The clinical benefits and adverse effects of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) derive from inhibition of the enzyme cyclooxygenase (Cox).Two isoforms of Cox are recognized: Cox-1, which is constitutively expressed in platelets, in the gastric mucosa and in most tissues where it is thought to exert """"""""housekeeping"""""""" functions, and Cox-2 which is commonly termed """"""""inducible"""""""", because it is transiently expressed in response to inflammatory mediators, tumor promoters and growth factors. Conventional NSAIDs inhibit both Cox-1 and Cox-2 with limited selectivity. It is generally assumed that their anti-inflammatory and analgesic activity is mediated via Cox-2 inhibition. Inhibition of Cox-1, by contrast, is thought responsible for the gastric toxicity and bleeding complications associated with NSAID treatment. It is unclear whether NSAID-induced renal toxicity is attributable to inhibition of Cox-1 or Cox-2. The intrarenal distribution and regulation of Cox-2 by sodium intake in rats, suggest a potential role for this enzyme in salt and water balance. Additionally, inactivation of Cox-2 by gene targeting in mice results in severe developmental nephropathy. Inhibitors of Cox-2 have been developed with the rationale that these compounds would exert anti- inflammatory activity without the adverse gastric effects and increased bleeding risk associated with non-selective NSAID treatment. The present study will be undertaken to assess the effects of L748,731, a selective Cox-2 inhibitor, during chronic administration to elderly subjects, the population most susceptible to NSAID-induced nephrotoxicity. Healthy older adults (59 to 80 years of age; n=36) will be admitted to the Clinical Research Center, placed on a constant diet (200 mEq sodium daily) and randomized under double blind conditions to receive the selective Cox-2 inhibitor, L748,731, 50 mg qd, a non-selective Cox-1/Cox-2 inhibitor, indomethacin 50 mg tid, or placebo for two weeks. Sodium excretion and other indices of renal function will be assessed under conditions of controlled sodium intake. It is hypothesized that selective inhibition of Cox-2 would fail to reduce urinary 11-dehydro TXB2 (TX-M) and serum TXB2, indices of Cox-1 dependent thromboxane biosynthesis by platelets. It is also postulated that Cox-2 inhibition would not affect the urinary excretion of 2,3 dinor 6-keto PGF1a (PGI- M), the major metabolite of prostacyclin in vivo.

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