title: Adenosine A(2A) receptors mediate coronary microvascular dilation to adenosine: role of nitric oxide and ATP-sensitive potassium channels.
abstract: Adenosine is a potent vasodilator that plays an important role in the regulation of coronary microvascular diameter. Although multiple adenosine receptor subtypes have been recently cloned, the specific adenosine receptor subtypes and the underlying mechanisms responsible for the vasodilation to adenosine in the coronary microcirculation remain unknown. Therefore, in the present study we determined the receptor subtypes for coronary arteriolar dilation to adenosine and investigated the role of nitric oxide (NO) and ATP-sensitive potassium (K(ATP)) channels in this vasodilatory response. Pig coronary arterioles (50-100 microm in situ) were isolated, cannulated, and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated in a concentration-dependent manner to adenosine and to adenosine receptor agonists (2S)-N(6)-[2-endo-norbornyl]adenosine (A(1)), 2-[p-(2-carboxyethyl)]phenylethyl-amino-5'-N-ethylcarboxamidoadenosin e (CGS21680; A(2A)), N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (A(3)), and N-ethylcarboxamidoadenosine (nonselective adenosine receptor activation). The selective A(2A) receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-y l amino]ethyl)phenol attenuated vasodilation to adenosine and to all adenosine receptor agonists tested, suggesting that the vasodilatory responses were primarily mediated by A(2A) receptors. Adenosine- and CGS21680-induced dilations were attenuated in a similar manner by endothelial removal and by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. In denuded vessels, both adenosine- and CGS21680-induced dilations were nearly abolished by the K(ATP) channel inhibitor glibenclamide. The selective A(2A) agonist CGS21680 mechanistically mimics the vasodilation in response to adenosine. Collectively, our results suggest that the dilation of coronary arterioles to adenosine is mediated predominantly by A(2A) receptors. Activation of this receptor subtype elicits vasodilation by endothelial release of NO and by the smooth muscle opening of K(ATP) channels.
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, College Station, Texas 77843-1114, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Hein
authors.forename: L
authors.initials: L
authors.lastname: Belardinelli
authors.forename: L
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000145:classification / Q000502:physiology*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D010627:Phenethylamines; D015221:Potassium Channels; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D000241:Adenosine; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester