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T. Nagaoka, T.W. Hein, A. Yoshida, L. Kuo; Simvastatin Elicits Vasodilation of Retinal Arterioles Through Nitric Oxide Synthase Activation and Cyclic GMP Signaling Pathway . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3765.
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Increasing evidence suggests that statins, which are hypolipidemic agents used in the treatment of hypercholesterolemia, may have pleiotropic effects on vascular wall and endothelial function independent of their cholesterol lowering properties. We recently demonstrated that systemic administration of simvastatin increases blood flow in retinal arteries and veins in healthy men (Nagaoka et al., Arch Ophthalmol, in press). However, the mechanism of the vasodilator effect of simvastatin in retinal microcirculation remains unclear. Herein, we examined the direct vasomotor action of simvastatin in retinal arterioles.
Porcine retinal arterioles (60–90 µm in internal diameter) were isolated, cannulated and pressurized (55 cmH2O) without flow for functional study. Videomicroscopic techniques were employed to record diameter change in response to simvastatin.
Retinal arterioles dilated dose–dependently to simvastatin (1 nM to 10 µM) with 48±5% maximal dilation at the highest concentration. This vasodilation was not affected in the presence of either cyclooxygenase inhibitor indomethacin (10 µM) or cytochrome–P450 (CYP) monooxygenase inhibitor sulfaphenazole (1 µM). However, the nitric oxide (NO) synthase inhibitor L–NAME (10 mM) nearly abolished the response to simvastatin. Inhibition of soluble guanylyl cyclase by 1H–[1,2,4]oxadiazolo[4,3,–a]quinoxalin–1–one (0.1 µM) also significantly attenuated the vasodilation to simvastatin.
The present results indicate that simvastatin elicits a significant vasodilation of retinal arterioles. This dilation is not dependent on the synthesis of prostanoids or CYP–related endothelium–derived hyperpolarizing factor, but is mediated by the production of NO from NO synthase and the subsequent activation of guanylyl cyclase.
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