Kane K A, Leprán I, McDonald F M, Parratt J R, Szekeres L
J Cardiovasc Pharmacol. 1980 Jul-Aug;2(4):411-23. doi: 10.1097/00005344-198007000-00008.
We determined the antidysrhythmic activity of acute or prolonged administration of Org 6001 on dysrhythmias following coronary artery ligation in conscious and anesthetized rats. Intravenous doses of 5 and 10 mg/kg of Org 6001 markedly protected against postligation dysrhythmias in anesthetized rats, whereas a single oral dose of 10 mg/kg given 1 hr prior to ligation did not. Prolonged oral administration of Org 6001, 10 mg/kg twice daily for 10 days, the last dose given 1 hr before ligation, reduced the incidence of ventricular fibrillation and increased survival in both conscious and anesthetized animals. This effective antidysrhythmic dose regimen resulted in drug concentrations of 335 +/- 68 ng/ml in plasma and 2,940 +/- 408 ng Org 6001/g in the whole heart. At 24 hr after the last dose no protection against the dysrhythmias remained, and drug levels in both plasma and heart tissue were low. A good correlation was observed between the levels of Org 6001 in the heart and the reduction in the rate of rise of phase zero of cardiac action potentials obtained from drug-pretreated animals. It is concluded that prolonged administration of Org 6001 is effective against postligation dysrhythmias and that this effect may be associated with the drug's Class I activity.
我们测定了急性或长期给予Org 6001对清醒和麻醉大鼠冠状动脉结扎后心律失常的抗心律失常活性。静脉注射5和10 mg/kg的Org 6001可显著保护麻醉大鼠免受结扎后心律失常的影响，而在结扎前1小时单次口服10 mg/kg则无此效果。长期口服Org 6001，每日两次，每次10 mg/kg，连续10天，最后一剂在结扎前1小时给予，可降低清醒和麻醉动物的室颤发生率并提高存活率。这种有效的抗心律失常剂量方案导致血浆中药物浓度为335±68 ng/ml，全心组织中Org 6001含量为2,940±408 ng/g。最后一剂给药24小时后，对心律失常的保护作用消失，血浆和心脏组织中的药物水平均较低。在心脏中Org 6001的水平与药物预处理动物心脏动作电位0期上升速率的降低之间观察到良好的相关性。结论是，长期给予Org 6001对结扎后心律失常有效，且这种作用可能与该药物的I类活性有关。
