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OtherRENAL PHARMACOLOGY

Comparison of the Water Diuretic Activity of KappaReceptor Agonists and a Vasopressin Receptor Antagonist in Dogs

David P. Brooks, Maurizio Valente, Giuseppe Petrone, P. Dennis Depalma, Massimo Sbacchi and Geoffrey D. Clarke
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1176-1183;
David P. Brooks
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Maurizio Valente
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Giuseppe Petrone
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P. Dennis Depalma
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Massimo Sbacchi
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Geoffrey D. Clarke
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Abstract

Strategies for developing selective water diuretic agents have involved development of kappa opioid receptor agonists and vasopressin V2 receptor antagonists; however, these two classes of compounds have not been compared directly. We have investigated the activity of three kappa receptor agonists and one nonpeptide vasopressin receptor antagonist in conscious dogs. SB 215520, SB 215519 and niravoline are selective kappaagonists with variable abilities to cause a water diuresis and ataxia in rats. When administered to conscious hydropenic dogs, thekappa agonists resulted in an increase in free water clearance; however, these effects were associated with an antinatriuresis, an increase in heart rate and, at the higher doses, central nervous system side effects. Conversely, the vasopressin receptor antagonist, OPC 31260, resulted in a significant water diuresis without any accompanying changes in sodium excretion and heart rate, and with no apparent central nervous system effects. These studies suggest that, at least in dogs, a vasopressin receptor antagonist is a more selective water diuretic than akappa receptor agonist.

Footnotes

  • Send reprint requests to: David P. Brooks, Ph.D., SmithKline Beecham, Dept. of Renal Pharmacology, UW2521, P.O. Box 1539, King of Prussia, PA 19406-0939.

  • Abbreviations:
    VP
    vasopressin
    DAMGO
    [d-Ala2,MePhe4,Gly-ol]enkephalin
    DPDPE
    [d-Pen2,d-Pen5]enkephalin
    • Received July 12, 1996.
    • Accepted November 25, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherRENAL PHARMACOLOGY

Comparison of the Water Diuretic Activity of KappaReceptor Agonists and a Vasopressin Receptor Antagonist in Dogs

David P. Brooks, Maurizio Valente, Giuseppe Petrone, P. Dennis Depalma, Massimo Sbacchi and Geoffrey D. Clarke
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1176-1183;

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OtherRENAL PHARMACOLOGY

Comparison of the Water Diuretic Activity of KappaReceptor Agonists and a Vasopressin Receptor Antagonist in Dogs

David P. Brooks, Maurizio Valente, Giuseppe Petrone, P. Dennis Depalma, Massimo Sbacchi and Geoffrey D. Clarke
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1176-1183;
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