Renovascular hypertension in bradykinin B2-receptor knockout mice

We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B-2 receptor in the contralateral kidney. BK B-2-receptor knockout (B-2(-/-)), wild-type (B-2(+/+)), and heterozygous (B-2(+/-)) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B-2(-/-) mice than in B-2(+/-) B-2(+/-) mice (121 +/- 2 versus 113 +/- 2 and 109 +/- 1 mm Hg P<0.05 for both comparisons). SEP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SEP was greater in 2K1C B-2(-/-) mice than in B-2(+/-) or B-2(+/+) mice (28 +/- 2 versus 14 +/- 2 and 14 +/- 2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B-2 receptor by Icatibant enhanced the pressure response to clipping in B-2(+/+) mice (29 +/- 2 mmHg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B-2(-/-) mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B-2(+/+) mice given Icatibant (30 and 32 mm Hg) than in B-2(+/+) mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B-2(-/-) and B-2(+/-) mice, but this effect was delayed in B-2(+/+) mice. However, the HR response to clipping in B-2(+/+) mice was enhanced by Icatibant, Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B-2(-/-): 5.7 +/- 0.1 versus 5.2 +/- 0.1; B-2(+/+): 5.1 +/- 0.1 versus 4.5 +/- 0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B-2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.