10,965 results on '"Angiotensin receptor"'
Search Results
202. Ventricular arrhythmias and ARNI: is it time to reappraise their management in the light of new evidence?
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Attilio Iacovoni, Jacopo Marazzato, Andrea Lorenzo Vecchi, Michele Senni, Andrea Mortara, Roberto De Ponti, Raffaele Abete, Vecchi, A, Abete, R, Marazzato, J, Iacovoni, A, Mortara, A, De Ponti, R, and Senni, M
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medicine.medical_specialty ,Angiotensin receptor ,medicine.medical_treatment ,Cardiomyopathy ,Tetrazoles ,030204 cardiovascular system & hematology ,Implantable cardioverter-defibrillator ,Sudden cardiac death ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,Ventricular arrhythmias ,0302 clinical medicine ,Internal medicine ,Heart failure reduced ejection fraction ,medicine ,Humans ,Angiotensin receptor neprilysin inhibitor ,Angiotensin receptor neprilysin inhibitors ,Sacubitril/valsartan ,030212 general & internal medicine ,Heart Failure ,Receptors, Angiotensin ,Ejection fraction ,business.industry ,Mechanism (biology) ,Aminobutyrates ,Biphenyl Compounds ,Arrhythmias, Cardiac ,Stroke Volume ,medicine.disease ,Heart failure ,Ventricular arrhythmia ,Cardiology ,Valsartan ,Cardiology and Cardiovascular Medicine ,business ,Sacubitril, Valsartan - Abstract
The remarkable scientific progress in the treatment of patients with heart failure (HF) and reduced ejection fraction (HFrEF) has more than halved the risk of sudden cardiac death (SCD) in this setting. However, SCD remains one of the major causes of death in this patient population. Beyond the acknowledged role of beta blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS), a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNI), proved to reduce the overall cardiovascular mortality and, more specifically, the risk of SCD in HFrEF patients. The mechanism by which ARNI may reduce the mortality connected with harmful ventricular arrhythmias is not utterly clear. A variety of direct and indirect mechanisms have been suggested, but a favorable left ventricular reverse remodeling seems to play a key role in this setting. Furthermore, the well-known protective effect of implantable cardioverter-defibrillator (ICD) has been debated in HFrEF patients with non-ischemic cardiomyopathy (NICM) arguing against the role of primary prevention ICD in this setting, particularly when ARNI therapy is considered. The purpose of this review was to provide insights into the SCD mechanisms involved in HFrEF patients together with the current role of electrical therapies and new drug agents in this setting. [Figure not available: see fulltext.].
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- 2020
203. Angiotensin Receptor Neprilysin Inhibitors—2019 Update
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George Chalikias and Dimitrios Tziakas
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0301 basic medicine ,medicine.medical_specialty ,Angiotensin receptor ,Cost-Benefit Analysis ,Tetrazoles ,030204 cardiovascular system & hematology ,Risk Assessment ,Drug Costs ,Sacubitril ,Drug compound ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Humans ,Protease Inhibitors ,Pharmacology (medical) ,Dosing ,Intensive care medicine ,Neprilysin ,Randomized Controlled Trials as Topic ,Heart Failure ,Pharmacology ,Evidence-Based Medicine ,business.industry ,Aminobutyrates ,Biphenyl Compounds ,Recovery of Function ,General Medicine ,medicine.disease ,Drug Combinations ,Critical appraisal ,Treatment Outcome ,030104 developmental biology ,Valsartan ,Heart failure ,Quality of Life ,Patient Safety ,Cardiology and Cardiovascular Medicine ,business ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.
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- 2020
204. Comment on ‘Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?’
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Erkan Cure and Medine Cumhur Cure
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2019-20 coronavirus outbreak ,Angiotensin receptor ,Coronavirus disease 2019 (COVID-19) ,Physiology ,Blocking (radio) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pharmacology ,Correspondence ,Pandemic ,Internal Medicine ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Coronavirus Infections - Published
- 2020
205. Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice
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Xueling Li, Lihong Wang, Yaru Zheng, Qinggang Zhang, Qin Zhu, Qingcheng Wang, and Qinyang Jin
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Male ,0301 basic medicine ,Angiotensin receptor ,Inflammasomes ,Cardiac fibrosis ,Tetrazoles ,030204 cardiovascular system & hematology ,Ventricular Function, Left ,Sacubitril ,0302 clinical medicine ,Pharmacology (medical) ,Ventricular Remodeling ,Aminobutyrates ,NF-kappa B ,General Medicine ,Drug Combinations ,Valsartan ,Cardiology ,Hypertrophy, Left Ventricular ,Neprilysin ,Original Article ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,medicine.drug ,Cardiac function curve ,medicine.medical_specialty ,03 medical and health sciences ,Internal medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Protease Inhibitors ,Sacubitril/valsartan ,Cardiac remodeling ,Pharmacology ,Pressure overload ,business.industry ,Myocardium ,Pressure unloading ,Biphenyl Compounds ,medicine.disease ,Fibrosis ,NLRP3 inflammasome ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Heart failure ,business ,Angiotensin II Type 1 Receptor Blockers ,Sacubitril, Valsartan - Abstract
Background/aims The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. Methods and results Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. Conclusion Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.
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- 2020
206. A review of clinically significant drug-drug interactions involving angiotensin II receptor antagonists and antiepileptic drugs
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Stanisław J. Czuczwar and Marta Rusek
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Drug ,Angiotensin receptor ,media_common.quotation_subject ,Angiotensin II Receptor Blockers ,Pharmacology ,Toxicology ,030226 pharmacology & pharmacy ,Losartan ,Renin-Angiotensin System ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Seizures ,Animals ,Humans ,Medicine ,Drug Interactions ,media_common ,business.industry ,General Medicine ,medicine.disease ,Neuroprotective Agents ,030220 oncology & carcinogenesis ,Heart failure ,Anticonvulsants ,business - Abstract
Angiotensin II receptor blockers are widely used for the treatment of arterial hypertension and heart failure. However, recent studies on animal models of seizures showed that in the brain, the renin-angiotensin-aldosterone system might be involved in neuroinflammation; therefore, the administration of angiotensin II receptor blockers that cross the blood/brain barrier, reduces not only blood pressure but reduces neuroinflammation-induced neuronal injury. Apart from this neuroprotective effect, these drugs exhibit anticonvulsant activity in animal models of seizures, and losartan is associated with a probable anti-epileptogenic activity.In this review, we intended to highlight the role of drug-drug interactions involving angiotensin II receptor antagonists with antiepileptic drugs accompanied by a brief characteristic of the role of RAS in neuroinflammation.Some combinations of antiepileptic drugs (lamotrigine or valproate) with sartans are particularly effective in terms of enhanced seizure control. Considering a possible anti-epileptogenic activity of losartan, its combinations with antiepileptic drugs may prove especially beneficial in epileptogenesis inhibition.
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- 2020
207. Impact of mineralocorticoid receptor blockade with direct renin inhibition in angiotensin II-dependent hypertensive mice
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Shigehiro Karashima, Yoshiyu Takeda, Seigo Konishi, Masashi Demura, Takuya Higashitani, Atsushi Hashimoto, Daisuke Aono, Takashi Yoneda, Mitsuhiro Kometani, and Y. Takeda
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Male ,medicine.medical_specialty ,Angiotensin receptor ,Physiology ,medicine.drug_class ,Drug Evaluation, Preclinical ,030204 cardiovascular system & hematology ,Renin inhibitor ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mineralocorticoid receptor ,Fumarates ,Internal medicine ,Internal Medicine ,medicine ,Animals ,030212 general & internal medicine ,Aldosterone ,Antihypertensive Agents ,Mineralocorticoid Receptor Antagonists ,business.industry ,Aliskiren ,Amides ,Angiotensin II ,Eplerenone ,Candesartan ,Endocrinology ,chemistry ,Hypertension ,Drug Therapy, Combination ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
It has been suggested that aldosterone breakthrough during treatment with a type 1 angiotensin II receptor (AT1R) blocker (ARB) may be an important risk factor for the progression of renal and cardiovascular disease. We examined whether the direct renin inhibitor, aliskiren caused aldosterone breakthrough in angiotensin II (Ang II)-dependent hypertensive mice. The effect of combination therapy with aliskiren and eplerenone was compared with that of therapy using renin–angiotensin system (RAS) blockade. Tsukuba hypertensive mice were treated for 12 weeks with aliskiren (30 mg/kg/day, i.p), candesartan (5 mg/kg/day, p.o), eplerenone (100 mg/kg/day, p.o) aliskiren and candesartan, aliskiren and eplerenone or candesartan and eplerenone. Blood pressure, urinary aldosterone and angiotensinogen (AGTN) excretion; plasma endothelin-1 concentration; kidney weight; urinary albumin excretion (UAE); glomerular injury; and renal messenger RNA (mRNA) levels for transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, angiotensin-converting enzyme (ACE) and AT1R were measured. Combination therapy with aliskiren and candesartan caused a further decrease in blood pressure (p
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- 2020
208. Treatment of Patients with COVID-19 and Concomitant Cardiovascular Diseases: Do not Forget About the Principles of Evidence-based Medicine
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S. Yu. Martsevich
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Angiotensin receptor ,Coronavirus disease 2019 (COVID-19) ,Adverse outcomes ,RM1-950 ,030204 cardiovascular system & hematology ,Bioinformatics ,03 medical and health sciences ,angiotensin converting enzyme inhibitors ,0302 clinical medicine ,angiotensin receptor antagonists ,Diseases of the circulatory (Cardiovascular) system ,Medicine ,Pharmacology (medical) ,In patient ,030212 general & internal medicine ,Angiotensin Receptor Antagonists ,business.industry ,food and beverages ,Evidence-based medicine ,covid-19 ,RC666-701 ,Concomitant ,Therapeutics. Pharmacology ,Viral disease ,Cardiology and Cardiovascular Medicine ,business - Abstract
The recent discussion about the dangers of using angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA) in patients with COVID-19 is analyzed in the article. There is controversy over the hypothesis that these drugs can be factors contributing to an unfavorable outcome of a viral disease, as well as the absence of any clinical evidence for this hypothesis. The opinion that withdrawal of ACE inhibitors and ARA in patients with COVID-19 may increase the risk of adverse outcomes is presented.
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- 2020
209. Characteristic Renal Histology of a 81-Year-Old Patient with a 30-Year History of Diabetes Mellitus: A Case Report
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Masayuki Yamanouchi, Eiko Hasegawa, Rikako Hiramatsu, Akinari Sekine, Hiroki Mizuno, Natsuki Shima, Kenmei Takaichi, Takeshi Fujii, Naoki Sawa, Kenichi Ohashi, Tatsuya Suwabe, Yoshifumi Ubara, Junichi Hoshino, Noriko Hayami, and Masahiro Kawada
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Male ,Nephrology ,medicine.medical_specialty ,Angiotensin receptor ,Biopsy ,Hyperfiltration ,Kidney Glomerulus ,030232 urology & nephrology ,Urology ,Case Report ,Diabetic nephropathy ,Vascular Remodeling ,030204 cardiovascular system & hematology ,Kidney ,Diabetes Complications ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hyperperfusion ,Internal medicine ,Diabetes mellitus ,Polar vasculosis ,medicine ,Humans ,Diabetic Nephropathies ,Diabetic kidney disease ,Antihypertensive Agents ,Aged, 80 and over ,Creatinine ,medicine.diagnostic_test ,business.industry ,General Medicine ,Diabetic retinopathy ,medicine.disease ,Proteinuria ,Blood pressure ,chemistry ,Hyperglycemia ,Hypertension ,Renal biopsy ,business ,Glomerular Filtration Rate - Abstract
A renal histology of an 81-year-old man with a 30-year history of diabetes mellitus (DM), as well as diabetic retinopathy and neuropathy, was examined. The patient’s blood pressure was controlled within the normal range (less than 140/75 mmHg) using antihypertensive agents including angiotensin receptor blocker. Edematous management was achieved by a strict salt diet (less than 6 g/per day). However, this patient’s glycemic control was poor with HbA1c 8–10%. Serum creatinine was 0.87 mg/dL and estimated globular filtration rate (eGFR) was 64 ml/min/1.73m2. Urinary protein excretion was 1.5 g/day. This patient’s renal biopsy showed linear staining for IgG along the GBM by immunofluorescence microscopy, but light microscopy showed almost intact glomeruli, and the GBM was not thickened as revealed by electron microscopy with a width of 288–368 nm (
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- 2020
210. Angiotensin-Converting Enzyme Inhibitor / Angiotensin II Receptor Blocker in COVID-19: a Double-edged Sword or a Myth
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Jung Rae Cho, Kunal Bikram Shaha, Ashok Adhikari, Sajjad Safi, Yubaraj Sharma, and Bimal Pandey
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Angiotensin receptor ,biology ,Coronavirus disease 2019 (COVID-19) ,Chemistry ,lcsh:R ,coronavirus ,lcsh:Medicine ,Angiotensin-converting enzyme ,Pharmacology ,inhibitor ,angiotensin-converting enzyme ,covid-19 ,biology.protein ,acute respiratory syndrome ,blocker ,angiotensin ii receptor - Abstract
Angiotensin-converting enzyme-2 receptor has been unearthed as a prime site of entry of Severe Acute Respiratory Syndrome Coronavirus 2 owing to its strong affinity towards spike protein of Severe Acute Respiratory Syndrome Coronavirus 2, resulting in down-regulation of Angiotensin-converting enzyme -2 receptors and hyperstimulation of Angiotensin-converting enzyme-1 pathway. This proposed theory has led to the birth of a new controversy regarding the use of Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in Coronavirus disease 2019 patients. A theory is against the use of Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, as it enhances the effect of Angiotensin-converting enzyme -2 pathway and upregulation of Angiotensin-converting enzyme -2 receptors resulting in a large number of internalizations of Severe Acute Respiratory Syndrome Coronavirus -2 into cells culminating into a high load of viremia with overwhelming infection and severity. The other theory considers Angiotensin-converting enzyme inhibitors / Angiotensin receptor blockers useful as it blocks deleterious Angiotensin-converting enzyme -1 pathway triggered by Severe Acute Respiratory Syndrome Coronavirus 2 and enhances Angiotensin-converting enzyme -2 receptor upregulation and activation of angiotensin-(1-7) leading to beneficial effects, i.e vasodilation, anti-apoptosis, anti-proliferative, & antifibrosis. Hence, Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers may prove beneficial in countering the Angiotensin-converting enzyme -1 mediated damage by Severe Acute Respiratory Syndrome Coronavirus 2. The recommendations by (European & American) societal guidelines still hold good of not discontinuing Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in COVID-19 patients as it is further supported by current evidence of large observational studies.
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- 2020
211. Potential Role of ACE2 in Coronavirus Disease 2019 (COVID-19) Prevention and Management
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Jianping Li, Yutong Zhao, Ting Wang, Mengyuan Liu, Yun Zhou, and Yan Zhang
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Angiotensin receptor ,medicine.medical_specialty ,Review Article ,Lung injury ,Pharmacology ,spike protein ,Virus ,Pathogenesis ,angiotensin-converting enzyme 2 (ACE2) ,03 medical and health sciences ,0302 clinical medicine ,Viral entry ,Internal medicine ,Renin–angiotensin system ,Internal Medicine ,medicine ,angiotensin II (Ang II) ,030304 developmental biology ,0303 health sciences ,business.industry ,acute lung injury (ALI) ,Angiotensin II ,030220 oncology & carcinogenesis ,ACE inhibitor ,coronavirus disease 2019 (COVID-19) ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
COVID-19 is the current public health threat all over the world. Unfortunately, there is no specific prevention and treatment strategy for this disease. We aim to explore the potential role of angiotensin-converting enzyme 2 (ACE2) in this regard through this literature review. As a crucial enzyme of renin-angiotensin-aldosterone system (RAAS), ACE2 not only mediates the virus entry but also affects the pathophysiological process of virus-induced acute lung injury (ALI), as well as other organs’ damage. As interaction of COVID-19 virus spike and ACE2 is essential for virus infection, COVID-19-specific vaccine based on spike protein, small molecule compound interrupting their interaction, human monoclonal antibody based on receptor-binding domain, and recombinant human ACE2 protein (rhuACE2) have aroused the interests of researchers. Meanwhile, ACE2 could catalyze angiotensin II (Ang II) to form angiotensin 1-7 (Ang 1-7), thus alleviates the harmful effect of Ang II and amplifies the protection effect of Ang1-7. ACE inhibitor and angiotensin II receptor blocker (ARB) have been shown to increase the level of expression of ACE2 and could be potential strategies in protecting lungs, heart, and kidneys. ACE2 plays a very important role in the pathogenesis and pathophysiology of COVID-19 infection. Strategies targeting ACE2 and its ligand, COVID-19 virus spike protein, may provide novel method in the prevention and management of novel coronavirus pneumonia.
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- 2020
212. RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models
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Julia Bercher, Ralf Dechend, Nadine Haase, Ivo Bendix, Babbette LaMarca, Alexandra Gellhaus, Donald Foster, Stuart Milstein, Sarfraz Shaikh, Kristin Thiele, Michaela Golic, Florian Herse, Hanna Napieczynska, Arnd Heuser, Kristin Kräker, Dominik N. Müller, Jeff Rollins, Tuyen Nguyen, Svetlana Shulga-Morskaya, Mark W. Cunningham, Gerd Wallukat, and Meray Serdar
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0301 basic medicine ,Angiotensin receptor ,medicine.medical_specialty ,Medizin ,Angiotensinogen ,Intrauterine growth restriction ,Systemic inflammation ,Preeclampsia ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Pre-Eclampsia ,Pregnancy ,Internal medicine ,medicine ,Animals ,Fetus ,Proteinuria ,business.industry ,General Medicine ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Blood pressure ,Cardiovascular and Metabolic Diseases ,030220 oncology & carcinogenesis ,Female ,RNA Interference ,Rats, Transgenic ,medicine.symptom ,business ,Reperfusion injury ,Research Article - Abstract
Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow midgestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia.
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- 2020
213. The anti‐fibrotic actions of relaxin are mediated through AT2R‐associated protein phosphatases via RXFP1‐AT2R functional crosstalk in human cardiac myofibroblasts
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Anita A. Pinar, Mohammed Akhter Hossain, Ross A. D. Bathgate, Robert E Widdop, Chao Wang, Barbara K Kemp-Harper, Kate M. Denton, and Chrishan S. Samuel
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0301 basic medicine ,Relaxin ,endocrine system ,Angiotensin receptor ,Chemistry ,Cardiac fibrosis ,Phosphatase ,Okadaic acid ,Protein phosphatase 2 ,Pharmacology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,Crosstalk (biology) ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Genetics ,medicine ,Signal transduction ,Molecular Biology ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Fibrosis is a hallmark of several cardiovascular diseases. The relaxin family peptide receptor 1 (RXFP1) agonist, relaxin, has rapidly occurring anti-fibrotic actions which are mediated through RXFP1 and angiotensin II receptor crosstalk on renal and cardiac myofibroblasts. Here, we investigated whether this would allow relaxin to indirectly activate angiotensin II type 2 receptor (AT2 R)-specific signal transduction in primary human cardiac myofibroblasts (HCMFs). The anti-fibrotic effects of recombinant human relaxin (RLX; 16.8 nM) or the AT2 R-agonist, Compound 21 (C21; 1 μM), were evaluated in TGF-β1-stimulated HCMFs, in the absence or presence of an RXFP1 antagonist (1 μM) or AT2 R antagonist (0.1 μM) to confirm RXFP1-AT2 R crosstalk. Competition binding for RXFP1 was determined. Western blotting was performed to determine which AT2 R-specific protein phosphatases were expressed by HCMFs; then, the anti-fibrotic effects of RLX and/or C21 were evaluated in the absence or presence of pharmacological inhibition (NSC95397 (1 μM) for MKP-1; okadaic acid (10 nM) for PP2A) or siRNA-knockdown of these phosphatases after 72 hours. The RLX- or C21-induced increase in ERK1/2 and nNOS phosphorylation, and decrease in α-SMA (myofibroblast differentiation) and collagen-I expression by HCMFs was abrogated by pharmacological blockade of RXFP1 or the AT2 R, confirming RXFP1-AT2 R crosstalk in these cells. HCMFs were found to express AT2 R-dependent MKP-1 and PP2A phosphatases, while pharmacological blockade or siRNA-knockdown of either phosphatase also abolished RLX and/or C21 signal transduction in HCMFs (all P < .05 vs RLX or C21 alone). These findings demonstrated that RLX can indirectly activate AT2 R-dependent phosphatase activity in HCMFs by signaling through RXFP1-AT2 R crosstalk, which have important therapeutic implications for its anti-fibrotic actions.
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- 2020
214. Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis
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Ulysses Diva, Radko Komers, William E. Rote, Andrea Loewen, Howard Trachtman, and Jula K. Inrig
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medicine.medical_specialty ,Angiotensin receptor ,030232 urology & nephrology ,Urology ,030204 cardiovascular system & hematology ,lcsh:RC870-923 ,angiotensin II type 1 receptor blockade ,03 medical and health sciences ,0302 clinical medicine ,Irbesartan ,Focal segmental glomerulosclerosis ,Clinical Research ,irbesartan ,Clinical endpoint ,Medicine ,sparsentan ,focal segmental glomerulosclerosis ,business.industry ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,Interim analysis ,endothelin type A receptor blockade ,Angiotensin II ,Tolerability ,Nephrology ,proteinuria ,business ,Kidney disease ,medicine.drug - Abstract
Introduction: Focal segmental glomerulosclerosis (FSGS), a histologic lesion in the kidney caused by varied pathophysiological processes, leads to end-stage kidney disease in a large proportion of patients. Sparsentan is a first-in-class orally active compound combining endothelin type A (ETA) receptor blockade with angiotensin II type 1 (AT1) receptor antagonism in a single molecule. A Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS (DUPLEX) study evaluates the long-term antiproteinuric efficacy, nephroprotective potential, and safety profile of sparsentan compared with an AT1 receptor blocker alone in patients with FSGS. Methods: DUPLEX is a multicenter, international, phase 3, randomized, double-blind, active-controlled study of sparsentan in patients with FSGS. Approximately 300 patients aged 8 to 75 years, inclusive (United States), and 18 to 75 years, inclusive (outside United States) will be randomized 1:1 to daily treatment with sparsentan or irbesartan. After renin-angiotensin-aldosterone system inhibitor washout, treatment will be administered for 108 weeks, with the final assessment at week 112, four weeks after withdrawal of study drug. Results: The primary endpoint will be the slope of estimated glomerular filtration rate from week 6 to week 108. A novel surrogate efficacy endpoint, the proportion of patients achieving urinary protein-to-creatinine (UP/C) ratio of ≤1.5 g/g and >40% reduction from baseline in UP/C (FSGS partial remission endpoint: FPRE), will be evaluated at a planned interim analysis at week 36. Safety and tolerability of sparsentan will also be assessed. Conclusion: The phase 3 DUPLEX study will characterize the long-term antiproteinuric efficacy and nephroprotective potential of dual ETA and AT1 receptor blockade with sparsentan in patients with FSGS. Keywords: angiotensin II type 1 receptor blockade, endothelin type A receptor blockade, focal segmental glomerulosclerosis, irbesartan, proteinuria, sparsentan
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- 2020
215. Effect of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker on the patients with sepsis
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Sang Min Lee, Hyun Woo Lee, Jae Kyung Suh, and Eun Jin Jang
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Adult ,medicine.medical_specialty ,Angiotensin receptor ,Pulmonology ,Population ,Angiotensin-Converting Enzyme Inhibitors ,law.invention ,Sepsis ,Renin-Angiotensin System ,03 medical and health sciences ,Angiotensin Receptor Antagonists ,0302 clinical medicine ,law ,Internal medicine ,medicine ,Humans ,Hospital Mortality ,Mortality ,education ,education.field_of_study ,biology ,business.industry ,Angiotensin II ,Angiotensin-converting enzyme ,Odds ratio ,medicine.disease ,Intensive care unit ,ACE inhibitor ,biology.protein ,Medicine ,030211 gastroenterology & hepatology ,Original Article ,business ,medicine.drug - Abstract
Background/Aims: Inhibitors of the renin-angiotensin system, angiotensin-con verting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), reportedly have anti-inflammatory effects. This study assessed the association of prior use of ACE inhibitors and ARBs with sepsis-related clinical outcomes. Methods: A population-based observational study was conducted using the Health Insurance Review and Assessment Service claims data. Among the adult patients hospitalized with new onset of sepsis in 2012, patients who took ARBs or ACE inhibitors at least 30 days prior to hospitalization were analyzed. Generalized linear models and logistic regression were used to examine the relation between the prior use of medication and clinical outcomes, such as in-hospital mortality, mechanical ventilation, and length of stay. Results: Of a total of 27,628 patients who were hospitalized for sepsis, the ACE in hibitor, ARB, and non-user groups included 1,214 (4.4%), 3,951 (14.4%), and 22,463 (82.1%) patients, respectively. As the patients in the ACE inhibitor and ARB groups had several comorbid conditions, higher rates of intensive care unit admission, hemodialysis, and mechanical ventilation were observed. However, after covariate adjustment, the use of ACE inhibitor (odds ratio [OR], 0.752; 95% confidence inter val [CI], 0.661 to 0.855) or ARB (OR, 0.575; 95% CI, 0.532 to 0.621) was significantly associated with a lower rate of in-hospital mortality. Conclusions: Pre-hospitalization use of ACE inhibitors or ARBs for sepsis was an independent factor for a lower rate of in-hospital mortality.
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- 2020
216. Exercise training attenuates angiotensin II‐induced vasoconstriction in the aorta of normotensive but not hypertensive rats
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Maria Angélica Spadella, Agnaldo Bruno Chies, Priscilla Bianca de Oliveira, Patrícia de Souza Rossignoli, Priscila Ramos de Oliveira, Marília Medical School, and Universidade Estadual Paulista (Unesp)
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Male ,Angiotensin receptor ,Physiology ,Blood Pressure ,angiotensin II ,030204 cardiovascular system & hematology ,Kidney ,medicine.disease_cause ,chemistry.chemical_compound ,0302 clinical medicine ,Aorta ,Nutrition and Dietetics ,exercise ,biology ,Angiotensin II ,General Medicine ,Nitric oxide synthase ,Hypertension, Renovascular ,NG-Nitroarginine Methyl Ester ,Hypertension ,cardiovascular system ,medicine.symptom ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Nitric Oxide ,Receptor, Angiotensin, Type 2 ,Nitric oxide ,03 medical and health sciences ,Physical Conditioning, Animal ,Physiology (medical) ,Internal medicine ,medicine.artery ,medicine ,Animals ,Rats, Wistar ,business.industry ,Rats ,aorta ,Oxidative Stress ,Endocrinology ,chemistry ,Vasoconstriction ,biology.protein ,Cyclooxygenase ,Nitric Oxide Synthase ,business ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Made available in DSpace on 2020-12-12T01:57:45Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-04-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) New Findings: What is the central question of this study? What are the effects of exercise on Ang II-induced vasoconstriction in aortas of normotensive rats and how do these effects occur in two-kidney–one-clip hypertensive animals? What is the main finding and its importance? In two-kidney rats, exercise training improves the Ang II-induced vasoconstriction by endothelium-derived NO released through AT2R activation. This effect of exercise training on the Ang II-induced vasoconstriction is blunted in two-kidney–one-clip hypertensive animals, possibly as a consequence of oxidative stress. Abstract: This study investigated the effects of both acute exercise and training on the Ang II-induced vasoconstriction in aorta of normotensive (two-kidney; 2K) and two-kidney–one-clip (2K1C) hypertensive rats, focusing on endothelial mechanisms related to nitric oxide (NO) and prostanoids. Aorta rings of 2K and 2K1C male Wistar rats, sedentary and trained, killed at rest and after acute exercise, were challenged with Ang II in either the absence or the presence of PD 123,319, a selective angiotensin receptor subtype 2 (AT2R) antagonist; Nω-nitro-l-arginine methyl ester (l-NAME), a non-selective inhibitor of nitric oxide synthase; indomethacin, a non-selective inhibitor of cyclooxygenase; or Tiron, an analogue of superoxide dismutase. Aortas of sedentary and trained animals studied at rest were also submitted to histomorphometric analysis. Exercise training reduced the Ang II-induced vasoconstriction in aorta of 2K but not of 2K1C animals. This reduction of Ang II response in aortas of 2K animals was not found after endothelial removal or treatment with PD 123,319 or l-NAME. These results suggest that exercise training improves the modulation of Ang II-induced vasoconstriction in aorta of 2K animals, by endothelium-derived NO released due to the activation of AT2R. No exercise-induced change of Ang II response occurred in 2K1C animals, except in the presence of Tiron, which was evidence for reduction of such responses only in resting trained 2K1C animals. In 2K1C animals, NO modulation of Ang II-induced vasoconstriction might be suppressed by local oxidative stress. Moreover, exercise training slightly reduced the media layer thickness in the aortas of the 2K1C, but not 2K animals, which may indicate cardiovascular protection of these animals. Laboratory of Pharmacology Marília Medical School Department of Physiotherapy and Occupational Therapy São Paulo State University (UNESP) Human Embryology Laboratory Marília Medical School Department of Physiotherapy and Occupational Therapy São Paulo State University (UNESP) CAPES: 1576988 FAPESP: 2013/22655-9
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- 2020
217. Comparison of Angiotensin-Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) for Heart Failure Treatment in Congenital Heart Diseases with Left-to-Right Shunt
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Mahrus Ahmad Rahman, Alit Utamayasa, Teddy Ontoseno, and Budiono Budiono
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lcsh:R5-920 ,Angiotensin receptor ,medicine.medical_specialty ,Ejection fraction ,medicine.diagnostic_test ,biology ,business.industry ,Medicine (miscellaneous) ,Angiotensin-converting enzyme ,Captopril ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Valsartan ,Heart failure ,Internal medicine ,Heart rate ,medicine ,biology.protein ,Cardiology ,cardiovascular diseases ,lcsh:Medicine (General) ,business ,Electrocardiography ,medicine.drug - Abstract
BACKGROUND: The angiotensin-converting enzyme inhibitors (ACEIs) have become the forefront of heart failure treatment for more than a decade. Currently, angiotensin receptor blockers (ARBs) are thought to have similar effectiveness. This study aimed to compare the impact of captopril, one of ACEI, and valsartan, one of ARB, on clinical presentation and echocardiographic, electrocardiographic, and chest x-ray improvement in patients with left-to-right shunt congenitalheart diseases.METHODS: This study used a double-blind randomized controlled trial of captopril and valsatran to children with left-to-right shunt congenital heart diseases who suffer from heart failure in the Dr. Soetomo General Hospital, Surabaya, Indonesia. Pediatric heart failure scores, echocardiography, electrocardiography (ECG), and chest photographs were examined at the beginning of the study and after 30 days of treatment.RESULTS: A decrease in pediatric heart failure scores were showed after the administration of ACEI (7.06±2.04 vs. 4.75±2.43; p
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- 2020
218. Telmisartan in the hypertension treatment: from pharmacological characteristics to clinical benefits
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E V Sayutina, E. M. Tuaeva, L I Butorova, and M A Osadchuk
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medicine.medical_specialty ,Angiotensin receptor ,hypertension ,Pharmacology ,telmisartan ,Left ventricular hypertrophy ,Hydrochlorothiazide ,Insulin resistance ,Pharmacokinetics ,target organ damage ,Internal medicine ,medicine ,Diseases of the circulatory (Cardiovascular) system ,high cardiovascular risk ,combination antihypertensive therapy ,fixed-dose combinations ,Hypertension treatment ,Adiponectin ,thiazide diuretics ,business.industry ,medicine.disease ,Blood pressure ,RC666-701 ,Telmisartan ,Cardiology and Cardiovascular Medicine ,business ,raas inhibitors ,medicine.drug - Abstract
The current study describes pharmacological features and benefits of using the angiotensin II receptor blocker telmisartan in actual clinical practice. This bifunctional agent has a number of unique pharmacokinetic features: the longest duration of action, high lipophilicity and maximum efficiency in PPARy activation. The results of numerous studies confirmed the high efficacy of telmisartan and the ability to control blood pressure during the day and the early-morning hours compared to other antihypertensive drugs. The main pleutrophic effects of telmisartan have been proven at most stages of the cardiovascular and renal continuum, the main of which are a decrease in insulin resistance, an adiponectin levels increase, an improvement of endothelial function, angioprotective and renoprotective effects, and the regression of left ventricular hypertrophy. The ability of telmisartan to improve prognosis of patients with high cardiovascular risk and to reduce mortality and the number of cardiovascular complications has been proven. Based on the data of large-scale studies, the possibilities of using telmisartan (80 mg/day) were considered, including in combination with hydrochlorothiazide, as the most effective dual fixed-dose combination and one of the main modern antihypertensive strategies.
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- 2020
219. Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats
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Malou Friederich-Persson and Patrik Persson
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Male ,0301 basic medicine ,medicine.medical_specialty ,Angiotensin receptor ,Physiology ,medicine.drug_class ,030204 cardiovascular system & hematology ,Mitochondrion ,Kidney ,Diabetes Mellitus, Experimental ,Nitric oxide ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Oxygen Consumption ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Receptor ,Receptors, Angiotensin ,Angiotensin II receptor type 1 ,Receptor antagonist ,Angiotensin II ,Mitochondria ,Rats ,Candesartan ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Endocrinology ,chemistry ,Protein Binding ,medicine.drug - Abstract
Exaggerated activation of the renin-angiotensin-aldosterone system (RAAS) is a key feature in diseases such as hypertension, diabetes, and chronic kidney disease. Recently, an intracellular RAAS was demonstrated with angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors expressed in nuclei and mitochondria. Diabetes is associated with both mitochondrial dysfunction and increased intracellular ANG II concentration in the kidney cortex. The present study investigated the role of ANG II signaling in kidney cortex mitochondria isolated from control and streptozotocin-induced diabetic rats. Mitochondrial oxygen consumption was evaluated after addition of ANG II alone or after preincubation with candesartan (AT1 receptor antagonist), PD-123319 (AT2 receptor antagonist), or the two in combination. ANG II binds to only mitochondrial AT2 receptors in control rats and both AT1 receptors and AT2 receptors in diabetic rats. ANG II decreased oxygen consumption in mitochondria from both control and diabetic rats. ANG II response was reversed to increased oxygen consumption by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. AT1 receptor inhibition did not affect the response to ANG II, whereas AT2 receptor inhibition abolished the response in mitochondria from control rats and reversed the response to increased oxygen consumption through superoxide-induced mitochondrial uncoupling in mitochondria from diabetic rats. ANG II decrease mitochondrial respiration via AT2 receptor-mediated nitric oxide release in both control and diabetic rats. AT1 receptors do not regulate mitochondria function in control rats, whereas ANG II via AT1 receptors increase mitochondria leak respiration in diabetic animals.
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- 2020
220. The Other Angiotensin II Receptor: AT2R as a Therapeutic Target
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Lucienne Juillerat-Jeanneret
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0303 health sciences ,Angiotensin receptor ,Chemistry ,Binding properties ,Pharmacology ,Angiotensin I converting enzyme ,01 natural sciences ,Angiotensin II ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Drug Discovery ,Renin–angiotensin system ,Molecular Medicine ,Receptor ,030304 developmental biology ,Hormone - Abstract
The active hormone of the renin-angiotensin system (RAS), angiotensin II (Ang II), is involved in several human diseases, driving the development and clinical use of several therapeutic drugs, mostly angiotensin I converting enzyme (ACE) inhibitors and angiotensin receptor type I (AT1R) antagonists. However, angiotensin peptides can also bind to receptors different from AT1R, in particular, angiotensin receptor type II (AT2R), resulting in biological and physiological effects different, and sometimes antagonistic, of their binding to AT1R. In the present Perspective, the components of the RAS and the therapeutic tools developed to control it will be reviewed. In particular, the characteristics of AT2R and tools to modulate its functions will be discussed. Agonists or antagonists to AT2R are potential therapeutics in cardiovascular diseases, for agonists, and in the control of pain, for antagonists, respectively. However, controlling their binding properties and their targeting to the target tissues must be optimized.
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- 2020
221. Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis
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Sebastian F. Salathe, Nathalie Baumlin, Philip L. Whitney, Juan R. Sabater, Matthias Salathe, Michael D. Kim, Adam Wanner, Frank T. Horrigan, Juliette Sailland, William M. Abraham, John Dennis, Deepika Polineni, Joseph K. David, Charles A. Peloquin, and Makoto Yoshida
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Pulmonary and Respiratory Medicine ,Angiotensin receptor ,biology ,business.industry ,Inflammation ,respiratory system ,Pharmacology ,Critical Care and Intensive Care Medicine ,medicine.disease ,Cystic fibrosis ,Mucus ,03 medical and health sciences ,0302 clinical medicine ,Losartan ,030228 respiratory system ,In vivo ,Neutrophil elastase ,biology.protein ,Medicine ,030212 general & internal medicine ,medicine.symptom ,business ,Airway ,medicine.drug - Abstract
Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction.Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-β1 (transforming growth factor β1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1.Conclusions: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.
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- 2020
222. Synergistic effect of sclerostin and angiotensin II receptor 1 polymorphism on arterial stiffening
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Markéta Mateřánková, Jan Filipovský, Alena Kučerová, Otto Mayer, Ondřej Topolčan, Štěpán Mareš, Julius Gelžinský, Veronika Kordíková, Jitka Seidlerová, Renata Cifkova, Martin Pesta, Václava Černá, and Radek Kucera
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Adult ,Male ,0301 basic medicine ,Angiotensin receptor ,medicine.medical_specialty ,Clinical Biochemistry ,Population ,Pulse Wave Analysis ,030204 cardiovascular system & hematology ,Polymorphism, Single Nucleotide ,Receptor, Angiotensin, Type 1 ,Bone remodeling ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,Vascular Stiffness ,0302 clinical medicine ,Polymorphism (computer science) ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Prospective cohort study ,education ,Pulse wave velocity ,Adaptor Proteins, Signal Transducing ,Aged ,education.field_of_study ,business.industry ,Biochemistry (medical) ,Middle Aged ,030104 developmental biology ,Endocrinology ,chemistry ,Disease Progression ,cardiovascular system ,Sclerostin ,Female ,business - Abstract
Aim: We aimed to establish the association between sclerostin (a glycoprotein involved in bone metabolism) and development of pulse wave velocity (PWV) in the general population. Methods: A prospective cohort study with a total of 522 subjects. Aortic PWV was measured twice (at baseline and after approximately 8 years of follow-up) and intraindividual change in PWV per year (ΔPWV/year) was calculated. Results: ΔPWV/year increased across the sclerostin quintiles, but generally in a strong age-dependent manner. However, a significant independent positive association between sclerostin and ΔPWV/year was observed exclusively in C allele carriers of rs5186 polymorphism for the angiotensin II receptor 1 (n = 246). Conclusion: Sclerostin concentrations were associated with an accelerated natural course of arterial stiffening, but only in interaction with renin-angiotension system.
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- 2020
223. Brain Angiotensinergic Regulation of the Immune System: Implications for Cardiovascular and Neuroendocrine Responses
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Tullio Messana, Vito Angelo Giagulli, Michele Iovino, Vincenzo Triggiani, Aldo Vanacore, Giovanni De Pergola, Edoardo Guastamacchia, Brunella Licchelli, and Emanuela Iovino
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0301 basic medicine ,Angiotensin receptor ,Vasopressin ,medicine.medical_specialty ,Neuroimmunomodulation ,Endocrinology, Diabetes and Metabolism ,Drinking ,030204 cardiovascular system & hematology ,Cardiovascular System ,Thirst ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Immunology and Allergy ,Arterial Pressure ,Circumventricular organs ,business.industry ,Area postrema ,Brain ,Water-Electrolyte Balance ,Neurosecretory Systems ,Angiotensin II ,Subfornical organ ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Immune System ,Hypertension ,medicine.symptom ,business ,Signal Transduction - Abstract
Objective: The Renin-Angiotensin-Aldosterone System (RAAS) plays a major role in the regulation of cardiovascular functions, water and electrolytic balance, and hormonal responses. We perform a review of the literature, aiming at providing the current concepts regarding the angiotensin interaction with the immune system in the brain and the related implications for cardiovascular and neuroendocrine responses. Methods: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. Results: Angiotensin II (ANG II), beside stimulating aldosterone, vasopressin and CRH-ACTH release, sodium and water retention, thirst, and sympathetic nerve activity, exerts its effects on the immune system via the Angiotensin Type 1 Receptor (AT 1R) that is located in the brain, pituitary, adrenal gland, and kidney. Several actions are triggered by the binding of circulating ANG II to AT 1R into the circumventricular organs that lack the Blood-Brain-Barrier (BBB). Furthermore, the BBB becomes permeable during chronic hypertension thereby ANG II may also access brain nuclei controlling cardiovascular functions. Subfornical organ, organum vasculosum lamina terminalis, area postrema, paraventricular nucleus, septal nuclei, amygdala, nucleus of the solitary tract and retroventral lateral medulla oblongata are the brain structures that mediate the actions of ANG II since they are provided with a high concentration of AT 1R. ANG II induces also T-lymphocyte activation and vascular infiltration of leukocytes and, moreover, oxidative stress stimulating inflammatory responses via inhibition of endothelial progenitor cells and stimulation of inflammatory and microglial cells facilitating the development of hypertension. Conclusion: Besides the well-known mechanisms by which RAAS activation can lead to the development of hypertension, the interactions between ANG II and the immune system at the brain level can play a significant role..
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- 2020
224. THE EFFECTS NEUROPROTECTION OF TELMISARTAN ON STROKE WITH HYPERTENSION
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Iin Ernawati, Hanik Badriyah Hidayati, and Sumarno
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Angiotensin receptor ,business.industry ,lcsh:R ,lcsh:Medicine ,030209 endocrinology & metabolism ,Pharmacology ,medicine.disease ,Neuroprotection ,Angiotensin II ,lcsh:RC321-571 ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,030212 general & internal medicine ,Telmisartan ,Prostaglandin E2 ,business ,Receptor ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Stroke ,medicine.drug - Abstract
Stroke is the second deadly disease in the world after ischemic heart disease. According to data of RISKESDAS ( Riset Kesehatan Dasar ), stroke was the highest cause of death in Indonesia in 2013. Hypertension is the one of the most important risk factors for stroke. Hypertension therapy is done by modification and the use of antihypertensives. The antihypertensives used is Telmisartan which is a class of Angiotensin Receptor Blocker (ARB) that works by inhibiting bind to angiotensin II type receptors that is angiotensin II type 1 receptors (AT-1R) which directly make angiotensin II bind to AT-2R (angiotensin receptor type 2 receptors). Telmisartan has a neuroprotectant effect that works by inhibiting the appearance of inflammatory cytokines, production of ROS (Reactive Oxygen Species), PGE2 (prostaglandin E2) and NMDA (N-Methyl-D-Aspartate) activity. Telmisartan activates PPAR-gamma (PPAR-γ), which is very useful in carbohydrate and lipid metabolism which directly protect blood vessels. Telmisartan has the advantage of structure and pharmacokinetics that support the effects of nerve protection. Based on lipophilicity and chemical structure, Telmisartan easily penetrates the brain barrier and high affinity to PPAR-γ, supporting the effects of Telmisartan neuroprotection. Based on pharmacokinetic aspects, telmisartan has the advantage of having a rapid onset that ranges from 30-60 minutes, with T ½ (half life) elimination is 24 hours. T 1/2 elimination for up to 24 hours from Telmisartan is clinically beneficial to improve medication adherence.
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- 2020
225. Angiotensin peptide synthesis and cyclic nucleotide modulation in sympathetic stellate ganglia
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Emma N. Bardsley, David J. Paterson, and Oliver C. Neely
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Angiotensin receptor ,Angiotensins ,Sympathetic Nervous System ,Stellate Ganglion ,Stellate ganglia ,030204 cardiovascular system & hematology ,Neurotransmission ,Models, Biological ,Article ,Young Adult ,Angiotensin ,03 medical and health sciences ,Cyclic nucleotide ,chemistry.chemical_compound ,0302 clinical medicine ,Spontaneously hypertensive rat ,Rats, Inbred SHR ,Internal medicine ,Renin ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Autonomic nervous system ,RNA, Messenger ,Rats, Wistar ,Cyclic GMP ,Molecular Biology ,Cyclic guanosine monophosphate ,Aged ,Principal Component Analysis ,Chemistry ,Middle Aged ,Angiotensin II ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Hypertension ,Female ,Nucleotides, Cyclic ,Transcriptome ,Cardiology and Cardiovascular Medicine ,Sympathetic - Abstract
Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments the activity of peripheral sympathetic nerves through activation of presynaptic angiotensin II receptors, thus contributing to sympathetic over-activity. Although some cells can synthesise angiotensin II locally, it is not known if this machinery is present in neurons closely coupled to the heart. Using a combination of RNA sequencing and quantitative real-time polymerase chain reaction, we demonstrate evidence for a renin-angiotensin synthesis pathway within human and rat sympathetic stellate ganglia, where significant alterations were observed in the spontaneously hypertensive rat stellate ganglia compared with Wistar stellates. We also used Förster Resonance Energy Transfer to demonstrate that administration of angiotensin II and angiotensin 1–7 peptides significantly elevate cyclic guanosine monophosphate in the rat stellate ganglia. Whether the release of angiotensin peptides from the sympathetic stellate ganglia alters neurotransmission and/or exacerbates cardiac dysfunction in states associated with sympathetic over activity remains to be established., Highlights • The stellate ganglia may act as a novel source for local angiotensin signaling. • Angiotensin peptides and receptors were identified in human and rat stellates. • Elevations in neuronal cGMP occur in response to angiotensin peptides. • RNA transcript expression was altered in young spontaneously hypertensive rats. • Angiotensin signaling at this site may be linked to dysautonomia in hypertension.
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- 2020
226. Differential Diagnosis of COVID-19: Importance of Measuring Blood Lymphocytes, Serum Electrolytes, and Olfactory and Taste Functions
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Takahiro Hasuo, Yoshitaka Nakamura, Chihiro Hasegawa, Yusuke Mori, Yuya Takenaka, Hiroki Nakanishi, Hiroyoshi Maeda, Yosuke Ikegami, and Motohiko Suzuki
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Male ,Angiotensin receptor ,Polymerase Chain Reaction ,Gastroenterology ,Electrolytes ,Olfaction Disorders ,Taste Disorders ,chemistry.chemical_compound ,0302 clinical medicine ,Hyperlipidemia ,Lymphocytes ,030212 general & internal medicine ,Child ,Aged, 80 and over ,biology ,General Medicine ,Middle Aged ,Diarrhea ,C-Reactive Protein ,Taste disorder ,030220 oncology & carcinogenesis ,Female ,Symptom Assessment ,medicine.symptom ,Coronavirus Infections ,Loose Stool ,Adult ,medicine.medical_specialty ,Adolescent ,Pneumonia, Viral ,General Biochemistry, Genetics and Molecular Biology ,Diagnosis, Differential ,Betacoronavirus ,Young Adult ,03 medical and health sciences ,Lactate dehydrogenase ,Internal medicine ,medicine ,Humans ,Pandemics ,Aged ,Retrospective Studies ,Atypical Lymphocyte ,L-Lactate Dehydrogenase ,SARS-CoV-2 ,business.industry ,C-reactive protein ,COVID-19 ,medicine.disease ,chemistry ,biology.protein ,business - Abstract
Coronavirus disease 2019 (COVID-19) is associated with various symptoms and changes in hematological and biochemical variables. However, clinical features, which can differentiate COVID-19 from non-COVID-19, are not clear. We therefore examined the key clinical features of COVID-19 and non-COVID-19 patients. This study included 60 COVID-19 patients and 100 non-COVID-19 patients, diagnosed by PCR, and no significant differences in the age and sex were seen between the two groups. The frequencies of fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, taste dysfunction, underlying hyperlipidemia, and the prescription of angiotensin II receptor blocker (ARB) were significantly higher in COVID-19 patients than those in non-COVID-19 patients. The counts of leucocytes, neutrophils, lymphocytes, eosinophils, monocytes, and basophils and the levels of chloride and calcium in blood of COVID-19 patients were significantly lower than those of non-COVID-19 patients. The frequencies of atypical lymphocytes and the levels of lactate dehydrogenase (LDH) and potassium were significantly higher in COVID-19 than those in non-COVID-19. The C-reactive protein (CRP) level in COVID-19 patients was significantly lower than that in non-COVID-19 patients, when we compared CRP levels among patients with elevated CRP. This study is the first to indicate that electrolyte levels and the frequency of atypical lymphocytes in COVID-19 are significantly different from those in non-COVID-19. Fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, and taste dysfunction were the key symptoms of COVID-19. Furthermore, hyperlipidemia and ARB may be risk factors of COVID-19. In conclusion, leucocytes, leucocyte fractions, CRP, LDH, and electrolytes are useful indicators for COVID-19 diagnosis.
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- 2020
227. Association of miR-155 and Angiotensin Receptor Type 1 Polymorphisms with the Risk of Ischemic Stroke in a Chinese Population
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Guoda Ma, You Li, Yaoqun Peng, Xinglan Chen, Linfa Chen, Mengxu Wang, Bin Zhao, Shaoyu Yao, Shaofeng Chen, Weidong Hu, Peiyi Zhu, Wangtao Zhong, Shengnan Li, and Fu Deng
- Subjects
Oncology ,Angiotensin receptor ,medicine.medical_specialty ,Haplotype ,Cell Biology ,General Medicine ,Biology ,Genotype frequency ,miR-155 ,Internal medicine ,Genotype ,microRNA ,Genetics ,medicine ,Allele ,Molecular Biology ,Genotyping - Abstract
There is increasing evidence suggesting that dysregulation of miR-155 and its target angiotensin receptor type 1 (AT1R) are linked to the incidence of ischemic stroke (IS), but the underlying mechanisms remain to be clarified. In this study, we therefore sought to investigate how miR-155 and AT1R polymorphisms affect IS risk. We included 579 IS patients and 509 age-matched controls in the present analysis, genotyping individuals for the rs767649 polymorphism in miR-155, as well as for the rs1492099 and rs275653 polymorphisms in AT1R via iMLDR-TM genotyping technology. The allele and genotype frequencies for the assessed polymorphisms were comparable in IS patients and controls, without any detectable association between AT1R haplotype and IS risk. We conducted additional trial of ORG 10172 in acute stroke treatment-mediated stratification, which indicated that the AT1R rs1492099 T allele was linked to a decreased risk of large-artery atherosclerosis (LAA) stroke. We further found that those with the AT1R rs275653 AA genotype had a decreased risk of small-artery occlusion (SAO) strokes. We further confirmed elevated miR-155 expression in IS patients, but observed no link between the rs767649 polymorphism and expression of this microRNA. Similarly, rs1492099 and rs275653 polymorphisms did not impact AT1R expression levels. The miR-155 rs767649 polymorphism does not seem to be a key determinant of IS risk, whereas the AT1R rs1492099 polymorphism is linked to reduced LAA-stroke risk, and the rs275653 AA genotype is potentially protective against SAO strokes.
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- 2020
228. Current Trends in the Treatment of Hypertension: Focus on Improving Prognosis. The Capabilities of an Amlodipine/Telmisartan Single-Pill Combination
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Olga D. Ostroumova and A. I. Kochetkov
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cardiovascular risk ,medicine.medical_specialty ,Angiotensin receptor ,arterial hypertension ,medicine.drug_class ,Calcium channel blocker ,RM1-950 ,amlodipine ,telmisartan ,Diabetes mellitus ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Pharmacology (medical) ,Amlodipine ,guidelines ,Intensive care medicine ,antihypertensive therapy ,fixed-dose combinations ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Concomitant ,RC666-701 ,Therapeutics. Pharmacology ,Telmisartan ,Metabolic syndrome ,Cardiology and Cardiovascular Medicine ,business ,Lipid profile ,medicine.drug - Abstract
Nowadays, the modern approach to antihypertensive therapy is to prescribe in the most hypertensive patients fixed-dose combinations of antihypertensive drugs as initial therapy. This concept is reflected in the latest revisions of European and Russian guidelines for the management of arterial hypertension (AH). Above mentioned principle is referred as “single-pill combination” strategy and is given high priority in clinical practice with a high evidence level. According to this approach, one of the possible first line single-pill combinations is the combination of an angiotensin II receptor blocker and a calcium channel blocker. In both classes, the reference and the best representatives include, respectively, telmisartan and amlodipine, as a result of broad experience in their practical application and, most importantly, extensive body of evidence regarding to its effectiveness and safety. Both antihypertensive drugs are distinguished by an extra-longstanding antihypertensive effect that exceeds such one of other representatives in their classes, thereby a stable blood pressure control throughout the day is realized, and most importantly, in the early morning hours, that are the most dangerous in terms of adverse cardiovascular and cerebrovascular events. Another important telmisartan and amlodipine characteristics is their targetorgan protective properties, which is realized at all the levels. In addition, telmisartan has a unique ability to activate PPAR-у-receptors and improves the carbohydrate metabolism and lipid profile, which is advantageous in patients with concomitant metabolic syndrome and diabetes mellitus. The telmisartan and amlodipine features and their proven ability to improve prognosis in hypertensive patients served as background for creating a singlepill combination of these antihypertensive drugs, which fully meet with the requirements of current clinical guidelines for AH management and in which these drugs synergistically coupling resulting in more effective blood pressure control, increases the reliability of target-organ protection, and also improves the therapy safety profile.
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- 2020
229. Reduction of blood pressure elevation by losartan in spontaneously hypertensive rats through suppression of LARG expression in vascular smooth muscle cells
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Yung-Zu Tseng, Chia Ti Tsai, Jyh-Ming Juang, Jiun-Yang Chiang, Wei-Chiao Chiu, Cho-Kai Wu, Fu-Tien Chiang, and Ming-Jai Su
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Male ,medicine.medical_specialty ,Angiotensin receptor ,Vascular smooth muscle ,Blood Pressure ,Isometric exercise ,Rats, Inbred WKY ,Losartan ,Muscle, Smooth, Vascular ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,Protein Phosphatase 1 ,Rats, Inbred SHR ,Internal medicine ,medicine.artery ,medicine ,Animals ,cardiovascular diseases ,Phosphorylation ,Antihypertensive Agents ,lcsh:R5-920 ,Aorta ,medicine.diagnostic_test ,business.industry ,General Medicine ,Angiotensin II ,Rats ,Blood pressure ,Endocrinology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Hypertension ,030211 gastroenterology & hepatology ,lcsh:Medicine (General) ,business ,Rho Guanine Nucleotide Exchange Factors ,medicine.drug - Abstract
Background/Purpose: This study sought to elucidate the mechanism by which losartan inhibits blood pressure (BP) elevation in spontaneously hypertensive rats (SHRs). Methods: Four-week-old Wistar-Kyoto (WKY) rats and SHRs were either treated with losartan (20 mg/kg/day) for 8 weeks or served as untreated controls. BP was measured by the tail-cuff method. At 12 weeks, isometric contraction of the aortic rings of the rats was evaluated with a force transducer and recorder. The mRNA and protein levels of the target Rho guanine nucleotide exchange factors (RhoGEFs), and the extent of myosin phosphatase target subunit 1 (MYPT-1) phosphorylation in the aorta, were determined using quantitative real-time polymerase chain reaction (qPCR) assay and Western blot analysis. Results: The BP of the four-week-old SHRs did not differ from that of the age-matched WKY rats, whereas the BP of the twelve-week-old control group SHRs was higher than that of the control group WKY rats. Losartan treatment, however, inhibited BP elevation in both rat strains, doing so to a greater extent in the treatment group SHRs. The contractile force in response to angiotensin II of the aortic rings from the SHRs treated with losartan was significantly lower than that of the aortic rings from the non-treated SHRs. The protein expression of leukemia-associated RhoGEF (LARG) was significantly higher in the non-treated SHRs compared to the non-treated WKY rats. Conclusion: The study results showed that the reduction of BP elevation by losartan in SHRs occurs through the suppression of LARG expression and MYPT-1 phosphorylation in vascular smooth muscle cells. Keywords: Angiotensin II receptor, Leukemia-associated rho guanine nucleotide exchange factor (LARG), Calcium sensitization, Myosin phosphatase target subunit 1, Losartan
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- 2020
230. Benefits and Risks of Continuing Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Antagonists, and Mineralocorticoid Receptor Antagonists during Hospitalizations for Acute Heart Failure
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Aaron Y. Kluger, Ebenezer T Oni, Kevin Bryan Lo, Estefania Oliveros, Janani Rangaswami, Peter A. McCullough, and Anum Shahzad
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medicine.medical_specialty ,Angiotensin receptor ,Exacerbation ,Urology ,Clinical Decision-Making ,030232 urology & nephrology ,Ultrafiltration ,Angiotensin-Converting Enzyme Inhibitors ,Cardiorenal syndrome ,030204 cardiovascular system & hematology ,Risk Assessment ,Renin-Angiotensin System ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Mineralocorticoid receptor ,medicine ,Humans ,Diuretics ,Intensive care medicine ,Mineralocorticoid Receptor Antagonists ,Heart Failure ,Clinical Trials as Topic ,Cardio-Renal Syndrome ,biology ,business.industry ,Acute kidney injury ,Angiotensin-converting enzyme ,Acute Kidney Injury ,medicine.disease ,Hospitalization ,Clinical trial ,Heart failure ,Acute Disease ,Disease Progression ,biology.protein ,Hyperkalemia ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: The renin-angiotensin-aldosterone axis plays a pivotal role in the pathophysiology of acute and chronic heart failure (HF) and represents an important target for guideline-directed medical therapy. Summary: The use of appropriate directed medical therapies for inhibition of the renin-angiotensin-aldosterone axis in chronic HF has been the subject of several landmark clinical trials, with high levels of adherence exhibited in the outpatient setting. However, less clarity exists with respect to the initiation, continuation, and cessation of renin-angiotensin-aldosterone system inhibitors (RAASi) in the setting of acute HF and exacerbation of HF necessitating hospitalization. In this review, we summarize relevant aspects of the physiology of the renin-angiotensin-aldosterone axis in acute HF and during decongestion. We also summarize the available evidence for the risks and benefits of initiating and continuing RAASi in acute HF. Key Message: We offer a decision-making pathway for the use of RAASi in the setting of acute HF that would help guide the cardiologist and nephrologist caring for patients with acute HF and cardiorenal syndrome.
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- 2020
231. Possibilities of antihypertensive therapy in correction of cognitive impairment in hypertensive patients
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V. A. Skybchyk and O. S. Pylypiv
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medicine.medical_specialty ,Angiotensin receptor ,hypertension ,business.industry ,medicine.drug_class ,Cognition ,Calcium channel blocker ,Middle age ,Education ,Blood pressure ,Internal medicine ,GV557-1198.995 ,medicine ,Medicine ,business ,Cognitive impairment ,antihypertensive therapy ,cognitive impairment ,Sports - Abstract
Skybchyk V. А., Pylypiv О. S. Possibilities of antihypertensive therapy in correction of cognitive impairment in hypertensive patients. Journal of Education, Health and Sport. 2020;10(1):150-157. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2020.10.01.017 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2020.10.01.017 http://dx.doi.org/10.5281/zenodo.3637573 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2020; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 20.12.2019. Revised: 25.12.2019. Accepted: 31.01.2020. POSSIBILITIES OF ANTIHYPERTENSIVE THERAPY IN CORRECTION OF COGNITIVE IMPAIRMENT IN HYPERTENSIVE PATIENTS V. А. Skybchyk1, О. S. Pylypiv2 1Danylo Halytsky Lviv Medical University 2Chervonograd Central City Hospital Abstract Data regarding possibilities of antihypertensive therapy to reduce a risk of the development of new cases of cognitive impairment are contradictory. So, the purpose of the study was to analyze the effect of antihypertensive therapy onto the dynamics of cognitive functions in hypertensive patients. We examined 90 patients with stage 1 and 2 hypertension, 2-3 degrees (middle age of patients was 49,66 ± 8,74 years). Clinical and anamnestic examination, laboratory and instrumental methods of examination were done to all patients. Neuropsychological tests, as GPCOG, MMSE, Schulte tables were used to study cognitive functions. Cognitive impairment were observed in 36 patients (40%). The combination of inhibitors of angiotensin-converting enzymes (іАCE) or angiotensin II receptor blockers (ARB) + calcium channel blocker (CCB) was used as antihypertensive therapy. While using this therapy not only the decrease and normalization of blood pressure but also improvement of cognitive functions were noticed. Particularly, in 61,29% cases patients gained obviously more points in the retesting MMSE(p=0,003) and GPCOG(p=0,01) and almost all patients (96,77%) needed less time to fulfill tasks by Schulte tables (p=0,0001). The total sum of points by MMSE scale increased by 3,66% (p=0,003), the total score by GPCOG scale increased by 22,24% (p=0,01), and in the control execution of Schulte test patients used less time by 14,39 % in comparison with initial results (p=0,0001). Key words: hypertension; cognitive impairment; antihypertensive therapy
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- 2020
232. Effects of sacubutril/valsartan on nutritional status in heart failure with reduced ejection fraction
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Seçkin Dereli, Ahmet Kaya, and Adil Bayramoğlu
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Adult ,Male ,medicine.medical_specialty ,Angiotensin receptor ,Time Factors ,Nutritional Status ,Tetrazoles ,030204 cardiovascular system & hematology ,Gastroenterology ,Ventricular Function, Left ,Sacubitril ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Protease Inhibitors ,Prospective Studies ,030212 general & internal medicine ,Prospective cohort study ,Aged ,Aged, 80 and over ,Heart Failure ,Ejection fraction ,Angiotensin II receptor type 1 ,Drug Substitution ,business.industry ,Aminobutyrates ,Biphenyl Compounds ,Malnutrition ,Stroke Volume ,Nutritional status ,Recovery of Function ,General Medicine ,Middle Aged ,medicine.disease ,Drug Combinations ,Nutrition Assessment ,Treatment Outcome ,Valsartan ,Heart failure ,Female ,Neprilysin ,Cardiology and Cardiovascular Medicine ,business ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
BACKGROUND Malnutrition commonly occurs in patients with heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan, which is an AT1 neprilysin inhibitor, has been shown to reduce mortality and hospitalization in patients with HFrEF. However, its effects on nutritional status remain unclear. METHODS Sacubitril/valsartan was initiated in 164 symptomatic patients with HFrEF receiving an optimal medical treatment with angiotensin inhibition (mean age: 63 ± 20 years; 120 males, 60% ischemic cause). The New York Heart Association (NYHA) functional class and nutritional statuses of the patients were evaluated at the switching to AT1 neprilysin inhibitor and at the 6th-month follow-up of the maximum sacubitril/valsartan dose using the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and prealbumin. RESULTS After the sacubutril/valsartan treatment, a significant reduction in the number (%) of malnourished patients was observed according to CONUT (before 47% vs. after 7%, P
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- 2020
233. Direct action of angiotensin II on the conduction through papillary muscle preparations of rat heart immediately after reoxygenation
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Daisuke Wakatsuki, Takeshi Tsutsumi, Yukei Higashi, Hiroshi Suzuki, and Youichi Takeyama
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Angiotensin receptor ,Conduction block ,Reperfusion arrhythmia ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
We investigated the direct action of angiotensin II (Ang II) on myocardial conduction and transmembrane action potential immediately after reoxygenation. Method: After superfusion in a simulated ischemic solution, ventricular papillary muscle preparations of rat heart were washed with oxygenated Tyrode solution containing Ang II, Ang II plus CV-11974 (an AT1 receptor blocker), or Ang II plus 5-hydroxydecanoic acid (mito-KATP blocker), under rapid electrical stimulation (RES) for 60 s. Results: In the control experiments, the incidence of conduction delay and block was the highest within the first 10 s, and subsequently, 1:1 conduction was established after 40 s. Ang II significantly enhanced the 2:1 conduction block during the later phase of RES (40–60 s after reoxygenation). This effect of Ang II was abolished by either CV-11974 (P
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- 2012
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234. Effect of Early Normotension with Olmesartan on Rho-kinase Activity in Hypertensive Patients
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Ulises Novoa, Luigi Gabrielli, Claudio Cantin, Juan F Bulnes, Samuel Córdova, María Paz Ocaranza, Paul MacNab, Jorge E. Jalil, and Iván Godoy
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Angiotensin receptor ,Time Factors ,Diastole ,Down-Regulation ,Tetrazoles ,Blood Pressure ,Pilot Projects ,030204 cardiovascular system & hematology ,Essential hypertension ,Peripheral blood mononuclear cell ,Myosin-Light-Chain Phosphatase ,03 medical and health sciences ,0302 clinical medicine ,Hydrochlorothiazide ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Phosphorylation ,Antihypertensive Agents ,Pharmacology ,rho-Associated Kinases ,business.industry ,Imidazoles ,Middle Aged ,medicine.disease ,Angiotensin II ,Treatment Outcome ,030104 developmental biology ,Blood pressure ,Endocrinology ,Leukocytes, Mononuclear ,Female ,Essential Hypertension ,Cardiology and Cardiovascular Medicine ,Olmesartan ,business ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
Background: Angiotensin II is a potent activator of the Rho-kinase (ROCK) pathway, through which it exerts some of its adverse vasoconstrictor effects. Clinical evidence on the effects of blocking the angiotensin II receptor 1 on ROCK activity in hypertensive patients is scarce. Objective: To demonstrate that ROCK activity in peripheral blood mononuclear cells (PMBCs) in patients with essential hypertension is reduced earlier than previously observed, along with blood pressure (BP) lowering on treatment with olmesartan. Methods: Prospective pilot open study; 17 hypertensive patients were treated with progressive olmesartan doses starting with 20 mg qd. BP was measured at 3, 6 and 9 weeks after treatment initiation. If treatment failed to normalize BP after 3 weeks, olmesartan dose was increased to 40 mg qd, and if still hypertensive after 6 weeks, 12.5 mg of hydrochlorothiazide qd was added. ROCK activity was measured at baseline and 9 weeks after treatment as myosin phosphatase target subunit 1 phosphorylation (MYPT1-p/T ratio) in PBMC. Results: Mean baseline BP was 162 ± 4.9/101 ± 2.4 mmHg. After 9 weeks of treatment, both systolic and diastolic BP were reduced by 41 and 22 mmHg, respectively (p Conclusion: Normotension achieved after 9 weeks in 82% of the patients treated with olmesartan was associated with a significant reduction of ROCK activity in PBMC.
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- 2019
235. The short‐term effects of angiotensin II receptor blockers on albuminuria and renal function in Korean patients
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Hun-Sung Kim, Juyoung Shin, Kun-Ho Yoon, Tong Min Kim, Hyeon Woo Yim, Hyunah Kim, Jae Hyoung Cho, Seung-Hwan Lee, and Hyunyong Lee
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Male ,Angiotensin receptor ,medicine.medical_specialty ,Urology ,Tetrazoles ,Renal function ,Angiotensin-Converting Enzyme Inhibitors ,Subgroup analysis ,Angiotensin II Receptor Blockers ,Kidney ,urologic and male genital diseases ,Toxicology ,030226 pharmacology & pharmacy ,Cohort Studies ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Irbesartan ,Republic of Korea ,Albuminuria ,Humans ,Medicine ,Potency ,cardiovascular diseases ,Retrospective Studies ,Pharmacology ,business.industry ,Biphenyl Compounds ,General Medicine ,Middle Aged ,female genital diseases and pregnancy complications ,Candesartan ,Benzimidazoles ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Each angiotensin II receptor blocker (ARB) asserts independent molecular effects. No study has compared the renoprotective potency of different types of ARBs in Korea. This study evaluated the differences among medications for treating albuminuria. Data were obtained from electronic medical records of adult patients who underwent albuminuria test and received treatment with either angiotensin-converting enzyme inhibitors (ACEIs) or ARBs between January 2009 and June 2016. Patients' albuminuria and renal function data were observed for three months after treatment initiation. In total, 1475 patients were included. Patients treated with ACEIs had no significant changes in albuminuria (from 127.7 ± 55.1 mg/g to 46.7 ± 18.7 mg/g, P = .127), but those treated with ARBs showed significant improvement (from 491.2 ± 33.2 mg/g to 372.0 ± 28.0 mg/g, P < .001). The ARB group had significantly more patients with normal albuminuria after treatment (from 55.8% to 59.3% for normal albuminuria, from 16.7% to 18.5% for moderately increased albuminuria and from 27.5% to 22.2% for severely increased albuminuria, P = .005), but renal function did not change significantly. Subgroup analysis of ARB types showed that candesartan (from 712.5 ± 71.1 to 489.8 ± 57.8 mg/g, P < .001) and irbesartan (from 522.6 ± 65.7 to 352.6 ± 54.3 mg/g, P < .001) had significant effects. Candesartan improved albuminuria in patients older than 60 years (from 506.9 ± 84.2 to 371.9 ± 70.6 mg/g, P = .004) and irbesartan improved albuminuria in patients with glomerular filtration rate
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- 2019
236. The expression of angiotensin II receptors mRNA in granulosa-lutein cells in endometriosis patients who underwent ovarian surgery before in vitro fertilization
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Takehiro Nakao, Kaori Shinya, Chuyu Hayashi, Takahiro Nakajima, K. Matsumoto, Fumihisa Chishima, Atsushi Komatsu, and Kei Kawana
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Ovarian surgery ,Messenger RNA ,Angiotensin receptor ,In vitro fertilisation ,business.industry ,medicine.medical_treatment ,Endometriosis ,Obstetrics and Gynecology ,medicine.disease ,Andrology ,Reproductive Medicine ,Medicine ,business ,Granulosa Lutein Cell - Published
- 2019
237. Current Status of Angiotensin Receptor Blocker Recalls
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Glenn M. Chertow, James Brian Byrd, Pradeep Moon Gunasekaran, and Vivek Bhalla
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Male ,Angiotensin receptor ,030204 cardiovascular system & hematology ,Pharmacology ,urologic and male genital diseases ,Losartan ,Article ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Internal Medicine ,Humans ,Medicine ,Drug Recalls ,cardiovascular diseases ,030212 general & internal medicine ,Receptor ,Antihypertensive Agents ,United States Food and Drug Administration ,business.industry ,female genital diseases and pregnancy complications ,Drug Utilization ,United States ,Hypertension ,Carcinogens ,Female ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Losartan was the ninth most prescribed drug in the United States in 2016, and several other angiotensin-II receptor blockers (ARBs) are widely prescribed. Since July 2018, >2 dozen specific ARB products have been recalled owing to the presence of potentially carcinogenic nitrosamine impurities in selected lots. As is the case with all U.S. drug recalls, the ARB recalls have been voluntary on the part of the companies involved. In April 2019, the Food and Drug Administration categorized marketed ARB products with respect to nitrosamine impurities: (1) not present, (2) to be determined with no prior lots removed from the market (TBD), or (3) to be determined in the context of prior lots having been removed from the market (TBD*). The data were structured as hundreds of rows of products. Owing to the complexity of these data, more than a year into the recalls, it remains difficult for clinicians to understand which ARB products are free of impurities.
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- 2019
238. Angiotensin II Type 2 Receptor–Expressing Neurons in the Central Amygdala Influence Fear-Related Behavior
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Robert C. Speth, Paul J. Marvar, Adam P. Swiercz, Lauren Hopkins, Jan Wiaderkiewicz, Zhe Yu, Cassandra Moshfegh, and Jeanie Park
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0301 basic medicine ,Agonist ,Angiotensin receptor ,medicine.drug_class ,Biology ,Amygdala ,Angiotensin II ,Periaqueductal gray ,Green fluorescent protein ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,nervous system ,medicine ,Fear conditioning ,Neuroscience ,030217 neurology & neurosurgery ,Biological Psychiatry ,Basolateral amygdala - Abstract
Background The renin-angiotensin system has been implicated in posttraumatic stress disorder; however, the mechanisms responsible for this connection and the therapeutic potential of targeting the renin-angiotensin system in posttraumatic stress disorder remain unknown. Using an angiotensin receptor bacterial artificial chromosome (BAC) and enhanced green fluorescent protein (eGFP) reporter mouse, combined with neuroanatomical, pharmacological, and behavioral approaches, we examined the role of angiotensin II type 2 receptor (AT2R) in fear-related behavior. Methods Dual immunohistochemistry with retrograde labeling was used to characterize AT2R-eGFP+ cells in the amygdala of the AT2R-eGFP-BAC reporter mouse. Pavlovian fear conditioning and behavioral pharmacological analyses were used to demonstrate the effects of AT2R activation on fear memory in male C57BL/6 mice. Results AT2R-eGFP+ neurons in the amygdala were predominantly expressed in the medial amygdala and the medial division of the central amygdala (CeM), with little AT2R-eGFP expression in the basolateral amygdala or lateral division of the central amygdala. Characterization of AT2R-eGFP+ neurons in the CeM demonstrated distinct localization to gamma-aminobutyric acidergic projection neurons. Mice receiving acute intra–central amygdala injections of the selective AT2R agonist compound 21 prior to tests for cued or contextual fear expression displayed less freezing. Retrograde labeling of AT2R-eGFP+ neurons projecting to the periaqueductal gray revealed AT2R-eGFP+ neuronal projections from the CeM to the periaqueductal gray, a key brain structure mediating fear-related freezing. Conclusions These findings suggest that CeM AT2R-expressing neurons can modulate central amygdala outputs that play a role in fear expression, providing new evidence for a novel angiotensinergic circuit in the regulation of fear.
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- 2019
239. Clinical features of angioedema induced by renin-angiotensin-aldosterone system inhibition: a retrospective analysis of 84 patients
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Anja Pfaue, Thomas K. Hoffmann, Jens Greve, Patrick J. Schuler, Janina Hahn, and Benjamin Mayer
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lcsh:Internal medicine ,medicine.medical_specialty ,Angiotensin receptor ,030204 cardiovascular system & hematology ,C1-inhibitor ,03 medical and health sciences ,0302 clinical medicine ,RAAS ,Internal medicine ,ACE inhibitor ,Internal Medicine ,Medicine ,030212 general & internal medicine ,Angioedema ,lcsh:RC31-1245 ,biology ,business.industry ,Angiotensin-converting enzyme ,Odds ratio ,medicine.disease ,Otorhinolaryngology ,Hereditary angioedema ,biology.protein ,medicine.symptom ,bradykinin ,business ,medicine.drug ,Research Article - Abstract
Background and objectives: Bradykinin-mediated angioedema (AE) induced by antihypertensive drugs primarily affect the head and neck region and may occur even after several years of uneventful treatment. Many facts about the clinical course remain unknown. Diagnosis is not easy, as the clinical appearance resembles allergic AE. No specific diagnostic markers are known and no officially approved treatment is currently available. Methods: All patients who presented to the ORL department between 2010 and 2016 with acute AE were included. Those with a history of renin-angiotensin-aldosterone system (RAAS) blocker intake were defined as RAE and their pathophysiological characteristics and clinical course of the disease were analyzed. Results: A total of 84 patients (median age of 71 years) with RAE was identified. The majority (80%) was on ACE inhibition. The oral cavity was most often affected. Nearly 60% were medicated for more than 1 year before AE occurred. RAE occurred more often during the morning hours. The necessity for emergency intubation and/or tracheostomy was nine times higher in patients with acute RAE compared to patients with AE due to other reasons. Conclusions: Event-free, long-term therapy with an RAAS blocker before the first development of edema does not exclude RAE. RAE is associated with an increased risk for emergency airway management. Abbreviations ACE: Angiotensin Converting Enzyme; ACEi AE: ACE inhibitor-induced angioedema; AE: Angioedema; ARB: Angiotensin II receptor 1 blocker; C1 INH: C1 Inhibitor; CI: Confidence Interval; CRP: C-reactive protein; DPP IV: Dipeptidyl peptidase IV; ENT: Ear, Nose and Throat; HAE: Hereditary Angioedema; ICD 10: International Statistical Classification of Diseases and Related Health Problems, 10th Edition; OR: Odds Ratio; ORL: Otorhinolaryngology; RAAS: Renin-Angiotensin-Aldosterone System; RAE: RAAS-blocker-induced angioedema
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- 2019
240. Neurohormonal Blockade During Left Ventricular Assist Device Support
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Gabriel Sayer, Ben Chung, Teruhiko Imamura, Bryan Smith, Daniel Rodgers, Jayant Raikhelkar, Nikhil Narang, Valluvan Jeevanandam, Ann Nguyen, Priya Mehta, Tae Song, Nir Uriel, Gene Kim, and Takeyoshi Ota
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Male ,Angiotensin receptor ,medicine.medical_specialty ,Gastrointestinal bleeding ,medicine.drug_class ,medicine.medical_treatment ,Adrenergic beta-Antagonists ,Biomedical Engineering ,Biophysics ,Hemodynamics ,Angiotensin-Converting Enzyme Inhibitors ,Bioengineering ,030204 cardiovascular system & hematology ,Biomaterials ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Beta blocker ,Aged ,Retrospective Studies ,Heart Failure ,Neurotransmitter Agents ,Aldosterone ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Blockade ,030228 respiratory system ,chemistry ,Heart failure ,Ventricular assist device ,Cardiology ,Female ,Heart-Assist Devices ,business - Abstract
Neurohormonal blockade (NHB) is the mainstay of therapy for patients with systolic heart failure (HF). However, the efficacy in patients with left ventricular assist devices (LVADs) remains unknown. Of all, 114 LVAD patients (57 [48, 65] years old and 78% male) were enrolled and followed during the early period (6 months after index discharge), and 98 were followed during the late period (6-12 months following index discharge). Of them, 46% were on beta-blocker (BB), 49% on angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin II receptor blocker (ARB), and 51% on aldosterone antagonist at baseline. Prevalence of BB and ACEi/ARB use increased during the study period. During the early period, similar event rates were found irrespective of the NHB uses. During the late period, BB was associated with reduced HF readmission, and ACEi/ARB was associated with reduced HF readmission and gastrointestinal bleeding (p < 0.05 for all). In conclusion, BB and ACEi/ARB use during the late period was associated with a reduction in HF recurrence in LVAD patients. Further prospective randomized control trials are warranted to clarify the utility of NHB therapy in LVAD patients.
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- 2019
241. Inhibition of the renin-angiotensin system in the cardiorenal syndrome with anaemia
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Gerasimos Filippatos, Costas Tsioufis, Athanasios J. Manolis, Demetrios Vlahakos, Giuseppe Mancia, Vasilios Papademetriou, and Katerina P. Marathias
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Angiotensin receptor ,medicine.medical_specialty ,Physiology ,Anemia ,Renal function ,Angiotensin-Converting Enzyme Inhibitors ,Cardiorenal syndrome ,030204 cardiovascular system & hematology ,Hematocrit ,urologic and male genital diseases ,Renin-Angiotensin System ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,otorhinolaryngologic diseases ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Heart Failure ,Cardio-Renal Syndrome ,medicine.diagnostic_test ,business.industry ,Angiotensin II ,medicine.disease ,Heart failure ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Glomerular Filtration Rate - Abstract
The term 'cardiorenal syndrome' (CRS) was introduced to describe problems related to the simultaneous existence of heart and renal insufficiency. The prevalence of anaemia in CRS is high and increases the risk of hospitalizations and death. Renin-angiotensin system (RAS) inhibition is the cornerstone therapy in cardiovascular and renal medicine. As angiotensin II regulates both glomerular filtration rate (GFR) and erythropoiesis, RAS inhibition can further deteriorate renal function and lower hematocrit or cause anaemia in patients with heart failure. The aim of this review is to explore the relationship among CRS, anemia and administration of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and summarize the evidence suggesting that RAS inhibition may be considered an iatrogenic cause of deterioration of CRS with anemia. It should be emphasized however, that RAS inhibition reduces mortality in both groups with and without worsening of renal function, and therefore, no patient with CRS should be denied an ACEi or ARB trial without careful evaluation.
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- 2019
242. Investigation Planning and Bioequivalence evaluation of Angiotensin II Receptor Antagonists
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D. P. Romodanovskii, A. L. Khokhlov, D. V. Goryachev, and A. N. Miroshnikov
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Pharmacology ,Angiotensin receptor ,010405 organic chemistry ,Chemistry ,Bioequivalence ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Candesartan ,Losartan ,Irbesartan ,Valsartan ,Drug Discovery ,medicine ,Telmisartan ,Olmesartan ,medicine.drug - Abstract
Results of a retrospective analysis of bioequivalence studies of generic angiotensin II receptor antagonists are presented. Losartan, valsartan, and telmisartan medicines can be considered highly variable with respect to the pharmacokinetic parameter for maximum blood-plasma concentration. Candesartan, irbesartan, and olmesartan medicines do not demonstrate high intra-individual variance in bioequivalence studies. Current regulatory recommendations and approaches to bioequivalence studies of highly variable medicines are discussed. Recommendations for the design and evaluation of test results of angiotensin II receptor antagonists are formulated.
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- 2019
243. Mineralocorticoid Receptor Antagonists and Renal Outcomes in Heart Failure Patients with and without Chronic Kidney Disease
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Nadia Giannetti, Thomas A. Mavrakanas, Ahsan Alam, and Ruth Sapir-Pichhadze
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Adult ,Male ,medicine.medical_specialty ,Angiotensin receptor ,Hyperkalemia ,Urology ,030232 urology & nephrology ,Renal function ,Angiotensin-Converting Enzyme Inhibitors ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Mineralocorticoid receptor ,Outcome Assessment, Health Care ,medicine ,Humans ,cardiovascular diseases ,Renal Insufficiency, Chronic ,Aged ,Mineralocorticoid Receptor Antagonists ,Retrospective Studies ,Heart Failure ,business.industry ,Acute kidney injury ,Retrospective cohort study ,Acute Kidney Injury ,Middle Aged ,medicine.disease ,female genital diseases and pregnancy complications ,Case-Control Studies ,Creatinine ,Heart failure ,Disease Progression ,Drug Therapy, Combination ,Female ,Safety ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Glomerular Filtration Rate ,Kidney disease - Abstract
Introduction: The effect of mineralocorticoid receptor antagonists (MRAs) on chronic kidney disease (CKD) progression in patients with heart failure (HF) and with or without preexisting CKD has not been adequately studied. Methods: We conducted a retrospective cohort study including consecutive adult patients followed at the HF clinic of a tertiary care center who had already been on an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). Exposure to MRAs was assessed at 6 months from registration. Patients who were never exposed to an MRA were the control group. Results: A total of 314 patients who were prescribed an MRA were compared to 1,116 patients who never received an MRA. Among them, 121 and 408 patients, respectively, had CKD (estimated glomerular filtration rate 2). MRAs had to be discontinued in 36/121 patients with CKD (29.8%) and 57/165 patients without CKD (34.5%) (p = 0.39). MRA treatment was associated with a higher risk for persistent creatinine doubling among patients without CKD (hazard ratio 4.07, 95% confidence interval 1.41–11.73). A numerically lower risk was identified among CKD patients (hazard ratio 0.33, 95% confidence interval 0.04–2.78) (p for interaction = 0.009). The primary safety outcome, a composite of any doubling of serum creatinine or any episode of serious hyperkalemia (K+ >6 mmol/L), occurred more commonly in MRA users compared with nonusers in the subgroup of patients without CKD, but not in CKD patients (p for interaction = 0.02). Conclusion: MRA treatment in addition to an ACEI or an ARB could be safely prescribed in HF patients with CKD as it is not associated with persistent renal function decline, acute kidney injury, or serious hyperkalemia, compared with ACEI/ARB monotherapy.
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- 2019
244. Therapeutic Progress and Knowledge Basis on the Natriuretic Peptide System in Heart Failure
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Zhenyu Chang, Shihui Fu, Leiming Luo, and Juelin Deng
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0301 basic medicine ,Angiotensin receptor ,Sympathetic nervous system ,medicine.drug_class ,030204 cardiovascular system & hematology ,Pharmacology ,Natriuresis ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Vasopeptidase Inhibitors ,Natriuretic peptide ,Animals ,Humans ,Enzyme Inhibitors ,Natriuretic Peptides ,Adverse effect ,Neprilysin ,Heart Failure ,business.industry ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Heart failure ,business - Abstract
Notwithstanding substantial improvements in diagnosis and treatment, Heart Failure (HF) remains a major disease burden with high prevalence and poor outcomes worldwide. Natriuretic Peptides (NPs) modulate whole cardiovascular system and exhibit multiple cardio-protective effects, including the counteraction of the Renin–Angiotensin–Aldosterone System (RAAS) and Sympathetic Nervous System (SNS), promotion of vasodilatation and natriuresis, and inhibition of hypertrophy and fibrosis. Novel pharmacological therapies based on NPs may achieve a valuable shift in managing patients with HF from inhibiting RAAS and SNS to a reversal of neurohormonal imbalance. Enhancing NP bioavailability through exogenous NP administration and inhibiting Neutral Endopeptidase (NEP) denotes valuable therapeutic strategies for HF. On the one hand, NEP-resistant NPs may be more specific as therapeutic choices in patients with HF. On the other hand, NEP Inhibitors (NEPIs) combined with RAAS inhibitors have proved to exert beneficial effects and reduce adverse events in patients with HF. Highly effective and potentially safe Angiotensin Receptor Blocker Neprilysin Inhibitors (ARNIs) have been developed after the failure of NEPIs and Vasopeptidase Inhibitors (VPIs) due to lacking efficacy and safety. Therapeutic progress and knowledge basis on the NP system in HF are summarized in the current review.
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- 2019
245. Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure
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Jens Erik Nielsen-Kudsk, Harm Jan Bogaard, Jens R. Nyengaard, Frances S. de Man, Julie Birkmose Axelsen, Asger Andersen, Steffen Ringgaard, Stine Andersen, Janus Adler Hyldebrandt, Pulmonary medicine, and ACS - Pulmonary hypertension & thrombosis
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Pulmonary Circulation ,Angiotensin receptor ,medicine.medical_specialty ,Heart Ventricles ,Hypertension, Pulmonary ,Ventricular Dysfunction, Right ,Tetrazoles ,Angiotensin II Type 2 Receptor Blockers ,Vascular Remodeling ,030204 cardiovascular system & hematology ,Right ventricular failure ,Pulmonary hypertension ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Natriuretic peptides ,030212 general & internal medicine ,Neprilysin ,Antihypertensive Agents ,Hypertrophy, Right Ventricular ,business.industry ,Angiotensin II ,Aminobutyrates ,Biphenyl Compounds ,Hypoxia (medical) ,medicine.disease ,Animal models ,Rats ,Disease Models, Animal ,Drug Combinations ,Blood pressure ,Heart failure ,Cardiology ,Valsartan ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
BACKGROUND: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure.METHODS: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks.RESULTS: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function.CONCLUSIONS: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.
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- 2019
246. Losartan Reverses Hippocampal Increase of Kynurenic Acid in Type 1 Diabetic Rats: A Novel Procognitive Aspect of Sartan Action
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Ewa M. Urbańska, Adam Perzyński, Bartosz Olajossy, Iwona Chmiel-Perzyńska, Janusz Kocki, and Paulina Gil-Kulik
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Male ,Angiotensin receptor ,Article Subject ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Pharmacology ,Kynurenic Acid ,Hippocampus ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Neuroprotection ,Losartan ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Endocrinology ,Kynurenic acid ,Diabetes mellitus ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Rats, Wistar ,Cognitive decline ,lcsh:RC648-665 ,business.industry ,medicine.disease ,Rats ,Diabetes Mellitus, Type 1 ,Neuroprotective Agents ,chemistry ,business ,Angiotensin II Type 1 Receptor Blockers ,Kynurenine ,Research Article ,medicine.drug - Abstract
Patients with diabetes mellitus (DM) type 1 and 2 are at a higher risk of cognitive decline and dementia; however, the underlying pathology is poorly understood. Kynurenic acid (KYNA), endogenous kynurenine metabolite, displays pleiotropic effects, including a blockade of glutamatergic and cholinergic receptors. Apart from well-known glial origin, kynurenic acid is robustly synthesized in the endothelium and its serum levels correlate with homocysteine, a risk factor for cognitive decline. Studies in an experimental DM model suggest that a selective, hippocampal increase of the kynurenic acid level may be an important factor contributing to diabetes-related cognitive impairment. The aim of this study was to assess the effects of chronic, four-week administration of losartan, angiotensin receptor blocker (ARB), on the brain KYNA in diabetic rats. Chromatographic and rt-PCR techniques were used to measure the level of KYNA and the expression of genes encoding kynurenine aminotransferases, KYNA biosynthetic enzymes, in the hippocampi of rats with streptozotocin-induced DM, treated with losartan. The effect of losartan on KYNA synthesis de novo was also evaluated in vitro, in brain cortical slices. The hippocampal increase of KYNA content occurred in diabetic rats treated and nontreated with insulin. Losartan did not affect KYNA levels when administered per se to naïve or diabetic animals but normalized KYNA content in diabetic rats receiving concomitantly insulin. The expression of CCBL1 (kat 1), AADAT (kat 2), and KAT3 (kat 3) genes did not differ between analyzed groups. Low concentrations of losartan did not affect KYNA production in vitro. The neuroprotective effect of ARBs in diabetic individuals may be, at least partially, linked to modulation of KYNA metabolism. The ability of ARB to modulate synthesis of KYNA in diabetic brain does not seem to result from changed expression of genes encoding KATs. We propose possible involvement of angiotensin AT4 receptors in the observed action of losartan.
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- 2019
247. Improvement of functional capacity in sacubitril-valsartan treated patients assessed by cardiopulmonary exercise test
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Claudia Baratto, A. Sorropago, Gabriella Malfatto, Silvia Ravaro, Gianfranco Parati, Alessandra Villani, Alessia Giglio, Michele Tomaselli, Sergio Caravita, Malfatto, G, Ravaro, S, Caravita, S, Baratto, C, Sorropago, A, Giglio, A, Tomaselli, M, Parati, G, and Villani, A
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Adult ,Male ,medicine.medical_specialty ,Angiotensin receptor ,systolic function ,heart failure ,Renal function ,Settore MED/11 - Malattie dell'Apparato Cardiovascolare ,030204 cardiovascular system & hematology ,Ventricular Function, Left ,Sacubitril ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Internal medicine ,medicine ,Humans ,echocardiography ,Sacubitril/valsartan ,030212 general & internal medicine ,Aged ,Aged, 80 and over ,Exercise Tolerance ,Ejection fraction ,cardiopulmonary test ,drug treatment ,business.industry ,Aminobutyrates ,Biphenyl Compounds ,Stroke Volume ,General Medicine ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Drug Combinations ,Valsartan ,Heart failure ,Exercise Test ,Quality of Life ,Cardiology ,Female ,Neprilysin ,Cardiology and Cardiovascular Medicine ,business ,Sacubitril, Valsartan ,medicine.drug - Abstract
Neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). ARNI increase survival and quality of life; due to their hemodynamic effects, ARNI could also affect exercise tolerance. We studied the effects of ARNI on cardiopulmonary test (CPET) after six months of treatment in 35 patients [67 ± 11 years; LVEF 31 ± 6%; NT-proBNP 1822 ± 1651 pg/ml; ICD/CRT since at least 6 months in 26/35], treated with increasing doses of Sacubitril/Valsartan up to 318 ± 36 mg/die. In addition, levels of NT-proBNP, renal function, electrolytes, and echocardiocolorDoppler were assessed in the same time periods. No variations of renal function and/or potassium levels were observed; NT-proBNP decreased. Most CPET variables were improved by ARNI (p
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- 2019
248. Association of Angiotensin Modulators With the Course of Idiopathic Pulmonary Fibrosis
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Mark Atwood, Klaus-Uwe Kirchgaessler, Maria Molina-Molina, Imre Noth, Vincent Cottin, Derek Weycker, Lutz Frankenstein, David J. Lederer, Michael Kreuter, and Claudia Valenzuela
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Angiotensin receptor ,Angiotensin-Converting Enzyme Inhibitors ,Critical Care and Intensive Care Medicine ,Placebo ,Angiotensin Receptor Antagonists ,03 medical and health sciences ,FEV1/FVC ratio ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Internal medicine ,Post-hoc analysis ,medicine ,Humans ,cardiovascular diseases ,030212 general & internal medicine ,Aged ,business.industry ,Hazard ratio ,Interstitial lung disease ,Middle Aged ,medicine.disease ,Comorbidity ,Idiopathic Pulmonary Fibrosis ,030228 respiratory system ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF. Methods All patients randomized to placebo (n = 624) in the CAPACITY and ASCEND studies were categorized by antihypertensive treatment at baseline. Outcomes of disease progression (first occurrence of ≥ 10% absolute decline in % predicted FVC, ≥ 50-m decline in 6-min walk distance, or death) and all-cause mortality were assessed over 52 weeks. Results At baseline, 111 and 121 patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), respectively; 392 were receiving neither. In multivariable analyses adjusted for differences in baseline characteristics compared with the non-ACEi/ARB group, ACEi treatment (hazard ratio [HR], 0.6 [95% CI, 0.4-0.9]; P = .026), but not ARB (HR, 0.9 [95% CI, 0.6-1.2]; P = .413), was associated with slower disease progression. Furthermore, the increase in all-cause mortality associated with cardiovascular disease was not observed in the ACEi group (HR, 1.1 [95% CI, 0.5-2.9]; P = .782), which presented a similar percentage of IPF-related mortality as the non-ACEi/ARB group (3.6% vs 3.6%). In contrast, patients in the ARB group had greater risk of all-cause mortality (HR, 2.5 [95% CI, 1.2-5.2]). These observations were validated in a pooled analysis that included patients from the INSPIRE trial. Conclusions Prospective clinical trials are needed to evaluate whether angiotensin modulators may be beneficial to clinical outcomes in IPF. Trial Registry ClinicalTrials.gov ; Nos.: NCT01366209 , NCT00287716 , NCT00287729 , NCT00075998 ; URL: www.clinicaltrials.gov ).
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- 2019
249. Olmesartan Medoxomil, An Angiotensin II-Receptor Blocker, Ameliorates Renal Injury In db/db Mice
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Ye Zhu, Ze-Liang Li, Weiping Zhu, Tongxia Cui, Huitao Zhang, Ao Ding, Hua Zhang, and Hui Yang
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0301 basic medicine ,Pharmacology ,medicine.medical_specialty ,Kidney ,Angiotensin receptor ,business.industry ,Pharmaceutical Science ,Renal function ,medicine.disease ,Streptozotocin ,Angiotensin II ,Diabetic nephropathy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Internal medicine ,Diabetes mellitus ,Drug Discovery ,Medicine ,business ,Olmesartan ,medicine.drug - Abstract
Background Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an angiotensin II receptor blocker (ARB) and has been shown to exhibit renoprotective effects on a streptozotocin (STZ)-induced diabetic rat model. Yet, whether OM affects DN progression and renal injury in db/db mice, a type 2 diabetic murine model, has not been established. Methods Wild-type (n = 15) and db/db mice (n = 15) were treated with control saline or OM via oral gavage. The physiological and biochemical parameters were evaluated and histological examinations of kidney specimens were performed. Results Compared with saline-treated db/db mice, db/db mice administered with OM showed ameliorated diabetic physiological and biochemical parameters. In addition, OM decreased urinary albumin excretion and plasma creatinine level in db/db mice. Moreover, histologically, OM reduced glomerular hypertrophy and injury, and also ameliorated tubular injury, thus suggesting that OM improves renal function and minimizes renal pathological deterioration in db/db mice. Conclusion Our study reveals a beneficial role of OM in ameliorating DN in db/db mice, which is associated with its renoprotective function.
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- 2019
250. Effect of Irbesartan-Poloxamer-188 Solid Dispersion on Intercellular Cell Adhesion Molecule-1 and Interleukin-8 on Hypertension Rats
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Ellyza Nasrul, Yufri Aldi, Fifi Harmely, and Erizal Zaini
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Angiotensin receptor ,ICAM-1 ,IL-8 ,business.industry ,Solid dispersion ,lcsh:R ,lcsh:Medicine ,General Medicine ,Poloxamer ,Pharmacology ,medicine.disease ,Biopharmaceutics Classification System ,Bioavailability ,Irbesartan ,Basic Science ,medicine ,Interleukin 8 ,Endothelial dysfunction ,business ,medicine.drug - Abstract
BACKGROUND: Based on the Biopharmaceutics Classification System (BCS) system, irbesartan is a drug that belongs to the class II BCS group which has limitations in terms of dissolution rates with low bioavailability of 26% -60%. These limitations to bioavailability can be overcome by solid dispersion with hydrophilic matrices such as Poloxamer. Irbesartan is an angiotensin receptor blocker. At present, it is widely used in dealing with hypertension due to endothelial dysfunction. AIM: This study aims to determine endothelial function blood markers can be examined, such as adhesion molecules (ICAM-1) and IL-8 pro-inflammatory cytokines. MATERIAL AND METHODS: Research on the effects of irbesartan-poloxamer-188 solid dispersion on ICAM-1 and IL-8 in hypertensive rats has been carried out. The formation of solid dispersion through dissolution method while induction of hypertension using 2.5% NaCl and prednisone 1.5 mg/Kg BB orally in 3 treatment groups, irbesartan dose was 13.5 mg/kg. The parameters observed were serum ICAM-1 and IL-8 levels. RESULTS: The result showed that the solid dispersion of irbesartan-poloxamer-188 could reduce ICAM-1 and IL-8 levels in hypertensive rats which differed significantly from the positive control group (p < 0.05). CONCLUSION: This study concluded that the solid dispersion of irbesartan-poloxamer-188 effects and decreases ICAM-1 levels in the serum of hypertensive rats. Solid dispersion of irbesartan-poloxamer-188 can influence and reduce IL-8 in the serum of hypertensive rats.
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- 2019
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