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 positiveinotropic agents, isomazole or indolidan, in the diet for 104weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mgkg and 0.0,0.12, 0.40, or 1.3 mgkg, respectively. Only 17% of the malestreated with 48.0 mgkg isomazole survived the duration of thestudy. The male component of the indolidan study was terminatedat 22 months, with only 18% of the high-dose males surviving.Sixty-five percent of the males treated with 48.0 mgkg isomazoleand 70% of the males treated with 1.3 mgkg indolidan were foundto have severe periarteritis, often with thrombi located mainlyin the mesenteric arteries. Fifty-four percent of the male ratstreated with 48.0 mgkg isomazole and 55% of the male rats treatedwith 1.3 mgkg indolidan died from cardiovascular disease comparedto 1–2% among the control males. Animals in the low- andmiddle-dose groups of both studies had a lower incidence ofcardiovascular disease than did those in the high-dose group.Additional lesions associated with the long-term administrationof both drugs were markedly increased incidence of adrenal medullaryproliferative lesions (both hyperplasia and pheochromocytomas)and increased incidence of chronic progressive glomerulonephrosis.These lesions, like those in the cardiovascular system, occurredin a dose-dependent manner and were more frequent in males thanin females. Treatment-related effects in these studies werejudged to be related to the pharmacologic action of these compounds.