Genetic inactivation of the B2 receptor in mice worsens two-kidney, one-clip hypertension:: role of NO and the AT2 receptor

Objective Previous studies have suggested that activation of angiotensin II (ANG II) type 2 (AT(2)) receptors results in nitric oxide (NO) release via activation of endothelial bradykinin B-2 (B2R) receptors. The present study was performed to examine the interplay of AT(2) and B2R in the development and maintenance of two-kidney, one-clip (2K1C) Goldblatt hypertension. Methods B2R knockout (B2R-/-) mice and their wild-type controls (B2R+/+) underwent clipping of the right renal artery and were infused with either saline (SAL) or PD 123319, an AT(2) receptor antagonist (PD), via an osmotic pump implanted intraperitoneally. Systolic blood pressure (SBP) was measured in conscious mice. On day 27, mean arterial pressure (MAP) responses were measured in response to consecutive blockade of AT(2) receptors and NO synthase (NOS). Results A significant and sustained rise in SBP was observed in both 2K1C B2R+/+ and B2R-/- versus sham-operated groups from day 10 to day 24 after clipping. After this time, SBP rose to significantly higher levels in 2K1C/B2R-/- than in 21<1 C/B-2 R+/+ mice. MAP on day 27 was also higher in 2K1 C/B2R-/- than 2K1C<B2R+/+ mice. Chronic PD infusion did not alter the course of hypertension in 21<1 C/B2R+/+ or 2K1 C/B2R-/- mice as compared with saline-infused mice. Likewise, acute PD infusion did not affect MAP in any of the groups. However, acute NOS inhibition caused significantly greater increases in MAP in 2K1 C/B2R+/+ and PD/2K1 C/B2R+/+ than 2K1C/B2R-/- and PD/2K1C/B2R-/- mice. Conclusions These results indicate that B2R inactivation selectively worsens the maintenance phase of 2K1 C Goldblatt hypertension and support the notion that B2R-deficient mice exhibit an impaired ability to release NO in response to elevations of ANG IL levels. Chronic administration of an AT(2) receptor blocker did not modify the course of 2K1C Goldblatt hypertension in either B2R-/- or B2R+/+ mice. Therefore, the role of AT(2) receptors in B2R-mediated protection against ANG IL-dependent hypertension remains uncertain. (C) 2003 Lippincott Williams Wilkins.