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Res Commun Mol Pathol Pharmacol 1995 Feb;87(2):187-197
Department of Pharmaceutical Sciences, Campbell University, Buies Creek, NC 27506, USA.
Amiodarone and its major metabolite desethylamiodarone are potent antiarrhythmic drugs that have multiple pharmacological effects on the heart. We examined the effect of both drugs on the neonatal rat heart monolayer cell culture. The cells were stimulated with L-arterenol (10(-7) M) and choleratoxin (1.5 micrograms/ml). Both the spontaneous pulsation rate and intracellular cAMP level were followed. Amiodarone (10(-7) M) or desethylamiodarone (10(-7) M), incorporated into phosphatidylcholine vesicles, decreased the stimulated cell pulsation rate 3 min after addition of drugs, and the level of intracellular cAMP 30 min after addition as well. Propranolol (10(-7) M) had no further effect on the pulsation rate after 3 min. In the presence of amiodarone and propranolol the stimulation of L-arterenol was completely abolished and both the pulsation rate and cAMP level proved to be lower than the control values. The stimulation of choleratoxin on pulsation rate was also decreased by addition of amiodarone and the cAMP level was lowered after 30 min as well. Desethylamiodarone exhibited similar behavior to amiodarone although it proved to be less effective. It is unlikely that amiodarone and desethylamiodarone act on beta-adrenergic receptors in a competitive manner. Our data suggests that amiodarone and its metabolite could act in a nonspecific manner perturbing the hydrophobic interaction in the cell membrane and thereby decoupling the receptor or the nucleotide regulator protein and adenylate cyclase.
PMID: 7749656, UI: 95268734
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