Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: Importance of kinins and influence on angiotensin II type 1 receptor signaling pathway

Jean L. Rouleau, Gaston Kapuku, St́phane Pelletier, Hugues Gosselin, Albert Adam, Caroline Gagnon, Chantal Lambert, Sylvain Meloche

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Background - The role of kinins in the cardioprotective effects of ACE inhibitors remains controversial. Methods and Results - Right ventricular pressure overload in rabbits was produced by pulmonary artery banding for 21 days. Rabbits were untreated, or they received the ACE inhibitor ramipril with or without bradykinin B1 and B2 receptor blockers or the angiotensin (Ang) II type I (AT1) receptor blocker losartan. Pulmonary artery banding caused right ventricular hypertrophy, depressed papillary muscle contractility, and loss of Ang II contractile effects because of a signaling defect downstream of AT1 receptors. Paradoxically, AT1 receptor density and G protein α subunits αq and αi1/2 increased. Inotropic responsiveness to the α-receptor agonist phenylephrine was normal. Ramipril preserved cardiac contractility, but this effect was attenuated by simultaneous use of kinin receptor blockers. Ramipril also maintained responsiveness to Ang II and prevented AT1 receptor and G protein upregulation. The simultaneous use of a kinin receptor blocker attenuated but did not prevent upregulation in the AT1 receptor and G protein. Losartan had no effect on baseline contractility, but it maintained cardiac inotropic responsiveness to Ang II, prevented upregulation of AT1 receptors, but did not modify G protein upregulation. Conclusions - Pressure overload of the right ventricle decreases contractility, uncouples AT1 receptors to downstream signaling pathways, and changes the expression of components of the AT1 receptor signaling pathway. Ramipril attenuates these effects via kinins. Interventions that prevent local increases in Ang II or block AT1 receptors also prevent decreased responsiveness of the AT1 receptor in this model.

Original languageEnglish (US)
Pages (from-to)939-944
Number of pages6
JournalCirculation
Volume104
Issue number8
DOIs
Publication statusPublished - Aug 21 2001
Externally publishedYes

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Keywords

  • Angiotensin
  • Kinins
  • Losartan
  • Ramipril
  • Receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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