Dilated and Failing Cardiomyopathy in Bradykinin B 2 Receptor Knockout Mice

Abstract

Background —The activation of B 2 receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure. Methods and Results —To test whether the absence of bradykinin B 2 receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B 2 receptor gene knockout (B 2 −/− ), heterozygous (B 2 +/− ), and wild-type (B 2 +/+ ) mice. The BP of B 2 −/− mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B 2 +/+ , P <0.01). In B 2 +/− mice, BP elevation was delayed. At 40 days, the heart rate was higher ( P <0.01) in B 2 −/− and B 2 +/− than in B 2 +/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B 2 −/− and B 2 +/− mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B 2 +/+ mice. In B 2 −/− mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B 2 +/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B 2 +/+ mice, P <0.01), and reparative fibrosis. Conclusions —The disruption of the bradykinin B 2 receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.