M 3 Muscarinic Receptors Mediate an Increase in Both Inositol Trisphosphate Production and Cyclic AMP Formation in Dog Iris Sphincter Smooth Muscle

Abstract

ABSTRACT

Pharmacological studies on pirenzepine (PZ), 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) and AFDX-116 antagonism of carbachol (CCh)-induced contraction, inositol trisphosphate (IP₃) production and cAMP formation revealed the involvement of M₃ receptors in these responses. The PA₂ 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 responses. Further, 4-DAMP was a much more potent inhibitor than PZ of CCh-stimulation of IP₃ production and cAMP formation. Both L-type calcium channel blockers, which inhibit Ca²⁺ influx, and BAPTA, an intracellular calcium chelator, inhibited these biochemical and pharmacological responses due to CCh. It is concluded that both intracellular and extracellular Ca²⁺ mobilization are involved in muscarinic stimulation of cAMP production, and that M₃ receptors are coupled to the activation of both phospholipase C and adenylate cyclase in this tissue. The data presented here are consistent with previous work that stimulation of muscarinic receptors in dog iris sphincter with CCh (>5 μM) increases intracellular cAMP levels.