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Bradykinin

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Nancy J Brown – 1st expert on this subject based on the ideXlab platform

  • Bradykinin and Its Metabolite Bradykinin 1-5 Inhibit Thrombin-Induced Platelet Aggregation in Humans
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Laine J. Murphey, Hector A. Malave, Jeff Petro, Italo Biaggioni, Daniel W. Byrne, Douglas E. Vaughan, James M. Luther, Mias Pretorius, Nancy J Brown

    Abstract:

    Bradykinin 1-5 is a major stable metabolite of Bradykinin, formed by the proteolytic action of angiotensin-converting enzyme. In vitro and animal studies suggest that Bradykinin 1-5 possesses biological activity. This study tests the hypothesis that Bradykinin 1-5 affects vasodilation, fibrinolysis, or platelet aggregation in humans. Graded doses of Bradykinin (47-377 pmol/min) and Bradykinin 1-5 (47-18,850 pmol/min) were infused in the brachial artery in random order in 36 healthy subjects. Forearm blood flow (FBF) was measured, and simultaneously obtained venous and arterial plasma samples were analyzed for tissue plasminogen activator (t-PA) antigen. In seven subjects each, α- and γ-thrombin-induced platelet aggregation was measured in platelet-rich plasma obtained from antecubital venous blood at baseline and during peptide infusions. Bradykinin caused dose-dependent increases in FBF and net t-PA release ( P 1500 times physiologic. In contrast, both Bradykinin and Bradykinin 1-5 inhibited α-and γ-thrombin-induced platelet aggregation ( P < 0.01 versus baseline). Bradykinin 1-5 inhibited γ-thrombin-induced platelet aggregation 50% at a calculated dose of 183 ± 3 pmol/min. Neither Bradykinin nor Bradykinin 1-5 affected thrombin receptor-activating peptide-induced platelet aggregation, consistent with the hypothesis that Bradykinin and Bradykinin 1-5 inhibit thrombin-induced platelet aggregation by preventing cleavage of the thrombin receptor and liberation of thrombin receptor-activating peptide. This study is the first to demonstrate biological activity of Bradykinin 1-5 following in vivo administration to humans. By inhibiting thrombin-induced platelet aggregation without causing vasodilation, Bradykinin 1-5 may provide a model for small molecule substrate-selective thrombin inhibitors.

  • angiotensin converting enzyme insertion deletion polymorphism modulates the human in vivo metabolism of Bradykinin
    Circulation, 2000
    Co-Authors: Laine J. Murphey, Douglas E. Vaughan, James V Gainer, Nancy J Brown

    Abstract:

    Background —Bradykinin is a cardioprotective peptide metabolized by the angiotensin-converting enzyme (ACE). An insertion/deletion (I/D) polymorphism in the ACE gene determines plasma ACE levels. The D allele is associated with cardiovascular disease, which may relate to enhanced angiotensin II production or to increased Bradykinin degradation to the inactive metabolite Bradykinin 1–5 (BK1–5). Therefore, we determined the effect of the ACE I/D polymorphism on human Bradykinin metabolism in vivo. Methods and Results —Bradykinin (400 ng/min) was infused into the brachial artery of volunteers with ACE I/I, I/D, or D/D genotypes (n=9 each). The Bradykinin and BK1–5 levels in forearm venous return were quantified by liquid chromatography–mass spectroscopy. Plasma ACE activity was highest in those with the D/D genotype (36.8±6.2 U/mL), intermediate in those with the I/D genotype (25.3±3.3 U/mL), and lowest in those with the I/I genotype (20.3±2.3 U/mL; P =0.017 for effect of number of D alleles). Bradykinin concentrations were 726±242, 469±50, and 545±104 fmol/mL in I/I, I/D, and D/D subjects, respectively ( P >0.10). Significant correlations existed between the number of D alleles and BK1–5 concentrations (1113±290, 1520±318, and 1887±388 fmol/mL in the I/I, I/D, and D/D groups, respectively; P =0.027) and the ratio of BK1–5 to Bradykinin (1.87±0.35, 3.09±0.40, and 4.31±0.97 in the I/I, I/D, and D/D volunteers, respectively; P =0.010). The venous blood BK1–5:Bradykinin ratio correlated with plasma ACE activity ( r 2 =0.16, P =0.039), and total kinin concentration correlated with net tissue plasminogen activator release across the forearm ( r 2 =0.20, P =0.027). Conclusions —The ACE D allele has a significant effect on the in vivo degradation of Bradykinin in humans. The ratio of BK1–5:Bradykinin may serve as a marker for tissue ACE activity.

  • inhibition of aminopeptidase p potentiates wheal response to Bradykinin in angiotensin converting enzyme inhibitor treated humans
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Sandeep Kumar, William H. Simmons, Nancy J Brown

    Abstract:

    Bradykinin is a nonapeptide that contributes to the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors. During ACE inhibition, an increased proportion of Bradykinin is degraded through non-ACE pathways. Studies in animals suggest that aminopeptidase P (EC3.4.11.9) may contribute to the metabolism of Bradykinin. The purpose of the present study was to determine the contribution of aminopeptidase P to the degradation of Bradykinin in humans in the presence and absence of ACE inhibition. To do this, we measured the wheal response to intradermal injection of Bradykinin (0, 1, or 10 μg) in the presence or absence of intradermal administration of the specific aminopeptidase P inhibitor apstatin (5 or 10 μg) and oral administration of the ACE inhibitor quinapril (10 mg) in six healthy subjects. Both Bradykinin (ANOVA; F = 101.18, P F = 7.01, P = .049) caused a wheal of dose-dependent size. There was no significant interaction between apstatin and Bradykinin ( F = 4.94, P = .175). Pretreatment with 10 mg of quinapril significantly shifted the dose-response curve for Bradykinin to the left (effect of quinapril; F = 77.96, P F = 7.82, P = .041). The effect of quinapril was significantly potentiated by coinjection of 10 μg of apstatin (effect of apstatin; F = 21.60, P = .006), such that there was significant interactive effect of quinapril and apstatin ( F = 20.83, P = .006) on the wheal response to Bradykinin. Collectively, these data suggest that aminopeptidase P plays a minor role in the degradation of Bradykinin in human skin in the absence of ACE inhibition but contributes significantly to the degradation of Bradykinin in the presence of ACE inhibition.

David E Newby – 2nd expert on this subject based on the ideXlab platform

  • neutral endopeptidase inhibition augments vascular actions of Bradykinin in patients treated with angiotensin converting enzyme inhibition
    Hypertension, 2004
    Co-Authors: Nicholas L Cruden, Christopher A Ludlam, Neil R Johnston, David E Newby

    Abstract:

    Angiotensin-converting enzyme and neutral endopeptidase (EC 3.4.24.11; neprilysin) are metallopeptidases present on the endothelium that metabolize Bradykinin. Inhibitors of angiotensin-converting enzyme potentiate Bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. Combined angiotensin- converting enzyme and neutral endopeptidase inhibition may have additional beneficial cardiovascular effects mediated through Bradykinin potentiation. We investigated the effects of local neutral endopeptidase inhibition on the vascular actions of Bradykinin in heart failure patients maintained on chronic angiotensin-converting enzyme inhibition. Ten patients received intrabrachial infusion of thiorphan (30 nmol/min), a neutral endopeptidase inhibitor, in a randomized double-blind placebo-controlled crossover trial. Thiorphan was coinfused with Lys-des-Arg 9 –Bradykinin (1 to 10 nmol/min), Bradykinin (30 to 300 pmol/min), atrial natriuretic peptide (10 to 100 pmol/min), and sodium nitroprusside (2 to 8 g/min). Bradykinin, atrial natriuretic peptide, and sodium nitroprusside caused dose-dependent vasodilatation (peak blood flow 14.42.2, 3.60.6, and 8.61.3 mL per 100 mL/min, respectively; P0.0001). Bradykinin caused dose-dependent increases in tissue plasminogen activator antigen and activity (peak concentration 31.83.4 ng/mL and 21.97.6 IU/mL, respectively; P0.001) and estimated antigen and activity release (peak release 15246 ng per 100 mL/min and 15422 IU/100 mL/min, respectively; P0.005). Compared with placebo, thiorphan augmented Bradykinin-mediated vasodilatation (1.4-fold; P0.0001) and net tissue plasminogen activator release (1.5-fold; P0.005). Neutral endopeptidase contributes to Bradykinin metabolism in heart failure patients maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the clinical effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition, including the greater vasodepressor effect observed with combined therapy when compared with angiotensin-converting enzyme inhibition alone. (Hypertension. 2004;44:913-918.)

  • Bradykinin contributes to the vasodilator effects of chronic angiotensin converting enzyme inhibition in patients with heart failure
    Circulation, 2001
    Co-Authors: Fraser N Witherow, Ahmed Helmy, David J Webb, David E Newby

    Abstract:

    Background Bradykinin, an endogenous vasodilator peptide, is metabolized by ACE. The aims of the present study were to determine the doses of B9340, a Bradykinin receptor antagonist, that inhibit vasodilatation to exogenous Bradykinin and to assess the contribution of Bradykinin to the maintenance of basal vascular tone in patients with heart failure receiving chronic ACE inhibitor therapy. Methods and Results Forearm blood flow was measured using bilateral venous occlusion plethysmography. On three occasions in a double-blind randomized manner, 8 healthy volunteers received intrabrachial infusions of placebo or B9340 (at 4.5 and 13.5 nmol/min). On each occasion, placebo or B9340 was coinfused with Bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min). B9340 caused no change in basal FBF but produced dose-dependent inhibition of the vasodilatation to Bradykinin (P<0.001) but not substance P. The effects of Bradykinin antagonism were studied in 17 patients with NYHA grade II through IV heart …

Annmaree Duncan – 3rd expert on this subject based on the ideXlab platform

  • effects of converting enzyme inhibitors on angiotensin and Bradykinin peptides
    Hypertension, 1994
    Co-Authors: Duncan John Campbell, Athena Kladis, Annmaree Duncan

    Abstract:

    We examined the dose-related effects of angiotensin-converting enzyme inhibitors on circulating and tissue levels of angiotensin and Bradykinin peptides by administering perindopril or lisinopril to rats in drinking water for 7 days. A reduction in the ratio of plasma angiotensin II (Ang II) to Ang I was seen for 0.006 mg/kg per day perindopril, with an increase in plasma renin and Ang I at 0.017 mg/kg per day. Plasma Ang II levels did not decrease until 1.4 mg/kg per day perindopril, at which dose plasma Ang I levels reached a plateau of an approximate 25-fold increase. The effects of perindopril on Ang II and Ang I levels in heart, lung, aorta, and brown adipose tissue were parallel to those observed for plasma. By contrast, renal Ang I levels did not increase, and renal Ang II levels decreased by 40% at 0.017 mg/kg per day, the same threshold seen for the increase in plasma renin. Perindopril increased circulating Bradykinin-(1-9) levels approximately eightfold, with a threshold dose of 0.052 mg/kg per day, and increased Bradykinin-(1-9) levels in kidney, heart, and lung in parallel with the changes observed for plasma. By contrast, aortic and brown adipose tissue Bradykinin-(1-9) and Bradykinin-(1-7) levels increased severalfold for perindopril doses as low as 0.006 mg/kg per day. Lisinopril also increased aortic Bradykinin-(1-9) and Bradykinin-(1-7) levels at doses below the threshold for the decrease in the ratio of Ang II to Ang I. These data indicate that renal Ang II levels and vascular Bradykinin-(1-9) levels respond to low doses of converting enzyme inhibitor and may be important mediators of the effects of these compounds. The parallel increases in Bradykinin-(1-9) and Bradykinin-(1-7) levels in aorta and brown adipose tissue, at inhibitor doses below the threshold for inhibition of Ang I conversion, may result from a mechanism different from inhibition of “classic” angiotensin-converting enzyme.