Adenosine A2-receptor activation inhibits neutrophil-mediated injury to coronary endothelium.
Adenosine (ADO) attenuates polymorphonuclear neutrophil (PMN)-mediated damage, partly by inhibiting superoxide anion (O2-.) generation and PMN adherence to the coronary artery endothelium. This study tests the hypothesis that the antineutrophil effects of ADO are mediated by A2-receptor activation. Isolated canine PMN were activated by 100 nM platelet-activating factor (PAF). Compared with untreated activated PMN (100%), ADO attenuated O2-. production (46 +/- 9% of activated PMN), which was mimicked by the A2 agonist CGS-21680 (50 +/- 6% of activated PMN), unaltered by A1-selective antagonism with KW-3902 in the presence of ADO (40 +/- 7%), but blocked by combined A1-A2 blockade with 8-p-sulfophenyl theophylline (8-SPT, 94 +/- 14%). ADO reduced adherence of fluorescent PMN to endothelial surfaces of isolated canine coronary artery segments from 174 +/- 12 to 29 +/- 9/mm2 (P < 0.01), which was unaltered by A1 antagonism (35 +/- 7/mm2) but was reversed by 8-SPT (150 +/- 11/mm2). CGS-21680 inhibited adherence (48 +/- 8/mm2), comparable to that of ADO. Canine coronary artery rings were incubated with activated PMN to induce injury to the endothelium. The concentration of drug required to elicit 50% of maximal relaxation (-log M) derived from dose-relaxation responses to acetylcholine in PMN-damaged rings was significantly (P < 0.05) less in ADO-treated (6.88 +/- 0.08) and CGS-21680-treated (7.12 +/- 0.09) rings than untreated rings (6.54 +/- 0.10). This protection with ADO was reversed by inclusion of 8-SPT (6.49 +/- 0.12) but not KW-3902 (6.96 +/- 0.07). We conclude that ADO reduces PMN-induced coronary endothelial injury by A2-receptor-mediated inhibition of O2-. generation and adherence.
Department of Cardiothoracic Surgery, Bowman Gray School of Medicine, of Wake Forest University, Winston-Salem, North Carolina 27157, USA.
Z Q
ZQ
Zhao
H
H
Sato
M W
MW
Williams
A Z
AZ
Fernandez
J
J
Vinten-Johansen
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000473:pathology / Q000502:physiology; D002448:Cell Adhesion; D003331:Coronary Vessels / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D018047:Receptors, Purinergic P1; D013481:Superoxides; D000241:Adenosine