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CARDIOVASCULAR
Vascular Biology Center (E.D.L., J.C.S., D.A.O., D.M.P., and J.S.P.), Departments of Pharmacology (J.C.S., J.S.P.) and Surgery (D.M.P.), Medical College of Georgia, Augusta, Georgia
Experiments were designed to test the hypothesis that elevated levels of endothelin 1 (ET-1) in the vasculature activate NADPH oxidase and/or uncoupled nitric-oxide synthase (NOS), resulting in 
production, and mediate increased constriction. Rat aortic rings were incubated with ET-1 or vehicle in the presence and absence of superoxide dismutase (SOD), ebselen (glutathione peroxidase mimetic), apocynin (NADPH oxidase inhibitor), L-NAME (N
-nitro-L-arginine methyl ester) (NOS inhibitor), tetrahydrobiopterin (BH4) (NOS cofactor), or selective ETA and ETB receptor antagonists (BQ-123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] and A-192621 [[2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]], respectively). production was monitored by oxidized dihydroethidine staining and/or lucigenin chemiluminescence. ET-1 significantly increased production compared with vehicle. SOD, ebselen, and apocynin inhibited the ET-1-induced increase in in intact and endothelium-denuded aorta. L-NAME and BH4 inhibited the ET-1-induced increase in in intact tissue, whereas these two compounds had no effect on ET-1-induced in endothelium-denuded aorta. Preincubation with BQ-123 or A-192621, individually, had no effect on ET-1-induced ; however combining both antagonists inhibited the ET-1-stimulated increase in . Rat aortic rings were incubated with ET-1 or vehicle in the presence or absence of sepiapterin (BH4 synthesis substrate) or apocynin and mounted on wire myographs to determine isometric force generation in response to increasing KCl concentrations. ET-1 increased the contractile response to KCl compared with vehicle. Treatment with either sepiapterin or apocynin attenuated the ET-1-mediated increase with no effect of sepiapterin or apocynin alone. These data support the hypothesis that ET-1 increases vascular tone, in part, through ETA/ETB receptor activation of production from NADPH oxidase and NOS uncoupling.
Address correspondence to: Dr. Jennifer S. Pollock, Medical College of Georgia, CB-3213, 1459 Laney Walker Blvd., Augusta, GA 30912. E-mail: jpollock{at}mail.mcg.edu
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