Coronary vascular lesions in dogs treated with phosphodiesterase III inhibitors.
A treatment-related coronary arteriopathy has been observed in the dog following the oral or intravenous administration of 4 potent phosphodiesterase type III inhibiting inodilators at high multiples of their ED50 for periods from 1 day to 6 months. A fifth compound of a similar pharmacological class exhibited limiting toxicity at low multiples of its ED50 and this compound failed to induce coronary arterial lesions. The earliest treatment-related findings observed were medial hemorrhage and necrosis with focal breaks in the internal elastic lamina. Later changes, observed from day 9 onwards, included intimal thickening consisting of smooth muscle proliferation with a mucoid ground substance, variable and inconsistent inflammatory changes involving one or more arterial tunics and adventitial hemorrhage, fibrosis and neovascularization. The changes were restricted to the coronary arteries including the extramural and intramural branches. The distribution of lesions varied from widespread, multifocal involvement of both coronary arterial systems to focal lesions with no obvious site of predilection. Induction of this lesion may involve changes in coronary flow and pressure as a result of an exaggerated pharmacological response to this class of compound. The susceptibility of other species (rat, cynomolgus monkey, or pig) to this effect has been investigated with no treatment-related arteriopathy being observed.
Isaacs
K R
KR
Department of Pathology, Smith Kline and French Research Ltd., Frythe, Welwyn, Herts, United Kingdom.
Joseph
E C
EC
Betton
G R
GR
D000628:Aminophylline / Q000633:toxicity; D000818:Animals; D003327:Coronary Disease / Q000139:chemically induced* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004077:Digoxin / Q000633:toxicity; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011719:Pyrazines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology
D006146:Guanidines; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011724:Pyridazines; D011725:Pyridines; C060368:SK&F 95654; D000628:Aminophylline; C056215:siguazodan; D004077:Digoxin; C048350:5-(4-acetamidophenyl)pyrazin-2(1H)-one