A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung

Ischemia-reperfusion (I-R) injury of the lung occurs after lung transplantation, pulmonary thromboembolectomy, or cardiopulmonary bypass. In the heart, adenosine, A1 adenosine receptor agonists, and a brief period of preconditioning ischemia attenuate I-R injury. Moreover, in the lung, thromboxane is released during ischemia and is an important mediator of I-R injury. We previously reported that adenosine produces vasoconstriction in the feline pulmonary vascular bed by acting on A1 receptors to induce the release of thromboxane and that these vasoconstrictor responses are desensitized by low doses of A1 receptor agonists. Because A1 receptor agonists mimic the effect of preconditioning ischemia, we hypothesized, in contrast to previously proposed mechanisms, that small amounts of adenosine released during preconditioning ischemia desensitize A1 receptors. Also, we hypothesized that greater amounts of adenosine are released after longer periods of ischemia, which activate A1 receptors. Thus if desensitization of A1 receptors is the mechanism by which preconditioning attenuates I-R injury of the heart and A1 receptor activation during ischemia plays an important role in I-R injury of the lung, A1 receptor antagonists should provide a protective effect in I-R injury of the lung. In this study, 2 h of ischemia and 2 h of reperfusion of the left lower lobe in intact-chest, spontaneously breathing cats caused lung injury characterized by the presence of neutrophils, macrophages, and RBCs in alveoli and caused alveolar edema, which was blocked in a highly significant manner by the A1 receptor antagonists xanthine amine congener (XAC) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). An intralobar arterial infusion of XAC (30 min before ischemia) reduced the %injured alveoli (defined as presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 60 +/- 10 to 7 +/- 2%, which was not significantly different from controls (5 +/- 1%; P < 0.0001). DPCPX (iv) reduced the %injured alveoli to 13 +/- 7% when administered 30 min before ischemia and to 6 +/- 2% when administered after 1 h of reperfusion, not significantly different from controls (P < 0.0001). Preconditioning ischemia (10-min ischemia +10-min reperfusion) also reduced the %injured alveoli after 2 h ischemia and 2 h reperfusion to 23 +/- 13%, almost identical to 2 h ischemia and 1 h reperfusion. These data support the hypothesis that A1 receptor antagonists block I-R injury of the lung. A1 receptor antagonists may be useful in preventing I-R injury after transplant surgery and during surgical procedures associated with I-R injury of the heart, brain, kidney, and spinal cord.