Enhanced blood pressure sensitivity to deoxycorticosterone in mice with disruption of bradykinin B2 receptor gene

The renal kallikrein-kinin system is activated under conditions of mineralocorticoid excess. To evaluate whether endogenous kinins exert a protective role against the development of mineralocorticoid-induced hypertension, we studied the cardiovascular effects induced by long-term administration of deoxycorticosterone (DOC; 0.3 mu mol/g body wt SC once per week for 6 weeks) or vehicle in transgenic mice (Bk2r(-/-)) lacking the bradykinin B-2 receptor gene and in wild-type controls (Bk2r(+/+)). Under basal conditions, Bk2r(+/-) mice showed higher systolic blood pressure (tail-cuff plethysmography) than wild-type Bk2r(+/+) and heterozygous Bk2r(+/-) mice (121+/-2 versus 114+/-2 and 115+/-2 mm Hg, respectively; P<0.05 for both comparisons). Heart rate was higher in Bk2r(-/-) and Bk2r(+/-) than in Bk2r(+/+) (459+/-12 and 418+/-7 versus 390+/-7 bpm; P<0.05 for both comparisons). Systolic blood pressure was increased by DOC in transgenic as well as in wild-type mice, whereas no change was induced by the vehicle. The presser response to DOC was more rapid and pronounced in Bk2r(-/-) than in Bk2r(+/+) and Bk2r(+/-)(30+/-5 versus 15+/-4 and 6+/-3 mm Hg, respectively, at 3 weeks; P<0.01 for both comparisons). The difference in systolic blood pressure was consistent with that detected by direct intra-arterial measurements of mean blood pressure. Neither DOC nor its vehicle altered heart rate or gain in body weight over time. Under basal conditions, urinary sodium excretion did not differ between strains. During DOC administration, cumulative urinary sodium excretion was lower in Bk2r(-/-) than in Bk2r(+/+) (2.59+/-0.15 versus 3.31+/-0.22 mmol, respectively, during the first week; P<0.05), Urinary kinin excretion was increased by DOC in both Bk2r(-/-) (from 0.65+/-0.17 to 4.27+/-0.80 pmol/24 h; P<0.01) and Bk2r(+/+) (from 0.55+/-0.09 to 6.27+/-1.48 pmol/24 h; P<0.05). The increase in urinary kinin excretion was similar between strains. These results show that integrity of the bradykinin B-2 receptor is essential for regulation of blood pressure and heart rate under basal conditions. In addition, they indicate that activation of the kallikrein-kinin system represents a compensatory response against the development of hypertension induced by mineralocorticoid excess.