Phase I: This research project is designed to determine the effects of increasing physiological stresses on renal prostogladin (PG) production and kidney function in highly trained young men and women. Exercise, salt restriction, and/or dehydration cause transient reductions in renal functions that may be buffered by vasodilatory prostoglandins (PGs). Over the counter (OTC) analgesics have the potential to alter renal hemodynamics by inhibiting renal PGs. Therefore, we propose to test the renal effects of maximal OTC doses of acetominophen (ACET, 4 g/d) and ibuprofen (IBU, 1.2 g/d) vs a placebo (PL) in humans subjected to progressive renal stresses. ACET is thought to have minimal peripheral activity and would therefore not be predicted to adversely effect renal function in a renal PG-dependent state. Conversely, IBU has been previously shown to inhibit renal PGs and therefore has the potential to adversely effect renal function in certain pathological and physiological states. Accordingly, 12 fit young (<30 years) men and women will undergo three days of a low (10 mEq/d) Na+ diet while taking one of the drugs or PL (separate trials, random order). Day 4 will involve mild dehydration (approximately 1.5% of bodyweight) followed by 45 minutes of submaximal treadmill exercise (65% VO2max) in the heat (36 degrees C). These combined stressors are predicted to cause decreases in ERPF, GFR, and Na+ excretion. It is hypothesized that renal function will be impaired to a greater extent during the IBU trial as compared to the ACET and PL trials. All data has been collected and a manuscript is being finalized for publication. The results, indicate that, as predicted, OTC IBU had small but statistically significant effects on renal function in a sodium- and volume- depleted state. OTC ACET was associated with no such effects. Future Plans: Renal function during exercise is being measured in a cohort of older and younger women (phase II) in order to determine the renal effects of OTC NSAID use during exercise. Also, the well known age-related decline in the ability to reabsorb sodium and the potential for NSAIDs to further compromise sodium balance is being investigated (phase III) in older and younger women.Pase II: Clinical case studies have linked nonsteroidal anti- inflammatory drugs (NSAIDs) to acute renal failure during exercise in the heat. NSAIDs such as ibuprofen hve been shown to inhibit renal prostoglandins (PGs). Renal PGs are synthesized in the medulla and cortex of the kidney (from arachadonic acid, via cyclooxygenase) and exert a vasodilatory action on the efferent and afferent arteriols. Under resting conditions, PG inhibition with an NSAID has no appreciable effect on renal function because basal vasoconstriction tone is low. However, during exercise, there is both neural and endocrine stimuli (i.e., increases in sympathetic outflow and angiotension II) causing vasoconstriction. This causes abrupt decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) that is blunted by PGs. Therefore, PG inhibition with ibuprofen will have a deleterious effect on renal function. There is limited experimental data describing this phenomenon in younger subjects. Aging would be predicted to enhance the nephrotoxic effects of NSAIDs but there is no experimental data to support this statement. Eight older and eight younger women will be recruited for this study (men secrete PGs of non-renal origen in the urine, therefor, PG excretion does not equal renal PG synthesis, as it does in female subjects). EAch subject will complete 2 separate 1 day trials. A maximal over the counter dose of ibuprofen will be given in one of the trials and a placebo in the other (randomly assigned, double blind). Renal function (GFR, RPF, Na+/K+ excretion) will be determined at rest and during a submaximal exercise bout in the heat (treadmill exercise, 60% VO2max for 45 minutes). PG excretion will be measured in order to determine the degree to which renal PGs are inhibited with ibuprofen. Statistical comparisons of older vs younger subjects as well as ibuprofen vs placebo will be made using analysis of variance with repeated measures. This proposed investigation will test the following three hypotheses: 1) PG inhibition with ibuprofen will not alter resting renal function in older or younger subjects, 2) during exercise, PG inhibition will cause greater (transient) reductions in renal function than a placebo in older subjects and 3) inhibition of PGs will play a relatively greater role in altering renal function during exercise in older subjects. This will be shown by a greater decrease in renal function (as measured by GFR and RPF) in older vs younger subjects during the ibuprofen trial.
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