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(Circulation. 2001;104:939.)
© 2001 American Heart Association, Inc.

Basic Science Reports

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, MD; Gaston Kapuku, MD; Stéphane Pelletier, MSc; Hugues Gosselin, DT; Albert Adam, PhD; Caroline Gagnon, BSc; Chantal Lambert, PhD; Sylvain Meloche, PhD

From the Departments of Medicine, Montreal Heart Institute (G.K., H.G., J.L.R.); the Institut de recherches cliniques de Montréal (S.P., S.M.); the Department of Pharmacology (S.P., C.G., C.L., S.M.) and the Faculty of Pharmacy (A.A.), University of Montreal; and the University of Toronto (J.L.R.), Canada.

Correspondence to Jean Rouleau, MD, Toronto General Hospital, Eaton North 13-212, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail jean.rouleau{at}uhn.on.ca

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 subunits q and i1/2 increased. Inotropic responsiveness to the -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.

Key Words: angiotensin • kinins • ramipril • losartan • receptors

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