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Nancy J Brown - One of the best experts on this subject based on the ideXlab platform.
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Bradykinin and Its Metabolite Bradykinin 1-5 Inhibit Thrombin-Induced Platelet Aggregation in Humans
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Laine J. Murphey, Hector A. Malave, Jeff Petro, Italo Biaggioni, Daniel W. Byrne, Douglas E. Vaughan, James M. Luther, Mias Pretorius, Nancy J BrownAbstract: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.
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angiotensin converting enzyme insertion deletion polymorphism modulates the human in vivo metabolism of Bradykinin
Circulation, 2000Co-Authors: Laine J. Murphey, Douglas E. Vaughan, James V Gainer, Nancy J BrownAbstract: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.
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inhibition of aminopeptidase p potentiates wheal response to Bradykinin in angiotensin converting enzyme inhibitor treated humans
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Sandeep Kumar, William H. Simmons, Nancy J BrownAbstract: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 - One of the best experts on this subject based on the ideXlab platform.
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neutral endopeptidase inhibition augments vascular actions of Bradykinin in patients treated with angiotensin converting enzyme inhibition
Hypertension, 2004Co-Authors: Nicholas L Cruden, Christopher A Ludlam, Neil R Johnston, David E NewbyAbstract: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.)
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Bradykinin contributes to the vasodilator effects of chronic angiotensin converting enzyme inhibition in patients with heart failure
Circulation, 2001Co-Authors: Fraser N Witherow, Ahmed Helmy, David J Webb, David E NewbyAbstract: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 - One of the best experts on this subject based on the ideXlab platform.
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effects of converting enzyme inhibitors on angiotensin and Bradykinin peptides
Hypertension, 1994Co-Authors: Duncan John Campbell, Athena Kladis, Annmaree DuncanAbstract: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.
A Agostoni - One of the best experts on this subject based on the ideXlab platform.
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Bradykinin and the pathophysiology of angioedema
International Immunopharmacology, 2003Co-Authors: Massimo Cugno, J Nussberger, Marco Cicardi, A AgostoniAbstract:Abstract Angioedema has different causes and different clinical presentations. Some types of angioedema may be mediated by Bradykinin. We measured plasma levels of Bradykinin-(1–9)nonapeptide by radioimmunoassay after high-performance liquid chromatography in patients with different types of angioedema during acute attacks and/or in remission, i.e. hereditary C1-inhibitor deficiency, angiotensin converting enzyme (ACE) inhibitor treatment, idiopathic non histaminergic and responders to antihistamines. Eleven patients with the deficiency of C1-inhibitor had very high levels of Bradykinin during acute attacks of angioedema (18.0–90.0 pM) (normal range 0.2–7.1 pM). In three patients with history of ACE inhibitor-related angioedema, plasma Bradykinin was high during ACE inhibitor treatment (62.0, 8.9 and 27.0 pM) and in a fourth patient was 47.0 pM during an acute attack and decreased by 93% to 3.2 pM after withdrawal of the ACE inhibitor. The patient with idiopathic angioedema, during an acute attack involving the right arm, had high levels of Bradykinin in the venous blood refluent from the angioedematous arm (20.0 pM) while in the contralateral arm Bradykinin levels were normal (6.6 pM), similarly to what we previously observed in cases of brachial angioedema due to C1-inhibitor deficiency. The four patients with angioedema responsive to antihistamines had normal levels of Bradykinin even during acute attacks (5.7, 3.4, 4.7 and 1.2 pM). In one of these patients who had a brachial angioedema, Bradykinin levels were normal in the venous blood refluent from both arms. Bradykinin is involved in hereditary C1-inhibitor deficiency angioedema, in ACE inhibitor-related angioedema, and in idiopathic non-histaminergic angioedema, while Bradykinin is not related to allergen-dependent or idiopathic angioedema that are responsive to antihistamines.
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plasma Bradykinin in angio oedema
The Lancet, 1998Co-Authors: Juerg Nussberger, Massimo Cugno, Marco Cicardi, Catherine Amstutz, Andrea Pellacani, A AgostoniAbstract:Summary Background Bradykinin is believed to be the main mediator of symptoms in hereditary (HA) and acquired (AA) angio-oedema due to C1 esterase inhibitor deficiency, as well as in angio-oedema that complicates treatment with inhibitors of angiotensin-converting enzyme (ACE). Difficulties in the measurement of kinin concentrations, however, have so far precluded the demonstration of an incontrovertible change in plasma Bradykinin concentrations in these disorders. By developing a reliable assay we have been able to follow Bradykinin concentrations during attacks and during remission in HA and in AA, and also in a patient treated with an ACE-inhibitor. Methods Liquid-phase extraction, high-performance liquid chromatography, and RIA were used for specific measurement of plasma Bradykinin concentrations in 22 patients with HA and in 22 healthy volunteers of similar age and sex distribution. Four patients with AA and one hypertensive patient treated with the ACE inhibitor captopril were also studied. Findings Among the healthy volunteers plasma Bradykinin concentration was inversely proportional to age. The geometric mean plasma Bradykinin concentration in the healthy volunteers was 2·2 fmol/mL (SD 2·2), compared with 3·9 fmol/mL (3·7) among patients with HA during remission (p=0·095). Bradykinin was also high in the patients with AA (10·4 fmol/mL [1·6]). During acute attacks of oedema, in both HA and AA, plasma Bradykinin rose to two to 12 times the upper limit of normal. Infusion of C1-esterase inhibitor (the deficient factor in both HA and AA) immediately lowered Bradykinin concentrations. In the patient receiving the ACE-inhibitor captopril, Bradykinin concentration was very high at 47 fmol/mL during an acute attack of angio-oedema, but normal at 3·2 fmol/mL in remission after withdrawal of the drug. Interpretation A sensitive method for measurement of plasma Bradykinin provided the means to show that concentrations of this peptide decrease with age in healthy people. Although the differences between patients in remission and healthy controls did not reach statistical significance, there were substantial rises in Bradykinin during acute attacks of hereditary, acquired, or captopril-induced angio-oedema.
S. T. Holgate - One of the best experts on this subject based on the ideXlab platform.
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Cross-tachyphylactic airway response to inhaled Bradykinin, kallidin and [desArg9]-Bradykinin in asthmatic subjects.
European Respiratory Journal, 1993Co-Authors: R. Polosa, K. Rajakulasingam, G Prosperini, Lv Milazzo, G. Santonocito, S. T. HolgateAbstract:Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, Bradykinin and kallidin, but not [desArg9]-Bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled Bradykinin, kallidin, and [desArg9]-Bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of Bradykinin and kallidin, but not [desArg9]-Bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for Bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-Bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second Bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with Bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-Bradykinin reduced the airway response to Bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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Comparative Airway Response to Inhaled Bradykinin, Kallidin, and [des-Arg9]Bradykinin in Normal and Asthmatic Subjects
The American review of respiratory disease, 1990Co-Authors: R. Polosa, S. T. HolgateAbstract:Bradykinin, kallidin (lys-Bradykinin), and [des-Arg9]Bradykinin are oligopeptides that may contribute as mediators in the pathogenesis of asthma by interacting with specific receptors designated B1 and B2. In this study, we have investigated the airway response to inhaled Bradykinin, kallidin, and [des-Arg9]Bradykinin in normal and asthmatic subjects. Changes in airway caliber were followed as maximum expiratory flow at 30% of the vital capacity (Vp30) and as forced expiratory volume in 1 s (FEV1). Only one of the six normal subjects responded to Bradykinin at the maximum cumulative concentration (5.33 mg/ml). Neither kallidin nor [des-Arg9]Bradykinin had any measurable bronchoconstrictor effect in the normal subjects whether airway caliber was measured as Vp30 or FEV1. In the 10 subjects with asthma, Bradykinin and kallidin, but not [des-Arg9]Bradykinin, produced a concentration-related fall in FEV1. The geometric mean provocation concentrations of Inhaled agonist reducing FEV1 by 20% of baseline were 0....
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Comparative airway response to inhaled Bradykinin, kallidin, and [des-Arg9]Bradykinin in normal and asthmatic subjects.
The American review of respiratory disease, 1990Co-Authors: R. Polosa, S. T. HolgateAbstract:Bradykinin, kallidin (lys-Bradykinin), and [des-Arg9]Bradykinin are oligopeptides that may contribute as mediators in the pathogenesis of asthma by interacting with specific receptors designated B1 and B2. In this study, we have investigated the airway response to inhaled Bradykinin, kallidin, and [des-Arg9]Bradykinin in normal and asthmatic subjects. Changes in airway caliber were followed as maximum expiratory flow at 30% of the vital capacity (Vp30) and as forced expiratory volume in 1 s (FEV1). Only one of the six normal subjects responded to Bradykinin at the maximum cumulative concentration (5.33 mg/ml). Neither kallidin nor [des-Arg9]Bradykinin had any measurable bronchoconstrictor effect in the normal subjects whether airway caliber was measured as Vp30 or FEV1. In the 10 subjects with asthma, Bradykinin and kallidin, but not [des-Arg9]Bradykinin, produced a concentration-related fall in FEV1. The geometric mean provocation concentrations of inhaled agonist reducing FEV1 by 20% of baseline were 0.03, 0.08, and 0.44 mg/ml for Bradykinin, kallidin, and histamine, respectively. Bronchoconstriction produced by Bradykinin and kallidin was maximal within 3 to 5 min with recovery occurring over 30 to 45 min. Because Bradykinin and kallidin are agonists of B2 receptors and [des-Arg9]Bradykinin is an agonist for B1 receptors, these in vivo structure activity studies suggest that asthmatic, but not normal, airways are hyperresponsive to kinins when compared to histamine and that this potent bronchoconstrictor action is a specific pharmacologic effect compatible with the stimulation of B2 receptors or a variant of these.
