Document Detail


Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin.
MedLine Citation:
PMID:  12566370     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mias Pretorius; David Rosenbaum; Douglas E Vaughan; Nancy J Brown
Publication Detail:
Type:  Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  107     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2003 Feb 
Date Detail:
Created Date:  2003-02-04     Completed Date:  2003-02-13     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  579-85     Citation Subset:  AIM; IM    
Affiliation:
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tenn 37232-6602, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Angiotensin-Converting Enzyme Inhibitors / pharmacology*
Blood Flow Velocity / drug effects
Bradykinin / analogs & derivatives*,  metabolism*,  pharmacology
Dose-Response Relationship, Drug
Enalaprilat / pharmacology
Endothelium, Vascular / drug effects,  metabolism*
Female
Fibrinolysis / drug effects
Forearm / blood supply
Humans
Infusions, Intra-Arterial
Male
Methacholine Chloride / pharmacology
Muscarinic Agonists / pharmacology
Receptors, Bradykinin / antagonists & inhibitors
Regional Blood Flow / drug effects,  physiology
Smoking* / physiopathology
Tissue Plasminogen Activator / blood,  metabolism*
Vascular Resistance / drug effects
Grant Support
ID/Acronym/Agency:
HL007411/HL/NHLBI NIH HHS; HL60906/HL/NHLBI NIH HHS; HL65193/HL/NHLBI NIH HHS; RR00095/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Muscarinic Agonists; 0/Receptors, Bradykinin; 130308-48-4/icatibant; 58-82-2/Bradykinin; 62-51-1/Methacholine Chloride; 84680-54-6/Enalaprilat; EC 3.4.21.68/Tissue Plasminogen Activator

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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