Activation of A ₃ adenosine receptors attenuates lung injury after in vivo reperfusion

Background: A ₃ 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 A ₃AR 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 A ₃ receptor agonist IB-MECA (300 μg/kg intravenously) given 15 min before ischemia or with IB-MECA as described, with pretreatment 15 min earlier with the selective A ₃AR antagonist MRS-1191, the nonsulfonylurea adenosine triphosphate-sensitive potassium channel-blocking agent U-37883A, or the nitric oxide synthase inhibitor N ^w-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 A ₃AR antagonist MRS-1191 and the adenosine triphosphate-sensitive potassium channel blocking agent U-37883A but not the nitric oxide synthase inhibitor N ^wnitro-L-arginine benzyl ester. Conclusions: In the feline lung, the A ₃AR 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 A ₃AR may be an effective means of protecting the reperfused lung.