EFFECT OF MECLOFENAMATE OR KETOCONAZOLE ON THE NATRIURETIC RESPONSE TO INCREASED PRESSURE

Increases in renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion (DRIVE) decrease proximal sodium r eabsorption and increase urinary fractional sodium excretion (FE(Na)). This natriuretic response is blunted by inhibition of the cyclooxygen ase pathway. However, complicating the interpretation of the effects o f cyclooxygenase inhibition on sodium excretion are the following: (1) products of the other pathways of arachidonic acid metabolism, such a s the cytochrome P-450 metabolites, may be attenuated when cyclooxygen ase activity is reduced; (2) the proximal tubule has a high biosynthet ic capacity for cytochrome P-450 metabolites of arachidonic acid. Ther efore, the purpose of the present study was to compare blockade of the epoxygenase products of the cytochrome P-450 pathway with ketoconazol e to blockade of the cyclooxygenase pathway with meclofenamate on the natriuretic response to increased RIHP during DRIVE. RIHP, fractional excretion of lithium (FE(Li)), FE(Na), and glomerular filtration rate (GFR) were measured before and after DRIVE in control (n=6), meclofena mate-treated (n=6), and ketoconazole-treated (n=5) rats. DRIVE was ach ieved by infusing 100 mu l of 2.5% albumin solution directly into the renal interstitium. In control animals, DRIVE significantly increased RIHP (Delta 2.8+/-0.6 mm Hg), FE(Li) (Delta 13.4%+/-5.2%), and FE(Na) (Delta 1.29%+/-0.31%). In the ketoconazole-treated group, RIHP (Delta 3.9+/-0.8 mm Hg), FE(Li) (Delta 19.3%+/-2.0%), and FE(Na) (Delta 1.73% +/-0.43%) also significantly increased. However, the natriuretic respo nse to DRIVE was blunted during cyclooxygenose blockade with meclofena mate when compared with control or ketoconazole-treated animals (FE(Li ) (Delta 2.5%+/-1.4%, not significant) and FE(Na) (Delta 0.07%+/-0.18% , not significant)), even though the response of RIHP was intact (Delt a 4.5+/-0.4 mm Hg, P <0.001). These results suggest that the natriuret ic response to increased RIHP is dependent on the presence of, but not necessarily the increased synthesis of, products of cyclooxygenase ra ther than the cytochrome P-450 epoxygenase pathway for arachidonic aci d metabolism.