Carey R M, Howell N L, Jin X H, Siragy H M
Department of Medicine, University of Virginia Health System, Charlottesville 22908, USA.
Hypertension. 2001 Dec 1;38(6):1272-7. doi: 10.1161/hy1201.096576.
The type-2 (AT(2)) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT(1)) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT(2) receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT(1) receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112+/-3 to 168+/-7 mm Hg (P<0.001) and LOS (30 mg/kg) alone decreased BP to 89+/-7 mm Hg (P<0.0001 from control). Ang II administered together with LOS decreased BP further to 71+/-4 mm Hg (P<0.00001 from control and LOS alone). AT(2) receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (P=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98+/-5 to 86+/-3 mm Hg (P<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69+/-3 mm Hg (P<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 microg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119+/-3 mm Hg during the control period, decreased to 86+/-6 mm Hg during 3 days of VAL alone, (P<0.00001) and decreased further to 65+/-7 mm Hg (P<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT(2) receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT(1) receptor.
2型（AT(2)）血管紧张素（Ang）II受体被认为可能对Ang II在其1型（AT(1)）受体上的作用具有反调节作用。我们研究了Ang II和CGP-42112A（CGP）（一种选择性肽类AT(2)受体激动剂）对使用氯沙坦（LOS）或缬沙坦（VAL）对AT(1)受体进行药理学阻断或未阻断的大鼠血压（BP）的影响。在接受正常钠摄入的麻醉大鼠（每组n = 5）中，单独给予Ang II（200 pmol/kg每分钟静脉注射）可使血压从对照组的112±3 mmHg升高至168±7 mmHg（P<0.001），单独给予LOS（30 mg/kg）可使血压降至89±7 mmHg（与对照组相比P<0.0001）。与LOS一起给予Ang II可使血压进一步降至71±4 mmHg（与对照组和单独使用LOS相比P<0.00001）。AT(2)受体拮抗剂PD 123,319（PD）完全阻断了LOS与Ang II联合使用时的降压反应（与对照组相比P =无统计学意义）。在接受正常钠摄入的清醒大鼠（每组n = 5）中，单独给予VAL（10 mg/kg）可使血压从对照组的98±5 mmHg降至86±3 mmHg（P<0.00001）。Ang II与VAL联合使用可使血压持续且高度显著下降6天，降至最低点69±3 mmHg（与单独每日给予VAL相比P<0.01）。PD完全阻断了Ang II与VAL联合使用的慢性降压反应，使其恢复到VAL给药前的对照水平。在另一项针对清醒大鼠的研究（每组n = 5）中，CGP（70 μg/kg每分钟）也可使接受VAL治疗的清醒大鼠血压降低。对照期血压为119±3 mmHg，单独给予VAL 3天时降至86±6 mmHg（P<0.00001），在VAL存在的情况下给予CGP 7天时进一步降至65±7 mmHg（与单独每日给予VAL相比P<0.001）。在没有VAL的情况下，CGP可使血压连续4天降低，且该反应可被PD阻断。此外，CGP在7天内引起的血压降低可被一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯阻断。结果强烈表明，AT(2)受体诱导由一氧化氮介导的全身血管舒张反应，该反应可抵消Ang II在AT(1)受体上的血管收缩作用。
