title: The cellular mechanisms by which adenosine evokes release of nitric oxide from rat aortic endothelium.
abstract: Adenosine and nitric oxide (NO) are important local mediators of vasodilatation. The aim of this study was to elucidate the mechanisms underlying adenosine receptor-mediated NO release from the endothelium. In studies on freshly excised rat aorta, second-messenger systems were pharmacologically modulated by appropriate antagonists while a NO-sensitive electrode was used to measure adenosine-evoked NO release from the endothelium. We showed that A1-mediated NO release requires extracellular Ca2+, phospholipase A2 (PLA2) and ATP-sensitive K+ (KATP) channel activation whereas A2A-mediated NO release requires extracellular Ca2+ and Ca2+-activated K+ (KCa) channels. Since our previous study showed that A1- and A2A-receptor-mediated NO release requires activation of adenylate cyclase (AC), we propose the following novel pathways. The K+ efflux resulting from A1-receptor-coupled KATP-channel activation facilitates Ca2+ influx which may cause some stimulation of endothelial NO synthase (eNOS). However, the increase in [Ca2+]i also stimulates PLA2 to liberate arachidonic acid and stimulate cyclooxygenase to generate prostacyclin (PGI2). PGI2 acts on its endothelial receptors to increase cAMP, so activating protein kinase A (PKA) to phosphorylate and activate eNOS resulting in NO release. By contrast, the K+ efflux resulting from A2A-coupled KCa channels facilitates Ca2+ influx, thereby activating eNOS and NO release. This process may be facilitated by phosphorylation of eNOS by PKA via the action of A2A-receptor-mediated stimulation of AC increasing cAMP. These pathways may be important in mediating vasodilatation during exercise and systemic hypoxia when adenosine acting in an endothelium- and NO-dependent manner has been shown to be important.
authors.affiliation: Department of Physiology, The Medical School, University of Birmingham, Birmingham B15 2TT, UK. c.j.ray@bham.ac.uk
authors.forename: Clare J
authors.initials: CJ
authors.lastname: Ray
authors.forename: Janice M
authors.initials: JM
authors.lastname: Marshall
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001030:Apamin / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000187:drug effects; D043683:Receptors, Adenosine A2 / Q000187:drug effects; D015290:Second Messenger Systems / Q000187:drug effects; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014227:Triazines; D014230:Triazoles; D014665:Vasodilator Agents; D014970:Xanthines; C097270:ZM 241385; C081565:arachidonyltrifluoromethane; D001030:Apamin; D009569:Nitric Oxide; C064719:iberiotoxin; C051360:1,3-dipropyl-8-cyclopentylxanthine; D010741:Phospholipases A; D054467:Phospholipases A2; D000241:Adenosine; D002118:Calcium