Angiotensin II type 1 receptor blockade prevents cardiac remodeling in bradykinin B-2 receptor knockout mice

Knockout mice (B-2(-/-)) lacking the bradykinin (BK) B-2 receptor gene deve lop mild hypertension, cardiac hypertrophy, and myocardial damage. We hypot hesized that these effects are due to the hypertrophying and damaging actio ns of angiotensin II (Ang LI) in the absence of the balancing protection of BK. To verify this hypothesis, B-2(-/-) or wild-type mice (B-2(+/+)) were administered a nonpeptide antagonist of Ang II type 1 (AT(1)) receptors (A8 1988) from conception through 180 days of age. Untreated B-2(+/+) and B-2(- /-) served as controls. Blood pressure (BP) and heart rate were monitored w ith the use of tail-cuff plethysmography at regular intervals. Ventricular weights, diameters, wall thickness, chamber volume, and myocardial fibrosis were measured at 40 and 180 days. No differences were observed in BP, hear t rate, and cardiac weight and dimensions between treated and untreated B-2 (+/+). The BP of AT(1) antagonist-treated B-2(-/-) was reduced until 70 day s; then, it increased to the levels found in untreated B-2(-/-). AT(1) rece ptor blockade resulted in a reduction in left ventricular mass, chamber vol ume, and wall thickness and abrogated myocardial fibrosis in B-2(-/-). Thes e results indicate that Ang II is the major factor responsible for ventricu lar remodeling and myocardial damage in mice with disruption of BK B-2 rece ptor signaling. The interaction of Ang II and BK appears to be essential fo r the development of a normal heart.