title: Dilation of porcine retinal arterioles to cilostazol: roles of eNOS phosphorylation via cAMP/protein kinase A and AMP-activated protein kinase and potassium channels.
abstract: OBJECTIVE
  Cilostazol, a selective inhibitor of phosphodiesterase 3, has antiplatelet aggregation and peripheral vasodilation effects. We examined the effects of cilostazol on the retinal microvascular diameter to determine its dependence on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity.
  
  
  METHODS
  Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to cilostazol.
  
  
  RESULTS
  The retinal arterioles dilated in response to cilostazol in a dose-dependent (100 pM-10 μM) manner; the dilation decreased by 60% after endothelial removal. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited cilostazol-induced vasodilation comparable to denudation. Inhibition of soluble guanylyl cyclase and blockade of protein kinase A (PKA) were comparable to L-NAME. Compound C, an AMP-activated protein kinase (AMPK) inhibitor, partially inhibited cilostazol-induced vasodilation, which exhibited a weaker inhibitory effect on cilostazol-induced vasodilation than blockade of PKA. The large-conductance Ca²⁺-activated K channel (BK(Ca) channel) blocker, iberiotoxin, also inhibited cilostazol-induced vasodilation. The residual vasodilation decreased further with co-administration of L-NAME and iberiotoxin.
  
  
  CONCLUSIONS
  Cilostazol elicits endothelium-dependent and -independent dilation of the retinal arterioles mediated by NO release and BK(Ca) channel activation, respectively. Endothelial nitric oxide synthase (eNOS) phosphorylation via the cAMP/PKA and AMPK pathways and consequent activation of the soluble guanylyl cyclase/cyclic guanosine monophosphate pathway might play an important role in cilostazol-induced vasodilation of the retinal arterioles.
authors: Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
authors: Ichiro
authors: I
authors: Tanano
authors: Taiji
authors: T
authors: Nagaoka
authors: Tsuneaki
authors: T
authors: Omae
authors: Akihiro
authors: A
authors: Ishibazawa
authors: Takayuki
authors: T
authors: Kamiya
authors: Shinji
authors: S
authors: Ono
authors: Akitoshi
authors: A
authors: Yoshida
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism*; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; D013777:Tetrazoles; D014665:Vasodilator Agents; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; D000077407:Cilostazol