Abstract
Depression of GFR and antinatriuresis in response to high chloride has been linked to a cyclooxygenase (COX)-dependent mechanism involving thromboxane A2 (TxA2) and prostaglandin endoperoxide (PGH2), because inhibition of COX prevented the fall in GFR and antinatriuresis produced by hyperchloremia. However, hyperchloremia did not increase, but unexpectedly decreased, renal prostaglandin and TxA2 efflux (Yin et al., 1995). To resolve questions regarding the role of eicosanoids in mediating the renal functional effects of high chloride (117 mM), by stimulating either TxA2 synthesis or TxA2/PGH2 receptors, we compared the ability of indomethacin to block high-chloride effects in the rat isolated kidney with that of BMS 180291 and SQ 29548, antagonists of the TxA2/PGH2 receptor. These antagonists differ in terms of their selectivity and their capacity to inhibit isoforms of the TxA2/PGH2 receptor. Indomethacin and SQ 29548 had identical actions, preventing the decrease of GFR and antinatriuresis evoked by hyperchloremia, e.g., sodium excretion rate in the SQ 29548 and indomethacin groups increased to 7.2 ± 1.3 and 7.1 ± 1.2 μEq/min, respectively, compared with 2.6 ± 0.7 μEq/min in the control group. In contrast, neither BMS 180291 nor the TxA2 synthase inhibitors, OKY 046 and CGS 13080, modified the negative effects of high chloride on GFR or sodium excretion. These results argue against either TxA2 or PGH2 acting as mediator of the effects of high chloride on renal function and suggest a product of COX activity such as a 20-HETE analog of prostaglandin endoperoxide. Evidence to support this proposal was obtained: 1) Hyperchloremia increased 20-HETE release from the rat kidney by 2-fold when compared with low-chloride conditions of renal perfusion. 2) The renal vasoconstrictor action of 20-HETE was shown to be dependent on COX activity and to be antagonized by blockade of the TxA2/PGH2 receptor.
Footnotes
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Send reprint requests to: John C. McGiff, M.D., Professor and Chairman, Department of Pharmacology, New York Medical College, Valhalla, NY 10595.
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↵1 This work was supported by grants from the National Heart, Lung and Blood Institute, RO1-HL-25394, and The American Heart Association, New York Affiliate, 91-014G and 94-318.
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↵2 Part of this work has been presented in abstract form at the 48th Conference for High Blood Pressure, 1994.
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↵3 Current address: SmithKline Beecham, 709 Swedeland Rd., P.O. Box 1539, King of Prussia, PA 19406.
- Abbreviations:
- COX
- cyclooxygenase
- TxA2
- thromboxane A2
- TxB2
- thromboxane B2
- PGH2
- prostaglandin endoperoxide
- 20-HETE
- 20-hydroxyeicosatetraenoic acid
- AA
- arachidonic acid
- 5
- 6-EET, 5,6-eicosatrienoic acid
- GC/MS
- gas chromatography mass spectrometry
- RVR
- renal vascular resistance
- Received April 15, 1996.
- Accepted March 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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