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 simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (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-Arg(9)-BK levels in cardiac tissues 24 h after myocardial infarction (MI) in rats. The effect of the co-administration of both B(1) and B(2) kinin receptor antagonists (2.5 mg. kg(-1). day(-1) each) with metallopeptidase inhibitors was also evaluated. The pharmacological treatments were infused subcutaneously using micro-osmotic pumps for 5 days starting 4 days before the ligation of the left coronary artery. Immunoreactive kinins were quantified by highly sensitive and specific competitive enzyme immunoassays. The post-MI mortality 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 significantly different from that of the untreated MI rats. Cardiac BK levels were not significantly different in the MI vehicle-treated group compared with the sham-operated rats. Both omapatrilat and enalapril treatments of MI rats significantly increased cardiac BK concentrations compared with the sham-operated group (P < 0.05). However, cardiac BK levels were significantly increased 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 significantly 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 significant increase of cardiac BK concentrations by omapatrilat could be related to a biochemical or a cardiac hemodynamic parameter on early (24 h) post-MI state.
Blais
C
C
Faculté de Pharmacie, Université de Montréal, H3C 3J7, Montréal, (Québec), Canada.
Lapointe
N
N
Rouleau
J L
JL
Clément
R
R
Gervais
N
N
Geadah
D
D
Adam
A
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000096:biosynthesis; D065168:Bradykinin Receptor Antagonists; D003402:Creatine Kinase / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics; D007124:Immunoenzyme Techniques; D007705:Kinins / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors; D020107:Troponin T / Q000096:biosynthesis
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D007705:Kinins; D011480:Protease Inhibitors; D011725:Pyridines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013841:Thiazepines; D020107:Troponin T; C106266:omapatrilat; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases; D015260:Neprilysin