Cyclic AMP arrhythmias. Inhibition by choline esters.
Ventricular tachycardia (VT) was induced and maintained in open-chested pigs by subepicardial infusion (focal infusion 10 microliters/min) of norepinephrine (NE) (10(-5) M) in solution with CaCl2 (2.5 X 10(-3) M) and NaCl (0.9%). Choline esters and related compounds were then tested for their antiarrhythmic properties. The NE/Ca2+ VT was abolished within 60 sec by carbamylcholine (CCh) or methacholine (each 10(-6) M). Acetylcholine and butyrylcholine were less effective (each 10(-4) M). The fly mushroom poison muscarine had a strong antiarrhythmic effect (10(-6) M). Choline abolished the NE/Ca2+ VT at higher concentrations (10(-2) M). The antiarrhythmic effect of muscarine and CCh (10(-6) M) was blocked by atropine (10(-6) M) but not hexamethonium (up to 10(-4) M). The NE/Ca2+ VT was also abolished by beta-adrenoceptor blocking agents [pindolol (10(-6) M), propranolol (10(-4) M)] and calcium antagonists [isoptin, D-600 (10(-4) M each), MnCl2 (5 X 10(-4) M), NiCl2, CoCl2 (2.5 X 10(-3) M each)]. Tetrodotoxin (up to 10(-5) M) did not protect against NE/Ca2+ VT. Analysis of myocardial tissue obtained from the infusion sites showed that cAMP was increased when the NE/Ca2+ VT ensued and that choline esters in the absence of atropine prevent such accumulation of cAMP. It is concluded that activation of muscarinic receptors by choline esters inhibits ventricular arrhythmias induced by regional adrenergic overstimulation and accumulation of cAMP, possibly by decreasing the slow inward Ca2+ current.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000494:pharmacology; D009116:Muscarine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D013552:Swine
D007473:Ion Channels; D008688:Methacholine Compounds; D016210:Methacholine Chloride; C017100:butyrylcholine; D001285:Atropine; D009116:Muscarine; D002217:Carbachol; D000242:Cyclic AMP; D002794:Choline; D000109:Acetylcholine; D002118:Calcium; D009638:Norepinephrine; D004837:Epinephrine