(Circulation. 1999;100:1161-1168.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans
From the Departments of Pediatrics (P.M.K., R.L.B.) and Internal Medicine (C.A.S., M.A., H.R.K., W.G.H.) and General Clinical Research Center (C.A.S., M.A., H.R.K., W.G.H.), University of Iowa College of Medicine, Iowa City, Iowa.
Background—Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress.
Methods and Results—Oral administration of
L-methionine (100 mg/kg) was used to induce moderate
hyperhomocyst(e)inemia (
25 µmol/L) in healthy human subjects.
Endothelial function of forearm resistance vessels was
assessed by use of forearm vasodilatation to brachial artery
administration of the endothelium-dependent dilator
acetylcholine. Conduit vessel endothelial function was
assessed with flow-mediated dilatation of the brachial artery. Forearm
resistance vessel dilatation to acetylcholine was significantly
impaired 7 hours after methionine (methionine, 477±82%; placebo,
673±110%; P=0.016). Methionine did not alter
vasodilatation to nitroprusside and verapamil.
Flow-mediated dilatation was significantly impaired 8 hours after
methionine loading (0.3±2.7%) compared with placebo (8.2±1.6%,
P=0.01). Oral administration of the antioxidant ascorbic
acid (2 g) prevented methionine-induced endothelial
dysfunction in both conduit and resistance vessels
(P=0.03).
Conclusions—Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.
Key Words: endothelium • nitric oxide • free radicals • acetylcholine • antioxidants
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