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

Abstract

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 <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]). AT 1 -ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B 2 −/− mice (respective values for B 2 +/+ versus B 2 −/− 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 AT 1 -ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B 2 −/− mice. We concluded that (1) lack of B 2 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 B 2 receptor play an important role in the cardioprotective effect of ACEi and AT 1 -ant.