Hypotension in Transgenic Mice Overexpressing Human Bradykinin B 2 Receptor

Abstract

Bradykinin binds to its receptor at target organs and exerts a wide spectrum of biological activities including vasodilation, smooth muscle contraction and relaxation, pain, and inflammation. To gain a better insight into the physiological function of this potent vasoactive peptide, we created transgenic mice that harbor the human bradykinin B 2 receptor transgene under the control of the Rous sarcoma virus 3′-LTR promoter (RSV-cHBKR). Expression of HBKR in these transgenic mice was identified in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate gland by reverse transcription-polymerase chain reaction Southern blot analysis. Two transgenic mouse lines expressing the human B 2 receptor resulted in a significant reduction of blood pressure (84.2±0.6 mm Hg, n=28; 76.9±0.8 mm Hg, n=24; P <.001) compared with the control littermates (96.9±0.4 mm Hg, n=52). Administration of Hoe 140, a bradykinin B 2 receptor antagonist, restored the blood pressure of the transgenic mice to normal levels within 1 hour, and the effect diminished within 4 hours. The transgenic mice displayed enhanced blood pressure-lowering effect induced by a bolus intra-aortic injection of kinin and showed increased response in kinin-induced uterine smooth muscle contractility compared with control littermates. These studies show that overexpression of human bradykinin B 2 receptor causes a sustained reduction of blood pressure in transgenic mice. They also suggest that the B 2 receptor-mediated signal transduction pathway plays a role in blood pressure regulation.