© 1993 Oxford University Press
research-article |
Coronary Artery Toxicity in Beagle Dogs Given Indolidan, a Type III Phosphodiesterase Inhibitor
Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company Greenfield, Indiana 46140
Received October 13, 1992; accepted April 23, 1993
The hemodynamic changes and cardiovascular lesions produced by a single iv dose of 2.0 mg/kg indolidan were evaluated in four beagle (two male, two female) dogs. Four additional dogs (two male, two female) served as vehicle controls. This was followed by a multidose study in which the same dose of indolidan or vehicle was given iv to dogs (4/group) on 4 consecutive days. Both studies were followed for 4 days postdose before termination. Clinical signs, mean arterial blood pressure, and heart rate were evaluated. Seven sections of the heart, approximately 25 sections of the coronary arteries, and 3 sections of the carotid, subclavian, spermatic or ovarian, renal, and femoral arteries were examined. Mean blood pressure was decreased 20 to 25% over a 24-hr period and heart rates were increased 40 to 50% after treatment and remained elevated for at least a 24-hr period in both single and multidose treated groups. The earliest lesions occurred in three of four treated dogs after a single intravenous dose of 2.0 mg/kg. The main lesion was sporadic in distribution and seen in the outer one-half of the smooth muscle media of the coronary arteries. Smooth muscle degeneration and necrosis were present, with little secondary inflammation. No lesions were observed in the peripheral arteries or the myocardium. The coronary arterial lesions observed after the multidose study were more extensive and severe. The lesions were seen in large extramural and large intramural coronary arteries. These were characterized by marked smooth muscle necrosis involving most of the media, destruction of the internal elastic membrane, and marked adventitial fibroplasia. The inflammatory infiltrate varied from mild to moderate and was usually seen in the adventitia. No lesions were observed in the peripheral arteries or the myocardium in the multidose study.