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Pseudo-noncompetitive antagonism of muscarinic receptor-mediated cyclic GMP formation and phosphoinositide hydrolysis by pirenzepine

EE el-Fakahany, W Surichamorn, CL Amrhein, S Stenstrom, CL Cioffi, E Richelson and M McKinney

Department of Pharmacology and Toxicology, University of Maryland School of Pharmacy, Baltimore.

Pirenzepine selectively antagonized muscarinic receptor-mediated cyclic GMP formation in a noncompetitive fashion in mouse neuroblastoma cells (clone N1E-115). These effects of pirenzepine were time- and concentration-dependent and they were also reversible. Interestingly, whereas atropine elicited competitive antagonism of the cyclic GMP response at low concentrations, it also behaved like a noncompetitive antagonist at higher concentrations and its effects were partially reversible. Using additional approaches to study the mechanisms underlying this anomalous antagonistic profile of pirenzepine, we investigated whether this deviation from competition could be due to the short time of exposure to muscarinic agonists (30 sec) used in cyclic GMP measurements. Our data indicated that the mode of pirenzepine-induced antagonism of ligand binding to muscarinic receptors was different when assessed using nonequilibrium (30 sec) or equilibrium (1 hr) incubations. Thus, pirenzepine appeared to be noncompetitive and competitive under these two conditions, respectively. Furthermore, although pirenzepine blocked receptor- mediated phosphoinositide hydrolysis competitively when the response was measured at 20 min, it was clearly noncompetitive using 5-min incubations. Therefore, the noncompetitive antagonism by pirenzepine detected in cyclic GMP measurements might be only apparent and might be attributed, at least in part, to a lack of an equilibrium state under the specific conditions of these assays.

Volume 247, Issue 3, pp. 934-940, 12/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics




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