Experimental Approach Arteries dissected from parietal pericardium of cardiothoracic surgery patients were studied by myography and imaging techniques. Segments were sub-maximally contracted by K +, the TxA 2 analogue U46619 or endothelin-1 (ET-1). Key Results Relaxing effects of Na-nitroprusside were comparable, but those of bradykinin (BK) were bigger in the presence of ET-1 compared with K + or U46619. BK-induced relaxation was (i) abolished by L-NAME in K +-contracted arteries, (ii) partly inhibited by L-NAME in the presence of U46619 and (iii) not altered by indomethacin, L-NAME plus inhibitors of small and intermediate conductance calcium-activated K + channels, but attenuated by catalase, in ET-1-contracted arteries. This catalase-sensitive relaxation was unaffected by inhibitors of NADPH oxidases or allopurinol. Exogenous H 2O 2 caused a larger relaxation of ET-1-induced contractions than those evoked by K + or U46619 in the presence of inhibitors of other endothelium-derived relaxing factors. Catalase-sensitive staining of cellular ROS with CellROX Deep Red was significantly increased in the presence of both 1 μM BK and 2 nM ET-1 but not either peptide alone. Conclusions and Implications In resistance arteries from patients with CVD, exogenous ET-1 shifts the mediator of relaxing responses to the endothelium-dependent vasodilator BK from NO to H 2O 2 and neither NADPH oxidases, xanthine oxidase nor NOS appear to be involved in this effect. This might have consequences for endothelial dysfunction in conditions where intra-arterial levels of ET-1 are enhanced.
- Published
- 2016
36. Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth
- Author
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Michael Francis, Lawrence D. Longo, Carla Blum-Johnston, William J. Pearce, Sean M. Wilson, Alexander Brunelle, Quintin Blood, Chelsea Wee, Arlin B. Blood, Richard B. Thorpe, Rachael Wilson, Monica Romero, and Mark S. Taylor
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Arginine ,Nitric Oxide Synthase Type III ,Physiology ,Bradykinin ,Stimulation ,Vasodilation ,030204 cardiovascular system & hematology ,Pulmonary Artery ,Nitric Oxide ,Nitric oxide ,Contractility ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Hypoxia ,Sheep ,Cell Biology ,Hypoxia (medical) ,030104 developmental biology ,Endocrinology ,chemistry ,Call for Papers ,Endothelium, Vascular ,medicine.symptom - Abstract
Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of large-conductance Ca2+-activated K+(BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca2+. Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCachannels during bradykinin-induced vasorelaxation by examining endothelial Ca2+signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (∼140 days gestation) and newborn, 10- to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for >100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca2+responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 μM nitro-l-arginine methyl ester or 10 μM 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2pathways. BKCachannel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCachannel α1-subunit expression but increased β1-subunit expression. These results suggest that CH amplifies the contribution of BKCachannels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes.
- Published
- 2015
37. Receptor mediation and nociceptin inhibition of bradykinin-induced plasma extravasation in the knee joint of the rat
- Author
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Pamela Pierce Palmer, Yan Wang, Yilei Xing, Yeon Jang, Kumi Moriyama, Yun Jeong Chae, Guo-xi Xie, Xiaokang Han, Stefan Grond, Jia Liu, and James Mitchell
- Subjects
Male ,Opioid receptor-like ,Knee Joint ,Receptor, Bradykinin B2 ,Inflammatory mediator ,Receptor, Bradykinin B1 ,Rats, Sprague-Dawley ,Plasma ,chemistry.chemical_compound ,Bradykinin B2 Receptor Antagonists ,Coloring Agents ,Pharmacology/Toxicology ,Kinin ,Extravasation ,Original Research Paper ,Nociceptin receptor ,Opioid Peptides ,Neurology ,Allergology ,medicine.symptom ,Evans Blue ,Histamine ,Signal Transduction ,musculoskeletal diseases ,Serotonin ,medicine.medical_specialty ,Calcitonin Gene-Related Peptide ,Immunology ,Bradykinin ,Inflammation ,Dermatology ,Calcitonin gene-related peptide ,Dinoprostone ,Rheumatology ,Internal medicine ,medicine ,Animals ,Humans ,Pharmacology ,business.industry ,Rats ,Bradykinin B1 Receptor Antagonists ,Biomedicine ,Endocrinology ,chemistry ,business - Abstract
Objective and design The aim was to investigate the signaling mechanisms and regulation of bradykinin (BK)-induced inflammation in rat knee joint. Materials and methods Knee joints of anesthetized rats were perfused with BK (0.1–1.0 μM), and synovial plasma extravasation (PE) was evaluated by spectrophotometrical measurement of Evans Blue leakage. To examine the signaling pathway, B1 antagonist [des-Arg10]-HOE140 (0.1–1.0 μM) and B2 antagonist HOE140 (0.05–1.0 μM), calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 (0.5–1.0 μM), prostaglandin E2 antagonist AH-6809 (0.1–1.0 μM), and histamine H1 antagonist mepyramine (0.1–1.0 μM) were used. Nociceptin (0.0001–1.0 μM) and antagonist J-113397 were tested for modulation of BK-induced PE. The analyses were compared side-by-side with 5-hydroxytryptamine-induced PE. Results BK perfusion dose-dependently induced PE, which was blocked by HOE140, CGRP8-37, AH-6809, and mepyramine. It was also inhibited by nociceptin, which could be reversed by antagonist J-113397. In contrast, 5-hydroxytryptamine-induced PE was biphasically regulated by nociceptin and was not antagonized by CGRP8-37. Conclusions BK-induced PE is mediated by B2 receptors and may involve CGRP, prostaglandin, and histamine pathways. BK-induced PE is inhibited by nociceptin through the activation of ORL1 receptors. There are differences between BK- and 5-hydroxytryptamine-induced inflammation in signaling and modulation.
- Published
- 2009
38. An update on the cardiovascular pleiotropic effects of milk and milk products
- Author
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Steven G. Chrysant and George S. Chrysant
- Subjects
Vitamin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Bradykinin ,chemistry.chemical_element ,Angiotensin-Converting Enzyme Inhibitors ,Blood Pressure ,Coronary Disease ,Calcium ,chemistry.chemical_compound ,Internal medicine ,Casein ,Diabetes mellitus ,Internal Medicine ,medicine ,Animals ,Humans ,Minerals ,Review Paper ,business.industry ,Type 2 Diabetes Mellitus ,Caseins ,medicine.disease ,Atherosclerosis ,Milk Proteins ,Angiotensin II ,Blockade ,Endocrinology ,Milk ,Whey Proteins ,chemistry ,Diabetes Mellitus, Type 2 ,Hypertension ,Dairy Products ,Cardiology and Cardiovascular Medicine ,business - Abstract
Hypertension is a major risk factor in addition to atherosclerosis and type 2 diabetes mellitus for the development of coronary heart disease and strokes. Several prospective clinical studies have demonstrated a possible protective effect of milk and dairy product consumption on these conditions. The putative effects of milk and dairy products are possibly mediated through their mineral content of calcium, magnesium, potassium, and vitamin D. These dairy substances exercise their blood pressure-lowering effect either directly on the arterial wall by these minerals or indirectly through blockade of the angiotensin-converting enzyme (ACE) by the amino acids contained in the casein and whey of milk. The blockade of ACE results in the inhibition of production of angiotensin II, a potent vasoconstrictive peptide, and the prevention of degradation of bradykinin, a potent vasodilating peptide. For this concise review, a Medline search of the English language literature was conducted from 2006 to September 2012 and 16 pertinent papers were selected. The potential beneficial pleiotropic effects from these studies together with collateral literature will be discussed in this review.
- Published
- 2012
39. Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells
- Author
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Karl Deacon and Alan J. Knox
- Subjects
Pulmonary and Respiratory Medicine ,Transcriptional Activation ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Chemokine ,EGF Family of Proteins ,animal structures ,Physiology ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,Gene Expression ,Respiratory Mucosa ,Biology ,Bradykinin ,Amphiregulin ,Dinoprostone ,Proinflammatory cytokine ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Interleukin 8 ,skin and connective tissue diseases ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Interleukin-8 ,Recombinant Amphiregulin ,Epithelial Cells ,Cell Biology ,respiratory system ,Asthma ,3. Good health ,Cell biology ,respiratory tract diseases ,carbohydrates (lipids) ,Endocrinology ,Cytokine ,030228 respiratory system ,Cyclooxygenase 2 ,biology.protein ,Call for Papers ,Respiratory epithelium ,Signal Transduction - Abstract
Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production.
- Published
- 2014
40. Crosstalk between presynaptic angiotensin receptors, bradykinin receptors and α 2 -autoreceptors in sympathetic neurons: a study in α 2 -adrenoceptor-deficient mice
- Author
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Anne-Ulrike Trendelenburg, Serafim Guimarães, Werner Klebroff, Klaus Starke, and Angelika Meyer
- Subjects
Pharmacology ,medicine.medical_specialty ,Angiotensin receptor ,Rauwolscine ,Bradykinin ,Stimulation ,Angiotensin II ,Receptors, G-Protein-Coupled ,chemistry.chemical_compound ,Endocrinology ,Phentolamine ,chemistry ,GTP-Binding Proteins ,Internal medicine ,Papers ,Synapses ,medicine ,Autoreceptor ,Animals ,Humans ,Receptor ,medicine.drug - Abstract
In mouse atria, angiotensin II and bradykinin lose much or all of their noradrenaline release-enhancing effect when presynaptic α2-autoinhibition does not operate either because of stimulation with very brief pulse trains or because of treatment with α2 antagonists. We now studied this operational condition in α2-adrenoceptor-deficient mice. Release of 3H-noradrenaline was elicited by electrical stimulation. In tissues from wild-type (WT) mice, angiotensin II and bradykinin increased the overflow of tritium evoked by 120 pulses at 3 Hz. This enhancement did not occur or was much reduced when tissues were stimulated by 120 pulses at 3 Hz in the presence of rauwolscine and phentolamine, or when they were stimulated by 20 pulses at 50 Hz. In tissues from mice lacking the α2A-adrenoceptor (α2AKO) or the α2B-adrenoceptor (α2BKO), the concentration–response curves of angiotensin II and bradykinin (120 pulses at 3 Hz) were unchanged. In tissues from mice lacking the α2C-adrenoceptor (α2CKO) or both the α2A- and the α2C-adrenoceptor (α2ACKO), the concentration–response curves were shifted to the same extent downwards. As in WT tissues, angiotensin II and bradykinin lost most or all of their effect in α2AKO and α2ACKO tissues when rauwolscine and phentolamine were present or trains consisted of 20 pulses at 50 Hz. Rauwolscine and phentolamine increased tritium overflow evoked by 120 pulses at 3 Hz up to seven-fold in WT and α2BKO tissues, three-fold in α2AKO and α2CKO tissues, and two-fold in α2ACKO tissues. Results confirm that angiotensin II and bradykinin require ongoing α2-autoinhibition for the full extent of their release-enhancing effect. Specifically, they require ongoing α2C-autoinhibition. The peptide effects that remain in α2C-autoreceptor-deficient mice seem to be because of α2B-autoinhibition. The results hence also suggest that in addition to α2A- and α2C- mouse postganglionic sympathetic neurons possess α2B-autoreceptors. British Journal of Pharmacology (2003) 138, 1389–1402. doi:10.1038/sj.bjp.0705223
- Published
- 2003
41. Pharmacological modulation of secondary mediator systems–cyclic AMP and cyclic GMP–on inflammatory hyperalgesia
- Author
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Cunha, F Q, Teixera, M M, and Ferreira, S H
- Subjects
Inflammation ,Male ,Oxadiazoles ,Sulfonamides ,Interleukin-6 ,Phosphodiesterase Inhibitors ,Tumor Necrosis Factor-alpha ,Dopamine ,Interleukin-8 ,Bradykinin ,Carrageenan ,Isoquinolines ,Second Messenger Systems ,Dinoprostone ,Pyrrolidinones ,Rats ,Hyperalgesia ,Quinoxalines ,Papers ,Cyclic AMP ,Animals ,Rats, Wistar ,Cyclic GMP ,Rolipram ,Interleukin-1 - Abstract
1. The objective of the present paper was to evaluate the relevance of neuronal balance of cyclic AMP and cyclic GMP concentration for functional regulation of nociceptor sensitivity during inflammation. 2. Injection of PGE2 (10-100 ng paw-1) evoked a dose-dependent hyperalgesic effect which was mediated via a cyclic AMP-activated protein kinase (PKA) inasmuch as hyperalgesia was blocked by the PKA inhibitor H89. 3. The PDE4 inhibitor rolipram and RP73401, but not PDE3 and PDE5 inhibitors potentiated the hyperalgesic effects of PGE2. The hyperalgesic effect of dopamine was also enhanced by rolipram. Moreover, rolipram significantly potentiated hyperalgesia induced by carrageenan, bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. This suggests that neuronal cyclic AMP mediates the prostanoid and sympathetic components of mechanical hyperalgesia. Moreover, in the neuron cyclic AMP is mainly metabolized by PDE4. 4. To examine the role of the NO/cyclic GMP pathway in modulating mechanical hyperalgesia, we tested the effects of the soluble guanylate cyclase inhibitor, ODQ. This substance counteracts the inhibitory effects of the NO donor, SNAP, on the hyperalgesia induced by PGE2. 5. The ODQ potentiated hyperalgesia induced by carrageenan, bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. In contrast, ODQ had no significant effect on the hyperalgesia induced by PGE2 and dopamine. This indicates that the hyperalgesic cytokines may activate soluble guanylate cyclase, which down-regulate the ability of these substances to cause hyperalgesia. This event appears not to be mediated by prostaglandin or dopamine. 6. In conclusion, the results presented in this paper confirm an association between (i) hyperalgesia and elevated levels of cyclic AMP as well as (ii) antinociception and elevated levels of cyclic GMP. The intracellular levels of cyclic AMP that enhance hyperalgesia are controlled by the PDE4 isoform and appear to result in activation of protein kinase A whereas the intracellular levels of cyclic GMP results from activation of a soluble guanylate cyclase.
- Published
- 1999
42. Serine proteases and protease-activated receptor 2 mediate the proinflammatory and algesic actions of diverse stimulants
- Author
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Cattaruzza, F, Amadesi, S, Carlsson, JF, Murphy, JE, Lyo, V, Kirkwood, K, Cottrell, GS, Bogyo, M, Knecht, W, and Bunnett, NW
- Subjects
Male ,Benzylamines ,Serine Proteinase Inhibitors ,Pain ,PAR-2 ,Mice, Transgenic ,Inbred C57BL ,Bradykinin ,Transgenic ,Cell Line ,Mice ,Formaldehyde ,2.1 Biological and endogenous factors ,Animals ,Receptor, PAR-2 ,Trypsin ,Pharmacology & Pharmacy ,Aetiology ,Inflammation ,Foot ,Pain Research ,Pharmacology and Pharmaceutical Sciences ,Research Papers ,Mice, Inbred C57BL ,Azetidines ,Female ,Chronic Pain ,Serine Proteases ,Oligopeptides ,Receptor - Abstract
Background and purposeAlthough serine proteases and agonists of protease-activated receptor 2 (PAR2) cause inflammation and pain, the spectrum of proteases that are activated by proinflammatory and algesic stimuli and their contribution to inflammatory pain are uncertain.Experimental approachEnzymic assays and selective inhibitors were used to characterize protease activity in mice after intraplantar injections of formalin, bradykinin, PAR2 activating peptide (AP) or vehicle. The capacity of these proteases and of recombinant mouse trypsin 4 to cleave fragments of PAR2 and to activate PAR2 in cell lines was determined. Protease inhibitors and par2 (-/-) mice were used to assess the contributions of proteases and PAR2 to pain and inflammation.Key resultsIntraplantar injection of formalin, bradykinin or PAR2-AP led to the activation of proteases that were susceptible to the serine protease inhibitor melagatran but resistant to soybean trypsin inhibitor (SBTI). Melagatran inhibited mouse trypsin 4, which degraded SBTI. Proteases generated in inflamed tissues cleaved PAR2-derived peptides. These proteases and trypsin 4 increased [Ca(2+) ]i in PAR2-transfected but not in untransfected cells, and melagatran suppressed this activity. Melagatran or PAR2 deletion suppressed oedema and mechanical hypersensitivity induced by intraplantar formalin, bradykinin and PAR2-AP, but had no effect on capsaicin-induced pain.Conclusions and implicationsDiverse proinflammatory and algesic agents activate melagatran-sensitive serine proteases that cause inflammation and pain by a PAR2-mediated mechanism. By inducing self-activating proteases, PAR2 amplifies and sustains inflammation and pain. Serine protease inhibitors can attenuate the inflammatory and algesic effects of diverse stimuli, representing a useful therapeutic strategy.
- Published
- 2014
43. Kaempferol enhances endothelium-dependent relaxation in the porcine coronary artery through activation of large-conductance Ca(2+) -activated K(+) channels
- Author
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Y C, Xu, S W S, Leung, G P H, Leung, and R Y K, Man
- Subjects
Male ,Nitroprusside ,Patch-Clamp Techniques ,Swine ,Myocytes, Smooth Muscle ,Bradykinin ,Nitric Oxide ,Coronary Vessels ,Research Papers ,Vasodilation ,Animals ,Female ,Endothelium, Vascular ,Large-Conductance Calcium-Activated Potassium Channels ,Kaempferols ,Signal Transduction - Abstract
Kaempferol, a plant flavonoid present in normal human diet, can modulate vasomotor tone. The present study aimed to elucidate the signalling pathway through which this flavonoid enhanced relaxation of vascular smooth muscle.The effect of kaempferol on the relaxation of porcine coronary arteries to endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) relaxing agents was studied in an in vitro organ chamber setup. The whole-cell patch-clamp technique was used to determine the effect of kaempferol on potassium channels in porcine coronary artery smooth muscle cells (PCASMCs).At a concentration without direct effect on vascular tone, kaempferol (3 × 10(-6) M) enhanced relaxations produced by bradykinin and sodium nitroprusside. The potentiation by kaempferol of the bradykinin-induced relaxation was not affected by N(ω)-nitro-L-arginine methyl ester, an inhibitor of NO synthase (10(-4) M) or TRAM-34 plus UCL 1684, inhibitors of intermediate- and small-conductance calcium-activated potassium channels, respectively (10(-6) M each), but was abolished by tetraethylammonium chloride, a non-selective inhibitor of calcium-activated potassium channels (10(-3) M), and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channel (KCa 1.1; 10(-7) M). Iberiotoxin also inhibited the potentiation by kaempferol of sodium nitroprusside-induced relaxations. Kaempferol stimulated an outward-rectifying current in PCASMCs, which was abolished by iberiotoxin.The present results suggest that, in smooth muscle cells of the porcine coronary artery, kaempferol enhanced relaxations caused by endothelium-derived and exogenous NO as well as those due to endothelium-dependent hyperpolarization. This vascular effect of kaempferol involved the activation of KCa 1.1 channels.
- Published
- 2014
44. Cell‐to‐cell communication via nitric oxide modulation of oscillatory Cl−currents in rat intact cerebral arterioles
- Author
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Jun Yamazaki and Kenji Kitamura
- Subjects
Male ,Nitroprusside ,Periodicity ,Patch-Clamp Techniques ,Endothelium ,Physiology ,Indomethacin ,Bradykinin ,Cell Communication ,Nitric Oxide ,Nitroarginine ,Muscle, Smooth, Vascular ,Membrane Potentials ,Diffusion ,chemistry.chemical_compound ,Chlorides ,medicine ,Animals ,Cyclooxygenase Inhibitors ,Nitric Oxide Donors ,Patch clamp ,Enzyme Inhibitors ,Rats, Wistar ,Cyclic GMP ,Ion channel ,Endothelin-1 ,Chemistry ,Niflumic acid ,Gap junction ,Niflumic Acid ,Depolarization ,Hyperpolarization (biology) ,Research Papers ,Rats ,Arterioles ,medicine.anatomical_structure ,Biochemistry ,Cerebrovascular Circulation ,Oxyhemoglobins ,Biophysics ,Pia Mater ,medicine.drug - Abstract
1. Diffusion-mediated changes in ion channel function within blood vessels have not been demonstrated directly in a patch-clamp study. Here, we examined the hypothesis that endothelium-derived diffusible bioactive substances would modify endothelin-1 (ET-1)-evoked membrane currents in smooth muscle cells situated within intact arterioles. 2. In pieces of arterioles dissected from the rat cerebral pial membrane, patch electrodes were placed on single smooth muscle cells identified under the microscope. Under perforated patch-clamp conditions, ET-1 evoked an oscillatory inward current at negative potentials in such cells in the presence of the gap junction disrupter 18alpha-glycyrrhetinic acid. ET-1 also elicited an oscillation superimposed on a membrane depolarization in current-clamp mode. 3. The oscillatory current exhibited an outwardly rectifying current-voltage relationship, a sensitivity to niflumic acid, a requirement for inositol 1,4,5-trisphosphate (IP(3))- and caffeine-sensitive Ca(2+) stores and for external Ca(2+) and a rank order of anion permeabilities characteristic of Ca(2+)-activated Cl(-) currents (I(Ca(Cl))). 4. This oscillatory response was inhibited by bradykinin (an effect distinct from the electrical propagation of hyperpolarization) and this effect was attenuated by the NO-synthase inhibitor N(omega)-nitro-L-arginine and by the NO scavenger oxyhaemoglobin but not by the cyclo-oxygenease inhibitor indomethacin. 8-Bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) and nitroprusside closely mimicked the effect of bradykinin. 5. The present patch-clamp study has revealed diffusion-mediated cell-to-cell interaction in an intact blood vessel: bradykinin appears to cause NO to move from endothelium to smooth muscle, there to inhibit an ET-1-evoked oscillatory I(Ca(Cl)) via the NO-cGMP pathway.
- Published
- 2001
45. Indirect actions of bradykinin on neonatal rat dorsal root ganglion neurones: a role for non‐neuronal cells as nociceptors
- Author
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R. J. Docherty, S. England, and Fay Heblich
- Subjects
Patch-Clamp Techniques ,Time Factors ,Physiology ,Bradykinin ,Satellite Cells, Perineuronal ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Dorsal root ganglion ,Ganglia, Spinal ,Neurites ,medicine ,Noxious stimulus ,Animals ,Neurons, Afferent ,Cells, Cultured ,Protein kinase C ,Kainic Acid ,Phospholipase C ,Chemistry ,Nociceptors ,Research Papers ,Rats ,Cell biology ,medicine.anatomical_structure ,Nociception ,nervous system ,Neuromuscular Depolarizing Agents ,Hyperalgesia ,Potassium ,Nociceptor ,Calcium ,medicine.symptom ,Neuroscience - Abstract
Bradykinin (Bk) is an inflammatory mediator that has been implicated in the pathogenesis of rheumatoid and other painful or inflammatory conditions (Colman, 1980) where kinin-induced activation of sensory neurones may contribute to the pain associated with inflammation. Pain and hyperalgesia evoked by Bk are believed to result from an increase in firing of nociceptive sensory neurones or an increase in the sensitivity of these neurones to noxious stimuli (Dray & Perkins, 1993). It has been demonstrated that Bk binding to B2 receptors in sensory neurones induces sensitisation (Weinreich et al. 1995) which results in activation of phospholipase C, release of diacyl glycerol (DAG) and hence activation of protein kinase C (PKC) (Steranka et al. 1988; Burgess et al. 1989; Dray & Perkins, 1993). The e form of PKC has been implicated in Bk-induced sensitisation of the nociceptive heat response (Cesare et al. 2000) and a calcium-dependent cation conductance that is indirectly activated by heat has been described in sensory neurones (Reichling & Levine, 1997). Many types of non-neuronal cells have been demonstrated to express Bk receptors (Estacion, 1991; Cholewinski et al. 1991). Glial cells depolarise by increased Cl− conductance (De Roos et al. 1997) and display an inward current in concert with intracellular Ca2+ increase, in response to Bk (Cholewinski et al. 1991; Gimpl et al. 1992). In dorsal root ganglia (DRG), neurones are closely associated with non-neuronal satellite cells. These non-neuronal cells display Bk sensitivity, Bk acting via B2 Bk receptors to elicit a Ca2+-dependent chloride conductance and a rise in intracellular Ca2+ (England et al. 2001). We postulated therefore that the non-neuronal DRG satellite cells may influence the neuronal response to Bk. An interaction between non-neuronal cells and neurones has been demonstrated in many cell types (Parpura et al. 1994; Araque et al. 1998), including sensory neurones (Undem et al. 1993). Although the role of non-neuronal cells in the inflammatory process is unclear at present, it is reasonable to suppose that Bk acts on the DRG non-neuronal satellite cells and that these cells influence the electrical activity of the neurones by releasing chemical messages, e.g. amino acids or eicosanoids, in response to Bk. Preliminary data have been presented previously (Heblich et al. 1999).
- Published
- 2001
46. Taking the sting out of pain
- Author
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I, Nagy, C, Paule, J, White, and L, Urban
- Subjects
Analgesics ,Receptor, Bradykinin B2 ,Kallikrein-Kinin System ,Animals ,Brain ,Humans ,Pain ,Wasp Venoms ,Bradykinin ,Research Papers ,Rats - Abstract
While the role of the brain kallikrein-kinin system in the development of various pathological processes, such as oedema formation following brain injury or induction of central hypertonia has generated major interest, the possible role of this system in nociceptive processing has received little attention. In their present paper, Mortari et al. (2007) show that bradykinin B2 receptor activation in the brain by the bradykinin analogue, Thr(6)-bradykinin, isolated from the venom of the social wasp, Polybia occidentalis potently reduces acute, noxious heat-evoked reflex responses in naive rats. The unknown underlying mechanism of this powerful antinociceptive effect reminds us that the supraspinal antinociceptive system is still a "black box" in many aspects and awaits thorough investigation.
- Published
- 2007
47. Calcium regulation of a slow post-spike hyperpolarization in vagal afferent neurons
- Author
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Joseph P. Y. Kao, Ruth Cordoba-Rodriguez, Daniel M. Weinreich, and Kimberly A. Moore
- Subjects
Serotonin ,medicine.medical_specialty ,Guinea Pigs ,Action Potentials ,Bradykinin ,Dinoprostone ,Colloquium Paper ,Internal medicine ,medicine ,Animals ,Neurons, Afferent ,Evoked Potentials ,Multidisciplinary ,Voltage-dependent calcium channel ,Prostaglandin D2 ,Ryanodine receptor ,Chemistry ,Endoplasmic reticulum ,Vagus Nerve ,Cardiac action potential ,Nodose Ganglion ,Hyperpolarization (biology) ,Calcium Channel Blockers ,Leukotriene C4 ,Potassium channel ,Vagus nerve ,Endocrinology ,Biophysics ,Calcium ,Calcium Channels ,Rabbits ,Histamine - Abstract
Activation of distinct classes of potassium channels can dramatically affect the frequency and the pattern of neuronal firing. In a subpopulation of vagal afferent neurons (nodose ganglion neurons), the pattern of impulse activity is effectively modulated by a Ca 2+ -dependent K + current. This current produces a post-spike hyperpolarization (AHP slow ) that plays a critical role in the regulation of membrane excitability and is responsible for spike-frequency accommodation in these neurons. Inhibition of the AHP slow by a number of endogenous autacoids (e.g., histamine, serotonin, prostanoids, and bradykinin) results in an increase in the firing frequency of vagal afferent neurons from 10 Hz. After a single action potential, the AHP slow in nodose neurons displays a slow rise time to peak (0.3–0.5 s) and a long duration (3–15 s). The slow kinetics of the AHP slow are due, in part, to Ca 2+ discharge from an intracellular Ca 2+ -induced Ca 2+ release (CICR) pool. Action potential-evoked Ca 2+ influx via either L or N type Ca 2+ channels triggers CICR. Surprisingly, although L type channels generate 60% of action potential-induced CICR, only Ca 2+ influx through N type Ca 2+ channels can trigger the CICR-dependent AHP slow . These observations suggest that a close physical proximity exists between endoplasmic reticulum ryanodine receptors and plasma membrane N type Ca 2+ channels and AHP slow potassium channels. Such an anatomical relation might be particularly beneficial for modulation of spike-frequency adaptation in vagal afferent neurons.
- Published
- 1999
48. Bradykinin induced dilatation of human epicardial and resistance coronary arteries in vivo: effect of inhibition of nitric oxide synthesis
- Author
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Goro Kajiyama, Nobuo Shiode, Hideo Matsuura, Togo Yamagata, and Masaya Kato
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Adult ,Male ,medicine.medical_specialty ,Endothelium ,Bradykinin ,Coronary Angiography ,chemistry.chemical_compound ,Coronary circulation ,Coronary Circulation ,Internal medicine ,medicine ,Humans ,Aged ,omega-N-Methylarginine ,business.industry ,Middle Aged ,Coronary Vessels ,Vasodilation ,Coronary arteries ,medicine.anatomical_structure ,chemistry ,Papers ,Circulatory system ,Cardiology ,Vascular resistance ,Omega-N-Methylarginine ,Female ,Vascular Resistance ,Nitric Oxide Synthase ,Cardiology and Cardiovascular Medicine ,business ,Pericardium ,Artery - Abstract
Objective—To clarify whether endothelium derived nitric oxide contributes to exogenous bradykinin induced dilatation of human epicardial and resistance coronary arteries in vivo. Design—Quantitative coronary angiography and Doppler flow velocity measurements were used to determine the effects of the nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), on bradykinin induced dilatation of the epicardial and resistance coronary arteries. Setting—Hiroshima University Hospital. Patients—20 patients (16 men and four women, mean (SD) age 56 (9) years) with angiographically normal smooth epicardial coronary arteries. Interventions—Serial infusions of bradykinin (0.5, 1.5, and 2.5 µg/min) were given into the left coronary ostium before and after L-NMMA infusion (60 µmol/min). Main outcome measures—Epicardial coronary diameter, coronary blood flow, and coronary vascular resistance. Results—Bradykinin-induced epicardial coronary vasodilatation after L-NMMA (dilatation by 2.5 µg/min, 3.8(1.4)% in the proximal and 5.9(1.8)% in the distal segments, mean (SEM)) was less (p
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- 1997
49. Carbon monoxide formation in the ductus arteriosus in the lamb: implications for the regulation of muscle tone
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H J Vreman, Brian E. McLaughlin, Marlene Rabinovitch, David K. Stevenson, Cameron Ackerley, Lois Kelsey, Flavio Coceani, Eric Seidlitz, and Gerald S. Marks
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Muscle Relaxation ,Blotting, Western ,Protoporphyrins ,Bradykinin ,Vasodilation ,Muscle, Smooth, Vascular ,Nitric oxide ,chemistry.chemical_compound ,Fetus ,Ductus arteriosus ,medicine ,Animals ,Myocyte ,Enzyme Inhibitors ,Pharmacology ,Carbon Monoxide ,Sheep ,Sarcolemma ,Chemistry ,Age Factors ,Ductus Arteriosus ,Immunohistochemistry ,Molecular biology ,Isoenzymes ,Heme oxygenase ,medicine.anatomical_structure ,Muscle relaxation ,Biochemistry ,Heme Oxygenase (Decyclizing) ,Papers ,Hemin - Abstract
1. We have previously shown that carbon monoxide (CO) potently relaxes the lamb ductus arteriosus and have ascribed this response to inhibition of a cytochrome P450-based mono-oxygenase reaction controlling the formation of endothelin-1 (ET-1). In the present study, we have examined whether CO is formed naturally in the vessel. 2. The CO-forming enzyme, haem oxygenase (HO), was identified in ductal tissue in its constitutive (HO-2) and inducible (HO-1) isoforms by Western immunoblotting and immunological staining procedures (both light and electron microscopy). HO-1 was localized to endothelial and muscle cells, while HO-2 was found only in muscle cells. Inside the muscle cells, HO-1 and HO-2 immunoreactivity was limited to the perinuclear region, and the Golgi apparatus in particular. However, upon exposure to endotoxin, HO-1 became more abundant, and both HO isoforms migrated towards the outer region of the cytoplasm close to the sarcolemma. 3. CO was formed enzymatically from added substrate (hemin, 50 microM) in the 10,000 g supernatant of the ductus and its formation was inhibited by zinc protoporphyrin IX (ZnPP, 200 microM). 4. ZnPP (10 microM) had no effect on the tone of the ductus under normal conditions (2.5 to 95% O2), but it contracted the endotoxin-treated ductus (at 2.5% O2). At the same concentration, ZnPP also tended to contract the hypoxic vessel (zero O2). 5. ZnPP (10 microM) curtailed the relaxant response of the oxygen (30%)/indomethacin (2.8 microM)-contracted ductus to bradykinin (35 nM), while it left the sodium nitroprusside (35 nM) relaxation unchanged. 6. We conclude that CO is formed in the ductus and may exert a relaxing influence when its synthesis is upregulated by an appropriate stimulus.
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- 1997
50. The identification of an orally active, nonpeptide bradykinin B2receptor antagonist, FR173657
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Kunio Nakahara, Teruo Oku, Noriaki Inamura, Masayuki Asano, Takayuki Inoue, Akira Katayama, Hiroe Sawai, Hiroshi Kayakiri, Chie Hatori, Yoshito Abe, Masakuni Okuhara, Tatsujiro Fujiwara, Yuki Sawada, and Shigeki Satoh
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Male ,medicine.medical_specialty ,Receptor, Bradykinin B2 ,Bronchoconstriction ,Guinea Pigs ,Administration, Oral ,Bradykinin ,Biology ,Peptide hormone ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Ileum ,In vivo ,Internal medicine ,medicine ,Animals ,Humans ,Receptor ,IC50 ,Bradykinin Receptor Antagonists ,Cells, Cultured ,Inflammation ,Pharmacology ,Dose-Response Relationship, Drug ,Receptors, Bradykinin ,Uterus ,Antagonist ,Muscle, Smooth ,Biological activity ,Rats ,Endocrinology ,chemistry ,Papers ,Quinolines ,Female ,Acetylcholine ,medicine.drug - Abstract
1. An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl] acrylamide) has been identified. 2. This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 x 10(-10) M and in rat uterus with an IC50 of 1.5 x 10(-9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 x 10(-9) M and a Ki of 3.6 x 10(-10) M, but did not reduce [3H]-des]Arg10-kallidin binding to B1 receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 x 10(-9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(-6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(-9) M and 3.2 x 10(-9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(-8) M. Analysis of the data yield a pA2 of 9.2 +/- 0.2 (n = 5) and a slope of 1.5 +/- 0.2 (n = 5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg-1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg-1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg-1 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.
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- 1997
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