Cardiac Effects of ST‐6, a Novel Cyclohexane Dicarboximide Derivative

Na(+) channel blockade is thought to be involved in the cardioprotection against ischemia/reperfusion injury. We synthesized various cyclohexane dicarboximides and examined their cardioprotective actions. Some of these derivatives had local anesthetic action and were capable of enhancing post-hypoxic contractile recovery of the isolated perfused rat heart. Among them, 2-[4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-isoindol-1,3(2H)-dione hydrochloride (ST-6) was most effective in the enhancement of post-hypoxic contractile recovery of isolated perfused rat hearts subjected to 20-min hypoxia and 45-min reoxygenation. This enhanced recovery by 30 mg/min of ST-6 was associated with attenuation of Na(+), but not of Ca(2+), accumulation during ischemia and prevention of creatine kinase release from the heart during reperfusion. When hearts subjected to 30-min ischemia followed by 60-min reperfusion were pretreated with 30 muM ST-6, the post-ischemic contractile recovery was enhanced and ischemia-induced accumulation of Na(+), as well as reperfusion-induced accumulation of Na(+) and Ca(2+), was attenuated. Also the reperfusion-induced release of creatine kinase was reduced, while restoration of myocardial high-energy phosphates was enhanced during reperfusion. Na(+) channel blockade by ST-6, as assessed by the depression of the Vmax of the action potential, was similar to that produced by flecainide but more pronounced than with either lidocaine or disopyramide. ST-6, 1, or 2 mg/kg i.v. or 10 mg/kg i.p., abolished ventricular fibrillation induced by 4 min of ischemia and subsequent 4 min of reperfusion in rats. The prevention of ventricular fibrillation by the continuous injection of 0.2 mg/kg per min ST-6 from the first min after ischemia to the end of reperfusion was similar in degree to that produced by 0.1 mg/kg/min lidocaine or 0.5 mg/kg/min diltiazem. The former treatment elicited a transient decrease in the systemic blood pressure in anesthetized rats during ischemia, whereas treatment with the latter did not reduce systemic blood pressure. These findings suggest that ST-6 may have cardioprotective effects in ischemia/reperfusion injury.