Leung Susan Wai Sum, Lim Su Lin, Pang Catherine Cheuk Ying, Man Ricky Ying Keung
Department of Pharmacology & Therapeutics, Faculty of Medicine, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
J Cardiovasc Pharmacol. 2002 Apr;39(4):533-43. doi: 10.1097/00005344-200204000-00009.
Endothelin-1 (ET-1) is known to cause a transient (<1 min) depressor followed by a sustained (>1 h) pressor response. The former through the activation of ET(B) receptors, and the latter through the activation of ET(A) and ET(B) receptors. This study examines if ET(B) receptors mediate sustained mesenteric and renal dilation in anesthetized rats. Intravenous bolus ET-1 (0.8, 1.4, and 2 nmol/kg) and IRL-1620 (ET(B) agonist, 2, 5, and 10 nmol/kg) caused transient decrease followed by sustained increases in mean arterial pressure (MAP) that were accompanied by increases in total peripheral resistance (TPR), reductions in cardiac output (CO), and mesenteric and renal vasoconstriction. Pretreatment with FR-139317 (ET(A) antagonist, 1 mg/kg) attenuated the pressor and constrictor effects of ET-1 but did not alter responses to IRL-1620. IRL-2500 (ET(B) antagonist, 5 mg/kg) slightly inhibited the renal constrictor effect of IRL-1620, whereas A-192621 (ET(B) antagonist, 5 mg/kg) abolished all hemodynamic responses to IRL-1620. Both IRL-2500 and A-192621 markedly enhanced MAP, TPR, and mesenteric, and the renal constrictor effects of ET-1. Therefore, A-192621 was more effective than IRL-2500 in blocking IRL-1620-induced vasoconstriction, but both augmented constrictor responses to ET-1. The potentiation of ET-1-induced vasoconstriction by ET(B) receptor antagonists revealed a sustained vasodilator role of ET(B) receptors.
已知内皮素 -1（ET-1）会引发短暂（<1分钟）的降压反应，随后是持续（>1小时）的升压反应。前者通过激活ET(B)受体，后者通过激活ET(A)和ET(B)受体。本研究探讨ET(B)受体是否介导麻醉大鼠肠系膜和肾血管的持续扩张。静脉推注ET-1（0.8、1.4和2 nmol/kg）和IRL-1620（ET(B)激动剂，2、5和10 nmol/kg）导致平均动脉压（MAP）先短暂下降，随后持续升高，同时伴有总外周阻力（TPR）增加、心输出量（CO）降低以及肠系膜和肾血管收缩。用FR-139317（ET(A)拮抗剂，1 mg/kg）预处理可减弱ET-1的升压和血管收缩作用，但不改变对IRL-1620的反应。IRL-2500（ET(B)拮抗剂，5 mg/kg）轻微抑制IRL-1620的肾血管收缩作用，而A-192621（ET(B)拮抗剂，5 mg/kg）消除了对IRL-1620的所有血流动力学反应。IRL-2500和A-192621均显著增强MAP、TPR以及ET-1的肠系膜和肾血管收缩作用。因此，A-192621在阻断IRL-1620诱导的血管收缩方面比IRL-2500更有效，但两者均增强了对ET-1的收缩反应。ET(B)受体拮抗剂增强ET-1诱导的血管收缩作用揭示了ET(B)受体的持续血管舒张作用。
