{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T12:34:50Z","timestamp":1760099690779},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,5,10]],"date-time":"2005-05-10T00:00:00Z","timestamp":1115683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2005,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The present study was to investigate the effects and action mechanisms of digoxin and ouabain on steroidogenesis in human adrenocortical NCI\u2010H295 cells. Administration of digoxin or ouabain for 24 h decreased the basal and angiotensin II (Ang II)\u2010stimulated release of aldosterone by NCI\u2010H295 cells. The conversions of corticosterone (substrate of cytochrome P450 aldosterone synthase, P450c11AS) to aldosterone or deoxycortisol (substrate of cytochrome P450 11\u03b2\u2010hydroxylase, P450c11\u03b2) to cortisol were reduced by digoxin or ouabain. The basal and 22\u2010hydroxy\u2010cholesterol (a membrane\u2010permeable cholesterol, substrate of cytochrome P450 side\u2010chain cleavage enzyme, P450scc)\u2010stimulated pregnenolone release in mitochondria was inhibited by digoxin or ouabain. Digoxin or ouabain suppressed the basal and Ang II\u2010stimulated protein expression of steroidogenic acute regulatory (StAR) protein and P450scc. Incubation of digoxin or ouabain for 24 h reduced P450c11AS mRNA expression in NCI\u2010H295 cells. Digoxin or ouabain (10<jats:sup>\u22126<\/jats:sup> M, 24 h)\u2010treated cells showed a lower resting intracellular Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and an attenuated response of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> to Ang II. Since no significant cytotoxicity was observed at 10<jats:sup>\u22126<\/jats:sup> M digoxin or ouabain, the digoxin\u2010 or ouabain\u2010induced decrease of aldosterone or cortisol release was not associated with cytotoxicity. These results demonstrate that digoxin or ouabain inhibits the aldosterone or cortisol release via reduction of P450c11AS or P450c11\u03b2 and P450scc activities, inhibition of StAR and P450scc protein expression, suppression of P450c11AS mRNA expression, and attenuation of Ca<jats:sup>2+<\/jats:sup> mobilization in NCI\u2010H295 cells. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.20415","type":"journal-article","created":{"date-parts":[[2005,5,10]],"date-time":"2005-05-10T22:18:39Z","timestamp":1115763519000},"page":"393-401","source":"Crossref","is-referenced-by-count":15,"title":["Inhibitory effects of digoxin and ouabain on aldosterone synthesis in human adrenocortical NCI\u2010H295 cells"],"prefix":"10.1002","volume":"205","author":[{"given":"Mei\u2010Mei","family":"Kau","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu\u2010Fen","family":"Kan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiing\u2010Rong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulus S.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,5,10]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.81.6.2335"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0050191"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1988.tb01108.x"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703974"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod67.2.416"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.10.7085"},{"key":"e_1_2_6_8_1","first-page":"408","volume-title":"Digitalis. 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