SELECTIVE-INHIBITION OF RECEPTOR-MEDIATED PULMONARY VASORELAXATION INENDOTOXIN-INDUCED ACUTE LUNG INJURY

We hypothesized that pulmonary vasorelaxation mediated by receptors th at require generation of cyclic adenosine monophosphate (cAMP) is impa ired in endotoxin-induced acute lung injury. The purpose of this study was to determine the effect of endotoxin on the following pathways of pulmonary vasorelaxation that require the generation of cAMP: 1) beta -adrenoreceptor stimulation (response to isoproterenol, ISO), 2) P-2 p urinoreceptor stimulation (response to adenosine diphosphate, ADP), 3) H-2-histamine receptor stimulation (response to dimaprit), 4) adenosi ne A(2) receptor stimulation (response to adenosine, ADO), 5) type 2 E prostaglandin (EP(2)) receptor stimulation (response to prostaglandin E(1), PGE(1)), and 6) direct adenylate cyclase stimulation (response to forskolin, FSK). We used isolated pulmonary artery rings harvested from rats injected with endotoxin or saline. We found that endotoxin i mpaired the response to beta-adrenoreceptor stimulation (ISO) and P-2 purinoreceptor stimulation (ADP). Endotoxin converted the vasorelaxant effect of H-2-histamine receptor stimulation (dimaprit) to vasoconstr iction. On the other hand, the response to A(2) receptor stimulation ( ADO) and EP(2) receptor stimulation (PGE(1)) was normal. The dose resp onse to direct adenylate cyclase stimulation (FSK) was the same as con trol except at a single concentration (10(-7) M). These data suggest t hat endotoxin causes selective impairment of pulmonary vasorelaxation through receptors coupled to cAMP generation. This impaired pulmonary vasorelaxation may contribute to the increased pulmonary vascular resi stance seen in acute lung injury. These data may lead to therapy that will prevent or improve the pathophysiologic pulmonary circulation in acute lung injury.