VASCULAR MUSCARINIC RECEPTORS - PHARMACOLOGICAL CHARACTERIZATION IN THE BOVINE CORONARY-ARTERY

Abstract

The goal of this study was to make functional comparisons between muscarinic receptors mediating endothelial-dependent relaxation responses in the rabbit ear artery and receptors mediating endothelial-independent contractile responses. Ring segments of the bovine coronary artery with the endothelium removed proved to be an excellent model for studying the properties of muscarinic receptors mediating vascular smooth muscle contraction. Although endothelial-dependent relaxation responses could be seen with the calcium ionophore A-23187, no relaxation to cholinergic agonists were seen in the bovine coronary artery, whether or not the endothelium was present or in the presence or absence of smooth muscle tone. In ring segments of the bovine coronary artery or the rabbit ear artery, the cholinergic agonists, acetylcholine, methacholine and carbachol, proved to be approximately equipotent in evoking contraction or relaxation, respectively. In contrast, the putative M1 selective agonist McN-A-343 did not produce any effect in either tissue; nor did McN-A-343 have any effect on a perfused rabbit ear artery segment. Measurement of antagonist affinities indicated that the bovine coronary artery muscarinic receptors show low affinity for both pirenzepine (pKB = 6.9) and AF-DX 116 (11-2-[[2-[diethylaminomethyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one) (pKB = 6.3). Pirenzepine affinity was also low in the perfused rabbit ear artery preparation. Values for pirenzepine and AF-DX 116 affinities are quite similar to those reported previously for endothelial-dependent relaxation in the rabbit ear artery, suggesting the conclusion that vascular muscarinic receptors mediating endothelial-dependent relaxation and those mediating contraction have similar properties and can be classified as M2 receptors based on low affinity for pirenzepine. Furthermore, their low affinity for AF-DX 116 suggests that vascular muscarinic receptors can be distinguished from those in cardiac tissue. Further studies will be necessary using additional muscarinic antagonists to determine whether vascular muscarinic receptors conform to the recently described M3 subclass.