Angiotensin II Type 2 Receptor–Mediated Inhibition of NaCl Absorption Is Blunted in Thick Ascending Limbs From Dahl Salt-Sensitive Rats
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Abstract
NO reduces NaCl absorption by thick ascending limbs (TALs) by inhibiting the Na/K/2Cl cotransporter (NKCC2). We have shown that NO-induced inhibition of Na transport is reduced in Dahl salt-sensitive rat (SS) TALs. Angiotensin II increases NO production in TALs via angiotensin II type 2 receptor (AT2R). It is unknown whether AT2Rs regulate TAL NaCl absorption and whether this effect is reduced in SS rats. We hypothesized that AT2R activation decreases TAL Na transport via NO, and this effect is blunted in SS rats. In the presence of angiotensin II type 1 receptor antagonist losartan, AT2R activation with angiotensin II inhibited NKCC2 activity by 32±7% (P<0.03). AT2R antagonist PD-123319 abolished the effect of angiotensin II. Activation with the AT2R-selective agonist CGP42112A (10 nmol/L) decreased NKCC2 activity by 29±6% (P<0.03). The effect of CGP42112A on NKCC2 activity was blocked by PD-123319 and by NO synthase inhibitor NG-nitro-l-arginine methyl ester. In Dahl salt-resistant rat TALs, 1 nmol/L of CGP42112A decreased NKCC2 activity by 23±4% (P<0.01). In SS TALs, it had no effect. TAL AT2R mRNA did not differ in SS versus salt-resistant rats. We conclude the following: (1) TAL AT2R activation decreases Na absorption; (2) this effect is mediated by AT2R-induced stimulation of NO; (3) AT2R-induced reduction of NKCC2 activity is blunted in SS rats; and (4) defects in AT2R/NO signaling rather than decreased AT2R expression likely account for the blunted effect in SS TALs. Impaired AT2R-mediated signaling in TALs could contribute to the Na retention associated with salt-sensitive hypertension.
- Received May 22, 2012.
- Revision received June 4, 2012.
- Accepted June 17, 2012.
- © 2012 American Heart Association, Inc.
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- Angiotensin II Type 2 Receptor–Mediated Inhibition of NaCl Absorption Is Blunted in Thick Ascending Limbs From Dahl Salt-Sensitive RatsNancy J. Hong and Jeffrey L. GarvinHypertension. 2012;HYPERTENSIONAHA.112.199216, originally published July 9, 2012https://doi.org/10.1161/HYPERTENSIONAHA.112.199216
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- Angiotensin II Type 2 Receptor–Mediated Inhibition of NaCl Absorption Is Blunted in Thick Ascending Limbs From Dahl Salt-Sensitive RatsNancy J. Hong and Jeffrey L. GarvinHypertension. 2012;HYPERTENSIONAHA.112.199216, originally published July 9, 2012https://doi.org/10.1161/HYPERTENSIONAHA.112.199216