Carbachol inhibits electrophysiological effects of cyclic AMP in ventricular myocytes.
Muscarinic agonists inhibit beta-adrenoceptor-mediated electrophysiological effects in mammalian cardiac ventricular tissues. However, the site or sites of interaction are not entirely clarified. To address this problem, the effect of carbachol on isoproterenol-, 3-isobutyl-1-methylxanthine-, and forskolin-induced action potential changes was examined in guinea pig ventricular myocytes. Following enzymatic dispersion, myocytes had a resting membrane potential of -81.3 +/- 3 mV in 5.4 mM K+ Tyrode solution, and stimulated action potentials were 348 +/- 17 ms in duration (n = 17). Elevated extracellular [K+] ([K+]o) depolarized the membrane 56.5 mV per 10-fold increase in [K+]o. The estimated intracellular K+ activity was 115.7 mM. Carbachol (10(-6) M) alone produced no electrophysiological changes but antagonized isoproterenol-, 3-isobutyl-1-methylxanthine-, and forskolin-induced action potential prolongation by 84 +/- 11, 88 +/- 17, and 83 +/- 14%, respectively. Transient depolarizations produced in isoproterenol (10(-8) M), 3-isobutyl-1-methylxanthine (10(-5) M), and forskolin (10(-7) M), but not those produced in ouabain (10(-6) M), were antagonized by carbachol (10(-6) M). These data show that enzymatically dispersed myocytes maintain pharmacological and electrophysiological properties similar to those of cells in tissues, carbachol antagonizes electrophysiological effects of isoproterenol, 3-isobutyl-1-methylxanthine, and forskolin, and carbachol inhibits cyclic AMP-mediated effects at a site or sites in the cyclic AMP cascade distal to the catalytic unit of adenylate cyclase.
D015056:1-Methyl-3-isobutylxanthine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002469:Cell Separation; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D013997:Time Factors
D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine