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.