Joseph X, Whitehurst V E, Bloom S, Balazs T
Fundam Appl Toxicol. 1981 Nov-Dec;1(6):443-7. doi: 10.1016/s0272-0590(81)80025-5.
To examine the cardiotoxic interaction between beta-adrenergic bronchodilators and theophylline, we tested the effects of isoproterenol or bitolterol alone and in combinations with aminophylline in experimental animals, both electrocardiographically and histologically. The sc LD50 values for isoproterenol in 4- to 5-month-old, 500-600 g (heavy) and 1.5- to 2-month-old, 150-200 g (small) male Sprague-Dawley rats were 0.6 mg/kg and 1300 mg/kg, respectively, and values for bitolterol were 4 mg/kg and greater than 1800 mg/kg, respectively. Results of the electrocardiographic studies in heavy rats, using the calculated LD20 dosage of isoproterenol with or without pretreatment of aminophylline, demonstrated that both mortality and the arrhythmia-inducing effect of isoproterenol were significantly potentiated by aminophylline but only mortality was increased in small rats. Aminophylline also potentiated the electrocardiographic effects of 1/40 of the LD50 dosage of isoproterenol in heavy rats but did not enhance the effects of bitolterol at this dose level. Potentiation of the arrhythmogenic effect of isoproterenol was also observed in rabbits. The severity of the myocardial lesions produced by isoproterenol or bitolterol in heavy rats was significantly enhanced by aminophylline. The heavy rat appears to be a sensitive model for studying the interaction of these classes of drugs.
为研究β-肾上腺素能支气管扩张剂与茶碱之间的心脏毒性相互作用，我们在实验动物中通过心电图和组织学方法测试了异丙肾上腺素或比托特罗单独使用以及与氨茶碱联合使用的效果。4至5月龄、体重500 - 600克（较重）和1.5至2月龄、体重150 - 200克（较小）的雄性Sprague-Dawley大鼠中，异丙肾上腺素的皮下半数致死量（LD50）值分别为0.6毫克/千克和1300毫克/千克，比托特罗的值分别为4毫克/千克和大于1800毫克/千克。在较重的大鼠中进行的心电图研究结果显示，使用计算得出的异丙肾上腺素LD20剂量，无论有无氨茶碱预处理，氨茶碱均显著增强了异丙肾上腺素的死亡率和致心律失常作用，但在较小的大鼠中仅增加了死亡率。氨茶碱还增强了较重大鼠中1/40 LD50剂量的异丙肾上腺素的心电图效应，但在该剂量水平下未增强比托特罗的效应。在兔中也观察到异丙肾上腺素致心律失常作用的增强。氨茶碱显著加重了较重大鼠中异丙肾上腺素或比托特罗所致的心肌损伤程度。较重的大鼠似乎是研究这类药物相互作用的敏感模型。
