Contractile and calorimetrical effects of amiodarone in isolated hearts exposed to ischemia/reperfusion from euthyroid and hypothyroid rats under oral subacute treatment

Abstract

The antiarrhythmic amiodarone is frequently used but induces a risk of hypothyroidism. Moreover, its properties on coronary disease were not clarified. The aim of this work was to evaluate the effects of a subacute oral treatment with amiodarone to rats on cardiac recovery during ischemia and reperfusion (I/R), 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 antagonists it was demonstrated that amiodarone cardioprotection in EuT rat hearts was strongly reduced by blocking PI3K/AKT, PKC, iNOS and mKATP channels. Moreover, the reduced postischemic recovery in HypoT hearts treated with amiodarone was reversed by perfusing the scavenger of oxygen reactive species MPG. Results suggest that cardioprotective effects of amiodarone in EuT rat hearts involved a pathway with scavenging of hydroxyl radicals and activation of iNOS, PKC, PI3K/AKT and mitochondrial ATP-dependent K + channels (mKATP). However, in HypoT rat hearts amiodarone increased the ROS production causing the reduced post-ischemic recovery of hearts.