Burke S E, Nelson R A, Lubbers N L, Ford T T, Fu K I, Padley R J, Wegner C D, Cox B F
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA.
J Cardiovasc Pharmacol. 2000 Jun;35(6):838-44. doi: 10.1097/00005344-200006000-00002.
Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in a number of cardiovascular diseases, including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertension. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET(A) receptors on vascular smooth muscle cells. Recent studies have indicated that vasoconstriction also may be mediated by stimulation of an ET(B)-receptor subtype. Increased use of the pig as a cardiovascular model prompted us to examine the receptor profile in this species using ABT-627, a potent, nonpeptide antagonist of the ET(A) receptor. The precursor to ET-1, big ET-1 (0.02 nmol/kg/min), was infused intravenously in domestic swine, resulting in a sustained increase in mean blood pressure of 38 +/- 3 mm Hg. After stabilization of the pressor response, ABT-627 (0.1-10 microg/kg/min) or vehicle was infused for 30 min. Whereas vehicle infusion had no appreciable effect, a dose-related reversal of the pressor response to big ET-1 (11-100%) was observed by the end of the ABT-627 infusion. Blood samples were assayed for plasma concentrations of ABT-627; peak levels ranged from 9 +/- 2 to 937 +/- 168 ng/ml. In a separate group of pigs, the highest dose of ABT-627 produced only a modest reversal of the hypertensive response to an infusion of angiotensin II (300 ng/kg/min). Additional results indicate that the vasoconstrictor effects produced by sarafotoxin 6C (0.03 and 0.3 nmol/kg), an agonist of the ET(B) receptor, are not blocked by treatment with ABT-627 (10 microg/kg/min). However, complete blockade of the S6C response could be achieved using the ET(B) antagonist, A-192621 (0.33 mg/kg/min). Our results define the dose-response relation for the ET(A)-receptor antagonist ABT-627 in the vasculature of the domestic pig and suggest the presence of an ET(B)-receptor subtype that mediates vasoconstriction in this species.
内皮素-1（ET-1）是一种强效的血管活性和促有丝分裂肽，与多种心血管疾病有关，包括充血性心力衰竭、与再狭窄相关的新生内膜增生以及高血压。ET-1诱导的血管收缩被认为主要是通过其对血管平滑肌细胞上ET(A)受体的作用介导的。最近的研究表明，血管收缩也可能由ET(B)受体亚型的刺激介导。猪作为心血管模型的使用增加促使我们使用ABT-627（一种强效的ET(A)受体非肽拮抗剂）来研究该物种的受体特征。将ET-1的前体大ET-1（0.02 nmol/kg/分钟）静脉内注入家猪体内，导致平均血压持续升高38±3 mmHg。在升压反应稳定后，注入ABT-627（0.1 - 10 μg/kg/分钟）或赋形剂30分钟。注入赋形剂没有明显效果，而在ABT-627注入结束时观察到对大ET-1的升压反应出现剂量相关的逆转（11% - 100%）。对血液样本检测ABT-627的血浆浓度；峰值水平范围为9±2至937±168 ng/ml。在另一组猪中，最高剂量的ABT-627对注入血管紧张素II（300 ng/kg/分钟）引起的高血压反应仅产生适度的逆转。其他结果表明，ET(B)受体激动剂沙拉毒素6C（0.03和0.3 nmol/kg）产生的血管收缩作用不会被ABT-627（10 μg/kg/分钟）处理所阻断。然而，使用ET(B)拮抗剂A-192621（0.33 mg/kg/分钟）可以完全阻断S6C反应。我们的结果确定了ET(A)受体拮抗剂ABT-627在家猪血管系统中的剂量反应关系，并表明存在介导该物种血管收缩的ET(B)受体亚型。
