Effects of the vasopeptidase inhibitor omapatrilat on cardiac endogenous kinins in rats with acute myocardial infarction

The purposes of this study were to evaluate and to compare the effects of s imultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 2 4.11 (NEP) inhibition by the vasopeptidase inhibitor omapatrilat (1 mg.kg(- 1).day(-1)) with those of the selective ACE inhibitor enalapril (1 mg.kg(-1 ).day(1)) on survival, cardiac hemodynamics, and bradykinin (BK) and des-Ar g(9)-BK levels in cardiac tissues 24 h after myocardial infarction (MI) in rats. The effect of the co-administration of both B, and B, kinin receptor antagonists (2.5 mg.kg(-1.) day(-1) each) with metallopeptidase inhibitors was also evaluated. The pharmacological treatments were infused subcutaneou sly using micro-osmotic pumps for 5 days starting 4 days before the ligatio n of the left coronary artery. Immunoreactive kinins were quantified by hig hly sensitive and specific competitive enzyme immunoassays. The post-MI mor tality of untreated rats with a large MI was high; 74% of rats dying prior to the hemodynamic study. Mortality in the other MI groups was not signific antly different from that of the untreated MI rats. Cardiac BK levels were not significantly different in the MI vehicle-treated group compared with t he sham-operated rats. Both omapatrilat and enalapril treatments of MI rats significantly increased cardiac BK concentrations compared with the sham-o perated group (P < 0.05). However, cardiac BK levels were significantly inc reased only in the MI omapatrilat-treated rats compared with the MI vehicle -treated group (P < 0.01). Cardiac des-Arg(9)-BK concentrations were not si gnificantly modified by MI, and MI with omapatrilat or enalapril treatment compared with the sham-operated group. The co-administration of both kinin receptor antagonists with MI omapatrilat- and enalapril-treated rats had no significant effect on cardiac BK and des-Arg(9)-BK levels. Thus, the signi ficant increase of cardiac BK concentrations by omapatrilat could be relate d to a biochemical or a cardiac hemodynamic parameter on early (24 h) post- MI state. (C) 2001 Elsevier Science Inc. All rights reserved.