Characterization of coronary arterial lesions in the dog following administration of SK&F 95654, a phosphodiesterase III inhibitor

Drugs that inhibit the low-K-g, cGMP-inhibitable form of phosphodiesterase III (PDE III) are associated with arterial lesions in the extramural coronary arteries of dogs following oral and intravenous administration at high doses. Acute coronary arterial lesions have been investigated following administration to the dog of SK&F 95654, a potent PDE LII inhibitor, and the progression of the lesion defined. Groups of 3 male beagle dogs received a single 2-hr infusion of SK&F 95654 at 8 mg/kg/hr and the characteristics of the coronary arterial lesions were evaluated at 1, 3, 10, and 34 days postdosing by light, scanning, and transmission electron microscopy. At 24 hr postdosing, the arterial lesion was characterized by segmental or circumferential necrosis of medial smooth muscle cells and hemorrhage; adventitial hemorrhage was also noted, particularly in the right atrial artery. Ultrastructural evaluation showed extensive medial necrosis, characterized by loss of smooth muscle cells and their replacement by cellular debris with ingress of erythrocytes, platelets, and inflammatory cells into the media. Associated with medial changes, significant endothelial effects were observed consisting of widening of intercellular boundaries, loss of normal elongated cellular appearance, and the attachment of numerous leukocytes and platelets. During the 10-34-day postdosing period, substantial repair of the arterial lesions occurred such that by day 34 all sections of extramural coronary artery were normal. The lesions induced in the dog are consistent with a hemodynamic effect induced by the pharmacological action of SK&F 95654.