Pharmacological evidence for distinct muscarinic receptor subtypes coupled to the inhibition of adenylate cyclase and to the increased generation of inositol phosphates in the guinea pig myometrium.
In the guinea pig myometrium, muscarinic receptor activation leads to contraction and elicits two biochemical responses viz. an increased formation of inositol phosphates (via a guanine nucleotide regulatory protein, distinct from the stimulatory and inhibitory G proteins of the adenylate cyclase system and a decreased synthesis of cyclic AMP involving inhibitory G protein activation. We now describe two major differences in the effects of muscarinic agonists. First, the greater potency of carbachol in inhibiting cyclic AMP formation (EC50 = 8 nM) than in stimulating the accumulation of inositol phosphates and tension (EC50 = 15 and 2 microM, respectively). Second, carbachol, oxotremorine and pilocarpine were equally effective in eliciting cyclic AMP inhibition but the order of potency for inositol phosphate formation was carbachol greater than oxotremorine and pilocarpine was without effect. The partial agonists, pilocarpine and oxotremorine, inhibited carbachol-mediated inositol phosphate formation. Pirenzepine, selective for muscarinic M1 receptor subtype, displayed a low affinity for antagonizing cyclic AMP inhibition, inositol phosphate generation and tension due to carbachol (Ki = 286, 92 and 110 nM, respectively). AF-DX116 (11-[( 2-[(diethylamino)methyl]-1- piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine- 6-one), selective for cardiac M2 receptors blocked cyclic AMP inhibition with high affinity (Ki = 1.14 nM) while it antagonized inositol phosphate formation with low affinity (Ki = 346 nM). Both high (Ki = 1 nM) and low (Ki = 100 nM) affinities were displayed by AF-DX116 in antagonizing contractions due to carbachol (24 and 76% inhibition, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Leiber
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Endocrinologie et Régulations Cellulaires, Centre National de la Recherche Scientifique URA 1131, Université Paris-Sud, Orsav, France.
Marc
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Harbon
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D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D010862:Pilocarpine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000032:analysis / Q000187:drug effects*; D010738:Type C Phospholipases / Q000032:analysis; D014590:Uterine Contraction / Q000187:drug effects
D000067956:Adenylyl Cyclase Inhibitors; D007295:Inositol Phosphates; D010880:Piperidines; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; D000242:Cyclic AMP; D010738:Type C Phospholipases; C048593:otenzepad