Abstract
Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxicity. The present study was undertaken to assess the renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomized under double-blind conditions to receive the specific Cox-2 inhibitor, MK-966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decline in urinary sodium excretion during the first 72 h of treatment. Blood pressure and body weight did not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1α was decreased by both MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a role in the systemic biosynthesis of prostacyclin in healthy humans. Selective inhibition of Cox-2 by MK-966 caused a clinically insignificant and transient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline in GFR. Our data suggest that acute sodium retention by nonsteroidal anti-inflammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1.
Footnotes
-
Send reprint requests to: Francesca Catella-Lawson, M.D., University of Pennsylvania, GCRC, 160 Dulles Building, 3400 Spruce St., Philadelphia, PA 19104. E-mail: francesca{at}spirit.GCRC.upenn.edu
-
↵1 This work was supported in part by Grants HL 57847 and M01RR00040 from the National Institutes of Health and by funds from Merck & Co. G.A.F. is the Robinette Foundation Professor of Cardiovascular Medicine. Abstracts have been presented at the Vascular Biology Meeting (American Heart Association) in San Francisco in April and at the Second International Workshop on Cox-2 in Maui in July of this year.
-
↵2 F.C-L. and B.M. have contributed equally to the design and execution of the study.
-
↵3 Present address: Vanderbilt University, Nashville, TN 37232.
- Abbreviations:
- Cox
- cyclooxygenase
- GFR
- glomerular filtration rate
- NSAID
- nonsteroidal inflammatory drug
- NICI-GC/MS
- negative ion chemical ionization–gas chromatography/mass spectrometry
- PG
- prostaglandin
- PGI2
- prostacyclin
- PGI-M
- 2,3-dinor-6-keto PGF1α
- TX
- thromboxane
- TX-M
- 11-dehydrothromboxane2
- TXB2
- thromboxane 2
- q.d.
- every day
- Received October 19, 1998.
- Accepted December 22, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|