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Vol. 289, Issue 2, 735-741, May 1999
The EUPenn Group of Investigators at the Center for Experimental
Therapeutics, 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
F1
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.
0022-3565/99/2892-0735$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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F. Catella-Lawson, M. P. Reilly, S. C. Kapoor, A. J. Cucchiara, S. DeMarco, B. Tournier, S. N. Vyas, and G. A. FitzGerald Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin N. Engl. J. Med., December 20, 2001; 345(25): 1809 - 1817. [Abstract] [Full Text] [PDF]
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S. Verma, S. R. Raj, L. Shewchuk, K. J. Mather, and T. J. Anderson Cyclooxygenase-2 Blockade Does Not Impair Endothelial Vasodilator Function in Healthy Volunteers: Randomized Evaluation of Rofecoxib Versus Naproxen on Endothelium-Dependent Vasodilatation Circulation, December 11, 2001; 104(24): 2879 - 2882. [Abstract] [Full Text] [PDF]
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J. P. Killen, C. M. Nzerue, S. A. Rich, G. A. FitzGerald, and C. Patrono The Coxibs, Selective Inhibitors of Cyclooxygenase-2 N. Engl. J. Med., December 6, 2001; 345(23): 1708 - 1709. [Full Text] [PDF]
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 G. E. Caughey, L. G. Cleland, P. S. Penglis, J. R. Gamble, and M. J. James Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2 J. Immunol., September 1, 2001; 167(5): 2831 - 2838. [Abstract] [Full Text] [PDF]
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 F. Catella-Lawson Vascular biology of thrombosis: Platelet-vessel wall interactions and aspirin effects Neurology, September 1, 2001; 57(90002): S5 - 7. [Abstract] [Full Text]
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D. Mukherjee, S. E. Nissen, and E. J. Topol Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors JAMA, August 22, 2001; 286(8): 954 - 959. [Abstract] [Full Text] [PDF]
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G. A. FitzGerald and C. Patrono The Coxibs, Selective Inhibitors of Cyclooxygenase-2 N. Engl. J. Med., August 9, 2001; 345(6): 433 - 442. [Full Text] [PDF]
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M. D. Fernandez, J. L. Z. Garcia, F. D. Garcia, S. Gupta, C. Bombardier, L. Laine, and A. Reicin Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen N. Engl. J. Med., May 3, 2001; 344(18): 1398 - 1399. [Full Text] [PDF]
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I. A. Mardini and G. A. FitzGerald Selective Inhibitors of Cyclooxygenase-2: A Growing Class of Anti-Inflammatory Drugs Mol. Interv., April 1, 2001; 1(1): 30 - 38. [Abstract] [Full Text]
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 M Ostensen and P M Villiger Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus Lupus, March 1, 2001; 10(3): 135 - 139. [Abstract] [PDF]
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 D. Praticò, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 1, 2001; (2001) 61607398. [Abstract] [Full Text]
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J. D. Imig Eicosanoid regulation of the renal vasculature Am J Physiol Renal Physiol, December 1, 2000; 279(6): F965 - F981. [Abstract] [Full Text] [PDF]
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M ostensen and P M Villiger Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus Lupus, October 1, 2000; 9(8): 566 - 572. [Abstract] [PDF]
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 S. J. Vane Aspirin and other anti-inflammatory drugs Thorax, October 1, 2000; 55(90002): 3S - 9. [Full Text]
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 F. A. Wollheim Selective Cox-2 inhibition in man--therapeutic breakthrough or cosmetic advance? Rheumatology, September 1, 2000; 39(9): 935 - 938. [Full Text] [PDF]
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O. Belton, D. Byrne, D. Kearney, A. Leahy, and D. J. Fitzgerald Cyclooxygenase-1 and -2-Dependent Prostacyclin Formation in Patients With Atherosclerosis Circulation, August 22, 2000; 102(8): 840 - 845. [Abstract] [Full Text] [PDF]
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 S. K. Swan, D. W. Rudy, K. C. Lasseter, C. F. Ryan, K. L. Buechel, L. J. Lambrecht, M. B. Pinto, S. C. Dilzer, O. Obrda, K. J. Sundblad, et al. Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet: A Randomized, Controlled Trial Ann Intern Med, July 4, 2000; 133(1): 1 - 9. [Abstract] [Full Text] [PDF]
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L. P. Audoly, B. Rocca, J.-E. Fabre, B. H. Koller, D. Thomas, A. L. Loeb, T. M. Coffman, and G. A. FitzGerald Cardiovascular Responses to the Isoprostanes iPF2{alpha}-III and iPE2-III Are Mediated via the Thromboxane A2 Receptor In Vivo Circulation, June 20, 2000; 101(24): 2833 - 2840. [Abstract] [Full Text] [PDF]
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A. Whelton, G. Schulman, C. Wallemark, E. J. Drower, P. C. Isakson, K. M. Verburg, and G. S. Geis Effects of Celecoxib and Naproxen on Renal Function in the Elderly Arch Intern Med, May 22, 2000; 160(10): 1465 - 1470. [Abstract] [Full Text] [PDF]
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W. Young, K. Mahboubi, A. Haider, I. Li, and N. R. Ferreri Cyclooxygenase-2 Is Required for Tumor Necrosis Factor-{alpha}- and Angiotensin II-Mediated Proliferation of Vascular Smooth Muscle Cells Circ. Res., April 28, 2000; 86(8): 906 - 914. [Abstract] [Full Text] [PDF]
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P. E. Lipsky, P. Brooks, L. J. Crofford, R. DuBois, D. Graham, L. S. Simon, L. B. A. van de Putte, and S. B. Abramson Unresolved Issues in the Role of Cyclooxygenase-2 in Normal Physiologic Processes and Disease Arch Intern Med, April 10, 2000; 160(7): 913 - 920. [Abstract] [Full Text] [PDF]
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E. M. Smyth, S. C. Austin, M. P. Reilly, and G. A. FitzGerald Internalization and Sequestration of the Human Prostacyclin Receptor J. Biol. Chem., October 6, 2000; 275(41): 32037 - 32045. [Abstract] [Full Text] [PDF]
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G. E. Caughey, L. G. Cleland, J. R. Gamble, and M. J. James Up-regulation of Endothelial Cyclooxygenase-2 and Prostanoid Synthesis by Platelets. ROLE OF THROMBOXANE A2 J. Biol. Chem., October 5, 2001; 276(41): 37839 - 37845. [Abstract] [Full Text] [PDF]
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D. Pratico, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 13, 2001; 98(6): 3358 - 3363. [Abstract] [Full Text] [PDF]
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