Down-regulation of nitric oxide production by ibuprofen in human volunteers.
Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production 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 in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen 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, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions.
Vandivier
R W
RW
Department of Critical Care Medicine Warren G. Magnusen Clinical Center, Office of Research Services, National Institutes of Health, Bethesda, Maryland, USA.
Eidsath
A
A
Banks
S M
SM
Preas
H L
HL
Leighton
S B
SB
Godin
P J
PJ
Suffredini
A F
AF
Danner
R L
RL
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000032:analysis; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D009566:Nitrates / Q000097:blood / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000502:physiology*; D015203:Reproducibility of Results; D016037:Single-Blind Method
D004731:Endotoxins; D009566:Nitrates; D002245:Carbon Dioxide; D009599:Nitroprusside; D009569:Nitric Oxide; D006152:Cyclic GMP; D007052:Ibuprofen