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 μM 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.