Document Detail


Omapatrilat limits infarct size and lowers the threshold for induction of myocardial preconditioning through a bradykinin receptor-mediated mechanism.
MedLine Citation:
PMID:  15162074     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the angiotensin-converting enzyme inhibitor, captopril. Langendorff perfused rat hearts were subjected to 35 min left coronary artery occlusion and 120 min reperfusion. Full IPC was induced with 5 min global ischemia/10 min reperfusion and substantially limited infarct size (21.5 +/- 3.5% of risk zone vs 53.4 +/- 2.0% in controls, P < 0.01). Sub-IPC (2 min global ischemia/10 min reperfusion) did not limit infarct size (48.4 +/- 3.8%). Omapatrilat (10 micromol/L) or captopril (200 micromol/L) were administered alone or in conjunction with Sub-IPC. Reduced infarct size comparable to that observed with the full IPC protocol was seen when sub-IPC was combined with either omapatrilat (19.7 +/- 2.5%) or captopril (20.3 +/- 4.9%). Omapatrilat alone caused modest reduction of infarct size (34.6 +/- 1.5%, P < 0.01 v control), an effect not observed with captopril. Hoe140, a selective kinin B(2) receptor antagonist, eliminated the cardioprotective effect of omaptrilat alone or in combination with sub-IPC. We conclude that omapatrilat elicits cardioprotection via inhibition of bradykinin degradation and that dual inhibition of angiotensin-converting enzyme and neutral endopeptidase may have beneficial effects beyond standard angiotensin-converting enzyme inhibitor therapy in patients with acute coronary syndromes who are at risk of myocardial infarction.
Authors:
Z Ebrahim; G F Baxter; D M Yellon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy     Volume:  18     ISSN:  0920-3206     ISO Abbreviation:  Cardiovasc Drugs Ther     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-05-26     Completed Date:  2004-10-12     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  8712220     Medline TA:  Cardiovasc Drugs Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  127-34     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
Animals
Body Weight / drug effects
Captopril / therapeutic use
Ischemic Preconditioning, Myocardial / methods*
Male
Myocardial Infarction / drug therapy*
Organ Size / drug effects
Pyridines / therapeutic use*
Rats
Rats, Sprague-Dawley
Receptors, Bradykinin / drug effects*
Thiazepines / therapeutic use*
Chemical
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Pyridines; 0/Receptors, Bradykinin; 0/Thiazepines; 36NLI90E7T/omapatrilat; 9G64RSX1XD/Captopril

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