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CARDIOVASCULAR

Bradykinin and Its Metabolite Bradykinin 1-5 Inhibit Thrombin-Induced Platelet Aggregation in Humans

From the Divisions of Clinical Pharmacology (L.J.M., J.P., I.B., J.M.L., M.P., N.J.B.) and Cardiovascular Medicine (H.A.M., D.E.V.), Departments of Medicine and Pharmacology, Department of Biostatistics and the General Clinical Research Center (D.W.B.), and Department of Anesthesiology (M.P.), School of Medicine, Vanderbilt University, Nashville, Tennessee; and the Veterans Affairs Medical Center, Nashville, Tennessee (M.P.)

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, - and -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 < 0.001 for both). Bradykinin 1-5 did not affect FBF (P = 0.13) or net t-PA release (P = 0.46) at concentrations >1500 times physiologic. In contrast, both bradykinin and bradykinin 1-5 inhibited -and -thrombin-induced platelet aggregation (P < 0.01 versus baseline). Bradykinin 1-5 inhibited -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.

Address correspondence to: Dr. Nancy J. Brown, 560B RRB, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail: nancy.j.brown{at}vanderbilt.edu