Wehling Martin
Institute of Clinical Pharmacology, Faculty for Clinical Medicine at Mannheim, University of Heidelberg, 68167 Mannheim, Germany/AstraZeneca R&D, Mölndal, Sweden.
Heart Fail Rev. 2005 Jan;10(1):39-46. doi: 10.1007/s10741-005-2347-z.
Genomic mechanisms of mineralocorticoid action have been increasingly elucidated over the past four decades. In renal epithelia, the main effect is an increase in sodium transport through activation and de novo synthesis of epithelial sodium channels. This leads to increased concentrations of intracellular sodium activating sodium-potassium-ATPase molecules mainly at the basolateral membrane which extrude sodium back into the blood stream. In contrast, rapid steroid actions have been widely recognized only recently. The present article summarizes both traditional and rapid effects of mineralocorticoid hormones on intracellular electrolytes, e.g. free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. Latter effects are almost immediate, reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca(2+) effect appears to involve the release of intracellular Ca(2+), as shown by the inhibitory effect of thapsigargin. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to result in rapid fine tuning of cardiovascular responsivity. As a landmark feature of these rapid effects, insensitivity to classic antimineralocorticosteroids, e.g. spironolactone or canrenone has been found in the majority of observations. In an integrated view, mineralocorticoids seem to mainly effect intracellular electrolytes genomically to induce transepithelial transport, and induce nongenomically mediated alterations of cell function (e.g. vasoconstriction) by rapid effects on intracellular electrolytes such as free intracellular calcium.
在过去的四十年里，盐皮质激素作用的基因组机制已得到越来越多的阐明。在肾上皮细胞中，主要作用是通过激活和从头合成上皮钠通道来增加钠转运。这导致细胞内钠浓度升高，主要在基底外侧膜激活钠钾ATP酶分子，将钠重新排回血流中。相比之下，类固醇的快速作用直到最近才被广泛认识。本文总结了盐皮质激素对细胞内电解质的传统和快速作用，例如通过fura 2荧光分光光度法在大鼠主动脉单个培养细胞中测定的血管平滑肌细胞内游离钙。后者的作用几乎是即时的，仅在3至5分钟后达到平台期，其特点是对盐皮质激素与糖皮质激素具有高度特异性。醛固酮的作用被新霉素和佛波酯短期处理所阻断，但被星形孢菌素增强，表明涉及磷脂酶C和蛋白激酶C。Ca(2+)效应似乎涉及细胞内Ca(2+)的释放，如毒胡萝卜素的抑制作用所示。这种机制在生理亚纳摩尔醛固酮浓度下起作用，似乎导致心血管反应性的快速微调。作为这些快速作用的一个标志性特征，在大多数观察中发现对经典抗盐皮质激素，如螺内酯或坎利酮不敏感。综合来看，盐皮质激素似乎主要通过基因组方式影响细胞内电解质以诱导跨上皮转运，并通过对细胞内电解质如细胞内游离钙的快速作用诱导非基因组介导的细胞功能改变（如血管收缩）。
