title: Fenofibrate, an anti-dyslipidemia drug, elicits the dilation of isolated porcine retinal arterioles: role of nitric oxide and AMP-activated protein kinase.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Porcine retinal arterioles (internal diameter, 60-90 μm) were isolated, cannulated, and pressurized (55 cmH(2)O) without flow in vitro. Video-microscopic techniques recorded the diameter responses to fenofibrate.
  
  
  RESULTS
  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. N(ω)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Omae
authors.forename: Taiji
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tanano
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kamiya
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Yoshida
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012161:Retinal Artery / Q000187:drug effects*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D055372:AMP-Activated Protein Kinases; D006162:Guanylate Cyclase; D011345:Fenofibrate