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An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target. Adipose tissue thermogenesis plays a role in appropriate response to cold exposure through incompletely understood mechanisms. Here the authors report that acute cold exposure increases the serum levels of bradykinin, which induces brown adipose tissue thermogenesis and white adipose tissue browning in male mice. [ABSTRACT FROM AUTHOR]

The type 2 bradykinin receptor (B2R) is a G protein-coupled receptor (GPCR) in the cardiovascular system, and the dysfunction of B2R leads to inflammation, hereditary angioedema, and pain. Bradykinin and kallidin are both endogenous peptide agonists of B2R, acting as vasodilators to protect the cardiovascular system. Here we determine two cryo-electron microscopy (cryo-EM) structures of human B2R-Gq in complex with bradykinin and kallidin at 3.0 Å and 2.9 Å resolution, respectively. The ligand-binding pocket accommodates S-shaped peptides, with aspartic acids and glutamates as an anion trap. The phenylalanines at the tail of the peptides induce significant conformational changes in the toggle switch W2836.48, the conserved PIF, DRY, and NPxxY motifs, for the B2R activation. This further induces the extensive interactions of the intracellular loops ICL2/3 and helix 8 with Gq proteins. Our structures elucidate the molecular mechanisms for the ligand binding, receptor activation, and Gq proteins coupling of B2R. Type 2 bradykinin receptor (B2R) is essential in vasodilation and cardioprotection. Here the authors present two cryo-EM structures of human B2R-Gq in complex with bradykinin and kallidin to elucidate the mechanisms for ligand binding, receptor activation, and Gq proteins coupling. [ABSTRACT FROM AUTHOR]

Eleven multiple analogs of bradykinin—a peptide that is a natural ligand of B1 and B2 receptors but does not bind or activate the B1 receptor unless Arg9 is removed from the sequence by the action of carboxypeptidase N—were synthesized. Their biological activity was examined on T-REx cell lines expressing B1 or B2 receptors using the intracellular IP1 assay. The mRNA expression of B1R and B2R in the lysate of tumor cell lines, e.g., U87-MG (human astrocytoma), SHP-77 (human small cell lung cancer), and H4 (human brain glioma), was determined. For five B1R antagonists, adsorption at the liquid/solid interface (Au nanoparticles (AuNPs) served as the solid surface) was discussed in terms of the vibrations of molecular fragments (structural factors) responsible for the biological properties of these analogs. [ABSTRACT FROM AUTHOR]

Background: Acute airway angioedema commonly occurs through two distinct mechanisms: histamine- and bradykinin-dependent. Although they respond to distinct treatments, these two potentially life-threatening states present similarly. Poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of multiple pharmacologic options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. Here, we consider the pathophysiology and clinical features of bradykinin-induced angioedema, and we present a systematic literature review exploring the effectiveness of the available therapies for managing such cases. Methods: PubMed searches using 'emergency', 'bradykinin' and various therapeutic product names identified studies reporting the efficacy of treatments for bradykinin-induced angioedema in the ED setting. In all, 22 studies met prespecified criteria and are analysed here. Findings: Whereas histamine-induced angioedema has a faster onset and often presents with urticaria, bradykinin-induced angioedema is slower in onset, with greater incidence of abdominal symptoms. Acute airway angioedema in the ED should initially be treated with anaphylactic protocols, focusing on airway management and treatment with epinephrine, antihistamine and systemic steroids. Bradykinin-induced angioedema should be considered if this standard treatment is not effective, despite proper dosing and regard of beta-adrenergic blockade. Therapeutics currently approved for HAE appear as promising options for this and other forms of bradykinin-induced angioedema encountered in the ED. Conclusion: Diagnostic algorithms of bradykinin-induced angioedema should be followed in the ED, with early use of approved therapies to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) is known to secrete regulatory factors in response to thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein–kinin system as a relevant component of BAT thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT. Brown adipose tissue, known produce heat by metabolizing fat, is also secretes molecules capable of communicating with other organs. Here the authors show that brown adipose tissue secretes kininogen, a component of heat system regulation, that provides auto-regulatory inhibitory signaling in brown adipose tissue. [ABSTRACT FROM AUTHOR]

Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function. [ABSTRACT FROM AUTHOR]

There is now abundant evidence that treatment with angiotensin-converting enzyme inhibitors (ACE-I) ameliorates the progression of chronic renal disease. Attention has therefore focused on the role of the renin angiotensin-aldosterone (RAA) system in mediating the development of progressive glomerulosclerosis and angiotensin II (Ang II) has been implicated in several processes thought to be important in the pathogenesis of this entity. Conversely, ACE is also known to catalyse the breakdown of bradykinin. Thus, ACE-I treatment results in elevated bradykinin levels which may cause selective efferent arteriolar dilatation, suggesting an alternative explanation for the beneficial effects of this class of drugs in chronic renal disease. The development of specific angiotensin type 1 receptor antagonists (AT[sub1]RA) has provided a means of testing the relative importance of these two mechanisms. In addition, AT[sub1]RAs differ from ACE-I in their effect on the RAA system in other aspects which may represent therapeutic advantages. This paper reviews studies which have compared ACE-I and AT[sub1]RAs in several rat models of chronic renal disease. Most have found similar beneficial effects including amelioration of proteinuria and glomerulosclerosis, which suggests that the effects of ACE-I are due to a reduction in Ang II activity and not due to increased levels of bradykinin. One long-term study has suggested greater renal protection with candesartan than with enalapril. However, conclusions as regards the relative efficacy of these two groups of agents in ameliorating the progression of chronic renal disease await the results of further long-term studies. [ABSTRACT FROM AUTHOR]

The reaction of some physiologically active peptides with bacterial strain B-9 has been investigated. Bradykinin, β-endorphin, and [Leu]enkephalin were quickly degraded, with half-lives of <5 min. Somatostatin, substance P, and angiotensin I were degraded relatively smoothly, with half-lives of 10 min to 1 h, whereas oxytocin and insulin were slowly degraded, with half-lives of 1 and 4 days, respectively. Vasopressin was barely degraded, with a half-life of >7 days. Linearized vasopressin, prepared by the reductive cleavage of the disulfide bond followed by alkylation with iodoacetamide, was degraded significantly faster than intact vasopressin, with a half-life of 2.5 h. A loop formed by disulfide bond formation was regarded as one of the degradation-resistant factors. Hydrolysis of the peptides in this study took place through cleavage of various peptide bonds, and the strain B-9 may bear similarities to the neutral endopeptidase in terms of its broad selectivity. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Overwhelming evidence indicates that endothelial cell dysfunction in diabetes is characterised by diminished endothelium-dependent relaxation, but the matter of the underlying molecular mechanism remains unclear. As nitric oxide (NO) production from the endothelium is the major player in endothelium-mediated vascular relaxation, we investigated the effects of high glucose on NO production, and the possible alterations of signalling pathways implicated in this scenario. Methods. NO production and intracellular Ca2+ levels ([Ca2+]i) were assessed using the fluorescent probes 4,5-diaminofluorescein diacetate and fura-2 respectively. Results. Exposure of cultured bovine aortic endothelial cells to high glucose for 5 or 10 days significantly reduced NO production induced by bradykinin (but not by Ca2+ ionophore) in a time- and dose-dependent manner. This was probably due to an attenuation in bradykinin-induced elevations of [Ca2+]i under these conditions, since a close correlation between [Ca2+]i increases and NO generation was observed in intact bovine aortic endothelial cells. Both bradykinin-promoted intracellular Ca2+ mobilisation and extracellular Ca2+ entry were affected. Moreover, bradykinin-induced formation of Ins(1,4,5)P3, a phospholipase C product leading to increases in [Ca2+]i, was also inhibited following high glucose culture. This abnormality was not attributable to a decrease in inositol phospholipids, but possibly to a reduction in the number of bradykinin receptors. The alterations in NO production, the increases in [Ca2+]i, and the bradykinin receptor number due to high glucose could be largely reversed by protein kinase C inhibitors and D-α-tocopherol (antioxidant). Conclusions/interpretation. Chronic exposure to high glucose reduces NO generation in endothelial cells, probably by impairing phospholipase-C-mediated Ca2+ signalling due to excess protein kinase C activation. This defect in NO release may contribute to the diminished endothelium-dependent relaxation and thus to the development of cardiovascular diseases in diabetes. [ABSTRACT FROM AUTHOR]

Presents information on a study that delineated a biochemical mechanism through which bradykinin and nerve growth factor produce hypersensitivity. Research methods; Results and discussion.

Focuses on the relationship between the vasopressor angiotensin II and the vasodepressor Bradykinin. Their role as antagonists to each other; Communication between the hormone receptors of angiotensin II and bradykinin to form stable heterodimers.

Focuses major breakthroughs in the design of angiotensin converting enzyme (ACE) inhibitors. Discovery of bradykinin-potentiating peptides; Amino-acid sequence of ACE inhibitors; Potential value of ACE inhibitors in the treatment of hypertension.

A neurogenic pathway, involving airway TRPV-1, has been implicated in acute cardiovascular events occurring after peaks of air pollution. We tested whether inhaled prostaglandin-E2 (PGE2) and bradykinin (BK) regulate TRPV-1 activity in vivo by changing cough response to capsaicin (CPS) and affecting heart rate variability (HRV), while also taking into account the influence of TRPV-1 polymorphisms (SNPs). Moreover, we assessed the molecular mechanism of TRPV-1 modulation in vitro. Seventeen healthy volunteers inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge and the sympathetic activity by HRV, expressed by low (nLF) and high (nHF) normalized frequency components, as well as nLF/nHF ratio. Intracellular [Ca2+] was measured in HeLa cells, transfected with wild-type TRPV-1, pre-treated with increasing doses of PGE2, BK or diesel exhaust particulate (DEP), after CPS stimulation. Six functional TRPV-1 SNPs were characterized in DNA from each subject. Inhalation of PGE2 and BK was associated with significant increases in cough response induced by 30 μM of CPS (cough number after PGE2 = 4.20 ± 0.42; p < 0.001, and after BK = 3.64 ± 0.37; p < 0.01), compared to diluent (2.77 ± 0.29) and in sympathetic activity (nLF/nHF ratio after PGE2 = 6.1; p < 0.01, and after BK = 4.2; p < 0.05), compared to diluent (2.5–3.3). No influence of SNPs was observed on autonomic regulation and cough sensitivity. Unlike PGE2 and BK, DEP directly activated TRPV-1. Inhalation of PGE2 and BK sensitizes TRPV-1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects. [ABSTRACT FROM AUTHOR]