indolidan and Pheochromocytoma

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.

Topics: Adrenal Gland Neoplasms; Adrenal Glands; Animals; Body Weight; Cardiotonic Agents; Cardiovascular Diseases; Eating; Female; Imidazoles; Indoles; Male; Organ Size; Oxindoles; Pheochromocytoma; Phosphodiesterase Inhibitors; Pyridazines; Rats; Rats, Inbred F344

Both epinephrine (E) and norepinephrine (NE) cells in the rat adrenal medulla are able to proliferate in response to pharmacologic stimulation. However, previous biochemical studies have suggested that drug-induced or spontaneous pheochromocytomas in rats are almost invariably NE-producing. To resolve these apparently conflicting data, immunocytochemical techniques were utilized to establish functional profiles of adrenal medullary lesions classified as pheochromocytoma or nodular hyperplasia in rats treated chronically with a phosphodiesterase inhibitor which induced pheochromocytomas. Sixteen of 17 pheochromocytomas and all hyperplastic nodules stained positively for tyrosine hydroxylase and dopamine beta-hydroxylase, consistent with an ability to produce NE. No lesion of either type stained for phenylethanolamine N-methyltransferase, consistent with an inability to produce epinephrine. Lesions of both types showed variable staining for chromogranin proteins. The findings indicate that qualitative functional differences cannot be used to discriminate hyperplastic nodules from small pheochromocytomas in rats. Some lesions currently classified as hyperplastic nodules might in fact be small pheochromocytomas. Others might represent diffuse hyperplasia within pre-existing islands of NE-cells in a background of hyperplastic epinephrine-cells.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Animals; Cardiotonic Agents; Cell Division; Chromogranins; Dopamine beta-Hydroxylase; Histocytochemistry; Hyperplasia; Indoles; Nerve Tissue Proteins; Oxindoles; Phenylethanolamine N-Methyltransferase; Pheochromocytoma; Pyridazines; Rats; Reference Values; Staining and Labeling; Tyrosine 3-Monooxygenase