11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat.
11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat.
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11 α-和 11 β-羟基孕酮是 11 β-羟基类固醇脱氢酶的有效抑制剂，在大鼠中具有致高血压活性。
DOI：
10.1161/01.hyp.27.3.421
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Morris,DJ
中科院分区：
文献类型：
--
作者：
Souness,GW;Morris,DJ
孕酮衍生物11α-和11β-羟孕酮在体外是11β-羟类固醇脱氢酶（亚型1和2）的有效抑制剂，在体内可赋予大鼠皮质酮盐皮质激素活性。11β-羟基类固醇脱氢酶将活性糖皮质激素代谢为其非活性11-β-羟基类固醇产物，并保护肾盐皮质激素受体免受内源性糖皮质激素高循环水平的影响。11β-羟基类固醇脱氢酶不仅在控制肾钠潴留方面，而且在控制血压方面也很重要。为了评估11α-和11β-羟孕酮可能的血压调节作用，我们将这些物质连续输注到完整和肾上腺切除的Sprague-Dawley大鼠体内14天。11α-和11β-羟孕酮均在3天内引起血压显著升高，这种作用在整个14天输注期间持续存在。肾上腺切除可消除11α-羟孕酮的高血压作用，而11α-羟孕酮与盐皮质激素受体拮抗剂RU 28318联用可显著减弱其高血压作用。在另一系列实验中，11α-羟孕酮显著增强肾上腺切除自发性高血压大鼠中皮质酮的高血压效应，但在该实验动物中本身没有效应。这些结果表明，11α-和11β-羟孕酮在大鼠中均具有强的高血压原性，并且这种活性依赖于完整的肾上腺，至少部分依赖于盐皮质激素受体的激活。11β-羟孕酮和抑制11β-羟类固醇脱氢酶的类似内源性孕酮代谢物可能参与某些高血压状态的病理学。
The progesterone derivatives 11α- and 11β-hydroxyprogesterone are potent inhibitors of 11β-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11β-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11β-Hydroxysteroid dehydrogenase has been suggested to be important not only in the control of renal sodium retention but also of blood pressure. To assess the possible blood pressure–modulating effects of 11α- and 11β-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11α- and 11β-hydroxyprogesterone caused a significant elevation in blood pressure within 3 days, an effect that persisted throughout the 14-day infusion. The hypertensive effects of 11α-hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11α-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11α-hydroxyprogesterone significantly amplified the hypertensive effects of corticosterone in adrenalectomized spontaneously hypertensive rats but had no effects by itself in this experimental animal. These results demonstrate that both 11α- and 11β-hydroxyprogesterone are potently hypertensinogenic in the rat and that this activity depends on an intact adrenal and at least in part on the activation of mineralocorticoid receptors. 11β-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11β-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states.
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