Amiodarone is a potent calmodulin antagonist.

The possible interaction between amiodarone, a potent antiarrhythmic and antianginal agent, and calmodulin (CaM) was investigated by three avenues of approach: (a) Effect of amiodarone on cardiac and vascular Ca2+/calmodulin-activated cyclic nucleotide phosphodiesterase (CaM-PDE); (b) Effect on the CaM-activated (Ca2+ + Mg2+)-ATPase from human erythrocytes; (c) Direct interaction between amiodarone and calmodulin measured by the effect of the drug on the fluorescence of 9-anthroylcholine (9AC) bound to calmodulin. Results show that amiodarone did not interact with basal activities of CaM-PDE and other isolated CaM-insensitive PDE forms as well as with (Ca2+ + Mg2+)-ATPase. Amiodarone inhibited calmodulin-activation of aortic CaM-PDE (Ki = 650 nM, substrate cGMP) and calmodulin-activation of erythrocyte ghosts (Ca2+ + Mg2+)-ATPase (IC50 = 4.5 microM) in an apparently competitive manner. Amiodarone decreased the fluorescence of the hydrophobic probe 9AC bound to calmodulin (IC50 = 5 microM). It is concluded that amiodarone is a potent calmodulin antagonist.

Protective effects of amiodarone pretreatment on mitochondrial function and high energy phosphates in ischaemic rat heart.

The effects of the antianginal and antiarrhythmic drug amiodarone on mitochondrial function and high-energy phosphate content were assessed during normothermic ischaemic cardiac arrest and reperfusion in Langendorff-perfused rat heart. Total ischaemia for 30 min at 37 degrees C produced highly significant changes in mitochondrial oxidative phosphorylation and high-energy phosphate content. Pretreatment of the rats with one single dose of amiodarone (20 mg/kg i.v., 30 min before killing) markedly attenuated the deleterious effect of ischaemia on mitochondrial function and slightly reduced ATP depletion. In normally perfused hearts, amiodarone pretreatment did not modify any parameter of mitochondrial respiratory function nor did it influence high-energy phosphate or glycogen content. After reperfusion for 15 min, amiodarone-treated hearts showed improved recovery of mitochondrial oxidative phosphorylation and tissue high-energy phosphate content as compared to control hearts. Pretreatment of hearts with amiodarone did not reduce ischaemia-induced leakage of total adenylic nucleotides but highly significantly reduced lactate dehydrogenase release during reperfusion. These results indicate that amiodarone could exert substantial protection on the infarcting myocardium.

Effect of amiodarone on myosin isoenzymic distribution in rat ventricular myocardium.

Rats were given amiodarone (50 mg X kg-1 X day-1, orally) for 4 weeks and the distribution of ventricular isomyosins, a sensitive index of the effects of thyroid hormones on cardiac tissue, was analyzed. Amiodarone treatment induced a marked increase in both T4 and rT3 and tended to decrease T3 serum levels. At the pharmacologically active dosage we used, the drug induced a moderate redistribution of ventricular isomyosins in favour of V, at the expense of V1. Our results do not support the hypothesis that the major mechanism of action of amiodarone is mediated through hypothyroid-like effects.