Published Online
on July 29, 2002

A more recent version of this article appeared on September 1, 2002

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Submitted on April 9, 2002
Revised on April 29, 2002

Role of AT₂ Receptors in the Cardioprotective Effect of AT₁ Antagonists in Mice

Jiang Xu; Oscar A. Carretero; Yun-He Liu; Edward G. Shesely; Fang Yang; Alissa Kapke; and Xiao-Ping Yang^*

From the Hypertension and Vascular Research Division (J.X., O.A.C., Y.-H.L., E.G.S., F.Y., A.K., X.-P.Y), Department of Internal Medicine, and the Division of Biostatistics and Research Epidemiology (A.K.), Henry Ford Hospital, Detroit, Mich; and Wuhan University School of Medicine (J.X.), Wuhan, People's Republic of China.

^* To whom correspondence should be addressed. E-mail: xpyang1{at}hfhs.org.

Abstract—Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT₁ and AT₂. Most of the known biological actions of Ang II are mediated by AT₁ receptors; however, the role of AT₂ receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT₁ receptor antagonists (AT₁-ant) after myocardial infarction (MI) are partially mediated by activation of AT₂ receptors; thus in AT₂ receptor gene knockout mice (AT₂-/Y), the effect of AT₁-ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT₂-/Y and their wild-type littermates (AT₂+/Y) were started on vehicle, AT₁-ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT₂+/Y and AT₂-/Y. AT₁-ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT₂+/Y, and these effects were significantly diminished in AT₂-/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT₂ during AT₁ blockade plays an important role in the therapeutic effect of AT₁-ant and (2) the AT₂ receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.

Key words: receptors, angiotensin • angiotensin antagonist • myocardial infarction • heart failure • mice

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