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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 (AT2 R). It is unknown whether AT2 Rs regulate TAL NaCl absorption and whether this effect is reduced in SS rats. We hypothesized that AT2 R 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, AT2 R activation with angiotensin II inhibited NKCC2 activity by 32±7% (P &lt;0.03). AT2 R antagonist PD-123319 abolished the effect of angiotensin II. Activation with the AT2 R-selective agonist CGP42112A (10 nmol/L) decreased NKCC2 activity by 29±6% (P &lt;0.03). The effect of CGP42112A on NKCC2 activity was blocked by PD-123319 and by NO synthase inhibitorN G -nitro-l -arginine methyl ester. In Dahl salt-resistant rat TALs, 1 nmol/L of CGP42112A decreased NKCC2 activity by 23±4% (P &lt;0.01). In SS TALs, it had no effect. TAL AT2 R mRNA did not differ in SS versus salt-resistant rats. We conclude the following: (1) TAL AT2 R activation decreases Na absorption; (2) this effect is mediated by AT2 R-induced stimulation of NO; (3) AT2 R-induced reduction of NKCC2 activity is blunted in SS rats; and (4) defects in AT2 R/NO signaling rather than decreased AT2 R expression likely account for the blunted effect in SS TALs. Impaired AT2 R-mediated signaling in TALs could contribute to the Na retention associated with salt-sensitive hypertension.

Angiotensin II Type 2 Receptor–Mediated Inhibition of NaCl Absorption Is Blunted in Thick Ascending Limbs From Dahl Salt-Sensitive Rats