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Amiodarone (A) is a highly effective drug against a wide range of cardiac
arrhythmias. A contains 37% iodine by weight. The mechanism of action of
A seems to be an induction of a local hypo-like condition of the heart
(123,124). Amiodarone induces bradycardia, lengthening of the cardiac action
potential, and depression of myocardial oxygen consumption. These phenomena
are identical to those observed in hypo (59,60). The duration of cardiac
action potential is viewed as a postreceptor effect of nuclear T3
receptors in the heart. Receptor occupancy is decreased in hypo and in
A-treated patients resulting in an identical lengthening of the action
potential (125,126). A has no direct effect, independent of T3,
on cardiac b-adrenoceptors, but A may inhibit the T3-induced
increase in receptor density (127). At low T3 concentrations,
A decreases the efflux rate of internalised ß-adrenoreceptors to
the cell surface, presumably via an extranuclear action of the drug on
membranes, whereas at higher T3 concentrations, A decreases
synthesis of b-adrenoceptors via a genomic action of the drug on the T3-responsive
gene encoding for the b-adrenergic receptor.
In A-treated rats a shift from the myosin isoenzyme V1 to V3 is seen, although the decrease is less than in hypo animals. The changes are found in mRNA and protein levels, and the effect of A is abolished by the addition of T3 (128,129). The effect of A is also smaller when given to hypo animals, again suggesting that the effect is T3 dependent. The Ca++ATPase activities of myosin also decrease in hearts of A-treated rats, although to a lesser extent than in hearts of hypo rats; the effect of A is abolished by T3. The acute increase in cardiac performance (130) in response to intravenous T3 is blunted in pigs pre- treated with A. The data indicate that A impairs myocardial contractility through hypo-like changes in the gene expression of a- and b-MHC. This genomic effect seems to be dependent on T3. Finally, A-therapy increases the number of voltage-operated Ca++ channels in rat heart membranes (131); the effect is smaller but otherwise similar to that observed in hypo. |
