The combined use of prostaglandin I2 analogue (OP-2507) and thromboxane A2 synthetase inhibitor (OKY-046) strongly inhibits atherosclerosis of aortic allografts in rats.
BACKGROUND
Atherosclerosis is the main lesion in allografts undergoing chronic rejection. We investigated the effect of OP-2507 (prostaglandin I2 analogue) and OKY-046 (thromboxane A2 synthetase inhibitor) on graft atherosclerosis morphologically and the production of eicosanoids in grafts in a rat aortic allograft model.


METHODS
Abdominal aortic allografts of Lewis (RT-1(l)) rats were transplanted orthotopically into fully major histocompatibility complex mismatched Wistar King A/Qdj (RT-1(u)) rats that were subcutaneously administered OP-2507 (0.1 mg/kg/d) or OKY-046 (125 mg/kg/d), or both, with an osmotic pump. Four, 8, or 12 weeks later, the grafts were harvested and examined histologically, and the concentration of eicosanoids in the grafts were analyzed.


RESULTS
Lewis aortic allografts in Wistar King A recipients with no treatment displayed atherosclerosis, which involved gradual intimal thickening and medial thinning with continuous inflammation in adventitia. Neither OP-2507 nor OKY-046 treatment affected the intensity of adventitial inflammation. Although inhibition of medial thinning or a decrease in medial nuclear density was not observed, OKY-046 administration alone significantly inhibited an increase in intimal thickness. OP-2507 administration alone significantly inhibited a decrease in medial nuclear density and intimal thickening. Combined treatment with OP-2507 and OKY-046 further decreased the alteration of media and intima. The ratio of thromboxane B2 and 6-keto-prostaglandin F(1alpha) in the grafts was significantly reduced by OKY-046 but not by OP-2507 alone.


CONCLUSIONS
We have demonstrated that atherosclerosis in aortic allografts is inhibited by the continuous administration of either OP-2507 or OKY-046, and a combination of both agents strongly increases this inhibitory effect. Amelioration of balance in eicosanoid production in the grafts by the use of thromboxane A2 synthetase inhibitor and the simultaneous usage of stable prostaglandin I2 analogue may be a strategy for preventing atherosclerosis that results from chronic rejection.
Hirano
T
T
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakafusa
Y
Y
Kawano
R
R
Motoyama
K
K
Arima
T
T
Sugitani
A
A
Tanaka
M
M
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control; D002467:Cell Nucleus / Q000473:pathology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous
D004791:Enzyme Inhibitors; D008689:Methacrylates; D013481:Superoxides; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C049453:OP 2507; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; C034364:ozagrel