Barber M N, Sampey D B, Widdop R E
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Hypertension. 1999 Nov;34(5):1112-6. doi: 10.1161/01.hyp.34.5.1112.
In the present study, we investigated the role of the angiotensin type 2 (AT(2)) receptor in the regulation of blood pressure in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We tested the hypothesis that AT(2) receptor activation may contribute to the antihypertensive effects of angiotensin type 1 (AT(1)) receptor antagonists. Mean arterial pressure (MAP) and heart rate were measured over a 4-day protocol in various groups of rats that received the following drug combinations: the AT(1) receptor antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, the AT(2) receptor agonist CGP42112 (1 microg/kg per minute) alone, and candesartan plus CGP42112. In both SHR and WKY, 4-hour infusions of saline and CGP42112 alone did not alter MAP. In WKY, both doses of candesartan alone caused small decreases in MAP, which were similar when combined with CGP42112. In SHR, candesartan (0.1 mg/kg) caused an immediate, marked decrease in MAP, which was unaffected when combined with CGP42112. By contrast, in separate SHR, a 10-fold lower dose of candesartan (0.01 mg/kg) caused a slower-onset depressor response, which was enhanced when combined with CGP42112. The involvement of AT(2) receptors was confirmed in another group of SHR, since this facilitation of the antihypertensive effect of candesartan by CGP42112 was abolished by the coinfusion of the AT(2) receptor antagonist PD123319 (50 microg/kg per minute) with the candesartan/CGP42112 combination. Collectively, these data suggest that in SHR, AT(2) receptor activation can facilitate the initial depressor response caused by an AT(1) receptor antagonist.
在本研究中，我们调查了2型血管紧张素（AT(2)）受体在自发性高血压大鼠（SHR）和Wistar-Kyoto大鼠（WKY）血压调节中的作用。我们检验了以下假设：AT(2)受体激活可能有助于1型血管紧张素（AT(1)）受体拮抗剂的降压作用。在接受以下药物组合的各组大鼠中，通过4天的实验方案测量平均动脉压（MAP）和心率：单独使用AT(1)受体拮抗剂坎地沙坦（0.01或0.1 mg/kg静脉注射）、单独使用AT(2)受体激动剂CGP42112（每分钟1微克/千克）以及坎地沙坦加CGP42112。在SHR和WKY中，单独输注生理盐水和CGP42112 4小时均未改变MAP。在WKY中，单独使用的两种剂量的坎地沙坦均导致MAP小幅下降，与CGP42112合用时相似。在SHR中，坎地沙坦（0.1 mg/kg）导致MAP立即显著下降，与CGP42112合用时不受影响。相比之下，在另一组单独的SHR中，剂量低10倍的坎地沙坦（0.01 mg/kg）引起的降压反应起效较慢，与CGP42112合用时增强。在另一组SHR中证实了AT(2)受体的参与，因为CGP42112对坎地沙坦降压作用的这种促进作用在与AT(2)受体拮抗剂PD123319（每分钟50微克/千克）与坎地沙坦/CGP42112组合共同输注时被消除。总体而言，这些数据表明，在SHR中，AT(2)受体激活可促进AT(1)受体拮抗剂引起的初始降压反应。
