The cardioprotective effect of dual metallopeptidase inhibition: Respective roles of endogenous kinins and natriuretic peptides

Marie Josée Dumoulin, Albert Adam, John Burnett, Denise Heublein, Nobuharu Yamaguchi, Daniel Lamontagne

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 cardioprotective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B 1-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.

Original languageEnglish (US)
Pages (from-to)166-173
Number of pages8
JournalCanadian Journal of Physiology and Pharmacology
Volume83
Issue number2
DOIs
StatePublished - Feb 1 2005

Keywords

  • ACE inhibitors
  • Bradykinin
  • Ischemia
  • Natriuretic peptide
  • Omapatrilat
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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