title: Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans.
abstract: BACKGROUND
  The endogenous nucleoside adenosine plays an important role in the regulation of vascular tone, especially during ischemia. Experimental data derived from animal models suggest that nitric oxide (NO) contributes to the vasodilator effect of adenosine. The primary purpose of this investigation was to determine whether the endothelial release of NO contributes to adenosine-induced vasodilation in humans.
  
  
  RESULTS
  Venous occlusion plethysmography was used to assess the forearm blood flow (FBF) responses to graded intra-arterial infusions of adenosine (1.5 to 500 micrograms/min). Dose-response curves were constructed before and during intra-arterial infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (2 mg/min, n = 6) or vehicle (n = 6). Before infusion of L-NMMA, adenosine caused a dose-dependent increase in FBF from 2.3 to 15.9 mL.min-1.dL-1. During concurrent infusion of L-NMMA, adenosine increased FBF from 1.7 to 10.0 mL.min-1.dL-1, and this change from baseline was significantly reduced compared with that before L-NMMA (P < .05). L-NMMA also attenuated the FBF response to adenosine when the basal constrictor effect of L-NMMA was prevented by coinfusion of the NO donor sodium nitroprusside (n = 6, P < .01). In contrast, L-NMMA did not affect the FBF response to intra-arterial infusion of the endothelium-independent vasodilator verapamil (from 2.0 to 13.9 mL.min-1.dL-1 before L-NMMA and from 1.3 to 13.6 mL.min-1.dL-1 during L-NMMA; n = 6, P = NS). The second objective of this study was to determine whether the adenosine-induced release of NO is mediated by activation of endothelial potassium channels, putatively coupled to adenosine receptors. Thus, the FBF response to adenosine was measured before and during infusion of the ATP-dependent potassium channel blocker tolbutamide (1 mg/min, n = 6), or the potassium channel blocker quinidine (0.5 mg/min, n = 6). The adenosine-mediated increments in FBF were not attenuated by either potassium channel blocker.
  
  
  CONCLUSIONS
  Adenosine-induced vasodilation in humans is mediated, at least in part, by endothelial release of NO. The transducing mechanism of this phenomenon is not known, but it does not appear to involve the activation of either ATP-dependent or quinidine-sensitive potassium channels.
authors.affiliation: Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: P
authors.initials: P
authors.lastname: Smits
authors.forename: S B
authors.initials: SB
authors.lastname: Williams
authors.forename: D E
authors.initials: DE
authors.lastname: Lipson
authors.forename: P
authors.initials: P
authors.lastname: Banitt
authors.forename: G A
authors.initials: GA
authors.lastname: Rongen
authors.forename: M A
authors.initials: MA
authors.lastname: Creager
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D010991:Plethysmography; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011802:Quinidine / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014044:Tolbutamide / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D019323:omega-N-Methylarginine
chemical_list: D004791:Enzyme Inhibitors; D015221:Potassium Channels; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D014044:Tolbutamide; D014700:Verapamil; D019001:Nitric Oxide Synthase; D011802:Quinidine; D000241:Adenosine