JTV-519, a novel cardioprotective agent, improves the contractile recovery after ischaemia-reperfusion in coronary perfused guinea-pig ventricular muscles.

Abstract

A newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective. However, the precise mechanism underlying the cardioprotective effect of this drug is unknown. Coronary-perfused guinea-pig ventricular muscles were subjected to 20-min no-flow ischaemia followed by 60-min reperfusion (I/R). I/R significantly decreased the contraction in untreated preparations (control group, 34+/-4% of baseline value, n=6). Brief administration of JT (1.0 microM) prior to ischaemia significantly improved the postischaemic contractile recovery (63+/-5% of baseline value, n=4), as compared to the control group. JT (1.0 microM) slightly prolonged action potential duration before ischaemia and induced conduction disturbance (2 : 1 block) after the initiation of ischaemia. The cardioprotective effect of JT was antagonized by chelerythrine (CH, 5.0 microM), an inhibitor of protein kinase C (PKC) or by 5-hydroxydecanoic acid (5-HD, 400 microM), an inhibitor of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. These results suggest that the protective effect of JT is due to the opening of mitochondrial K(ATP) channels, which, in turn, is linked to PKC activation.