Reactive oxygen species play a central role in vascular inflammation and atherogenesis, with enhanced superoxide (02-) production contributing significantly to impairment of nitric oxide (NO)-dependent relaxation of vessels from cholesterol-fed rabbits. We investigated potential sources of 02-production, which contribute to this loss of endothelium-dependent vascular responses. The vasorelaxation elicited by acetylcholine (ACh) in phenylephrinecontracted, aortic ring segments was impaired by cholesterol feeding. Pretreatment of aortic vessels with either heparin, which competes with xanthine oxidase (XO) for binding to sulfated glycosaminoglycans, or the XO inhibitor allopurinol resulted in a partial restoration (36-40o at 1 ,uM ACh) of ACh-dependent relaxation. Furthermore, 027-dependent lucigenin chemiluminescence, measured in intact ring segments from hypercholesterolemic rabbits, was decreased by addition of heparin, allopurinol or a chimeric, heparin-binding superoxide dismutase. XO activity was elevated more than two-fold in plasma of hypercholesterolemic rabbits. Incubation of vascular rings from rabbits on a normal diet with purified XO (10 milliunits/ml) also impaired 'NO-dependent relaxation but only in the presence of purine substrate. As with vessels from hypercholesterolemic rabbits, this effect was prevented by heparin and allopurinol treatment. We hypothesize that increases in plasma cholesterol induce the release of XO into the circulation, where it binds to endothelial cell glycosaminoglycans. Only in hypercholesterolemic vessels is sufficient substrate available to sustain the production of 02-and impair NO-dependent vasorelaxation. Chronically, the continued production of peroxynitrite, (ONOO-) which the simultaneous generation of NO and 02 -implies, may irreversibly impair vessel function.In recent years, numerous studies have shown that vascular function is compromised in a number of pathological conditions including atherosclerosis and hypertension (1-3). In atherosclerosis, blood vessels undergo marked changes in both structure and function that may predispose for angina and myocardial infarction. Defects in lipoprotein metabolism and vascular reactivity are fundamental pathological responses to hypercholesterolemia, with reactive oxygen species playing an important role in the initiation and progression of these lesions (4, 5). Isolated blood vessels from atherosclerotic patients (6, 7) and hypercholesterolemic animals (8-11) exhibit impaired, endothelium-dependent vascular relaxation. In these models, superoxide (02-) is generated at greater rates in both intracellular and extracellular compartments, ren.cting with 'NO to inhibit endothelium-dependent relaxation ard yielding peroxynitrite (ONOO-) (12). Since ONOO-is capable of oxidizing lipids and proteins, it may further contribute to foam cell formation in the atherosclerotic lesion (13-15).While oxidative injury plays a pivotal role in these processes, the cellular mechanisms of 0i-production and sites of reaction remain to be...

When incubated with a hydroxyl radical (HO•)‐generating system (ascorbic acid/Fe2+‐EDTA/O2/H2O2), 5‐hydroxytryptamine (5‐HT; serotonin) is rapidly oxidized initially to a mixture of 2,5‐, 4,5‐, and 5,6‐dihydroxytryptamine (DHT). The major reaction product is 2,5‐DHT, which at physiological pH exists as its keto tautomer, 5‐hydroxy‐3‐ethylamino‐2‐oxindole (5‐HEO). Rapid autoxidation of 4,5‐DHT gives tryptamine‐4,5‐dione (T‐4,5‐D), which reacts with the C(3)‐centered carbanion of 5‐HEO to give 3,3′‐bis(2‐aminoethyl)‐5‐hydroxy‐[3,7′‐bi‐1H‐indole]‐2,4′,5′‐3H‐trione (7). The latter slowly cyclizes to 3′‐(2‐aminoethyl)‐1′,6′,7′,8′‐tetrahydro‐5‐hydroxyspiro[3H‐indole‐3,9′‐[9H]pyrrolo[2,3‐f]quinoline]‐2,4′,5′(1H)‐ trione (9). A minor amount of T‐4,5‐D dimerizes to give 7,7′‐bi‐(5‐hydroxytryptamine‐4‐one) (7,7′‐D). In the presence of GSH, the reaction of T‐4,5‐D with 5‐HEO is diverted and, in the presence of sufficient concentrations of this tripeptide, completely blocked. This is because GSH preferentially reacts with T‐4,5‐D to give 7‐S‐glutathionyltryptamine‐4,5‐dione (11). The results of this investigation suggest that 5,6‐DHT, 5‐HEO, 7, and 9 are products unique to the HO•‐mediated oxidation of 5‐HT. Thus, the observation of other investigators that 5,6‐DHT is formed in the brains of rats following a large dose of methamphetamine (MA) suggests that this drug might evoke HO• formation. However, the present in vitro study indicates that 5,6‐DHT is a rather minor, unstable product of the HO•‐mediated oxidation of 5‐HT and suggests that detection of 5‐HEO, 7/9, and 11 in rat brain following MA administration could provide additional support for HO• formation. Furthermore, one or more of the intermediates and major products of oxidation of 5‐HT by HO• might, in addition to 5,6‐DHT, contribute to the MA‐induced degeneration of serotonergic neurons.

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Desflurane anesthesia increased xanthine oxidase-dependent alveolar-capillary membrane compromise after aortic occlusion-reperfusion in concert with depletion of a key tissue antioxidant.

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