Stimulation of angiotensin AT2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats
Stimulation of angiotensin AT2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats
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DOI：
10.1111/j.1476-5381.2009.00575.x
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发表时间：
2010-02-01
影响因子：
7.3
通讯作者：
Jones, E. S.
中科院分区：
文献类型：
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作者：
Bosnyak, S.;Welungoda, I. K.;Jones, E. S.
背景与目的：血管紧张素2受体(AT(2)受体)在体外和体内均可激发血管扩张效应，与血管紧张素1型受体(AT(1)受体)的血管收缩效应相反。最近，一种新的非肽AT(2)受体激动剂化合物21被报道，它具有很高的AT(2)受体选择性。实验方法：利用体外小鼠离体主动脉和大鼠肠系膜动脉以及清醒的自发性高血压大鼠(SHR)，评价候选化合物21对心血管功能的影响。关键结果：化合物21对主动脉和肠系膜血管的作用呈剂量依赖性，被AT(2)受体拮抗剂PD123319阻断。在体内，化合物21单独给药，剂量在50~1000 ng中心点·kg~(-1)·中心点·分~(-1)，持续4h不能降低清醒正常血压Wistar-京都大鼠或SHR的血压。然而，当与AT(1)受体拮抗剂坎地沙坦联合使用时，化合物21(300 ng中心点kg-1中心点min-1)仅降低SHR的血压。在清醒SHR的不同组中的进一步分析显示，在较低剂量的6倍时，化合物21(50 ng中心点kg-1中心点min-1)与不同剂量的坎地沙坦(0.01或0.1 mg中心点kg-1)联合应用仍能在成年SHR引起显著的降压反应(类似于30毫米汞)。此外，联合应用AT(2)受体拮抗剂PD123319(50 mg中心点·kg~(-1)中心点·min~(-1)，2 h)可完全消除化合物21引起的降压效应。结论与提示：本研究结果提示，急性给予化合物21可通过刺激AT(2)受体而引起血压下降。因此，化合物21可以被认为是进一步研究AT(2)受体在心血管疾病中功能的一个很好的候选药物。
Background and purpose:Angiotensin type 2 receptor (AT(2) receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT(1) receptors). Recently, a novel non-peptide AT(2) receptor agonist, Compound 21, was described, which exhibited high AT(2) receptor selectivity.Experimental approach:Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR).Key results:Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT(2) receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng center dot kg-1 center dot min-1 over 4 h did not decrease blood pressure in conscious normotensive Wistar-Kyoto rats or SHR. However, when given in combination with the AT(1) receptor antagonist, candesartan, Compound 21 (300 ng center dot kg-1 center dot min-1) lowered blood pressure in SHR only. Further analysis in separate groups of conscious SHR revealed that, at a sixfold lower dose, Compound 21 (50 ng center dot kg-1 center dot min-1) still evoked a significant depressor response in adult SHR (similar to 30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg center dot kg-1). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 mu g center dot kg-1 center dot min-1 for 2 h) with the AT(2) receptor antagonist PD123319.Conclusion and implications:Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT(2) receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT(2) receptor function in cardiovascular disease.