Navaratnam S, Khatter J C
Department of Medicine, University of Manitoba, Winnipeg, Canada.
Arch Int Pharmacodyn Ther. 1989 Sep-Oct;301:151-64.
The present study was undertaken to determine the effect of diabetes on the manifestation of digitalis cardiotoxicity in whole animal model. Animals after 4, 8, 12 and 16 weeks of streptozotocin treatment (60 mg/kg i.v.) were anesthetized (45 mg/kg alpha-chloralose and 500 mg/kg urethane), chest opened and instrumented for the recording of EKG, carotid pressure, left ventricular pressure and dp/dt. Ouabain was infused at a fixed rate (0.4 mg/kg/min) via the femoral vein. Animals at all stages of diabetes had sinus bradycardia, but the basal mechanical function was found to be depressed only after 12 weeks of streptozotocin treatment. After 16 weeks of streptozotocin injection, 40% of the animals showed some spontaneous arrhythmic activity, which lasted only a few seconds, and prolonged QTc (QT interval corrected for heart rate). In response to ouabain infusion, diabetic animals showed less maximal inotropic effect (30-40% reduction from the weight-matched control rats) and required at least 3-fold more ouabain for the initiation of cardiac arrhythmias than the nondiabetic rats (24.031 +/- 1.52 mg/kg vs 8.05 +/- 1.3 mg/kg). The reduced sensitivity to ouabain could not be explained by the presence of bradycardia. Response to a toxic dose of ouabain was restored to the nondiabetic state on treatment with insulin. These observations suggest that the diseased diabetic myocardium shows diminished sensitivity to digitalis toxicity.
本研究旨在确定糖尿病对全动物模型中洋地黄心脏毒性表现的影响。用链脲佐菌素（60mg/kg静脉注射）处理4、8、12和16周后的动物被麻醉（45mg/kgα-氯醛糖和500mg/kg氨基甲酸乙酯），打开胸腔并安装仪器以记录心电图、颈动脉压力、左心室压力和dp/dt。哇巴因通过股静脉以固定速率（0.4mg/kg/min）输注。糖尿病各阶段的动物均出现窦性心动过缓，但仅在链脲佐菌素处理12周后发现基础机械功能受到抑制。链脲佐菌素注射16周后，40%的动物出现一些自发的心律失常活动，仅持续几秒，且QTc延长（校正心率后的QT间期）。在输注哇巴因时，糖尿病动物的最大正性肌力作用较小（比体重匹配的对照大鼠降低30 - 40%），并且引发心律失常所需的哇巴因比非糖尿病大鼠至少多3倍（24.031±1.52mg/kg对8.05±1.3mg/kg）。对哇巴因敏感性降低不能用存在心动过缓来解释。用胰岛素治疗后，对毒性剂量哇巴因的反应恢复到非糖尿病状态。这些观察结果表明，患病的糖尿病心肌对洋地黄毒性的敏感性降低。
