Published online before print January 27, 2003, doi: 10.1161/01.CIR.0000046268.59922.A4
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(Circulation. 2003;107:579.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin
From the Department of Anesthesiology (M.P.) and the Divisions of Clinical Pharmacology (N.J.B.) and Cardiovascular Medicine (D.E.V., D.R.), Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tenn; and the Veterans Affairs Medical Center (D.E.V., M.P.), Nashville, Tenn.
Correspondence to Nancy J. Brown, MD, 560 RRB, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail nancy.j.brown{at}vanderbilt.edu
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 µg/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 µg/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 µg/kg intravenously) or vehicle. There was no specific effect of HOE 140 on FBF or forearm vascular resistance (FVR, 29.9±3.6 versus 29.7±3.6 mm Hg · mL-1 · min-1 · 100 mL-1 after vehicle and HOE 140, respectively, P=0.956 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 (22.0±2.7 and 24.1±2.9 mm Hg · mL-1 · min-1 · 100 mL-1, respectively, P=0.610). In contrast, enalaprilat significantly increased resting net t-PA release (from 0.6±0.4 to 1.7±0.6 ng · min-1 · 100 mL-1, P=0.002); this effect was abolished by HOE 140 (0.1±0.3 ng · min-1 · 100 mL-1, P=0.036 versus enalaprilat alone). Enalaprilat increased the effect of exogenous bradykinin on FBF 60% (from 17.5±2.5 to 28.1±4.0 mL · min-1 · 100 mL-1 during 100 ng/min bradykinin, P=0.001) and on t-PA release 14-fold (from 21.2±7.9 to 317.4±118.9 ng · min-1 · 100 mL-1, P=0.024). Enalaprilat increased the t-PA response to bradykinin to a greater extent than the FBF response, shifting the relationship between net t-PA release and FBF (P=0.005). HOE 140 blocked these effects. There was no effect of enalaprilat or HOE 140 on the FBF or t-PA response to methacholine.
Conclusion— ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin.
Key Words: angiotensin • bradykinin • fibrinolysis
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