CHARACTERIZATION OF CORONARY ARTERIAL LESIONS IN THE DOG FOLLOWING ADMINISTRATION OF SK-AND-F-95654, A PHOSPHODIESTERASE-III INHIBITOR

Drugs that inhibit the low-K-g, cGMP-inhibitable form of phosphodieste rase III (PDE III) are associated with arterial lesions in the extramu ral coronary arteries of dogs following oral and intravenous administr ation at high doses. Acute coronary arterial lesions have been investi gated 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 e valuated at 1, 3, 10, and 34 days postdosing by light, scanning, and t ransmission electron microscopy. At 24 hr postdosing, the arterial les ion was characterized by segmental or circumferential necrosis of medi al smooth muscle cells and hemorrhage; adventitial hemorrhage was also noted, particularly in the right atrial artery. Ultrastructural evalu ation showed extensive medial necrosis, characterized by loss of smoot h muscle cells and their replacement by cellular debris with ingress o f erythrocytes, platelets, and inflammatory cells into the media. Asso ciated with medial changes, significant endothelial effects were obser ved consisting of widening of intercellular boundaries, loss of normal elongated cellular appearance, and the attachment of numerous leukocy tes and platelets. During the 10-34-day postdosing period, substantial repair of the arterial lesions occurred such that by day 34 all secti ons of extramural coronary artery were normal. The lesions induced in the dog are consistent with a hemodynamic effect induced by the pharma cological action of SK&F 95654.