DELAYED UNCOUPLING CONTRIBUTES TO THE PROTECTIVE EFFECT OF HEPTANOL AGAINST ISCHAEMIA IN THE RAT ISOLATED HEART

Abstract

1. It is known that infusion of the gap junction uncoupler heptanol, before ischaemia or during reperfusion, limits myocardial infarct size. However, whether this cardiac effect is linked to the effect of heptanol on communication across gap junctions has not been elucidated. The aims of the present study were to examine the effect of heptanol on infarct size, arrhythmias and myocardial tissue resistance and to assess whether changes in electrical coupling correlate with cardiac protection. 2. Rat isolated, perfused hearts were subjected to a 24 min infusion of heptanol (0.05, 0.1, 0.5 or 1.0 mmol/L) followed by 20 min regional ischaemia and 60 min reperfusion, or by 70 min global no-flow ischaemia. The effective refractory period, action potential and conduction velocity were measured in papillary muscles from the right ventricle. Heptanol markedly decreased arrhythmia scores during ischaemia and reperfusion, as well as reducing infarct size to a degree similar to that induced by ischaemic preconditioning. In the prolonged ischaemia model, heptanol delayed the onset of uncoupling, increased time to plateau and decreased the maximal rate of uncoupling during ischaemia. Ischaemic preconditioning had similar effects on these parameters. In papillary muscle, heptanol reduced the conduction velocity of the action potential in a dose-dependent manner, but had no significant effect on resting potential, action potential amplitude, action potential duration, maximal upstroke of depolarization or effective refractory period. 3. These results demonstrate that treatment with the gap junction uncoupler heptanol confers cardioprotection against ischaemia and this effect is related to delayed electrical uncoupling during prolonged ischaemia.