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Strenuous exercise induces a marked reduction in renal hemodynamics. Prostaglandins (PG) play an important role in maintaining renal integrity in the face of hemodynamic changes. Inhibition of cyclooxygenase (COX) and thus PG formation can further compromise renal perfusion. The role of selective COX-2 inhibition on renal hemodynamics during exercise has not been investigated.Twelve healthy males (22–47 yr) took part in a randomized placebo controlled study investigating the effects of nonselective COX inhibition (indomethacin) and COX-2 selective inhibition (celecoxib) on renal hemodynamics during exercise. Renal blood flow (RBF), glomerular filtration rate (GFR), and free water clearance were measured using standard clearance techniques. Each experimental session was performed at least a week apart. The medications were taken for 36 h before study with the last dose at 0700 h on the day of study. Following baseline studies, each participant exercised for 30 min at 80% of their maximal aerobic power. Renal function was monitored for 2 h postrecovery.RBF and GFR fell by 40% after exercise with no significant difference between placebo, indomethacin, or celecoxib. Indomethacin (−2.43 ± 0.95 mL·min−1, P < 0.007) and celecoxib (−3.88 ± 0.94 mL·min−1, P < 0.0001) significantly reduced free water clearance compared with placebo during recovery.This study has confirmed that selective and nonselective COX inhibition can induce significant inhibition of free water clearance, indicating that these acute changes are regulated predominantly via COX-2. Acute cerebral edema with hyponatremia has been reported after major endurance sporting events. Identifiable risk factors include excessive hydration and use of NSAID. Impaired free water clearance during exercise potentiated by COX inhibition provides a pathophysiological explanation for these observations.