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Received for publication June 29, 2005.
Revised August 25, 2005.
Accepted for publication August 25, 2005.
Experiments were designed to test the hypothesis that elevated levels of ET-1 in the vasculature activate NADPH oxidase and/or uncoupled NOS resulting in O2·- production and mediate increased constriction. Rat aortic rings were incubated with ET-1 or vehicle in the presence and absence of SOD, ebselen (glutathione peroxidase mimetic), apocynin (NADPH oxidase inhibitor), L-NAME (NOS inhibitor), BH4 (NOS cofactor), or selective ETA and ETB receptor antagonists (BQ-123 and A-192621, respectively). O2·- production was monitored by oxidized dihydroethidine staining and/or lucigenin chemiluminescence. ET-1 significantly increased O2·- production compared to vehicle. SOD, ebselen, and apocynin inhibited the ET-1 induced increase in O2·- in intact and endothelium-denuded aorta. L-NAME and BH4 inhibited the ET-1 induced increase in O2·- in intact tissue, while these two compounds had no effect on ET-1 induced O2·- in endothelium-denuded aorta. Pre-incubation with BQ-123 or A-192621, individually, had no effect on ET-1 induced O2·-; however, combining both antagonists inhibited the ET-1 stimulated increase in O2·-. 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 to 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 O2·- production from NADPH oxidase and NOS uncoupling.
Key words:
NADPH oxidase, aorta, endothelin, superoxide, uncoupled NOS, vasoconstriction
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