Background-Angiotensin-converting enzyme (ACE) inhibition potentiates the tissue-type plasminogen activator (t-PA) response to exogenous bradykinin. This study tested the hypothesis that ACE inhibition increases endothelial t-PA release through endogenous bradykinin. Methods and Results-We measured the effect of intra-arterial enalaprilat (5 g/min) on forearm blood flow (FBF) and net t-PA release before and during intra-arterial infusion of bradykinin (25 to 400 ng/min) and methacholine (3.2 to 12.8 g/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 g/kg intravenously) or vehicle.There was no specific effect of HOE 140 on FBF or forearm vascular resistance (FVR, 29.9Ϯ3.6 versus 29.7Ϯ3.6 mm Hg · mL Ϫ1 · min Ϫ1 · 100 mL Ϫ1 after vehicle and HOE 140, respectively, Pϭ0.956 between groups). Resting FVR decreased during enalaprilat compared with vehicle or HOE 140, but not compared with baseline, and the effect was similar in the 2 groups (22.0Ϯ2.7 and 24.1Ϯ2.9 mm Hg · mL Ϫ1 · min Ϫ1 · 100 mL

Abstract-Bradykinin stimulates tissue plasminogen activator release from human endothelium through a flow-independent, B 2 receptor-dependent mechanism. The present study tests the hypothesis that smoking impairs bradykinin-stimulated tissue plasminogen activator release. Graded doses of nitroprusside (1.6 to 6.4 g/min), methacholine (3.2 to 12.8 g/min), and bradykinin (100 to 400 ng/min) were infused in the brachial artery in random order in 20 smokers and 12 nonsmokers matched for age, gender, and body mass index. Forearm blood flow was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in forearm blood flow, with no significant difference between smokers and nonsmokers. Key Words: bradykinin Ⅲ t-PA release Ⅲ smoking Ⅲ endothelium Ⅲ plethysmography A cute rupture of a coronary atheromatous plaque and subsequent coronary thrombosis play a critical role in the pathogenesis of myocardial infarction and sudden cardiac death. 1 The prevention of thrombosis in the coronary and other vascular beds is heavily dependent on the vascular endothelium. The endothelium generates and secretes shortlived potent platelet inhibitors, including NO and prostacyclin. 2 The endothelial receptor thrombomodulin promotes the thrombin-dependent activation of protein C, which in turn inhibits coagulation factors V and VIII. 3 The endothelium contributes to fibrinolysis by synthesizing, storing, and secreting tissue-type plasminogen activator (t-PA) and by expressing receptors that bind t-PA and enhance its activity. 4 It has been suggested that the plasminogen activator system serves as one of the major endogenous defenses against coronary thrombosis. 5Although studies of endothelial function in humans have focused on the vasodilatory capacity of the endothelium, the effect of risk factors for coronary artery disease on the fibrinolytic capacity of the endothelium has been less well characterized. In hypertensive subjects, Jern and coworkers 6 have reported decreased desmopressin-stimulated, but not methacholine-stimulated, release of t-PA activity and antigen across the forearm compared with that of normal controls.Newby et al 7 reported decreased venous t-PA antigen concentrations and activity and impaired vasodilation after intrabrachial artery infusion of substance P in smokers compared with nonsmokers. Similarly, this group has observed impaired coronary release of active t-PA in response to substance P in smokers compared with nonsmokers. 8 Bradykinin is a potent stimulus to t-PA synthesis and release in endothelial cells 9 and in perfused tissue preparations such as the pig ear or the rat hind limb. 10,11 Bradykinin stimulates t-PA release from the human forearm and coronary vasculature in a dose-dependent fashion. 12,13 In addition, endogenous bradykinin contributes to many of the cardioprotective effects of ACE inhibitors, 14 and ACE inhibition potentiates both the vasodilator and the t-PA responses to exogenous bradykinin. 13,15 Despite the potential clinical relevance of bradykinin-stimulat...

Abstract-Previous studies indicate that the vasodilator response to bradykinin (BK) and other endothelium-dependent and -independent agonists is decreased in black Americans compared with white Americans. The purpose of the present study was to determine the effect of ethnicity on fibrinolytic function in humans. Graded doses of BK (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 g/min; Nϭ20), or methacholine (3.2, 6.4, 12.8 g/min; Nϭ20), and sodium nitroprusside (0.8, 1.6, and 3.2 g/min) were infused via brachial artery in 19 white and 21 black age-matched normotensive subjects. Forearm blood flow (FBF) was measured by plethysmography, and venous and arterial samples were collected for tissue plasminogen activator (tPA) antigen. Compared with whites (increase in FBF from 3.7Ϯ0.5 to 23.9Ϯ2.5 mL · min Ϫ1 · 100 mL Ϫ1 ), blacks (increase in FBF from 2.8Ϯ0.3 to 15.2Ϯ1.9 mL · 100 mL Ϫ1 · min Ϫ1 ) exhibited a blunted FBF response to BK (Pϭ0.035). Responses to sodium nitroprusside and methacholine or acetylcholine were similarly decreased. In contrast, there was no effect of ethnicity on net tPA antigen release in response to BK (increase from Ϫ0.2Ϯ0.4 to 67.3Ϯ15.2 ng · min Ϫ1 ⅐ 100 mL Ϫ1 in blacks; from 0.04Ϯ0.9 to 65.9Ϯ13.6 ng · min Ϫ1 · 100 mL Ϫ1 in whites). Thus, ethnicity significantly influenced the relationship between the flow and tPA release responses to BK (Pϭ0.037). These data suggest that the BK-dependent alterations in vascular fibrinolytic function are preserved in black Americans compared with white Americans. Key Words: bradykinin Ⅲ vasodilator Ⅲ fibrinolysis Ⅲ ethnicity Ⅲ endothelium T he prevalence of hypertension, stroke, congestive heart failure, and diabetic nephropathy is higher in black Americans than in white Americans. 1 Black Americans exhibit decreased vasodilation in response to a number of agonists, including bradykinin (BK), isoproterenol, methacholine (MCh), acetylcholine (ACh), and sodium nitroprusside (SNP). [2][3][4][5] This decreased vasodilation in response to both endothelium-dependent and -independent agonists suggests a generalized impairment in vascular smooth muscle relaxation, the mechanism of which is uncertain.BK contributes to many of the cardiovascular effects of angiotensin-converting enzyme (ACE) inhibitors. 6,7 In addition to causing vasodilation, BK stimulates release of tissue plasminogen activator (tPA) from the vascular endothelium through a BK subtype B 2 receptor-dependent pathway. 8 Although BK-mediated vasodilation reflects both endothelial production of nitric oxide (NO) and other mediators and subsequent vascular smooth muscle relaxation, 9 tPA release reflects a direct effect of BK on the endothelium. 10 Several lines of evidence suggest that endogenous BK levels are decreased in blacks. Compared with whites, blacks have lower excretion of urinary kallikrein, an index of activity of the kallikrein-kinin system. 11 Decreased levels of endogenous BK would be expected to result in upregulation of its major receptor and increased sensitivity to exogenous ...