6-ketoprostaglandin-f1-alpha and Hyperplasia

The efficacy of OPC-29030, a newly developed inhibitor of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) production, was evaluated on intimal hyperplasia of experimental autologous vein grafts in a distal poor-runoff model and a hyperlipidemic model in rabbits. First, rabbits were divided into two groups, the distal poor-runoff group (PR group) and the hyperlipidemic group (HL group). After 4 weeks preparing the PR model and the HL model, the femoral vein was implanted into the ipsilateral femoral artery. Then they were subdivided into two groups, depending on the diet provided; diet group with 0.1% OPC-29030 (OPC-29030 group) and normal diet group (control group). At 4 weeks, the grafts were harvested, and intimal hyperplasia of the graft was measured with an ocular cytometer. Intimal cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation at 2 weeks after surgery. In addition, the effect of OPC-29030 on the proliferation or migration of rat aortic smooth muscle cells in culture was investigated. In the in vivo study in the PR group, the intimal hyperplasia and the plasma 12-HETE levels in the OPC-29030 group were significantly inhibited, compared with those of the control group. However, in the HL group, the intimal hyperplasia in both the OPC-29030 and control groups showed a remarkable degree of intimal hyperplasia. There was no significant difference between those two groups. Furthermore, there was no significant difference in the plasma 12-HETE levels in the HL group irrespective of the presence of OPC-29030. The BrdU labeling index at 2 weeks after grafting was significantly lower in the OPC-29030 group compared with that in the control group in the PR group. In the in vitro study, OPC-29030 did not inhibit smooth muscle cell proliferation; however, OPC-29030 inhibited the migration. These results demonstrate the efficacy of OPC-29030 in reducing the degree of intimal hyperplasia under PR conditions, but not under hyperlipidemic conditions. The mechanism of reducing the intimal hyperplasia may be that OPC-29030 inhibited 12-HETE production, which did not inhibit proliferation while inhibiting migration of the smooth muscle cell. These results suggested the possible involvement of 12-HETE with the intimal hyperplasia under PR conditions.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Cholesterol; Femoral Vein; Graft Survival; Hypercholesterolemia; Hyperplasia; Imidazoles; Male; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Quinolones; Rabbits; Rats; Sulfur Compounds; Thromboxane B2; Tunica Intima

The effect of purified eicosapentanoic acid on intimal fibrous hyperplasia in expanded polytetrafluoroethylene grafts was examined in 18 rabbits undergoing infrarenal aorta reconstruction. Six rabbits received commercial rabbit chow (control group), six a regular diet supplemented with 1% cholesterol (cholesterol group), and six the cholesterol diet with 91.1% pure eicosapentanoic acid 500 mg/day (eicosapentanoic acid group). Grafts were harvested 3 months after surgery for histologic examination. The platelet count and serum beta-thromboglobulin and platelet factor 4 concentrations were not significantly different between groups. Serum arachidonic acid level in the cholesterol group was significantly higher than in the control group, and serum eicosapentanoic acid levels in the eicosapentanoic acid group were significantly higher than in the remaining two groups. Intergroup differences in serum 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations were not significant. Intimal thickness at midgraft was 5.2 +/- 6.2 microns in the control group, 67.6 +/- 46.9 microns in the cholesterol group, and 19.2 +/- 18.4 microns in the eicosapntanoic acid group. intimal thickness in the cholesterol group was greater than in either the control or licosapentanoic acid group (p less than 0.01 and p less than 0.05, respectively). These data suggest that eicosapentanoic acid reduces intimal fibrous proliferation in expanded polytetrafluoroethylene grafting as a result of hypercholesterolemia and that this effect is independent of the platelet count, activated platelet factors, and the prostacyclin/thromboxane A2 ratio.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Abdominal; Arachidonic Acid; Arachidonic Acids; beta-Thromboglobulin; Blood Vessel Prosthesis; Cholesterol, Dietary; Eicosapentaenoic Acid; Elastic Tissue; Endothelium, Vascular; Hypercholesterolemia; Hyperplasia; Male; Platelet Count; Platelet Factor 4; Polytetrafluoroethylene; Rabbits; Radiography; Thromboxane B2; Wound Healing