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 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.
Ergul
Adviye
A
Clinical and Experimental Therapeutics Program, Univeristy of Georgia College of Pharmacy, Augusta, GA 30912, USA. aergul@mail.mcg.edu
Johansen
Jeanette Schultz
JS
Strømhaug
Catherine
C
Harris
Alex K
AK
Hutchinson
Jimmie
J
Tawfik
Amany
A
Rahimi
Ali
A
Rhim
Edward
E
Wells
Bryan
B
Caldwell
R William
RW
Anstadt
Mark P
MP
D015153:Blotting, Western; D001026:Coronary Artery Bypass; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology*; D003920:Diabetes Mellitus / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000502:physiology*; D004996:Ethidium / Q000031:analogs & derivatives*; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D019332:Endothelin-1; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; C067883:dihydroethidium; D019255:NADPH Oxidases; D004996:Ethidium