Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B 2 Kinin Receptor Gene Knockout Mice

Abstract —Using B 2 kinin receptor gene knockout mice (B 2 −/− ), we tested the hypothesis that (l) lack of B 2 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 (AT 1 -ant), whereas lack of B 2 receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B 2 −/− and 129/SvEvTac mice (wild-type control, B 2 +/+ ). An ACEi (ramipril, 2.5 mg/kg/d) or AT 1 -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 B 2 +/+ and B 2 −/− 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 B 2 −/− mice (respective values for B 2 +/+ versus B 2 −/− mice: overall increase in ejection fraction, 64±10% versus 21±5% [ P