Krause S M, Nolan N A, Clayton F C, Walsh T F, Williams D L
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Cardiovasc Pharmacol. 1999 Sep;34(3):359-67. doi: 10.1097/00005344-199909000-00007.
The pharmacology of endothelin (ET)-1, big ET-1, ET-3, and S6c were characterized in the anesthetized ferret to assess whether this species would provide a new and suitable nonrodent model to be used in characterization of endothelin antagonists. Unlike other species such as dog, rabbit, and rat, the ferret exhibited a dose-dependent pressor response to both ET-1 and big ET-1 with no preceding vasodilatory response. The median effective concentration (ED50) values were 0.047+/-0.009 and 0.469+/-0.003 nmol/kg for ET-1 and big ET-1, respectively. ET-3 and S6c, however, were found to elicit a transient vasodilatory response preceding the pressor response, with ED50 values of 0.23+/-0.09 and 0.18+/-0.03 nmol/kg, respectively. The rank potency of the agonists for the pressor response was found to be ET-1 > S6c > big ET-1 > ET-3. The ET(A)-specific antagonist BQ-123 was shown to block only partially the ET-1 and big ET-1 pressor response with median antagonistic dose (AD50) of 0.24+/-0.11 and 0.015+/-0.005 mg/kg, i.v., respectively, and blockade of the ET(A) receptor did not uncover an ET(B)-induced vasodilation. The dual ET(A/B) antagonist L-754,142 completely antagonized the ET-1 and big ET-1 pressor responses with AD50 values of 0.195+/-0.063 and 0.019+/-0.006 mg/kg, respectively. The ET(B) antagonist BQ-788 blocked the depressor response of S6c entirely but was unable to antagonize the pressor response completely. BQ-123 was shown to antagonize the S6c pressor response partially, suggesting a possible interaction between the ET(A) and ET(B) receptors in the ferret. The unexpected absence of an ET-1-mediated depressor response but the presence of ET-3 and S6c vasodilation in this species supports the theory that there may be subtypes of the ET(B) receptor. These studies demonstrate that the anesthetized ferret provides a suitable model for assessing the physiological potencies of the endothelins and may provide a tool for further understanding of the diversity of the ET(B) receptor.
在内毒素诱导的麻醉雪貂中研究了内皮素（ET）-1、大内皮素-1、ET-3和S6c的药理学特性，以评估该物种是否能成为一种新型且合适的非啮齿类动物模型，用于内皮素拮抗剂的特性研究。与狗、兔子和大鼠等其他物种不同，雪貂对ET-1和大内皮素-1均表现出剂量依赖性升压反应，且无先前的血管舒张反应。ET-1和大内皮素-1的半数有效浓度（ED50）值分别为0.047±0.009和0.469±0.003 nmol/kg。然而，发现ET-3和S6c在升压反应之前会引发短暂的血管舒张反应，ED50值分别为0.23±0.09和0.18±0.03 nmol/kg。发现激动剂对升压反应的效价顺序为ET-1＞S6c＞大内皮素-1＞ET-3。ET（A）特异性拮抗剂BQ-123仅部分阻断ET-1和大内皮素-1的升压反应，静脉注射的半数拮抗剂量（AD50）分别为0.24±0.11和0.015±0.005 mg/kg，阻断ET（A）受体并未揭示ET（B）诱导的血管舒张。双重ET（A/B）拮抗剂L-754,142完全拮抗ET-1和大内皮素-1的升压反应，AD50值分别为0.195±0.063和0.019±0.006 mg/kg。ET（B）拮抗剂BQ-788完全阻断S6c的降压反应，但无法完全拮抗升压反应。BQ-123被证明部分拮抗S6c的升压反应，表明雪貂中ET（A）和ET（B）受体之间可能存在相互作用。该物种中意外缺乏ET-1介导的降压反应，但存在ET-3和S6c血管舒张，这支持了ET（B）受体可能存在亚型的理论。这些研究表明，麻醉雪貂为评估内皮素的生理效能提供了一个合适的模型，并可能为进一步了解ET（B）受体的多样性提供一种工具。
