Endogenous Natriuretic Factors 7: Biospecificity of a Natriuretic γ-Tocopherol Metabolite LLU-α1
- E. David Murray, Jr.1,
- William J. Wechter1,
- Darko Kantoci1,
- Wen-Hui Wang2,
- Tim Pham1,
- David D. Quiggle1,
- Karina M. Gibson1,
- Douglas Leipold1 and
- Beatrice M. Anner3
- 1Laboratory of Chemical Endocrinology, Loma Linda University School of Medicine, Loma Linda, California (E.D.M. Jr., W.J.W., D.K., T.P., D.D.Q., K.M.G., D.L.), 2Department of Pharmacology, New York Medical College, Valhalla, New York (W.-H.W.) and 3Department of Pharmacology, Geneva University School of Medicine, Geneva, Switzerland (B.M.A.)
Abstract
The structural elucidation and mechanism of action of a potential component, LLU-α, of what is possibly a multifactorial complex known as “natriuretic hormone” was recently reported [Wechter, W.J.et al. (1996a) Proc. Natl. Acad. Sci. U.S.A. 93: 6002–6007]. “Natriuretic hormone,” a long-sought factor, is believed to regulate extracellular fluid volume and consequently be pathomimetic for hypertension, cirrhosis, congestive heart failure and other volume expanded states. The studies reported herein further characterize LLU-α. The precursor of the endogenous LLU-α was demonstrated to be γ-tocopherol by radiolabeling studies. The pharmacokinetics of infused rac-LLU-α proved to be biphasic (half-lives: 12 min and 6 h). Specificity of the inhibition of the 70 pS potassium channel of the thick ascending limb of the loop of Henle was examined with the naturalS-enantiomer being the most potent known inhibitor whereas the analogous α-tocopherol metabolite,rac-5-Me-LLU-α, showed no inhibition.Rac-LLU-α does not inhibit two isozymes of the Na+/K+-ATPase. LLU-α is natriuretic acting via inhibition of the 70 pS potassium channel and not Na+/K+-ATPase, the assumed mechanism of action of the “natriuretic hormone.” LLU-α, a metabolite of a vitamin, if it were found to play a role in the regulation of extracellular fluid volume, would be the second example of a vitamin acting as a precursor for a hormone. Of considerable interest is the fact that this manuscript reports the first biological activity of γ-tocopherol, a member of the vitamin E complex.
Footnotes
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Send reprint requests to: William J. Wechter, Ph.D., FCP, Laboratory of Chemical Endocrinology, Room 1512, Department of Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92350.
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↵1 This work was supported by Adventist Health Systems/Loma Linda (E.D.M., D.K., W.J.W.) and the National Institutes of Health (W.-H.W; grants DK 47402 and HL 34300) and Swiss National Science Foundation (B.M.A.; grant 31–37-552.93).
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↵2 The kinetic constants are:k 1 = 5.56 × 10−2 min−1;a = 118,000 cpm; k 2 = 1.82 × 10−3min−1; and b = 26,900 cpm. From the single-animal pilot experiment the first-phase half-life is 10.9 min and the second-phase half-life is 6 h in close agreement with the reported experiment.
- Abbreviations:
- TAL
- thick ascending limb
- MDBK
- Madin-Darby bovine kidney
- HPLC
- high-performance liquid chromatography
- 5-Me-LLU-α
- 5-methyl–LLU-α
- PBS
- phosphate-buffered saline
- Hepes
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
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- Received December 6, 1996.
- Accepted April 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
