Cardiovascular and adrenal proliferative lesions in Fischer 344 rats induced by long-term treatment with type III phosphodiesterase inhibitors (positive inotropic agents), isomazole and indolidan.
Male and female Fischer 344 rats were treated with the positive inotropic agents, isomazole or indolidan, in the diet for 104 weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mg/kg and 0.0, 0.12, 0.40, or 1.3 mg/kg, respectively. Only 17% of the males treated with 48.0 mg/kg isomazole survived the duration of the study. The male component of the indolidan study was terminated at 22 months, with only 18% of the high-dose males surviving. Sixty-five percent of the males treated with 48.0 mg/kg isomazole and 70% of the males treated with 1.3 mg/kg indolidan were found to have severe periarteritis, often with thrombi located mainly in the mesenteric arteries. Fifty-four percent of the male rats treated with 48.0 mg/kg isomazole and 55% of the male rats treated with 1.3 mg/kg indolidan died from cardiovascular disease compared to 1-2% among the control males. Animals in the low- and middle-dose groups of both studies had a lower incidence of cardiovascular disease than did those in the high-dose group. Additional lesions associated with the long-term administration of both drugs were markedly increased incidence of adrenal medullary proliferative lesions (both hyperplasia and pheochromocytomas) and increased incidence of chronic progressive glomerulonephrosis. These lesions, like those in the cardiovascular system, occurred in a dose-dependent manner and were more frequent in males than in females. Treatment-related effects in these studies were judged to be related to the pharmacologic action of these compounds.
Sandusky
G E
GE
Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140.
Vodicnik
M J
MJ
Tamura
R N
RN
D000310:Adrenal Gland Neoplasms / Q000139:chemically induced*; D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000633:toxicity*; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D004435:Eating / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000633:toxicity*; D007211:Indoles / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D000078183:Oxindoles; D010673:Pheochromocytoma / Q000139:chemically induced; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011724:Pyridazines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D002316:Cardiotonic Agents; D007093:Imidazoles; D007211:Indoles; D000078183:Oxindoles; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C050325:indolidan; C029758:sulmazole