Inhibition of 12(S)-Hydroxyeicosatetraenoic Acid (12-HETE) Production Suppressed the Intimal Hyperplasia Caused by Poor-Runoff Conditions in the Rabbit Autologous Vein Grafts

• Published in: Journal of cardiovascular pharmacology Vol. 36; no. 5; pp. 555 - 563
• Main Authors: Kawasaki, Katsumi, Komori, Kimihiro, Okazaki, Jin, Ozeki, Yasushi, Sugimachi, Keizo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lippincott Williams & Wilkins, Inc 01-11-2000; Hagerstown, MD Lippincott
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - biosynthesis; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - blood; 6-Ketoprostaglandin F1 alpha - blood; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Cells, Cultured; Cholesterol - blood; Femoral Vein - drug effects; Femoral Vein - metabolism; Femoral Vein - transplantation; Graft Survival; Hypercholesterolemia - metabolism; Hyperplasia - metabolism; Imidazoles; Male; Medical sciences; Miscellaneous; Muscle, Smooth, Vascular - drug effects; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - pharmacology; Quinolones; Rabbits; Rats; Sulfur Compounds; Thromboxane B2 - blood; Tunica Intima - drug effects; Tunica Intima - metabolism; Pathogenesis; Hyperplasia; Homograft; Rabbit; Cardiovascular disease; Lipids; Venous disease; Vascular disease; Prevention; Eicosanoid; Intima; Complication; Hyperlipemia; Dyslipemia; Vein; Metabolic diseases; Autologous system; Lagomorpha; In vitro; Thrombosis; In vivo; Vertebrata; Mammalia; Animal; Antiïschemic
• ISSN: 0160-2446; 1533-4023
• DOI: 10.1097/00005344-200011000-00003

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.