PHARMACOLOGICAL CHARACTERIZATION OF MUSCARINIC RECEPTORS MEDIATING ACETYLCHOLINE-INDUCED CONTRACTION AND RELAXATION IN RABBIT INTRAPULMONARY ARTERIES

Rabbit pulmonary arteries exhibit a biphasic response to acetylcholine consisting of an endothelium-dependent contraction in tissues at resting tone and an endothelium-dependent relaxation in vessels with elevated tone. Each response was studied separately by treating the arteries with inhibitors of nitric oxide synthase to block the relaxant response or with inhibitors of cyclooxygenase to inhibit the contractile response. In the present study, experiments in isolated pulmonary arteries were undertaken to characterize the muscarinic receptor subtypes mediating the two separate responses by utilizing subtype-selective antagonists and determining pA(2) values of the antagonists through Schild analysis. Both the relaxant and the contractile responses were inhibited most potently by atropine and by the M(3)-selective antagonist 4-diphenylacetoxy-N-methyl piperdine methiodide. The pA(2) values for inhibition of the contractile and relaxant responses were 9.44 and 8.79 for atropine and 8.92 and 9.29 for 4-diphenylacetoxy-N-methylpiperdine methiodide, respectively. The M(1)-selective antagonist pirenzepine and the M(2)-selective antagonist (11 -{[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl}-5,11 -dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one) displayed much lower;affinities for the muscarinic receptors mediating these responses. The pA(2) values for inhibition of the contractile and relaxant responses were 6.77 and 6.74 for pirenzepine and 6.06 and 5.70 for (11-{[2-[(diethyl-amino)methyl]-1 -piperidinyl]-acetyl}-5,11-dihydro-6H-pyrido[2,3-b][1 ,4]-benzodiazepine-6-one), respectively. The results suggest that a single, promiscuous muscarinic receptor subtype with an affinity profile consistent with the M(3) receptor mediates both the contractile and the relaxant responses to acetylcholine in rabbit intrapulmonary arteries.