Direct inhibitory effect of digitalis on progesterone release from rat granulosa cells

Chen, Jiann‐Jong; Wang, Paulus S.; Chien, Eileen-Jea; Wang, Shyi-Wu

doi:10.1038/sj.bjp.0703974

Cited by 21 publications

(29 citation statements)

References 36 publications

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“…Ouabain (an inhibitor of Na þ /K þ -ATPase) and other digitalis glycosides induced a potentiated effect on vasoconstrictors in vitro (Fleming, 1980;Lang and Blaustein, 1980), probably in part via intracellular accumulation of calcium ions after Na þ /K þ -ATPase inhibition as occurs in myocardium (Hougen and Smith, 1978). The inhibitory effects of digoxin on the production of gonadal hormones, such as testosterone and progesterone, have been demonstrated in rat testicular interstitial cells and granulosa cells Chen et al, 2001).…”

mentioning

confidence: 96%

Inhibitory effects of digoxin and ouabain on aldosterone synthesis in human adrenocortical NCI‐H295 cells

Kau

Kan²,

Wang

et al. 2005

Journal Cellular Physiology

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The present study was to investigate the effects and action mechanisms of digoxin and ouabain on steroidogenesis in human adrenocortical NCI-H295 cells. Administration of digoxin or ouabain for 24 h decreased the basal and angiotensin II (Ang II)-stimulated release of aldosterone by NCI-H295 cells. The conversions of corticosterone (substrate of cytochrome P450 aldosterone synthase, P450c11AS) to aldosterone or deoxycortisol (substrate of cytochrome P450 11beta-hydroxylase, P450c11beta) to cortisol were reduced by digoxin or ouabain. The basal and 22-hydroxy-cholesterol (a membrane-permeable cholesterol, substrate of cytochrome P450 side-chain cleavage enzyme, P450scc)-stimulated pregnenolone release in mitochondria was inhibited by digoxin or ouabain. Digoxin or ouabain suppressed the basal and Ang II-stimulated protein expression of steroidogenic acute regulatory (StAR) protein and P450scc. Incubation of digoxin or ouabain for 24 h reduced P450c11AS mRNA expression in NCI-H295 cells. Digoxin or ouabain (10(-6) M, 24 h)-treated cells showed a lower resting intracellular Ca2+ concentration ([Ca2+]i) and an attenuated response of [Ca2+]i to Ang II. Since no significant cytotoxicity was observed at 10(-6) M digoxin or ouabain, the digoxin- or ouabain-induced 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 P450c11beta and P450scc activities, inhibition of StAR and P450scc protein expression, suppression of P450c11AS mRNA expression, and attenuation of Ca2+ mobilization in NCI-H295 cells.

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mentioning

confidence: 96%

Inhibitory effects of digoxin and ouabain on aldosterone synthesis in human adrenocortical NCI‐H295 cells

Kau

Kan²,

Wang

et al. 2005

Journal Cellular Physiology

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“…It has been well known that digitalis glycosides produce a positive inotropic effect on cardiac muscle through an inhibition of the Na + /K + -ATPase and an elevation of intracellular calcium concentration [2]. Previous studies demonstrated that digoxin can directly inhibit the biosynthesis of testosterone, progesterone, or corticosterone by testicular interstitial cells, granulosa cells, or adrenal zona fasciculata-reticularis cells in rats, whereas ouabain (a selective inhibitor of Na + /K + -ATPase) cannot produce any effects [7,10,11]. In the same manner, ouabain did not affect aldosterone and cortisol secretion of monkeys in the present experiment.…”

Section: Discussionmentioning

confidence: 98%

“…Digoxin inhibits the production of testosterone through a decrease in adenosine 3′:5′-cyclic monophosphate (cyclic AMP) in rat testicular interstitial cells [7,8]. In addition, digoxin decreased progesterone release by rat granulosa cells involving the inhibition of postcyclic AMP pathway, cytochrome P450 side-chain cleavage enzyme, and steroidogenic acute regulatory protein functions [9,10]. Wang et al [11] also found that digoxin decreased the release of corticosterone by rat zona fasciculata-reticularis cells involving the inhibition of the activities of adenylyl cyclase, cytochrome P450 side-chain cleavage enzyme, and 11β-hydroxylase, as well as the functions of cyclic AMP and intracellular calcium [11].…”

Section: Introductionmentioning

confidence: 99%

Acute effects of digoxin on plasma aldosterone and cortisol in monkeys

Kau

Kan²,

Wang³

et al. 2009

Metabolism

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“…It has been well established that hCG increases cyclic AMP generation and then stimulates progesterone secretion in granulosa cells. 19,25,26,33 Some studies have shown that LH or hCG acts via its G protein-coupled receptor to increase intracellular cAMP further to activate the PKA pathway. 33,34 In the present study, we showed that ABM-Bu decreased not only 8-Br-cAMP-or forskolin-induced progesterone release but also hCG-induced cellular cAMP production.…”

Section: Discussionmentioning

confidence: 99%

“…[24][25][26] The granulosa cells (2 Â 10 6 cells) were incubated with medium containing ABM-Bu (0, 100 mg/ml), ABM-Bu-G (0, 100 mg/ml) or hCG (0.5 IU/ml) for 2 h. At the end of incubation, cells were washed twice with ice-cold saline and detached by trypsinization (1.25 mg/ml). The cells were collected and extracted in homogenization buffer (pH 8.0) containing 1.5% Na-lauroylsarcosine, 1 Â 10 À3 M EDTA, 2.5 Â 10 À3 M Tris-base, 0.68% PMSF and 2% proteinase inhibitor cocktail, and then disrupted by ultrasonic sonicator in an icebath.…”

Section: Gel Electrophoresis and Western Blottingmentioning

confidence: 99%

Downregulation of progesterone biosynthesis in rat granulosa cells by adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) bran extracts

et al. 2005

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has long been used as a traditional Chinese medicine for dysfunctions of the endocrine system and inflammation conditions. However, the effect of adlay seed on the endocrine system has not yet been reported. In the present study, the effects and the mechanisms of methanolic extract of adlay bran (ABM) on progesterone synthesis in rat granulosa cell were studied. ABM was further partitioned with different solvents including water, 1-butanol, ethyl acetate and n-hexane. Four subfractions named ABM-Wa (water fraction), ABM-Bu (1-butanol fraction), ABM-EA (ethyl acetate fraction) and ABM-Hex (n-hexane fraction) were obtained. ABM-Bu was further fractionated using Diaion HP-20 resin column chromatography with gradient elution. Granulosa cells were prepared from pregnant mare serum gonadotropinprimed immature female rats and challenged with different reagents including human chorionic gonadotropin (hCG 0.5 IU/ml), forskolin (10 lM), 8-bromo-adenosine-3 0 ,5 0 -cyclic monophosphate (8-Br-cAMP, 1 mM), A23187 (10 lM), phorbol 12-myristate 13-acetate (PMA, 0.01 lM), 25-OHcholesterol (0.1-10 lM) and pregnenolone (0.1-10 lM) in the presence or absence of ABM-Bu (100 lg/ ml). The functions of steroidogenic enzyme including protein expression of the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage enzyme (P450scc) protein were investigated. Expressions of both P450scc and StAR mRNA have also been explored. We found that ABM decreased progesterone production via an inhibition on (1) the cAMP-PKA and PKC signal transduction pathway, (2) P450scc and 3b-hydroxysteroid dehydrogenase (3b-HSD) enzyme activity, (3) P450scc and StAR protein and mRNA expressions and (4) the phosphorylation of ERK1/2 in rat granulosa cells.

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Direct inhibitory effect of digitalis on progesterone release from rat granulosa cells

Cited by 21 publications

References 36 publications

Inhibitory effects of digoxin and ouabain on aldosterone synthesis in human adrenocortical NCI‐H295 cells

Inhibitory effects of digoxin and ouabain on aldosterone synthesis in human adrenocortical NCI‐H295 cells

Acute effects of digoxin on plasma aldosterone and cortisol in monkeys

Downregulation of progesterone biosynthesis in rat granulosa cells by adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) bran extracts

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