M(3) MUSCARINIC RECEPTORS MEDIATE AN INCREASE IN BOTH INOSITOL TRISPHOSPHATE PRODUCTION AND CYCLIC-AMP FORMATION IN DOG IRIS SPHINCTER SMOOTH-MUSCLE

Pharmacological studies on pirenzepine (PZ), 4-diphenylacetoxy-N-methy lpiperidine (4-DAMP) and AFDX-116 antagonism of carbachol (Cch)-induce d contraction, inositol trisphosphate (IP3) production and cAMP format ion revealed the involvement of M(3) receptors in these responses. The PA(2) values for PZ and 4-DAMP antagonism to CCh-induced contraction were 7.1 and 9.0, respectively, and AFDX-116 had no effect on these re sponses. Further, 4-DAMP was a much more potent inhibitor than PZ of C Ch-stimulation of IP3 production and cAMP formation. Both L-type calci um channel blockers, which inhibit Ca2+ influx, and BAPTA, an intracel lular calcium chelator, inhibited these biochemical and pharmacologica l responses due to CCh. It is concluded that both intracellular and ex tracellular Ca2+ mobilization are involved in muscarinic stimulation o f cAMP production, and that M(3) receptors are coupled to the activati on of both phospholipase C and adenylate cyclase in this tissue. The d ata presented here are consistent with previous work that stimulation of muscarinic receptors in dog iris sphincter with CCh (> 5 mu M) incr eases intracellular cAMP levels.