Abstract
Summary
Non-arteriosclerotic (virgin) and arteriosclerotic (breeder), male Sprague-Dawley rats were treated with high (40 mg), moderate (10 mg) and low (5 mg) doses of the potent xanthine oxidase inhibiting agent, allopurinol. After 10 days of treatment, the animals began to die suddenly due to myocardial infarction, hepatic necrosis and nephrotoxic damage. Serum enzyme levels, e.g., CPK, SGOT and LDH, were abnormally elevated in both the myocardial infarct prone breeder rats and the otherwise healthy, virgin rats commensurate with a high incidence of heart damage in both the virgin and breeder rats. Although the high dose of allopurinol caused fatty infiltration of the liver, the experimental animals were hypolipidemic. The severity of islet beta cell degranulation paralleled the degree of hyperglycemia in all animals given allopurinol. Elevated BUN levels, high circulating urate levels, hydronephrosis, and urate stones were commensurate with the dose of allopurinol administered. Increased adrenal weight, hyperplasia, lipid depletion, and abnormally high circulating Cmpd. B levels, along with marked thymus gland involution, attested to the severe noxious effect of overdose with allopurinol. It is suggested that the unusual appearance of myocardial damage in the nonarteriosclerotic virgin and myocardial infarct-prone arteriosclerotic breeder rats is primarily related to the cardiotoxic and nephrotoxic effects of large doses of allopurinol and secondarily to its hepatotoxic effects.
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