Analysis of muscarinic cholinoceptors mediating phosphoinositide hydrolysis in guinea pig cardiac muscle.

The muscarinic receptor mediating stimulation of PI hydrolysis in guinea pig atria and ventricles has been studied. The non-selective muscarinic agonist (+)-cis-dioxolane elicited this response, concentration-dependently, with a potency indicative of a low receptor reserve. The potency of a novel, M2-selective agonist, L-660,863 (-log EC50 = 6.3, atria; 6.0, ventricles) was observed to be lower than its apparent affinity (-log KA = 7.6) for M2 receptors, indicating an action probably mediated by a population distinct from that producing negative inotropy in the same tissue. The inhibition of the response to (+)-cis-dioxolane by several muscarinic antagonists (atropine, pirenzepine, AF-DX 116, methoctramine, HHSiD and pFHHSiD) generated an affinity profile for this receptor also dissimilar to that described for the receptor mediating the classical cardiac 'M2' response. Although no other muscarinic receptor mRNA has been detected in this tissue, these data suggest the presence of a second population of muscarinic sites, which may signify an M2 receptor diversity.