Document Detail

Effect of meclofenamate or ketoconazole on the natriuretic response to increased pressure.
MedLine Citation:
PMID:  8765216     Owner:  NLM     Status:  MEDLINE    
Increases in renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion (DRIVE) decrease proximal sodium reabsorption and increase urinary fractional sodium excretion (FENa). This natriuretic response is blunted by inhibition of the cyclooxygenase pathway. However, complicating the interpretation of the effects of cyclooxygenase inhibition on sodium excretion are the following: (1) products of the other pathways of arachidonic acid metabolism, such as the cytochrome P-450 metabolites, may be attenuated when cyclooxygenase activity is reduced; (2) the proximal tubule has a high biosynthetic capacity for cytochrome P-450 metabolites of arachidonic acid. Therefore, the purpose of the present study was to compare blockade of the epoxygenase products of the cytochrome P-450 pathway with ketoconazole to blockade of the cyclooxygenase pathway with meclofenamate on the natriuretic response to increased RIHP during DRIVE. RIHP, fractional excretion of lithium (FELi), FENa and glomerular filtration rate (GFR) were measured before and after DRIVE in control (n = 6), meclofenamate-treated (n = 6), and ketoconazole-treated (n = 5) rats. DRIVE was achieved by infusing 100 microL of 2.5% albumin solution directly into the renal interstitium. In control animals, DRIVE significantly increased RIHP (delta 2.8 +/- 0.6 mm Hg), FELi (delta 13.4% +/- 5.2%), and FENa (delta 1.29% +/- 0.31%). In the ketoconazole-treated group, RIHP (delta 3.9 +/- 0.8 mm Hg), FELi (delta 19.3% +/- 2.0%), and FENa (delta 1.73% +/- 0.43%) also significantly increased. However, the natriuretic response to DRIVE was blunted during cyclooxygenase blockade with meclofenamate when compared with control or ketoconazole-treated animals (FELi (delta 2.5% +/- 1.4%, not significant) and FENa (delta 0.07% +/- 0.18%, not significant), even though the response of RIHP was intact (delta 4.5 +/- 0.4 mm Hg, p < 0.001). These results suggest that the natriuretic response to increased RIHP is dependent on the presence of, but not necessarily the increased synthesis of, products of cyclooxygenase rather than the cytochrome P-450 epoxygenase pathway for arachidonic acid metabolism.
J A Haas; F G Knox
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of laboratory and clinical medicine     Volume:  128     ISSN:  0022-2143     ISO Abbreviation:  J. Lab. Clin. Med.     Publication Date:  1996 Aug 
Date Detail:
Created Date:  1996-12-10     Completed Date:  1996-12-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0375375     Medline TA:  J Lab Clin Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  202-7     Citation Subset:  AIM; IM    
Department of Physiology and Biophysics, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
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MeSH Terms
Cyclooxygenase Inhibitors / pharmacology*
Cytochrome P-450 Enzyme System / antagonists & inhibitors*
Glomerular Filtration Rate / drug effects
Hydrostatic Pressure
Ketoconazole / pharmacology*
Kidney / enzymology,  physiopathology
Lithium / metabolism
Meclofenamic Acid / pharmacology*
Natriuresis / drug effects*
Rats, Sprague-Dawley
Sodium / metabolism
Grant Support
Reg. No./Substance:
0/Cyclooxygenase Inhibitors; 644-62-2/Meclofenamic Acid; 65277-42-1/Ketoconazole; 7439-93-2/Lithium; 7440-23-5/Sodium; 9035-51-2/Cytochrome P-450 Enzyme System

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