Interactions with the cardiac cholinergic system: effects of disopyramide and its mono-N-dealkylated metabolite.
The cardiac vagolytic effects of disopyramide and its mono-N-dealkylated metabolite (MND), and their interactions with the cardiac cholinergic system, were assessed using in vivo and in vitro experiments. In chloralose anesthetized dogs, disopyramide phosphate (0.25 mg/kg/min) and MND at equimolar dose (0.173 mg/kg/min) reduced vagal bradycardia. As indicated by the ED80, MND exhibits a vagolytic activity 1.5-2 times less potent than disopyramide. Concomitantly, increases in heart rate and mean blood pressure were observed with disopyramide, whereas with MND only a rise in mean blood pressure occurred. In conscious dogs, where vagal tone is fully expressed, disopyramide and MND increased heart rate and, interestingly, prevented any atropine-induced additional tachycardia, though heart rate was relatively low. Binding studies on rat heart membranes yielded Ki values 2-2.5 times higher for MND than for disopyramide, and demonstrated that neither disopyramide nor MND binding modified the cardiac muscarinic receptor sites. Taken together, these results show that disopyramide exhibits a more potent cardiac vagolytic action than MND, very likely linked to a greater ability to bind to cardiac muscarinic receptors. They also show that disopyramide and MND are very potent in preventing atropine-induced "excess tachycardia", very likely by inhibiting the ionic pacemaker current(s) involved in its genesis.
Boucher
M
M
INSERM U.195, Faculty of Medicine, Clermont-Ferrand, France.
Chassaing
C
C
Herbet
A
A
Duchêne-Marullaz
P
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004206:Disopyramide / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D011950:Receptors, Cholinergic; D004206:Disopyramide