Endothelial cell-derived relaxing factor has been identified to be nitric oxide, and the pathway responsible for its synthesis in human cells has been elucidated. Further, antagonists of this pathway have been shown to increase blood pressure in animals challenged with tumor necrosis factor and endotoxin, important mediators of septic shock. In this investigation, the nitric oxide pathway is being examined in normal volunteers given endotoxin both intravenously and intrabronchially. To clarify the role of this pathway in human disease, we are looking for evidence of nitric oxide synthase induction during systemic and local inflammatory responses. The initial phase of this project began in normal volunteers given either sodium nitroprusside or endotoxin (Abstract, American Thoracic Society). Methods were developed to measure exhaled nitric oxide, and serum and urine nitrite/nitrate and cGMP concentrations. We found that sodium nitroprusside produced a fall in mean arterial pressure (MAP) and measurable increases in exhaled nitric oxide and urinary nitrite/nitrate. Endotoxin also produced a fall in MAP, and a measurable increase in nitric oxide production. Ibuprofen administration prevented the endotoxin-induced rise in nitric oxide production, but the fall in MAP was unaffected. These data suggest that blood pressure regulation after endotoxin administration is complex and not wholly dependent on changes in nitric oxide production (manuscript submitted, 1998).Current studies are examining the role of the nitric oxide pathway in pulmonary inflammation after intrabronchial administration of endotoxin. This produces a localized inflammatory response characterized by neutrophil recruitment and cytokine production. A protocol has received approval to examine how the administration of L-arginine, a nitric oxide precursor, alters the hemodynamic and inflammatory responses to endotoxin.
