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.
Takeo
Satoshi
S
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan. takeos@ps.toyaku.ac.jp
Tanonaka
Kouichi
K
D000818:Animals; D006321:Heart / Q000187:drug effects*; D007094:Imides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D054833:Isoindoles; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*
C414319:2-(4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)butyl)hexahydro-1H-isoindol-1,3(2H)-dione; D007094:Imides; D054833:Isoindoles; D010880:Piperidines; D026941:Sodium Channel Blockers