WIN-62582

A reproducible model of a phosphodiesterase III (PDE III) inhibitor-induced arteriopathy has been developed in the rat after subcutaneous administration of SK&F 95654. Administration of this potent PDE III inhibitor induced an arteriopathy of mesenteric arteries within 24 hr that was dose-related in intensity and incidence over the range 0.174, 0.348, 0.523, and 0.697 mmol/kg. The arteriopathy was restricted to muscular arteries of external diameter of 100-800 μm and was shown microscopically to be focal or segmental medial necrosis and hemorrhage. A time-course experiment, conducted from 3 to 24 hr postdosing, showed that the first changes observed 6 hr postdosing were on the endothelium followed by focal hemorrhages into the media at 12 hr postdosing, causing compression, degeneration, and necrosis of myocytes. From 16 hr postdosing, there was focal endothelial cell necrosis and loss of confluence. Leukocytes and activated platelets were found adhering to exposed basement lamina and seen to pass through endothelial gaps into the subintima. By 24 hr postdosing, medial necrosis was extensive with large areas of media replaced by erythrocytes, cell debris, and a few leukocytes and platelets. The effect of 3 structurally dissimilar PDE III inhibitors administered subcutaneously at a dose of 0.697 mmol/kg was compared with that of SK&F 95654. The arteriopathy induced by these compounds were identical to that produced by SK&F 95654 with the incidence and severity of lesions ranked in the following order: SK&F 95654 > WIN 62582 > SK&F 94836, with no macroscopic lesions observed for SK&F 94120. Systolic blood pressure was measured for these 4 PDE III inhibitors at regular intervals over the 24-hr period postadministration by a plesthymographic method. The severity of the arterial lesions correlated with the magnitude of hypotension induced by these agents. It is postulated that the arterial damage is a consequence of profound vasodilation resulting in abnormal endothelial permeability and increased wall tension, resulting in progressive medial necrosis and hemorrhage.