ENDOGENOUS NATRIURETIC FACTORS .7. BIOSPECIFICITY OF A NATRIURETIC GAMMA-TOCOPHEROL METABOLITE LLU-ALPHA

The structural elucidation and mechanism of action of a potential comp onent, LLU-alpha, of what is possibly a multifactorial complex known a s ''natriuretic hormone'' was recently reported [Wechter, W.J. et al. (1996a) Proc. Natl. Acad. Sci. U.S.A. 93: 6002-6007]. ''Natriuretic ho rmone,'' a long-sought factor, is believed to regulate extracellular f luid volume and consequently be pathomimetic for hypertension, cirrhos is, congestive heart failure and other volume expanded states. The stu dies reported herein further characterize LLU-alpha. The precursor of the endogenous LLU-alpha was demonstrated to be gamma-tocopherol by ra diolabeling studies. The pharmacokinetics of infused rac-LLU-alpha pro ved to be biphasic (half-lives: 12 min and 6 h). Specificity of the in hibition of the 70 pS potassium channel of the thick ascending limb of the loop of Henle was examined with the natural S-enantiomer being th e most potent known inhibitor whereas the analogous alpha-tocopherol m etabolite, rac-5-Me-LLU-alpha, showed no inhibition. Rac-LLU-alpha doe s not inhibit two isozymes of the Na+/K+-ATPase. LLU-alpha is natriure tic acting via inhibition of the 70 pS potassium channel and not Na+/K +-ATPase, the assumed mechanism of action of the ''natriuretic hormone .'' LLU-alpha, a metabolite of a vitamin, if it were found to play a r ole in the regulation of extracellular fluid volume, would be the seco nd example of a vitamin acting as a precursor for a hormone. Of consid erable interest is the fact that this manuscript reports the first bio logical activity of gamma-tocopherol, a member of the vitamin E comple x.