Chang Y, Hoover D B, Hancock J C, Smith F M
Department of Pharmacology, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614-0577, USA.
J Pharmacol Exp Ther. 2000 Jul;294(1):147-54.
Selective tachykinin agonists were used to identify cardiac and coronary responses mediated by specific tachykinin receptor subtypes in isolated, perfused guinea pig hearts. Receptor desensitization with selective agonists and blockade with selective antagonists were used to determine the role of specific subtypes in generating responses to neurokinin A (NKA). Dose-dependent cardiac and coronary effects were evoked by bolus injections of ¿Sar(9), Met(O(2))(11)substance P (¿Sar(9),Met(O(2))(11)SP), GR64349, and ¿MePhe(7)neurokinin B (¿MePhe(7)NKB) (selective agonists for NK(1), NK(2), and NK(3) receptors, respectively). Each agonist caused bradycardia, but GR64349 was most effective (34 +/- 4% decrease in heart rate with 32 nmol, n = 8). Prominent increases in ventricular contractility and perfusion pressure also occurred with 32 nmol of GR64349 (25 +/- 6 and 33 +/- 4%, respectively). ¿Sar(9), Met(O(2))(11)SP was unique in having a high potency for decreasing ventricular contractility and perfusion pressure. Bolus injections of 25 nmol of NKA decreased rate (48 +/- 2%, n = 51), increased contractility (26 +/- 2%), and had biphasic effects on perfusion pressure (24 +/- 1% decrease followed by 9.2 +/- 1.4% increase). Desensitization with GR64349 or treatment with the NK(2) antagonist SR48968 reduced the bradycardic response to NKA by greater than 75% and eliminated the positive inotropic response. The remaining bradycardia occurred through NK(3) receptors. Desensitization with ¿Sar(9),Met(O(2))(11)SP or NK(1) blockade with FK888 eliminated the coronary relaxant action of NKA and enhanced the pressor response. It is concluded that three tachykinin receptor subtypes are present in the guinea pig heart and that each contributes to the overall response evoked by NKA.
选用选择性速激肽激动剂来确定在离体灌注豚鼠心脏中由特定速激肽受体亚型介导的心脏和冠状动脉反应。使用选择性激动剂进行受体脱敏以及使用选择性拮抗剂进行阻断，以确定特定亚型在产生对神经激肽A（NKA）反应中的作用。通过静脉注射[Sar(9),Met(O(2))(11)]P物质([Sar(9),Met(O(2))(11)]SP)、GR64349和[MePhe(7)]神经激肽B([MePhe(7)]NKB)（分别为NK(1)、NK(2)和NK(3)受体的选择性激动剂）引发剂量依赖性的心脏和冠状动脉效应。每种激动剂均引起心动过缓，但GR64349最为有效（32 nmol时心率降低34±4%，n = 8）。32 nmol的GR64349还使心室收缩力和灌注压显著增加（分别为25±6%和33±4%）。[Sar(9),Met(O(2))(11)]SP的独特之处在于其对降低心室收缩力和灌注压具有高效能。静脉注射25 nmol的NKA可使心率降低（48±2%，n = 51），增加收缩力（26±2%），并对灌注压产生双相作用（先降低24±1%，随后升高9.2±1.4%）。用GR64349进行脱敏或用NK(2)拮抗剂SR48968处理可使对NKA的心动过缓反应降低超过75%，并消除正性肌力反应。剩余的心动过缓通过NK(3)受体发生。用[Sar(9),Met(O(2))(11)]SP进行脱敏或用FK888阻断NK(1)可消除NKA的冠状动脉舒张作用并增强升压反应。得出结论，豚鼠心脏中存在三种速激肽受体亚型，且每种亚型均对NKA引发的总体反应有贡献。
