Tachykinin receptor subtypes in the isolated guinea pig heart and their role in mediating responses to neurokinin a

Selective tachykinin agonists were used to identify cardiac and coronary re sponses mediated by specific tachykinin receptor subtypes in isolated, perf used guinea pig hearts. Receptor desensitization with selective agonists an d blockade with selective antagonists were used to determine the role of sp ecific subtypes in generating responses to neurokinin A (NKA). Dose-depende nt 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 NK1, NK2, and NK3 rece ptors, respectively). Each agonist caused bradycardia, but GR64349 was most effective (34 +/- 4% decrease in heart rate with 32 nmol, n = 8). Prominen t increases in ventricular contractility and perfusion pressure also occurr ed 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 ventricu lar contractility and perfusion pressure. Bolus injections of 25 nmol of NK A 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 NK2 antagonist SR48968 reduced the bradycardic response to NKA by great er than 75% and eliminated the positive inotropic response. The remaining b radycardia occurred through NK3 receptors. Desensitization with [Sar(9),Met (O-2)(11)]SP or NK1 blockade with FK888 eliminated the coronary relaxant ac tion of NKA and enhanced the pressor response. It is concluded that three t achykinin receptor subtypes are present in the guinea pig heart and that ea ch contributes to the overall response evoked by NKA.