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

      The Journal of Biological Chemistry

      Transgenes, Amino Acid Sequence, Survival Rate, physiology, Second Messenger Systems, metabolism, genetics, Receptors, Bradykinin, Receptor, Bradykinin B1, Rats, Protein Structure, Secondary, Promoter Regions, Genetic, Mutation, Molecular Sequence Data, Mice, Transgenic, Mice, pharmacology, Lipopolysaccharides, Ligands, Inositol Phosphates, chemically induced, Inflammation, Humans, Female, Cell Line, toxicity, Carrageenan, analogs & derivatives, Bradykinin, drug effects, Blood Pressure, Animals

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          We demonstrated that rat kinin B(1) 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 Asn(130) in the third transmembrane domain resulted in additional constitutive activation of the B(1) receptor. The constitutively active mutant N130A receptor could be further activated by the B(1) receptor agonist des-Arg(9)-bradykinin. To gain insights into the physiological function of the B(1) 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 B(1) receptor transgene expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate of transgenic mice by reverse transcription-polymerase chain reaction/Southern blot analysis. Transgenic mice were fertile and normotensive. Overexpression of B(1) 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-Arg(9)-bradykinin inducing blood pressure increase when intravenously administered. Our study supports an important role for B(1) receptors in modulating inflammatory responses and for the first time demonstrates that B(1) receptors mediate a hypertensive response to des-Arg(9)-bradykinin.

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