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


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.


CONCLUSIONS
ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin.
Pretorius
Mias
M
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tenn 37232-6602, USA.
Rosenbaum
David
D
Vaughan
Douglas E
DE
Brown
Nancy J
NJ
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015773:Enalaprilat / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012907:Smoking / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D018721:Muscarinic Agonists; D016210:Methacholine Chloride; C065679:icatibant; D010959:Tissue Plasminogen Activator; D015773:Enalaprilat; D001920:Bradykinin