Chronic rejection in the rat aortic allograft. V. Mechanism of the angiopeptin (BIM23014C) effect on the generation of allograft arteriosclerosis.
Synthetic cyclic octapeptide analogues of somatostatin, such as angiopeptin (BIM23014C; AP) inhibit myointimal proliferation in chronically rejecting rabbit and rat allografts and following angioplasty in rabbits. We have investigated the mechanism of angiopeptin inhibition of allograft arteriosclerosis. DA (RT1a) aortic allografts were transplanted to WF (RT1v) recipients, which either received 80 micrograms/kg/day of AP (Alzet mini-pumps, s.c., 0-180 days) or were left untreated. AP administration did not affect the intensity of adventitial inflammation, nor reduced the disappearance of smooth-muscle cell nuclei from the media (media necrosis); however, it reduced their appearance in the intima and intimal thickening. The effect disappeared, however, from the 3rd month onward. In vivo labeling with tritiated thymidine and autoradiograms demonstrated that AP reduced slightly the proliferation of the inflammatory cells in adventitia and of smooth-muscle cells in the media, and reduced strongly and significantly (P < 0.01) the proliferation of smooth-muscle cells in the intima. Analysis of the major chronic-rejection associated eicosanoids from the vascular wall showed that AP had no effect on the release of the pro-inflammatory thromboxane B2 from the allograft. As AP did not reduce the intensity of perivascular inflammation, reduced only slightly the proliferation of inflammatory cells, and did not affect the release of thromboxane B2 from the inflammatory macrophages, it is likely that the AP effect is not directed to the inflammatory cells. As previous in vitro studies have demonstrated that vascular smooth-muscle cells proliferate in response to several growth factors, and as somatostatin analogues are inhibitory to their action, our data suggest that the action of AP on allograft arteriosclerosis is due to a direct effect on smooth-muscle-cell proliferation.
Mennander
A
A
Transplantation Laboratory, University of Helsinki, Finland.
Räisänen
A
A
Paavonen
T
T
Häyry
P
P
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000637:transplantation*; D001161:Arteriosclerosis / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002908:Chronic Disease; D006084:Graft Rejection; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000031:analogs & derivatives*
D010456:Peptides, Cyclic; C060347:lanreotide; D013004:Somatostatin