Cardiovascular Phenotype of a Mouse Strain With Disruption of Bradykinin B 2 -Receptor Gene

Abstract

Background To evaluate the role of kinins in the regulation of cardiovascular function, we studied the phenotype of a mouse strain with disruption of the bradykinin B 2 -receptor gene (Bk 2r −/− ). Methods and Results Under basal conditions, tail-cuff blood pressure was higher in Bk2r −/− than in wild-type Bk2r +/+ and heterozygous Bk2r +/− mice (124±1 versus 109±1 and 111±2 mm Hg, respectively; P<.01 for both comparisons), a difference that was confirmed by measurements of intra-arterial blood pressure in unanesthetized mice. Heart weight was greater in Bk2r −/− than in Bk2r +/+ and Bk2r +/− mice (505±10 versus 449±12 and 477±10 mg/100 g body wt, P<.05). Chronic blockade of B 2 -receptors by Icatibant (50 nmol/100 g body wt twice a day SC) or inhibition of nitric oxide synthase by nitro- l -arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r +/+ to the levels of Bk2r −/− mice. Compared with the wild-type strain, both Bk2r −/− and Bk2r +/− mice showed exaggerated vasopressor responses to angiotensin II. In addition, chronic administration of an angiotensin AT 1 -receptor antagonist reduced the basal blood pressure of Bk2r −/− by 21±3 mm Hg (P<.05) to the levels of Bk2r +/+ . No difference was detected between strains as far as plasma renin activity and the expression of renin and AT 1 -receptor genes are concerned. Chronic salt loading (0.84 mmol/g chow for 15 days) increased the blood pressure of Bk2r −/− and Bk2r +/− by 34±3 and 14±6 mm Hg, respectively, whereas it was ineffective in Bk2r +/+ . Conclusions Our results suggest that a normally functioning B 2 -receptor is essential for the maintenance of cardiovascular homeostasis in mice. Dysfunction of the kallikrein-kinin system could contribute to increase blood pressure levels by leaving the activity of vasoconstrictor agents unbalanced.