Down-regulation of nitric oxide production by ibuprofen in human volunteers

Ibuprofen has been shown in vitro to modulate production of nitric oxide (N O), a mediator of sepsis-induced hypotension. We sought to determine whethe r ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validate d in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endot oxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blind ed, crossover design to 12 other subjects randomized to receive either ibup rofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressu re (MAP; P = .002) and increased alveolar NO flow rates (P = .04) and urina ry excretion of nitrite and nitrate (P = .07). In both endotoxemic and norm al subjects, ibuprofen blunted the small fall in MAP associated with bed re st (P = .005) and decreased alveolar NO flow rates (P = .03) and urinary ex cretion of nitrite and nitrate (P = .02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO producti on to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P = .002). These are the first i n vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibup rofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, s uggesting that the hemodynamic response to endotoxin is not completely depe ndent on NO under these conditions.