Published Online
on January 27, 2003

A more recent version of this article appeared on February 4, 2003

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Submitted on July 12, 2002
Revised on October 14, 2002
Accepted on October 18, 2002

Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin

Mias Pretorius MBChB, DA (SA), David Rosenbaum MD, Douglas E. Vaughan MD, and Nancy J. Brown MD^*

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.

^* To whom correspondence should be addressed. 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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