Prevention of catecholamine-induced cardiac damage and death with a nucleoside transport inhibitor.

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.