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(Hypertension. 2001;37:967.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Angiotensin II–Induced Hypertension in Bradykinin B₂ Receptor Knockout Mice

Presented in part in abstract form at the Experimental Biology 2000 Meeting, April 10–13, 2000, San Diego, Calif.

Ludk ervenka; Jan Mal; Ludmila Karasová; Marcela imová; tefan Vítko; Soa Hellerová; Jií Heller; Samir S. El-Dahr

From the Department of Experimental Medicine (L.C., J.M., L.K., S.H., J.H.) and the Transplant Center (M.S., S.V.), Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Pediatrics (S.S.E.-D.), Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, La; and Department of Physiology, 2nd Medical Faculty Charles University, Prague, Czech Republic.

Correspondence to Ludk ervenka, MD, Department of Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeská, 140 00 Prague 4, Czech Republic. E-mail luce{at}medicon.cz

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 B₂ receptor knockout (B₂R^-/-) and wild-type (B₂R^+/+) 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/B₂R^+/+ and SAL/B₂R^-/- mice (128±5 versus 133±6 mm Hg, n=24/group). In contrast, SBP was higher on day 12 of infusion in Ang II/B₂R^-/- than in Ang II/B₂R^+/+ mice (173±6 versus 156±5 mm Hg; P<0.05, n=27 and 28). Mean arterial pressure (MAP) was also higher in anesthetized Ang II/B₂R^-/- mice than in Ang II/B₂R^+/+ mice (139±3 versus 124±3 mm Hg; P<0.05, n=16 and 14). Unlike Ang II, long-term norepinephrine (NE) infusion via an osmotic minipump (45 ng/min) caused equivalent increases in SBP in B₂R^+/+ and B₂R^-/- 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/B₂R^+/+ and NE/B₂R^-/- 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/B₂R^-/- mice than in Ang II/B₂R^+/+ mice (2.34±0.06 versus 4.33±0.19 mL · min^-1 · g^-1; P<0.05). Acute inhibition of NO synthase (NOS) with nitro-L-arginine-methyl ester (0.5 µg · g^-1 · min^-1) in SAL/B₂^+/+ and SAL/B₂^-/- 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/B₂R^+/+ mice than of Ang II/B₂R^-/- mice, such that MAP after NOS inhibition in Ang II/B₂R^+/+ approached that of Ang II/B₂R^-/- mice (156±2 versus 159±2 mm Hg). These changes were associated with a decrease in RPF in Ang II/B₂R^+/+ mice to values similar to those of Ang II/B₂R^-/- 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 B₂R^-/- mice to Ang II–induced hypertension and renal vasoconstriction is likely due to an impaired ability to release NO by endogenous kinins.

Key Words: kallikrein-kinin system • angiotensin II • nitric oxide • blood pressure • norepinephrine • blood flow

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