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(Circulation Research. 2001;88:1072.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B₂ Kinin Receptor Gene Knockout Mice

Xiao-Ping Yang, Yun-He Liu, Dharmesh Mehta, Maria A. Cavasin, Edward Shesely, Jiang Xu, Fang Liu, Oscar A. Carretero

From the Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich.

Correspondence to Xiao-Ping Yang, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202. E-mail xpyang1{at}hfhs.org

Abstract—Using B₂ kinin receptor gene knockout mice (B₂^-/-), we tested the hypothesis that (l) lack of B₂ receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT₁-ant), whereas lack of B₂ receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B₂^-/- and 129/SvEvTac mice (wild-type control, B₂^+/+). An ACEi (ramipril, 2.5 mg/kg/d) or AT₁-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B₂^+/+ and B₂^-/- mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B₂^-/- mice (respective values for B₂^+/+ versus B₂^-/- mice: overall increase in ejection fraction, 64±10% versus 21±5% [P<0.01]; increase in CO, 69±17% versus 23±9% [P<0.01]; overall decrease in LVDd, -24±3% versus -7±4% [P<0.01]; and decrease in LV mass, -38±3% versus -6±6% [P<0.01]). AT₁-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B₂^-/- mice (respective values for B₂^+/+ versus B₂^-/- mice: overall increase in ejection fraction, 46±10% versus 25±9% [P<0.01]; increase in CO, 44±14% versus 15±5% [P<0.01]; overall decrease in LVDd, -14±4% versus -6±3% [P<0.01]; and decrease in LV mass, -33±4 versus -16±7% [P<0.01]). The effect of ACEi or AT₁-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B₂^-/- mice. We concluded that (1) lack of B₂ kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B₂ receptor play an important role in the cardioprotective effect of ACEi and AT₁-ant.

Key Words: angiotensin-converting enzyme inhibitors • AT₁ receptor antagonist • heart failure • B₂ kinin receptors • mice

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