title: The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides.
abstract: The objective of the present study was to assess the cardioprotective effect of dual NEP-ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg.kg(-1).d(-1)). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.
authors.affiliation: Faculty of pharmacy, Université de Montréal, Canada.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Dumoulin
authors.forename: Albert
authors.initials: A
authors.lastname: Adam
authors.forename: John
authors.initials: J
authors.lastname: Burnett
authors.forename: Denise
authors.initials: D
authors.lastname: Heublein
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamontagne
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007705:Kinins / Q000502:physiology*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D045265:Natriuretic Peptides / Q000502:physiology*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D007705:Kinins; D045265:Natriuretic Peptides; D011725:Pyridines; D013841:Thiazepines; C058930:brain natriuretic peptide receptor; D020097:Natriuretic Peptide, Brain; C024626:bradykinin, des-Arg(9)-; C106266:omapatrilat; D015260:Neprilysin; D017461:Receptors, Atrial Natriuretic Factor; D017257:Ramipril; D001920:Bradykinin