Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha.
Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha.
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发表时间：
1997-08
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通讯作者：
E. D. Murray;W. Wechter;D. Kantoci;W. Wang;T. Pham;D. Quiggle;K. Gibson;D. Leipold;B. Anner
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作者：
E. D. Murray;W. Wechter;D. Kantoci;W. Wang;T. Pham;D. Quiggle;K. Gibson;D. Leipold;B. Anner
最近报道了可能是称为“利尿钠激素”的多因子复合物的潜在组分LLU-α的结构阐明和作用机制[Wechter，W. J.等人（1996 a）Proc.Natl. Acad. Sci. U.S.A. 93：6002-6007]。“利钠激素”，一种长期寻找的因子，被认为调节细胞外液体积，并因此是高血压、肝硬化、充血性心力衰竭和其他体积扩张状态的拟病理。本文报告的研究进一步表征了LLU-α。通过放射性标记研究证明内源性LLU-α的前体是γ-生育酚。输注的rac-LLU-α的药代动力学被证明是双相的（半衰期：12分钟和6小时）。用天然S-对映异构体作为最有效的已知抑制剂，而类似的α-生育酚代谢物rac-5-Me-LLU-α未显示出抑制作用，检查了Henle袢的粗升支的70 pS钾通道抑制的特异性。Rac-LLU-α不抑制Na+/K+-ATP酶的两种同工酶。LLU-α是通过抑制70 pS钾通道而不是Na+/K+-ATP酶（“利钠激素”的假定作用机制）发挥利钠作用的。“LLU-α是一种维生素的代谢产物，如果发现它在调节细胞外液体积中发挥作用，将是维生素作为激素前体的第二个例子。相当有趣的是，这份手稿报告了γ-生育酚的第一个生物活性，维生素E复合物的一个成员。
The structural elucidation and mechanism of action of a potential component, LLU-alpha, 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-alpha. The precursor of the endogenous LLU-alpha was demonstrated to be gamma-tocopherol by radiolabeling studies. The pharmacokinetics of infused rac-LLU-alpha 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 natural S-enantiomer being the most potent known inhibitor whereas the analogous alpha-tocopherol metabolite, rac-5-Me-LLU-alpha, showed no inhibition. Rac-LLU-alpha does not inhibit two isozymes of the Na+/K+-ATPase. LLU-alpha 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-alpha, 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 gamma-tocopherol, a member of the vitamin E complex.