Amiodarone oral subacute treatment prevents cardiac dysfunction of ischemia/reperfusion in rats: Mechanisms and influence of hypothyroidism

Abstract

The antiarrhythmic amiodarone is frequently used, but it induces a risk of hypothyroidism. Their effects on myocardial function after ischemia are unclear. The aim of this work was to evaluate the effects on cardiac recovery during ischemia and reperfusion (I/R) of a subacute oral treatment with amiodarone on rats, and the influence of hypothyroidism, as well as the underlying mechanisms. Hypothyroid rat model (HypoT) was obtained by oral intake of 0.02 % methimazole for 15 days. Amiodarone treatment (30 mg/kg/day) was administered in both HypoT and euthyroid (EuT) rats during a week. Isolated hearts were perfused inside a flow- calorimeter to measure contractile performance (P), total heat rate (Ht) and muscle economy (P/Ht). Hearts were exposed to 30 min I and 45 min R. Moreover, infarct size and western-blot were determined at the end of R. Amiodarone improved the postischemic recovery in EuT rat hearts but reduced it in HypoT rat hearts. By using several selective pharmacological tools, it was demonstrated that amiodarone cardioprotection in EuT rats was strongly reduced by blocking PI3K/AKT, PKC, iNOS and mitochondrial ATP-dependent K + channels (mK ). Moreover, the reduced postischemic recovery in HypoT hearts treated with amiodarone was reversed by perfusing a scavenger of oxygen reactive species. Results suggest that protective effects of amiodarone in EuT rat hearts involved a pathway with scavenging of hydroxyl radicals and activation of iNOS, PKC, PI3K/AKT and mK ATP ATP channels. However, ROS production was increased in hearts of HypoT rats treated with amiodarone, causing the reduced post-ischemic mechano-energetic recovery.