Goodfriend Theodore L, Ball Dennis L, Egan Brent M, Campbell William B, Nithipatikom Kasem
William S. Middleton Memorial Veterans Hospital and Department of Medicine of the University of Wisconsin 53705, USA.
Hypertension. 2004 Feb;43(2):358-63. doi: 10.1161/01.HYP.0000113294.06704.64. Epub 2004 Jan 12.
Plasma levels of aldosterone are not always predictable from the activity of renin and the concentration of potassium. Among the unexplained are elevated levels of aldosterone in some obese humans. Obesity is characterized by increased plasma fatty acids and oxidative stress. We postulated that oxidized fatty acids stimulate aldosteronogenesis. The most readily oxidized fatty acids are the polyunsaturated, and the most abundant of those is linoleic acid. We tested oxidized derivatives of linoleic acid for effects on rat adrenal cells. One derivative, 12,13-epoxy-9-keto-10(trans)-octadecenoic acid (EKODE), was particularly potent. EKODE stimulated aldosteronogenesis at concentrations from 0.5 to 5 micromol/L, and inhibited aldosteronogenesis at higher doses. EKODE's stimulatory effect was most prominent when angiotensin and potassium effects were submaximal. The lipid's mechanism of action was on the early pathway leading to pregnenolone; its action was inhibited by atrial natriuretic peptide. Plasma EKODE was measured by liquid chromatography/mass spectrometry. All human plasmas tested contained EKODE in concentrations ranging from 10(-9) to 5x10(-7) mol/L. In samples from 24 adults, levels of EKODE correlated directly with aldosterone (r=0.53, P=0.007). In the 12 blacks in that cohort, EKODE also correlated with body mass index and systolic pressure. Those other correlations were not seen in white subjects. The results suggest that oxidized derivatives of polyunsaturated fatty acids other than arachidonic are biologically active. Compounds like EKODE, derived from linoleic acid, may affect adrenal steroid production in humans and mediate some of the deleterious effects of obesity and oxidative stress, especially in blacks.
醛固酮的血浆水平并不总是能根据肾素活性和钾浓度来预测。一些肥胖人群中醛固酮水平升高的原因尚不明朗。肥胖的特征是血浆脂肪酸增加和氧化应激。我们推测氧化脂肪酸会刺激醛固酮生成。最容易被氧化的脂肪酸是多不饱和脂肪酸，其中最丰富的是亚油酸。我们测试了亚油酸的氧化衍生物对大鼠肾上腺细胞的影响。一种衍生物，12,13-环氧-9-酮-10（反式）-十八碳烯酸（EKODE），特别有效。EKODE在0.5至5微摩尔/升的浓度下刺激醛固酮生成，而在更高剂量下则抑制醛固酮生成。当血管紧张素和钾的作用未达到最大值时，EKODE的刺激作用最为显著。这种脂质的作用机制是作用于导致孕烯醇酮生成的早期途径；其作用被心钠素抑制。通过液相色谱/质谱法测量血浆EKODE。所有测试的人体血浆中都含有浓度范围为10^(-9)至5×10^(-7)摩尔/升的EKODE。在24名成年人的样本中，EKODE水平与醛固酮直接相关（r = 0.53，P = 0.007）。在该队列中的12名黑人中，EKODE也与体重指数和收缩压相关。在白人受试者中未观察到这些其他相关性。结果表明，除花生四烯酸外的多不饱和脂肪酸的氧化衍生物具有生物活性。源自亚油酸的EKODE等化合物可能会影响人类肾上腺类固醇的产生，并介导肥胖和氧化应激的一些有害影响，尤其是在黑人中。
