ADENOSINE A(2) RECEPTORS REVERSE ISCHEMIA-REPERFUSION LUNG INJURY INDEPENDENT OF BETA-RECEPTORS

To evaluate the adenosine systems ability to reverse the endothelial damage produced by ischemia and reperfusion (I/R), we studied several different selective adenosine-receptor agonists and antagonists, a protein kinase A inhibitor, and a beta-adrenoreceptor antagonist in isolated buffer-perfused rat lungs. I/R (45 min/105 min) produced a sixfold increase in endothelial permeability as measured by the capillary filtration coefficient. Both a selective A(2)-receptor agonist (CGS-21680, 300 nM) and a beta-receptor agonist (isoproterenol, 10 mu M) reversed the increased microvascular permeability. A nonselective adenosine-receptor antagonist (SPT, 20 mu M) and a selective A(1)-receptor antagonist (DPCPX, 10 nM) had no effect on increased microvascular permeability. Also, isoproterenol and CGS-21680 reversed the damage being introduced after a selective A(1)-receptor agonist (CCPA, 100 nM.). The nonspecific adenosine A(1)- and A(2)-receptor agonist NECA (12 nM) appeared to desensitize the A(2) receptors and a protein kinase A inhibitor, adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS, 100 mu M), blocked the reversal of endothelial damage by isoproterenol or A(2)-receptor agonist; Propranolol (100 mu M) blocked the effect of isoproterenol but not the effect of CGS-21680. From this study we conclude that A(2)-receptor activation reverses endothelial damage associated with I/R by a mechanism independent-of beta-receptors or G(i) protein. However, a protein kinase A-3',5',-cyclic adenosine monophosphate pathway is activated by both the adenosine systems and beta-receptor activation.