OBJECTIVE: Previous studies have suggested that activation of angiotensin II (ANG II) type 2 (AT2) receptors results in nitric oxide (NO) release via activation of endothelial bradykinin B2 (B2R) receptors. The present study was performed to examine the interplay of AT2 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 AT2 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 2K1C/B2R+/+ mice. MAP on day 27 was also higher in 2K1C/B2R-/- than 2K1C/B2R+/+ mice. Chronic PD infusion did not alter the course of hypertension in 2K1C/B2R+/+ or 2K1C/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 2K1C/B2R+/+ and PD/2K1C/B2R+/+ than 2K1C/B2R-/- and PD/2K1C/B2R-/- mice. CONCLUSIONS: These results indicate that B2R inactivation selectively worsens the maintenance phase of 2K1C Goldblatt hypertension and support the notion that B2R-deficient mice exhibit an impaired ability to release NO in response to elevations of ANG II levels. Chronic administration of an AT2 receptor blocker did not modify the course of 2K1C Goldblatt hypertension in either B2R-/- or B2R+/+ mice. Therefore, the role of AT2 receptors in B2R-mediated protection against ANG II-dependent hypertension remains uncertain.
OBJECTIVE: Previous studies have suggested that activation of angiotensin II (ANG II) type 2 (AT2) receptors results in nitric oxide (NO) release via activation of endothelial bradykinin B2 (B2R) receptors. The present study was performed to examine the interplay of AT2 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 AT2 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 2K1C/B2R+/+ mice. MAP on day 27 was also higher in 2K1C/B2R-/- than 2K1C/B2R+/+ mice. Chronic PD infusion did not alter the course of hypertension in 2K1C/B2R+/+ or 2K1C/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 2K1C/B2R+/+ and PD/2K1C/B2R+/+ than 2K1C/B2R-/- and PD/2K1C/B2R-/- mice. CONCLUSIONS: These results indicate that B2R inactivation selectively worsens the maintenance phase of 2K1C Goldblatt hypertension and support the notion that B2R-deficient mice exhibit an impaired ability to release NO in response to elevations of ANG II levels. Chronic administration of an AT2 receptor blocker did not modify the course of 2K1C Goldblatt hypertension in either B2R-/- or B2R+/+ mice. Therefore, the role of AT2 receptors in B2R-mediated protection against ANG II-dependent hypertension remains uncertain.
Authors: Federico Franchi; Bruce E Knudsen; Elise Oehler; Stephen C Textor; Lilach O Lerman; Joseph P Grande; Martin Rodriguez-Porcel Journal: Hypertens Res Date: 2013-05-16 Impact factor: 3.872
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