Pharmacologic Characterization of Receptor Types Mediating Coronary Vasodilator Actions of Sensory Neuropeptides in the Guinea Pig

The receptor types mediating sensory neuropeptide-induced coronary vasodilatation were elucidated on isolated guinea pig hearts perfused with isotonic buffer containing 20 mM KCl. Substance P and the selective neurokinin-1 (NK1) receptor agonist [Sar9, Met(O2)11]-substance P produced dose-dependent reductions in perfusion pressure, but the selective NK2 receptor agonist [Nle10]-neurokinin A4-10 and the selective NK3 receptor agonist [MePhe7]-neurokinin B produced no change. The vasorelaxant effects of substance P and the NK1 receptor agonist were abolished by the selective NK1 receptor antagonist FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), whereas the selective NK2 receptor antagonist SR48968 ((S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl )-butyl] benzamide) and the selective NK3 receptor antagonist SR142801 ((S)-(N)-( 1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)4-p henylpiperidin-4-yl)-N-methylacetamide) produced partial inhibition on their responses. Calcitonin gene-related peptide (CGRP) produced dose-dependent vasodilatation on the guinea pig coronary blood vessels, which was significantly (p = 0.0067) inhibited by the selective CGRP1 receptor antagonist hCGRP8-37. The selective CGRP2 receptor agonist [Cys(acetomethoxy)2,7]CGRP had no effect on perfusion pressure. These results demonstrate that the sensory neuropeptides substance P and CGRP are effective vasodilators of the guinea pig coronary vascular bed. The receptor types mediating their vasorelaxant effects were identified to be the NK1 receptors and CGRP1 receptors, respectively.