MECHANISMS OF IMPAIRMENT OF ENDOTHELIUM-DEPENDENT RELAXATION TO ACETYLCHOLINE IN WATANABE HERITABLE HYPERLIPIDEMIC RABBIT AORTAS

1, The mechanism of impairment of the endothelium-dependent relaxation in response to acetylcholine (ACh) in aortas from Watanabe heritable hyperlipidaemic (WHHL) rabbits was investigated using a modified sandw ich (layered) technique, intact aortas from WHHL rabbits or Japanese w hite (JW) rabbits as the control were used as donor strips of endothel ium-derived relaxing factor (EI)RF) and endothelium-denuded aortas fro m JW rabbits were used as detector strips, The EDRF released from a do nor strip could be directly deterred as the relaxation response In a d etector strip, 2, The endothelium-dependent relaxations in all rabbit arteries were almost abolished by treatment with N-G-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase), 3, The ACh-induc ed endothelium-dependent relaxations in the donor strips were impaired in WHHL rabbits in comparison with relaxations in JW and heterozygous WHHL rabbits, Similarly, the relaxation in the detector strips induce d bg EDRF released from donor strips was reduced in WHHL rabbits, Ther e was a good negative correlation;between the aortic total cholesterol content in the donor strips and the degree of relaxation in the detec tor strips horn WHHL rabbits. 4, The reduced relaxation in the detecto r strips when using donor strips with high cholesterol accumulation or atheromatous plaque was not affected by superoxide dismutase plus cat alase (scavengers of superoxide anions), indomethacin jan inhibitor of cyclo-oxygenase), ONO-3708 (an antagonist of endoperoxide thromboxane receptor) and 97-139 (an antagonist of endothelin ETA receptor), 5, T hese results suggest that the mechanism of impaired endothelium-depend ent relaxations in atherosclerotic WHHL rabbit aortas may be due to th e reduced amount of EDRF, probably nitric oxide, from the endothelium and not due to its inactivation by oxygen-derived free-radicals or mas king by increased production of endothelium-derived contracting factor s.