Vascular dysfunction of venous bypass conduits is mediated by reactive oxygen species in diabetes: role of endothelin-1

Diabetes is associated with increased risk for complications following coronary bypass grafting (CABG) surgery. Augmented superoxide (*O2*) production plays an important role in diabetic complications by causing vascular dysfunction. The potent vasoconstrictor endothelin-1 (ET-1) is also elevated in...

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Bibliographic Details
Published in:	The Journal of pharmacology and experimental therapeutics Vol. 313; no. 1; p. 70
Main Authors:	Ergul, Adviye, Johansen, Jeanette Schultz, Strømhaug, Catherine, Harris, Alex K, Hutchinson, Jimmie, Tawfik, Amany, Rahimi, Ali, Rhim, Edward, Wells, Bryan, Caldwell, R William, Anstadt, Mark P
Format:	Journal Article
Language:	English
Published:	United States 01-04-2005
Subjects:	Blotting, Western Coronary Artery Bypass Coronary Vessels - metabolism Coronary Vessels - pathology Diabetes Mellitus - pathology Dose-Response Relationship, Drug Endothelin-1 - physiology Ethidium - analogs & derivatives Female Fluorescent Dyes Humans Male Microscopy, Confocal Middle Aged Muscle Contraction - drug effects Muscle Relaxation - drug effects Muscle, Smooth, Vascular - drug effects NADPH Oxidases - metabolism Reactive Oxygen Species - metabolism
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Summary:	Diabetes is associated with increased risk for complications following coronary bypass grafting (CABG) surgery. Augmented superoxide (O2) production plays an important role in diabetic complications by causing vascular dysfunction. The potent vasoconstrictor endothelin-1 (ET-1) is also elevated in diabetes and following CABG; however, the effect of ET-1 on O2 generation and/or vascular dysfunction in bypass conduits remain unknown. Accordingly, this study investigated basal and ET-1-stimulated O2 production in bypass conduits and determined the effect of O2 on conduit reactivity. Saphenous vein specimens were obtained from nondiabetic (n = 24) and diabetic (n = 24) patients undergoing CABG. Dihydroethidium staining and NAD(P)H oxidase activity assays (5380 +/- 940 versus 16,362 +/- 2550 relative light units/microg) demonstrated increased basal O2 levels in the diabetes group (p < 0.05). Plasma ET-1 levels were associated with elevated basal O2 levels, and treatment of conduits with exogenous ET-1 further increased O2 production and augmented vasoconstriction. Furthermore, vascular relaxation was impaired in the diabetic group (75 versus 40%), which was restored by O2 scavenger superoxide dismutase. These findings suggest that ET-1 causes bypass conduits dysfunction via stimulation of O2 production in diabetes. Novel therapies that attenuate O2 generation in bypass conduits may improve acute and late outcome of CABG in diabetic patients.
ISSN:	0022-3565
DOI:	10.1124/jpet.104.078105