Van Belle H, Verheyen W, Ver Donck K, Janssen P A, Robertson J I
Janssen Research Foundation, Beerse, Belgium.
J Cardiovasc Pharmacol. 1992 Aug;20(2):173-8. doi: 10.1097/00005344-199208000-00001.
The effect of a potent and specific nucleoside transport inhibitor, R 75,231, on catecholamine-induced cardiac toxicity has been studied in rabbits. Epinephrine (1 mg/kg) or norepinephrine (2.5 mg/kg) subcutaneously were lethal in 25 (42%) of 60 control animals, while survivors showed major myocardial damage, as judged from high plasma lactate dehydrogenase (LDH) and its myocardial isoenzyme (LDH1) after 24 h. When a low dose of R 75,231 (0.1 mg/kg) was given intravenously either 1 h before or 1 h after the catecholamine insult, only 1 of 60 animals died. The plasma total LDH and the LDH1 myocardial isoenzyme were low in these animals compared with untreated survivors. Studies ex vivo on isolated perfused hearts confirmed that with treatment using R 75,231, there was both left ventricular nucleoside retention and functional preservation after in vivo exposure of the animals to epinephrine. R 75,231 did not affect the peripheral venous hyperglycemic response to epinephrine. Nucleoside transport inhibition offers a new approach to the prevention and treatment of several cardiac disorders characterized by a pathogenic effect of catecholamines.
强效特异性核苷转运抑制剂R 75,231对儿茶酚胺诱导的兔心脏毒性的作用已得到研究。肾上腺素（1 mg/kg）或去甲肾上腺素（2.5 mg/kg）皮下注射对60只对照动物中的25只（42%）具有致死性，而存活者显示出严重的心肌损伤，这可通过24小时后血浆高乳酸脱氢酶（LDH）及其心肌同工酶（LDH1）来判断。当在儿茶酚胺损伤前1小时或损伤后1小时静脉注射低剂量的R 75,231（0.1 mg/kg）时，60只动物中仅1只死亡。与未治疗的存活者相比，这些动物的血浆总LDH和LDH1心肌同工酶水平较低。对离体灌注心脏的体外研究证实，在用R 75,231治疗后，动物在体内暴露于肾上腺素后左心室核苷保留且功能得以保存。R 75,231不影响外周静脉对肾上腺素的高血糖反应。核苷转运抑制为预防和治疗几种以儿茶酚胺致病作用为特征的心脏疾病提供了一种新方法。
