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 rest ing tone and an endothelium-dependent relaxation in vessels with eleva ted tone. Each response was studied separately by treating the arterie s with inhibitors of nitric oxide synthase to block the relaxant respo nse or with inhibitors of cyclooxygenase to inhibit the contractile re sponse. In the present study, experiments in isolated pulmonary arteri es were undertaken to characterize the muscarinic receptor subtypes me diating the two separate responses by utilizing subtype-selective anta gonists and determining pA(2) values of the antagonists through Schild analysis. Both the relaxant and the contractile responses were inhibi ted most potently by atropine and by the M(3)-selective antagonist 4-d iphenylacetoxy-N-methyl piperdine methiodide. The pA(2) values for inh ibition of the contractile and relaxant responses were 9.44 and 8.79 f or atropine and 8.92 and 9.29 for 4-diphenylacetoxy-N-methylpiperdine methiodide, respectively. The M(1)-selective antagonist pirenzepine an d the M(2)-selective antagonist (11 [(diethylamino)methyl]-1-piperidin yl]-acetyl}-5,11 ihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one) di splayed much lower;affinities for the muscarinic receptors mediating t hese 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 peridinyl]-acetyl}-5,11-dihyd ro-6H-pyrido[2,3-b][1 ,4]-benzodiazepine-6-one), respectively. The res ults suggest that a single, promiscuous muscarinic receptor subtype wi th an affinity profile consistent with the M(3) receptor mediates both the contractile and the relaxant responses to acetylcholine in rabbit intrapulmonary arteries.