Overexpression of kinin B₁ receptors induces hypertensive response to Des-Arg⁹-bradykinin and susceptibility to inflammation

We demonstrated that rat kinin B₁ receptors displayed a ligand-independent constitutive activity, assessed through inositol phosphate production in transiently or stably transfected human embryonic kidney 293A cells. Substitution of Ala for Asn¹³⁰ in the third transmembrane domain resulted in additional constitutive activation of the B₁ receptor. The constitutively active mutant N130A receptor could be further activated by the B₁ receptor agonist des-Arg⁹-bradykinin. To gain insights into the physiological function of the B₁ receptor, we have generated transgenic mice overexpressing wild-type and constitutively active mutant receptors under the control of human cytomegalovirus immediately early gene enhancer/promoter. The rat B₁ receptor transgene expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate of transgenic mice by reverse transcriptionpolymerase chain reaction/Southern blot analysis. Transgenic mice were fertile and normotensive. Overexpression of B₁ receptors exacerbated paw edema induced by carrageenan and rendered transgenic mice more susceptible to lipopolysaccharide-induced endotoxic shock. Interestingly, the hemodynamic response to kinins was altered in transgenic mice, with des-Arg⁹-bradykinin inducing blood pressure increase when intravenously administered. Our study supports an important role for B₁ receptors in modulating inflammatory responses and for the first time demonstrates that B₁ receptors mediate a hypertensive response to des-Arg⁹-bradykinin.