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T. W. Hein, W. Xu, Y. Ren, L. Kuo; Endothelin-1 Impairs Endothelium-Dependent NO-Mediated Dilation of Retinal Arterioles: Role of Rho Kinase and NAD(P)H Oxidase. Invest. Ophthalmol. Vis. Sci. 2007;48(13):6038.
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Elevated levels of endothelin-1 (ET-1), a potent vasoconstrictor and stimulator of oxidative stress, are associated with retinal ischemic disease. However, it is unclear whether vasodilator function of retinal resistance arterioles is susceptible to ET-1. Herein, we examined whether ET-1 can affect endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles and whether ischemic-related signaling factors such as Rho kinase (ROCK) and reactive oxygen species superoxide are involved in the ET-1-mediated effect.
Porcine retinal arterioles were isolated and pressurized without flow for in vitro study. Videomicroscopic techniques were employed to record diameter change in response to agonists before and after exposure to a sub-vasoactive, pathophysiological concentration of ET-1 (10 pM). Vascular levels of superoxide anions were detected by dihydroethidium (DHE) fluorescence staining. Cellular localization of ROCK isoforms was identified by immunohistochemical analysis.
All vessels developed basal tone (62 ± 3 µm, resting diameter). Extraluminal treatment with ET-1 did not alter resting diameter (60 ± 4 µm) at 30 min but significantly decreased diameter (54 ± 3 µm) within 90 min. In addition, following the 90-min exposure to ET-1, vasodilation to endothelium-dependent NO-mediated agonist bradykinin, but not to endothelium-independent NO donor sodium nitroprusside, was significantly attenuated. DHE staining revealed that superoxide production in arteriolar endothelial cells was enhanced by ET-1 within 90 min but not 30 min. Co-administration of ET-1 with superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), ROCK inhibitor Y-27632 or NAD(P)H oxidase inhibitor apocynin, reduced the ET-1 induced superoxide production, as well as preserved normal resting basal tone and vasodilation to bradykinin. ROCK-2 but not ROCK-1 expression was localized to retinal endothelial cells.
A clinically relevant level of ET-1 elicits a temporal increase in basal tone and inhibition of endothelium-dependent NO-mediated dilation of retinal arterioles. Both ET-1-mediated actions appear to be dependent upon ROCK-2 activation and subsequent production of superoxide via NAD(P)H oxidase leading to a reduction in endothelial NO bioavailability. These data may partly explain the impaired retinal flow regulation in ocular diseases associated with an upregulation of the ET system.
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