Angiotensin II–Induced Hypertension in Bradykinin B 2 Receptor Knockout Mice

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Abstract
The present study was performed to examine the role of endogenous bradykinin (BK) in the development of angiotensin II (Ang II)–induced hypertension in mice. BK B 2 receptor knockout (B 2 R −/− ) and wild-type (B 2 R +/+ ) mice (22 to 26 g) were infused with either saline (SAL) or Ang II (40 ng/min) via an osmotic minipump implanted intraperitoneally. On day 12 after implantation, there was no difference in systolic blood pressure (SBP, tail-cuff plethysmography) between SAL/B 2 R +/+ and SAL/B 2 R −/− mice (128±5 versus 133±6 mm Hg, n=24/group). In contrast, SBP was higher on day 12 of infusion in Ang II/B 2 R −/− than in Ang II/B 2 R +/+ mice (173±6 versus 156±5 mm Hg; P 2 R −/− mice than in Ang II/B 2 R +/+ mice (139±3 versus 124±3 mm Hg; P 2 R +/+ and B 2 R −/− mice measured on day 12 after implantation (151±4 versus 149±5 mm Hg, n=9 and 8). MAP also did not differ on day 13 after implantation between NE/B 2 R +/+ and NE/B 2 R −/− mice (120±6 versus 122±4 mm Hg, n=9 and 8). There were no differences in glomerular filtration rate and urinary sodium excretion among the groups. However, renal plasma flow (RPF) was lower in Ang II/B 2 R −/− mice than in Ang II/B 2 R +/+ mice (2.34±0.06 versus 4.33±0.19 mL · min −1 · g −1 ; P −1 · min −1 ) in SAL/B 2 +/+ and SAL/B 2 −/− mice caused equal increases in MAP (142±1 versus 145±1 mm Hg) and decreases in RPF (2.06±0.06 versus 2.12±0.15 mL · min −1 · g −1 ). However, short-term NOS inhibition caused a greater increase in MAP of Ang II/B 2 R +/+ mice than of Ang II/B 2 R −/− mice, such that MAP after NOS inhibition in Ang II/B 2 R +/+ approached that of Ang II/B 2 R −/− mice (156±2 versus 159±2 mm Hg). These changes were associated with a decrease in RPF in Ang II/B 2 R +/+ mice to values similar to those of Ang II/B 2 R −/− mice before NOS inhibition (2.12±0.09 versus 2.34±0.06 mL · min −1 · g −1 ). These results demonstrate that the kallikrein-kinin system selectively buffers the vasoconstrictor activity of Ang II. Furthermore, the enhanced susceptibility of B 2 R −/− mice to Ang II–induced hypertension and renal vasoconstriction is likely due to an impaired ability to release NO by endogenous kinins.