Vol. 294, Issue 1, 147-154, July 2000

Tachykinin Receptor Subtypes in the Isolated Guinea Pig Heart and Their Role in Mediating Responses to Neurokinin A¹

Yingzi Chang, Donald B. Hoover, John C. Hancock and Frank M. Smith²

Department of Pharmacology, College of Medicine, East Tennessee State University, Johnson City, Tennessee (Y.C., D.B.H., J.C.H.); and Department of Anatomy and Neurobiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (F.M.S.)

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 [Sar⁹,Met(O₂)¹¹]substance P ([Sar⁹,Met(O₂)¹¹]SP), GR64349, and [MePhe⁷]neurokinin B ([MePhe⁷]NKB) (selective agonists for NK₁, NK₂, and NK₃ 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). [Sar⁹,Met(O₂)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 NK₂ antagonist SR48968 reduced the bradycardic response to NKA by greater than 75% and eliminated the positive inotropic response. The remaining bradycardia occurred through NK₃ receptors. Desensitization with [Sar⁹,Met(O₂)¹¹]SP or NK₁ 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.