title: Requisite roles of A2A receptors, nitric oxide, and KATP channels in retinal arteriolar dilation in response to adenosine.
abstract: OBJECTIVE
  Adenosine is a potent vasodilator of retinal microvessels and is implicated to be a major regulator of retinal blood flow during metabolic stress. However, the receptor subtypes and the underlying signaling mechanism responsible for the dilation of retinal microvessels in response to adenosine remain unclear. In the present study, the roles of specific adenosine receptor subtypes, nitric oxide (NO), and adenosine triphosphate (ATP)-sensitive K(+) (K(ATP)) channels in adenosine-induced dilation of retinal arterioles in vitro were examined.
  
  
  METHODS
  Porcine second-order retinal arterioles (40-70 mum in internal diameter) were isolated, cannulated, and pressurized to 55 cmH(2)O luminal pressure without flow. Diameter changes in response to agonists were recorded by using videomicroscopic techniques.
  
  
  RESULTS
  All vessels exhibited basal tone and dilated dose dependently in reaction to adenosine, N(6)-cyclopentyladenosine (an adenosine A(1) receptor agonist), and 2-[p-(2-carboxyethyl)]phenylethyl-amino-5'-N-ethylcarboxamidoadenosine(CGS21680; an adenosine A(2A) receptor agonist). These responses were not altered by the selective adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but were significantly attenuated by the selective adenosine A(2A) receptor antagonist 4-(2-{7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a] [1,3,5]triazin-5-ylamino}ethyl)phenol. Blockade of NO synthase, but not of cyclooxygenase or cytochrome P-450 epoxygenase, significantly attenuated the vasodilations in response to adenosine and CGS21680. The residual vasodilative reactions to both agonists was nearly abolished by the K(ATP) channel inhibitor glibenclamide.
  
  
  CONCLUSIONS
  These data suggest that adenosine evokes retinal arteriolar dilation via activation of A(2A) receptors and subsequent production of NO and opening of K(ATP) 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 after retinal ischemia.
authors.affiliation: Department of Surgery, Division of Ophthalmology, Scott and White Eye Institute, Texas A&M University System Health Science Center, Temple, 76504, USA. thein@tamu.edu
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.forename: Zhaoxu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Rosa
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D043682:Receptor, Adenosine A1 / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D012161:Retinal Artery / Q000187:drug effects*; D013552:Swine; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D004791:Enzyme Inhibitors; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014665:Vasodilator Agents; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000241:Adenosine