This project proposes to define the fundamental mechanisms of action of amiodarone with a particular reference to the possibility that it might exert its electrophysiologic effects by selectively interfering with T3 action in cardiac muscle. The precise understanding of the drug's action is of practical & theoretical importance. Its pharmacologic properties are unique & its potency in various arrhythmias is unusual. The drug is most effective against almost all arrhythmias when given chronically. When administered intravenously, the drug has minimal & varied effects. The latency of onset of the drug's action has been attributed in two factors: 1) Gradual formation of active metabolites; 2) The hypothyroid-like pharmacologic action of the drug. Amiodarone & desethylamiodarone are iodine-containing compounds & exhibit close structural resemblance to thyroid hormones. Both compounds alter thyroid hormone metabolism, resulting in a T3 deficient state. The electrophysiologic effects of long-term amiodarone treatment resemble those of hypothyroidism. If amiodarone's actions are due to a drug-induced hypothyroid state, it probably is a tissue selective phenomenon, since generalized hypothyroidism is a rate complication of amiodarone therapy attributable to iodine rather than to drug itself. Therefore, the claim that amiodarone & its principal metabolite desethylamiodarone exert their electropharmacologic actions on the heart since the drug-induced modest decrease in serum T3 by itself does not account for the observed hypothyroid-like effect on cardiac electrophysiology.
The specific aims of project are: 1) To define the mechanism of action of amiodarone & desethylamiodarone. 2) To examine the similarities & differences between amiodarone treatment & altered thyroid states. This work will be further extended to investigate the effects of the drugs & altered thyroid status under ischemia & reperfusion. My ultimate goals would be to acquire technical expertise in voltage-clamping & patch clamping which would allow me to determine the ionic translocations that underlie the electrophysiologic changes in hypothyroidism & in amiodarone treated cardiac muscle These data will be of importance in gaining further insight into the electrophysiologic & antiarrhythmic effects of amiodarone as compared to those of hypothyroidism.
| Weiss, J N; Venkatesh, N (1993) Metabolic regulation of cardiac ATP-sensitive K+ channels. Cardiovasc Drugs Ther 7 Suppl 3:499-505 |
| Venkatesh, N; Stuart, J S; Lamp, S T et al. (1992) Activation of ATP-sensitive K+ channels by cromakalim. Effects on cellular K+ loss and cardiac function in ischemic and reperfused mammalian ventricle. Circ Res 71:1324-33 |
| Weiss, J N; Venkatesh, N; Lamp, S T (1992) ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J Physiol 447:649-73 |
| Venkatesh, N; Lamp, S T; Weiss, J N (1991) Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle. Circ Res 69:623-37 |
