title: Adenosine inhibition of neutrophil damage during reperfusion does not involve K(ATP)-channel activation.
abstract: This study tests the hypothesis that cardioprotection exerted by adenosine A2-receptor activation and neutrophil-related events involves stimulation of ATP-sensitive potassium (K(ATP)) channels on neutrophils during reperfusion. The adenosine A2 agonist CGS-21680 (CGS) inhibited superoxide radical generation from isolated rabbit polymorphonuclear neutrophils (PMNs) in a dose-dependent manner from 17.7 +/- 2.1 to 7.4 +/- 1.3 nmol/5 x 10(6) PMNs (P < 0.05). Pinacidil, a K(ATP)-channel opener, partially inhibited superoxide radical production, which was completely reversed by glibenclamide (Glib). Incremental doses of Glib in combination with CGS (1 microM) did not alter CGS-induced inhibition of superoxide radical generation. CGS significantly reduced PMN adherence to the endothelial surface of aortic segments in a dose-dependent manner from 189 +/- 8 to 50 +/- 6 PMNs/mm2 (P < 0.05), which was also not altered by incremental doses of Glib. Infusion of CGS (0.025 mg/kg) before reperfusion reduced infarct size from 29 +/- 2% in the Vehicle group to 15 +/- 1% in rabbits undergoing 30 min of ischemia and 120 min of reperfusion (P < 0.05). Glib (0.3 mg/kg) did not change the infarct size (28 +/- 2%) vs. the Vehicle group and did not attenuate infarct size reduction by CGS (16 +/- 1%). Glib did not change blood glucose levels. Cardiac myeloperoxidase activity was decreased in the ischemic tissue of the CGS group (0.15 +/- 0.03 U/100 mg tissue) compared with the Vehicle group (0.37 +/- 0.05 U/100 mg tissue; P < 0.05). We conclude that adenosine A2 activation before reperfusion partially reduces infarct size by inhibiting neutrophil activity and that this effect does not involve K(ATP)-channel stimulation.
authors.affiliation: Department of Cardiothoracic Surgery, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1096, USA.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: J C
authors.initials: JC
authors.lastname: Todd
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: X L
authors.initials: XL
authors.lastname: Ma
authors.forename: J
authors.initials: J
authors.lastname: Vinten-Johansen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000201:enzymology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D015427:Reperfusion Injury / Q000473:pathology*; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D010627:Phenethylamines; D015221:Potassium Channels; D013481:Superoxides; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000255:Adenosine Triphosphate; D009195:Peroxidase; D003402:Creatine Kinase; D000241:Adenosine; D005905:Glyburide