A(1) ADENOSINE RECEPTOR ANTAGONISTS BLOCK ISCHEMIA-REPERFUSION INJURYOF THE LUNG

Ischemia-reperfusion (I-R) injury of the lung occurs after lung transp lantation, pulmonary thromboembolectomy, or cardiopulmonary bypass. In the heart, adenosine, A(1) adenosine receptor agonists, and a brief p eriod of preconditioning ischemia attenuate I-R injury. Moreover, in t he lung, thromboxane is released during ischemia and is an important m ediator of l-R injury. We previously reported that adenosine produces vasoconstriction in the feline pulmonary vascular bed by acting on A(1 ) receptors to induce the release of thromboxane and that these vasoco nstrictor responses are desensitized by low doses of A(1) receptor ago nists. Because A(1) receptor agonists mimic the effect of precondition ing ischemia, we hypothesized, in contrast to previously proposed mech anisms, that small amounts of adenosine released during preconditionin g ischemia desensitize A(1) receptors. Also, we hypothesized that grea ter amounts of adenosine are released after longer periods of ischemia , which activate Al receptors. Thus if desensitization of A(1) recepto rs is the mechanism by which preconditioning attenuates I-R injury of the heart and A(1) receptor activation during ischemia plays an import ant role in I-R injury of the lung, A(1) receptor antagonists should p rovide 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 c aused alveolar edema, which was blocked in a highly significant manner by the A(1) receptor antagonists xanthine amine congener (XAC) and 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX). An intralobar arterial infus ion of XAC (30 min before ischemia) reduced the %injured alveoli (defi ned as presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 60 +/- 10 to 7 +/- 2%, which was not significantly differe nt from controls (5 +/- 1%; P < 0.0001). DPCPX (iv) reduced the %injur ed alveoli to 13 +/- 7% when administered 30 min before ischemia and t o 6 +/- 2% when administered after 1 h of reperfusion, not significant ly different from controls (P < 0.0001). Preconditioning ischemia (10- min ischemia+ 10-min reperfusion) also reduced the %injured alveoli af ter 2 h ischemia and 2 h reperfusion to 23 +/- 13%, almost identical t o 2 h ischemia and 1 h reperfusion. These data support the hypothesis that A(1) receptor antagonists block I-R injury of the lung. A(1) rece ptor antagonists may be useful in preventing I-R injury after transpla nt surgery and during surgical procedures associated with I-R injury o f the heart, brain, kidney, and spinal cord.