Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA.
Hypertension. 2012 Sep;60(3):765-9. doi: 10.1161/HYPERTENSIONAHA.112.199216. Epub 2012 Jul 9.
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 (AT(2)R). It is unknown whether AT(2)Rs regulate TAL NaCl absorption and whether this effect is reduced in SS rats. We hypothesized that AT(2)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, AT(2)R activation with angiotensin II inhibited NKCC2 activity by 32±7% (P<0.03). AT(2)R antagonist PD-123319 abolished the effect of angiotensin II. Activation with the AT(2)R-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 N(G)-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 AT(2)R mRNA did not differ in SS versus salt-resistant rats. We conclude the following: (1) TAL AT(2)R activation decreases Na absorption; (2) this effect is mediated by AT(2)R-induced stimulation of NO; (3) AT(2)R-induced reduction of NKCC2 activity is blunted in SS rats; and (4) defects in AT(2)R/NO signaling rather than decreased AT(2)R expression likely account for the blunted effect in SS TALs. Impaired AT(2)R-mediated signaling in TALs could contribute to the Na retention associated with salt-sensitive hypertension.
一氧化氮（NO）通过抑制钠钾-2 氯共转运体（NKCC2）来减少厚升支（TAL）对 NaCl 的吸收。我们已经证明，在 Dahl 盐敏感型大鼠（SS）TAL 中，NO 诱导的钠转运抑制作用降低。血管紧张素 II（Ang II）通过血管紧张素 II 型 2 受体（AT2R）增加 TAL 中的 NO 产生。目前尚不清楚 AT2R 是否调节 TAL NaCl 吸收，以及这种效应在 SS 大鼠中是否减弱。我们假设 AT2R 激活通过 NO 降低 TAL 钠转运，而这种效应在 SS 大鼠中减弱。在血管紧张素 II 型 1 受体拮抗剂洛沙坦存在的情况下，用血管紧张素 II 激活 AT2R 抑制 NKCC2 活性 32±7%（P<0.03）。AT2R 拮抗剂 PD-123319 消除了血管紧张素 II 的作用。用 AT2R 选择性激动剂 CGP42112A（10nmol/L）激活 AT2R 可使 NKCC2 活性降低 29±6%（P<0.03）。CGP42112A 对 NKCC2 活性的作用被 PD-123319 和一氧化氮合酶抑制剂 N(G)-硝基-l-精氨酸甲酯阻断。在 Dahl 盐抵抗型大鼠 TAL 中，1nmol/L 的 CGP42112A 使 NKCC2 活性降低 23±4%（P<0.01）。在 SS TAL 中，它没有效果。SS 与盐抵抗型大鼠的 TAL AT2R mRNA 无差异。我们得出以下结论：（1）TAL AT2R 激活可降低 Na 吸收；（2）这种作用是由 AT2R 诱导的 NO 刺激介导的；（3）在 SS 大鼠中，AT2R 诱导的 NKCC2 活性降低作用减弱；（4）SS TAL 中这种作用减弱可能是由于 AT2R/NO 信号转导缺陷而不是 AT2R 表达减少所致。TAL 中 AT2R 介导的信号转导受损可能导致与盐敏感型高血压相关的 Na 潴留。
