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T.W. Hein, Z. Yuan, R.H. Rosa, Jr, L. Kuo; Activation of A2A Receptors by Adenosine Elicits Nitric Oxide– and KATP Channel–Mediated Dilation of Retinal Arterioles . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4718.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Adenosine is a potent vasodilator of retinal microvessels and is implicated to be a major regulator of retinal blood flow during metabolic stress. We have previously shown that activation of A2A receptors mediates the dilation of retinal arterioles to adenosine. However, the underlying signaling mechanisms linked to this A2A receptor–mediated response remain unknown. Therefore, we examined the roles of endothelium–derived vasodilators and smooth muscle ATP–sensitive K+ (KATP) channels in adenosine A2A receptor–mediated dilation of retinal arterioles in vitro. Methods: Porcine retinal arterioles (40–70 µm in internal diameter) were isolated, cannulated, and pressurized to 55 cmH2O lumenal pressure without flow. Diameter changes in response to agonists were recorded using videomicroscopic techniques. RT/PCR and in situ hybridization studies were performed to detect A2A receptor mRNA in retinal arterioles. Results: All vessels developed basal tone and dilated dose–dependently to adenosine (1 nM to 0.1 mM), CGS21680(A2A receptor agonist, 1 nM to 10 µM), and sodium nitroprusside (1 nM to 0.1 mM). The selective A2A receptor antagonist ZM241385 significantly attenuated the adenosine– and CGS21680ndash;mediated responses. Neither the cyclooxygenase inhibitor indomethacin nor the cytochrome P–450 epoxygenase inhibitor sulfaphenazole altered the vasodilation to adenosine. In contrast, the nitric oxide (NO) synthase inhibitor L–NAME significantly attenuated the response to adenosine. Likewise, L–NAME reduced the vasodilation to CGS21680 The residual vasodilation to both agonists was nearly abolished by the KATP channel inhibitor glibenclamide. The inhibitory effects of ZM241385, L–NAME, and glibenclamide appeared to be specific because they did not alter vasodilation to nitroprusside. RT/PCR data indicated that A2A receptor mRNA was encoded in retinal arterioles, while in situ hybridization data revealed that the A2A receptor transcript was localized in both endothelial and smooth muscle layers. Conclusions: These data suggest that activation of adenosine A2A receptors elicits dilation of retinal arterioles by endothelial production of NO and by smooth muscle opening of KATP channels. A better understanding of the fundamental signaling pathways responsible for adenosine–induced dilation of retinal arterioles may help shed light on the possible mechanisms contributing to impaired retinal blood flow regulation in patients following retinal ischemia.
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