Activation of A3 adenosine receptors attenuates lung injury after in vivo reperfusion.
BACKGROUND
A3 adenosine receptor (AR) activation worsens or protects against renal and cardiac ischemia-reperfusion (IR) injury, respectively. The aims of the current study were to examine in an in vivo model the effect of A3AR activation on IR lung injury and investigate the mechanism by which it exerts its effect.


METHODS
The arterial branch of the left lower lung lobe in intact-chest, spontaneously breathing cats was occluded for 2 h and reperfused for 3 h (IR group). Animals were treated with the selective A3 receptor agonist IB-MECA (300 microg/kg intravenously) given 15 min before ischemia or with IB-MECA as described, with pretreatment 15 min earlier with the selective A3AR antagonist MRS-1191, the nonsulfonylurea adenosine triphosphate-sensitive potassium channel-blocking agent U-37883A, or the nitric oxide synthase inhibitor N-nitro-l-arginine benzyl ester.


RESULTS
IB-MECA markedly (P < 0.01) reduced the percentage of injured alveoli (IR, 48 +/- 4%; IB-MECA, 18 +/- 2%), wet:dry weight ratio (IR, 8.2 +/- 0.4; IB-MECA, 4 +/- 2), and myeloperoxidase activity (IR, 0.52 +/- 0.06 U/g; IB-MECA, 0.17 +/- 0.04 U/g). This protective effect was completely blocked by pretreatment with the selective A3AR antagonist MRS-1191 and the adenosine triphosphate-sensitive potassium channel blocking agent U-37883A but not the nitric oxide synthase inhibitor N-nitro-l-arginine benzyl ester.


CONCLUSIONS
In the feline lung, the A3AR agonist IB-MECA confers a powerful protection against IR lung injury. This effect is mediated by a nitric oxide synthase-independent pathway and involves opening of adenosine triphosphate-sensitive potassium channels. Therefore, selective activation of A3AR may be an effective means of protecting the reperfused lung.
Rivo
Julia
J
Department of Anesthesiology and Critical Care Medicine and the Laboratory of Experimental Surgery, Hadassah University Medical Center, The Hebrew University of Jerusalem, Israel.
Zeira
Evelyne
E
Galun
Eithan
E
Matot
Idit
I
D018528:ATP-Binding Cassette Transporters; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D002415:Cats; D004095:Dihydropyridines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006632:Histamine / Q000097:blood; D066298:In Vitro Techniques; D054086:KATP Channels; D008168:Lung / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*
D018528:ATP-Binding Cassette Transporters; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D054086:KATP Channels; C107728:MRS 1191; D009025:Morpholines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D019335:Nitroarginine; C082658:U 37883A; D006632:Histamine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000241:Adenosine; D000218:Adamantane