Selective inhibition of receptor-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury

We hypothesized that pulmonary vasorelaxation mediated by receptors that require generation of cyclic adenosine monophosphate (cAMP) is impaired 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 purinoreceptor stimulation (response to adenosine diphosphate, ADP), 3) H-2-histamine receptor stimulation (response to dimaprit), 4) adenosine 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 impaired 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 vasoconstriction. On the other hand, the response to A(2) receptor stimulation (ADO) and EP(2) receptor stimulation (PGE(1)) was normal. The dose response to direct adenylate cyclase stimulation (FSK) was the same as control except at a single concentration (10(-7) M). These data suggest that endotoxin causes selective impairment of pulmonary vasorelaxation through receptors coupled to cAMP generation. This impaired pulmonary vasorelaxation may contribute to the increased pulmonary vascular resistance seen in acute lung injury. These data may lead to therapy that will prevent or improve the pathophysiologic pulmonary circulation in acute lung injury.