MESENTERIC ARTERIOPATHY IN THE RAT INDUCED BY PHOSPHODIESTERASE-III INHIBITORS - AN INVESTIGATION OF MORPHOLOGICAL, ULTRASTRUCTURAL, AND HEMODYNAMIC-CHANGES

Citation
Ec. Joseph et al., MESENTERIC ARTERIOPATHY IN THE RAT INDUCED BY PHOSPHODIESTERASE-III INHIBITORS - AN INVESTIGATION OF MORPHOLOGICAL, ULTRASTRUCTURAL, AND HEMODYNAMIC-CHANGES, Toxicologic pathology, 24(4), 1996, pp. 436-450
Citations number
40
Categorie Soggetti
Toxicology,Pathology
Journal title
ISSN journal
01926233
Volume
24
Issue
4
Year of publication
1996
Pages
436 - 450
Database
ISI
SICI code
0192-6233(1996)24:4<436:MAITRI>2.0.ZU;2-M
Abstract
A reproducible model of a phosphodiesterase III (PDE III) inhibitor-in duced arteriopathy has been developed in the rat after subcutaneous ad ministration of SK&F 95654. Administration of this potent PDE III inhi bitor induced an arteriopathy of mesenteric arteries within 24 hr that was dose-related in intensity and incidence over the range 0.174, 0.3 48, 0.523, and 0.697 mmol/kg. The arteriopathy was restricted to muscu lar arteries of external diameter of 100-800 mu m and was shown micros copically to be focal or segmental medial necrosis and hemorrhage. A t ime-course experiment, conducted from 3 to 24 hr postdosing, showed th at the first changes observed 6 hr postdosing were on the endothelium followed by focal hemorrhages into the media at 12 hr postdosing, caus ing compression, degeneration, and necrosis of myocytes. From 16 hr po stdosing, there was focal endothelial cell necrosis and loss of conflu ence. Leukocytes and activated platelets were found adhering to expose d basement lamina and seen to pass through endothelial gaps into the s ubintima. By 24 hr postdosing, medial necrosis was extensive with larg e areas of media replaced by erythrocytes, cell debris, and a few leuk ocytes 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 co mpounds were identical to that produced by SK&F 95654 with the inciden ce 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 inhib itors at regular intervals over the 24-hr period postadministration by a plesthymographic method. The severity of the arterial lesions corre lated with the magnitude of hypotension induced by these agents. It is postulated that the arterial damage is a consequence of profound vaso dilation resulting in abnormal endothelial permeability and increased wall tension, resulting in progressive medial necrosis and hemorrhage.