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Tsuneaki Omae, Taiji Nagaoka, Ichiro Tanano, Takayuki Kamiya, Akitoshi Yoshida; Fenofibrate, an Anti-Dyslipidemia Drug, Elicits the Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and AMP-Activated Protein Kinase. Invest. Ophthalmol. Vis. Sci. 2012;53(6):2880-2886. doi: 10.1167/iovs.11-8841.
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Although recent clinical trials have demonstrated that fenofibrate is effective for treating diabetic retinopathy, the mechanism of this beneficial effect remains unclear. In the current study, we examined the effect of the vasomotor action of fenofibrate on porcine retinal arterioles.
Porcine retinal arterioles (internal diameter, 60–90 μm) were isolated, cannulated, and pressurized (55 cmH2O) without flow in vitro. Video-microscopic techniques recorded the diameter responses to fenofibrate.
The retinal arterioles dilated in a dose-dependent manner in response to fenofibrate (10 nM to 30 μM). This vasodilation significantly decreased after the endothelium was removed. Nω-nitro-L-arginine methyl ester (a nitric oxide [NO] synthase inhibitor), 1H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (a soluble guanylyl cyclase inhibitor), wortmannin (a phosphatidylinositol [PI] 3-kinase inhibitor), and compound C (an AMP-activated protein kinase inhibitor) attenuated the effect of fenofibrate-induced vasodilation to an extent comparable to that produced by denudation. Pretreatment with GW6471, a peroxisome proliferator-activated receptor-α blocker, did not significantly inhibit fenofibrate-induced vasodilation.
Fenofibrate primarily elicited endothelium-dependent dilation of the retinal arterioles. The current findings suggested that fenofibrate-induced endothelium-dependent vasodilation is mediated by the release of NO, which probably mediates dilation via activation of guanylyl cyclase, the PI3-kinase pathway, and the AMP-activated protein kinase pathway. Understanding the vasodilatory effect of fenofibrate on the retinal microvasculature may improve potential therapy for diabetic retinopathy.
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