Information has emerged in the last few years to suggest that nucleotides and their purinoceptors may be important in mediating the pathophysiology of endotoxin-induced acute lung injury. With the use of an adenosine receptor (A1) antagonist we will investigate the hypothesis that endotoxin produces acute pulmonary hypertension and thromboxane release by acting on an A1 receptor. In animals receiving a continuous intravenous infusion of endotoxin, with the use of a 5'-nucleotidase inhibitor, we will investigate the hypothesis that endotoxin produces persistent pulmonary hypertension by altering 5' nucleotidase activity thus favoring the formation of the proaggregatory nucleotide ADP and vascular thrombosis. We will also investigate the therapeutic value of a potent pulmonary vasodilator and inhibitor of ADP-induced platelet-aggregation, an adenosine receptor (A2) agonist-5'-N-ethylcarboxamidoadenosine (NECA) in the treatment of endotoxin induced pulmonary hypertension. These investigations of mechanisms of acute lug injury may lead to the development of pharmacological interventions that may reduce the mortality of this disease which remains at 50- 70%. Moreover, we have previously shown, under conditions of controlled blood flow nad left atrial pressure that adenosine and ATP produce dose-dependent and tone-dependent responses in the pulmonary vascular (PV) bed of the intact chest, spontaneously breathing cat. With the use of an adenosine receptor antagonist BWA1433U, we have demonstrated that the vasodilator responses of adenosine receptor does not mediate vasodilation produced by ATP. Using selective probes of purinoceptors, adenosine sensitive (P1), A1 and A2 receptors and ATP sensitive (P2), P2x and P2y receptors, an adenosine uptake inhibitor and other pharmacological probes, we will complete the pharmacological analysis of these receptors in the PV bed and identify their mechanisms of action. Because nucleotides are released locally, metabolized locally by stereoselective ectonucleotidases and act on their own local receptors, defining the mechanisms of how these autacoids effects vascular tone may lead to the development of a selective pulmonary vasodilator.
