title: Cellular signalling pathways mediating dilation of porcine pial arterioles to adenosine A₂A receptor activation.
abstract: OBJECTIVE
  Adenosine is a potent vasodilator contributing to cerebral blood flow regulation during metabolic stress. However, the distribution of adenosine receptor subtypes and underlying signalling mechanisms for dilation of pial arterioles remain unclear. The present study aimed at addressing these issues.
  
  
  RESULTS
  Isolated porcine pial arterioles were subjected to study of vasomotor function, localization of adenosine receptors, and production of nitric oxide (NO). Concentration-dependent vasodilation to adenosine was inhibited by A₂A receptor antagonist ZM241385 but not by A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. A₂A receptors were detected in endothelium and smooth muscle of pial arterioles via immunohistochemistry. Adenosine significantly increased arteriolar production of NO, and the induced dilation was insensitive to KATP channel blocker glibenclamide but was attenuated by endothelial denudation, NO synthase inhibitor L-NAME, or guanylyl cyclase inhibitor ODQ in a similar manner. Both inward rectifier potassium (Kir) channel inhibitor barium and cAMP signalling inhibitor Rp-8-Br-cAMPS attenuated adenosine-induced dilation. In the presence of L-NAME or the absence of endothelium, addition of Rp-8-Br-cAMPS but not barium further reduced adenosine-induced responses. Barium diminished endothelium-independent vasodilation to NO donor sodium nitroprusside. Comparable to the adenosine-induced response, vasodilation to A₂A receptor agonist CGS21680 was attenuated by endothelial removal, ZM241385, L-NAME, barium, or Rp-8-Br-cAMPS, but not by glibenclamide.
  
  
  CONCLUSIONS
  Adenosine evokes dilation of porcine pial arterioles via parallel activation of endothelial and smooth muscle A₂A receptors. Stimulation of endothelial NO production activates smooth muscle guanylyl cyclase for vasodilation by opening Kir channels. Adenosine also activates smooth muscle cAMP signalling leading to vasodilation.
authors.affiliation: Department of Surgery, Scott & White Healthcare, College of Medicine, Texas A&M Health Science Center, 702 Southwest HK Dodgen Loop, Temple, TX 76504, USA. thein@tamu.edu
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D043683:Receptors, Adenosine A2; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase
keywords: Adenosine; Microcirculation; Nitric oxide; Potassium channels; Vasodilation
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