Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B-2 kinin receptor gene knockout mice

Using B-2 kinin receptor gene knockout mice (B-2(-/-)), we tested the hypot hesis that (1) lack of B2 receptors may affect blood pressure and cardiac f unction and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotens in-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor an tagonists (AT(1)-ant), whereas lack of B, receptors may diminish this cardi oprotective 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 we eks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastoli c LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myoc yte cross-sectional area and interstitial collagen fraction were studied hi stopathologically. We found that basal blood pressure and cardiac function were similar in B2(+/+) and B-2(-/-) mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACE improved cardia c function and remodeling in both strains; however, its effects were attenu ated 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 i n 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 i ncrease in ejection fraction, 46 +/- 10% versus 25 +/-9% [P <0.01]; increas e in CO, 44 +/- 14% versus 15 +/-5% [P <0.01]; overall decrease in LVDd, -1 4 +/-4% versus -6 +/-3% [P <0.01]; and decrease in LV mass, -33 +/-4 versus -16 +/-7% [P <0.011). The effect of ACEi or AT(1)-ant on myocyte cross-sec tional area was similar between strains; however, their effect on the inter stitial collagen fraction was diminished in B-2(-/-) mice. We concluded tha t (1) lack of B, kinin receptors does not affect cardiac phenotype or funct ion, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the Bz receptor play an important role in the cardioprotective effect of ACEi and AT(1)-ant.