Aguilera G, Fujita K, Catt K J
Endocrinology. 1981 Feb;108(2):522-8. doi: 10.1210/endo-108-2-522.
The mechanisms by which prolonged administration of ACTH causes a decrease in aldosterone secretion were studied in the rat. After 6 days of treatment with ACTH (2 U/day), blood corticosterone was elevated and plasma aldosterone was decreased in rats maintained on either a normal or low sodium diet. PRA was also decreased, probably secondary to increased sodium and/or fluid retention. In collagenase-dispersed glomerulosa cells from adrenals of ACTH-treated rats, angiotensin II receptors were markedly decreased, as were the in vitro aldosterone responses to angiotensin II, ACTH, 8-bromo-cAMP, and potassium. However, the production of deoxycorticosterone and precursor steroids was increased, indicating the presence of a block in the late aldosterone biosynthetic pathway. Measurement of the activity of biosynthetic enzymes of the steroidogenic pathway in isolated mitochondria revealed an 80% increase in side-chain cleavage enzyme in both glomerulosa and fasciculata mitochondria from ACTH-treated rats. Although ACTH injection also increased 11-hydroxylase activity in the fasciculata zone, this enzyme was reduced by 50% in capsular mitochondria. The 18-hydroxylase activity in adrenal capsular mitochondria was markedly decreased by ACTH treatment in both normal and sodium-restricted animals. The importance of ACTH-induced steroidogenesis in the development of altered glomerulosa cell function was indicated by the ability of aminoglutethimide to prevent the inhibitory effects of ACTH on angiotensin II receptors and PRA. It is likely that the observed inhibition of the renin-angiotensin system is responsible for the decrease in angiotensin II receptors and 18-hydroxylase, since both are highly dependent on the trophic effect of angiotensin II. The specific lesions produced in adrenal glomerulosa cells by long term ACTH treatment include decreased levels of angiotensin II receptors, 11-hydroxylase, and 18-hydroxylase. These changes are secondary to the suppression of renin-angiotensin activity and are responsible for the impaired aldosterone secretion that results from prolonged treatment with ACTH. (Endocrinology 108: 522, 1981)
在大鼠中研究了长期给予促肾上腺皮质激素（ACTH）导致醛固酮分泌减少的机制。用ACTH（2单位/天）治疗6天后，维持正常或低钠饮食的大鼠血皮质酮升高而血浆醛固酮降低。肾素活性（PRA）也降低，可能继发于钠和/或液体潴留增加。在经ACTH处理大鼠肾上腺的胶原酶分散的球状带细胞中，血管紧张素II受体明显减少，对血管紧张素II、ACTH、8-溴环磷腺苷（8-bromo-cAMP）和钾的体外醛固酮反应也减少。然而，脱氧皮质酮和前体类固醇的产生增加，表明醛固酮生物合成途径后期存在阻滞。对分离线粒体中类固醇生成途径生物合成酶活性的测定显示，经ACTH处理大鼠的球状带和束状带线粒体中侧链裂解酶活性增加80%。虽然注射ACTH也增加了束状带区11-羟化酶活性，但在被膜线粒体中该酶活性降低了50%。在正常和限钠动物中，ACTH处理均使肾上腺被膜线粒体中的18-羟化酶活性明显降低。氨鲁米特能够预防ACTH对血管紧张素II受体和PRA的抑制作用，这表明ACTH诱导的类固醇生成在球状带细胞功能改变的发展中具有重要性。观察到的肾素-血管紧张素系统的抑制可能是血管紧张素II受体和18-羟化酶减少的原因，因为两者都高度依赖于血管紧张素II的营养作用。长期ACTH处理在肾上腺球状带细胞中产生的特异性损害包括血管紧张素II受体、11-羟化酶和18-羟化酶水平降低。这些变化继发于肾素-血管紧张素活性的抑制，并导致ACTH长期治疗引起的醛固酮分泌受损。（《内分泌学》108: 522, 1981）
