Decreased aortic glutathione levels may contribute to impaired nitric oxide-induced relaxation in hypercholesterolaemia.
The aim of this study was to determine if the decrease in aortic total glutathione (GSH) levels in hypercholesterolaemia is related to the impairment of relaxation to acetylcholine (ACh) and exogenous nitric oxide (NO). Isometric tension and vascular GSH levels were measured in thoracic aortic rings from rabbits fed for 12 weeks with 0.5% cholesterol diet. Hypercholesterolaemia decreased aortic GSH levels and impaired relaxation to ACh and NO. To determine if GSH depletion impaired the response to NO, normal rabbit thoracic aorta was incubated with 1,3-bis [2-chloroethyl]-1-nitrosourea (BCNU; 0.2 mmol L(-1)), a GSH reductase inhibitor, or diazine-dicarboxylic acid bis [N, N dimethylamide] (diamide; 1 mmol L(-1)), a thiol oxidizing agent. BCNU or diamide decreased aortic GSH levels and impaired ACh and NO-induced relaxation. The effects of diamide on GSH levels and relaxation were partially prevented by co-incubation with GSH ester (GSE; 2 mmol L(-1)). Increasing GSH with GSE significantly enhanced NO-induced relaxation in aorta from both hypercholesterolaemic and normal rabbits, however relaxation of hypercholesterolaemic rabbit aorta was not restored to normal. These data suggest that other factors, perhaps related to the long-term decrease in GSH levels, are responsible for reduced NO bioactivity in hypercholesterolaemia.
Adachi
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Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston Medical Center, Boston, Massachusetts, MA 02118, USA.
Cohen
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism*; D002330:Carmustine / Q000494:pharmacology; D003958:Diamide / Q000494:pharmacology; D004036:Diet, Atherogenic; D005978:Glutathione / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D011817:Rabbits; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D016877:Oxidants; D013439:Sulfhydryl Reagents; D014665:Vasodilator Agents; D003958:Diamide; D009599:Nitroprusside; D009569:Nitric Oxide; D009249:NADP; D005978:Glutathione; D000109:Acetylcholine; D002330:Carmustine