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