Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin

Abstract

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 micro 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 microg/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 microg/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 x mL(-1) x min(-1) x 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 x mL(-1) x min(-1) x 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) x 100 mL(-1), P=0.002); this effect was abolished by HOE 140 (0.1+/-0.3 ng x min(-1) x 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) x 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 x min(-1) x 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.