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Sarah Lambert-Langlais,
Jean-Christophe Pointud,
Anne-Marie Lefrançois-Martinez,
Fanny Volat,
Michèle Manin,
François Coudoré,
Pierre Val,
Isabelle Sahut-Barnola,
Bruno Ragazzon,
Estelle Louiset, Catherine Delarue,
Hervé Lefebvre,
Yoshihiro Urade,
Antoine Martinez
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ABSTRACT: Prostaglandin F(2alpha) (PGF(2alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2alpha) release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF(2alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2alpha) action. By comparing PGF(2alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.
PLoS ONE 01/2009; 4(10):e7309. · 4.09 Impact Factor
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ABSTRACT: The synthesis of a series of aminoethylbiphenyls as novel 5-HT(7) receptor ligands is described. The novel derivatives exhibit high affinity for the 5-HT(7) receptor with selectivity toward 5-HT(1A) receptor.
Bioorganic & Medicinal Chemistry Letters 07/2007; 17(11):3018-22. · 2.55 Impact Factor
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Flavie Sicard,
Vincent Contesse,
Hervé Lefebvre,
Djida Ait-Ali,
Marjorie Gras,
Dorthe Cartier,
Annick Decker,
Nicolas Chartrel,
Youssef Anouar,
Hubert Vaudry, Catherine Delarue
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ABSTRACT: Neurotensin (NT) modulates corticosteroid secretion from the mammalian adrenal gland.
The objective of this study was to investigate the possible involvement of NT in the control of cortisol secretion in the human adrenal gland.
In vitro studies were conducted on cultured human adrenocortical cells.
This study was conducted in a university research laboratory.
Adrenal explants from patients undergoing expanded nephrectomy for kidney cancer were studied.
Cortisol secretion from cultured adrenocortical cells was measured.
NT1-11, the N-terminal fragment of NT, dose-dependently inhibited basal and ACTH-stimulated cortisol production by human adrenocortical cells in primary culture. In contrast, NT had no influence on cortisol output at concentrations up to 10(-6) m. HPLC and RT-PCR analyses failed to detect any significant amounts of NT and NT mRNA, respectively, in adrenal extracts. Molecular and pharmacological studies were performed to determine the type of NT receptor involved in the corticostatic effect of NT1-11. RT-PCR analysis revealed the expression of NT receptor type (NTR) 3 mRNA but not NTR1 and NTR2 mRNAs in the human adrenal tissue. However, the pharmacological profile of the adrenal NT1-11 receptor was different from that of NTR3, indicating that this receptor type is not involved in the action of NT1-11 on corticosteroidogenesis.
Our results indicate that NT1-11 may act as an endocrine factor to inhibit cortisol secretion through activation of a receptor distinct from the classical NTR1, NTR2, and NTR3.
Journal of Clinical Endocrinology & Metabolism 09/2006; 91(8):3131-7. · 6.50 Impact Factor
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ABSTRACT: We have previously shown that PACAP stimulates in vitro the secretion of corticosteroids by frog adrenal explants and that PACAP increases cAMP formation and cytosolic calcium concentration ('Ca2+'i) in adrenocortical cells. The aim of the present study was to investigate the involvement of cAMP and 'Ca2+'i in the stimulatory effect of PACAP on steroid production. Incubation of adrenal explants with PACAP resulted in a significant increase in total inositol phosphate formation. Administration of the protein kinase A inhibitor, H89, markedly reduced the stimulatory effect of PACAP on corticosterone and aldosterone secretion by perifused adrenal slices. In contrast, chelation of intracellular or extracellular calcium, or incubation with calcium channel blockers, had no effect on PACAP-evoked steroid secretion. Incubation of the cells with BAPTA or thapsigargin totally suppressed the stimulatory effect of PACAP on 'Ca2+'i. In contrast, suppression of extracellular calcium with EGTA or blockage of voltage-dependent Ca2+ channels did not impair PACAP-induced Ca2+ response. These data indicate that, in frog adrenocortical cells, the stimulatory effect of PACAP on steroid secretion is mediated through activation of the cAMP/PKA pathway. Concurrently, PACAP causes calcium mobilization from IP(3)-dependent intracellular stores through activation of a phospholipase C, while the calcium response is not involved in the stimulatory effect of PACAP on corticosteroid secretion.
Annals of the New York Academy of Sciences 08/2006; 1070:431-5. · 3.15 Impact Factor
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ABSTRACT: Arginine vasopressin (AVP) stimulates steroid secretion from the normal human adrenal gland and some cortisol-producing adrenocortical tumors or hyperplasia through activation of the V(1a) receptor.
The objective of the study was to investigate in vitro and in vivo the possible involvement of AVP in the physiopathology of primary aldosteronism.
The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion.
The study was conducted at a university hospital and research laboratory.
The study population included eight untreated patients with primary aldosteronism, four with APA and four with idiopathic hyperaldosteronism.
Aldosterone secretion of APA cells in vitro and plasma aldosterone, renin, and ACTH were measured.
SR 49059 (200 mg once daily) or placebo was administered during two 1-wk treatment periods separated by a 2-wk washout.
We observed the occurrence of AVP-containing cells in APA tissues. Administration of AVP to perifused APA cells induced an increase in aldosterone production, which was inhibited by a specific V(1a) antagonist. RT-PCR analysis showed the expression of V(1a) receptor mRNA in most APAs studied. In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH.
The present study indicates that functional V(1a) receptors are present in APA and suggests that AVP may exert an autocrine/paracrine control of aldosterone secretion in APA tissues.
Journal of Clinical Endocrinology & Metabolism 04/2006; 91(4):1566-72. · 6.50 Impact Factor
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Annals of the New York Academy of Sciences 02/2006; 839(1):270 - 274. · 3.15 Impact Factor
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ABSTRACT: In the study reported in this paper, we characterized PACAP in the human fetal adrenal gland and we investigated the effect of PACAP on steroid secretion from cultured fetal adrenal cells. The adrenal gland from 20-week-old fetuses contained substantial concentrations of PACAP-immunoreactive material (88.6 ng/g wet tissue). HPLC analysis of adrenal extracts revealed the presence of both PACAP27 and PACAP38, the latter being the predominant form. Incubation of cultured fetal adrenal cells with PACAP38 (10−7 M) significantly increased cortisol and DHEAS secretion. Administration of the β-adrenoreceptor agonist isoproterenol mimicked the stimulatory effect of PACAP on both steroid secretion whereas preincubation of fetal cells with the β-adrenoreceptor antagonist propranolol suppressed the steroidogenic effect of PACAP. These data, together with the observation that PACAP receptors are exclusively located on chromaffin cells, suggest that, in the fetal human adrenal gland, the effect of PACAP on steroid secretion is mediated via the local release of catecholamines.
Annals of the New York Academy of Sciences 01/2006; 921(1):429 - 433. · 3.15 Impact Factor
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ABSTRACT: Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT7 receptor ligands. The synthesis and the affinity for the 5-HT7 receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT7 receptors.
Bioorganic & Medicinal Chemistry Letters 09/2005; 15(16):3753-7. · 2.55 Impact Factor
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ABSTRACT: We have previously shown that endothelin (ET)-1 stimulates corticosterone and aldosterone secretion by the frog adrenal gland through activation of ETA receptors positively coupled to both the adenylyl cyclase and phospholipase C (PLC) pathways. The purpose of the present study was to investigate the involvement of calcium in ET-1-induced stimulation of corticosteroid secretion. Cytoautoradiographic labeling using [125I]ET-1 as a tracer revealed the presence of ET-1 binding sites on adrenocortical cells. Administration of graded concentrations of ET-1 in the vicinity of adrenocortical cells provoked a dose-dependent increase in cytosolic calcium concentrations ([Ca2+]i). ET-1 induced a biphasic response consisting of an immediate and transient peak of [Ca2+]i followed by a plateau phase. Preincubation of the cells with the calcium-ATPase inhibitor thapsigargin or the PLC inhibitor U-73122 reduced the amplitude of the transient phase. Administration of the calcium chelator EGTA or the protein kinase A inhibitor H-89 attenuated the plateau phase. The [Ca2+]i response to ET-1 was markedly reduced during concomitant administration of U-73122 and H-89. Preincubation of the cells with the L-type calcium channel blocker nifedipine attenuated the plateau phase. Corticosteroid secretion from perifused frog adrenal slices was almost completely suppressed by thapsigargin and reduced by nifedipine. Taken together, these data indicate that activation of ETA receptors in frog adrenocortical cells provokes immediate stimulation of PLC, which causes an early mobilization of calcium from intracellular stores, and activates adenylyl cyclase, which results in delayed calcium influx through L-type calcium channels. The resulting increase in [Ca2+]i plays a pivotal role in ET-1-induced corticosteroid secretion.
Endocrinology 02/2005; 146(1):119-29. · 4.46 Impact Factor
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ABSTRACT: Blood corticosterone levels (CORT) were measured before and after the completion of the elevated +-maze test in cerebellar Lurcher mutant and control mice. Consistent with the existence of a much more pronounced activation of the hypothalamo-pituitary-adrenal (HPA) system in the mutants, our results showed that while basal CORT were similar in mutants and controls, the surge of this stress indicator was enhanced in the Lurcher mice after completion of a behavioral test of anxiety. In contrast, at the behavioral level, we also observed that Lurcher exhibited significantly reduced anxiety related indices; they spent a significant greater amount of time in the aversive places of the apparatus and entered them more frequently than non mutant mice. It is proposed that rather than less anxious, the Lurcher mice are less inhibited than controls when placed in anxiogenic situation and that such poor inhibition could be causally related to changes in HPA system regulation. The overall patterns of our behavioral and endocrinological results thereby provided the evidence that cerebellar circuitry is involved in producing changes in physiological and behavioral stress-related emotional responses.
Brain Research 05/2004; 1003(1-2):108-12. · 2.73 Impact Factor
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Journal of Chemical Information and Modeling. 01/2004; 44:1148-1152.
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ABSTRACT: The cardiovascular effects of centrally and peripherally administered synthetic salmon corticotropin-releasing-hormone (CRH), a member of a family of stress-related neuropeptides, were investigated in the unanesthetized trout, Oncorhynchus mykiss. In group 1, trout bearing a cannula in the dorsal aorta, neither intracerebroventricular (i.c.v.) nor intra-arterial (i.a.) injections of CRH produced any significant change in mean heart rate (HR) and mean dorsal aortic blood pressure. These results stand in contrast to the previously reported hypertensive effects of i.a. and i.c.v. injections of trout urotensin-I. In group 2, non-cannulated trout bearing two subcutaneous electrocardiographic electrodes, conditions that are considered to be less stressful to the animals, the baseline level of HR was significantly reduced compared to the corresponding value for cannulated trout. In these trout, no significant change occurred in the HR after i.c.v. administration of 1 pmol of CRH. However, i.c.v. injection of 5 pmol of CRH caused a 12% (P<0.01) decrease in HR during the 20-25 min post-injection period. In addition, the heart rate variability (HRV), a marker of vagal input to the heart, was increased by 120%. The CRH antagonist, CRH-(9-41)-peptide alone had no effect on HR or HRV but blocked CRH-induced bradycardia. In the non-cannulated trout, i.c.v. injection of trout urotensin-I (5 pmol) produced no significant change in HR and HRV. In contrast, i.c.v. administration of angiotensin II (5 pmol) elicited a highly significant 33% (P<0.001) increase in the mean HR as well as inducing a marked (64%) reduction in HRV. Our results suggest that picomolar doses of CRH act centrally to evoke a bradycardia by a probable mechanism that involves enhancement of the parasympathetic drive to the heart.
Brain Research 08/2003; 982(2):211-8. · 2.73 Impact Factor
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ABSTRACT: Serotonin (5-HT) stimulates aldosterone secretion from the rat adrenal gland through 5-HT(7) receptors. The aim of the present study was to investigate the transduction mechanisms associated with activation of 5-HT(7) receptors in rat glomerulosa cells. The stimulatory effect of 5-HT on aldosterone secretion and cAMP formation was significantly reduced by the 5-HT(7) receptor antagonist LY 215840. Pretreatment of cells with the adenylyl cyclase inhibitor SQ 22536 or the PKA inhibitor H-89 markedly attenuated the effect of 5-HT on aldosterone secretion. Conversely, type 2 and 4 phosphodiesterase inhibitors potentiated the 5-HT-induced stimulation of aldosterone secretion. Administration of 5-HT in the vicinity of cultured glomerulosa cells induced a slowly developing and robust increase in cytosolic calcium concentration ([Ca(2+)](i)). The effect of 5-HT on [Ca(2+)](i) was suppressed by mibefradil, a T-type calcium channel blocker. Patch-clamp studies confirmed that 5-HT activated a T-type calcium current. Mibefradil also induced a dose-dependent inhibition of 5-HT-induced aldosterone secretion. The sequence of events associated with activation of 5-HT(7) receptors was investigated. The PKA inhibitor H-89 markedly attenuated both the [Ca(2+)](i) response and the activation of T-type calcium current induced by 5-HT. In contrast, reduction of the calcium concentration in the incubation medium did not affect 5-HT- induced cAMP formation. Preincubation of glomerulosa cells with cholera toxin abolished the stimulatory effect of 5-HT on aldosterone secretion, but pertussis toxin had no effect. Taken together, these data demonstrate that, in rat glomerulosa cells, activation of native 5-HT(7) receptors stimulates cAMP formation through a G(salpha) protein, which in turn provokes calcium influx through T-type calcium channels. Both the adenylyl cyclase/PKA pathway and the calcium influx are involved in 5-HT-induced aldosterone secretion.
Endocrinology 06/2002; 143(5):1748-60. · 4.46 Impact Factor
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ABSTRACT: We have previously shown that serotonin (5-HT) stimulates aldosterone secretion from the human adrenal gland through activation of 5-HT(4) receptors. The aim of the present study was to investigate in vivo and in vitro the presence of 5-HT(4) receptors in aldosterone-producing adenomas (aldosteronomas). Eight patients with aldosteronoma received a single oral dose of placebo or cisapride (10 mg). Cisapride administration significantly increased plasma aldosterone within 120 min without any significant change in renin, cortisol, or potassium levels. In two patients, a marked decrease in the plasma aldosterone response to cisapride was observed after surgical removal of the tumor. The effects of 5-HT and selective 5-HT(4) ligands on aldosterone production from aldosteronoma tissues were studied in vitro using a perifusion system technique. 5-HT and the 5-HT(4) receptor agonist cisapride (10(-7) M, 20 min) both stimulated aldosterone secretion from aldosteronoma slices. The 5-HT- and cisapride-evoked aldosterone responses were inhibited by concomitant administration of the specific 5-HT(4) receptor antagonist GR 113808 (10(-7) M, 150 min). PCR amplification revealed the expression of 5-HT(4) receptor mRNA in 13 of 14 aldosteronomas studied. Taken together, these data show that most aldosteronomas, like normal glomerulosa cells, express a functional 5-HT(4) receptor. Our results also suggest that 5-HT, which can be locally released by intratumoral mast cells, may play a role in the pathophysiology of these tumors.
Journal of Clinical Endocrinology & Metabolism 04/2002; 87(3):1211-6. · 6.50 Impact Factor
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Catherine Delarue,
Vincent Contesse,
Sébastien Lenglet,
Flavie Sicard,
Véronique Perraudin,
Hervé Lefebvre,
Magloire Kodjo,
François Leboulenger,
Laurent Yon,
Nicole Gallo-Payet,
Hubert Vaudry
Reviews in Endocrine and Metabolic Disorders 07/2001; 2(3):253-267. · 3.17 Impact Factor
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ABSTRACT: Nitric oxide (NO) has been found to modulate the response of rat, bovine and human adrenocortical cells to corticotropic factors. The aim of the present study was to investigate the possible involvement of NO in the control of corticosteroid secretion in the frog Rana ridibunda. Histochemical studies using the NADPH-diaphorase reaction and immunohistochemical labeling with antibodies against NO synthase (NOS) revealed that NOS is exclusively expressed in chromaffin cells. The NO donor sodium nitroprusside (SNP) and the NO synthase inhibitor Nw-nitro-l-arginine (l-NO2Arg) did not modify the spontaneous production of corticosterone and aldosterone by perifused adrenal slices. Similarly, l-NO2Arg had no effect on the secretory responses induced by ACTH, angiotensin II (AII) and endothelin-1 (ET-1). In contrast, SNP significantly inhibited the stimulatory effects of ACTH, AII and ET-1 on corticosterone and aldosterone secretion. These data provide the first evidence for a modulatory role of NO on adrenocortical cell activity in amphibians.
The Journal of Steroid Biochemistry and Molecular Biology 07/2001; · 3.05 Impact Factor
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ABSTRACT: We have recently reported the presence of calcitonin gene-related peptide (CGRP)-containing nerve fibers in the frog adrenal gland and we have shown that CGRP is a potent stimulator of corticosterone and aldosterone secretion by adrenocortical cells. The aim of the present study was to characterize the type of receptors mediating the effect of CGRP in the frog adrenal gland. Amylin and adrenomedullin, two members of the CGRP family, induced a weak stimulation of corticosterone and aldosterone secretion from perifused frog adrenal slices. In contrast, salmon and human calcitonin had no effect on corticosteroid secretion. Administration of the type-1 CGRP receptor antagonists human CGRP-(8-37) and human CGRP-(19-37) did not significantly affect the secretory response induced by frog CGRP. Concurrently, the type-2 CGRP receptor agonist [acetamidomethyl-Cys2,7]human CGRP ([Cys(ACM)2,7]human CGRP) provoked a dose-dependent stimulation of corticosterone and aldosterone secretion (EC50 = 1.6 × 10−7 M). Both frog CGRP and [Cys(ACM)2,7]human CGRP induced a significant increase in cAMP production by frog adrenal tissue. These data indicate that, in the frog adrenal gland, the stimulatory effect of CGRP is mediated through activation of a type-2 CGRP receptor positively coupled to adenylyl cyclase.
European Journal of Pharmacology 08/1996; · 2.52 Impact Factor
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ABSTRACT: We have previously shown that serotonin (5-hydroxytryptamine, 5-HT) stimulates corticosterone and aldosterone secretion from perifused frog adrenal gland in vitro through activation of 5-HT4 receptors. In the present study, we have used this model to investigate the effect of newly discovered 5-HT4 receptor agonists and antagonists on corticosteroid secretion. Serotonin, the benzamide derivatives (R,S)-zacopride ((R,S)-4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, HCl) and its enantiomers, the azabicycloalkyl benzimidazolone derivatives BIMU 1 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2-3-dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-caboxamide, HCl) and BIMU 8 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-31-methyl)ethyl-2-oxo-1H- benzimidazole-1-carboxamide, HCl) were all capable of enhancing corticosterone and aldosterone secretion in a dose-dependent manner. Serotonin was the most potent stimulator of steroidogenesis (EC50 = 1.5 × 10−7 M) while the potency of the benzamide and the benzimidazolone derivatives was approximately 10 times lower. The rank order of efficacy of the different 5-HT4 receptor agonists was:(S)-zacopride > BIMU 8 = (R,S)-zacopride > BIMU 1 = (R)-zacopride = 5-HT. The stimulatory effects of 5-HT and the benzimidazolone derivatives on corticosteroid secretion were not additive, suggesting that they activated the same receptor. The indoleamine derivatives ICS 205930 ((3α-tropanyl)-1H-indole-3-carboxylic acid, ester) and GR 113808 ([1-[2-(methylsulphonylamino)ethyl]-4-piperidinyl]methyl methyl-1H-indole-3-carboxylate, maleate), and the benzimidazolone derivative DAU 6285 (endo-8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-6-methoxy-2-oxo-1H- benzimidazole-1-carboxylate, HCl), all induced a dose-dependent inhibition of (R,S)-zacopride-induced stimulation of corticosteroid secretion. The affinity of GR 113808 (pKi = 10.34) was higher than that of DAU 6285 and ICS 205930 (pKi = 7.84 and 6.20, respectively). Together, these data indicate that the pharmacological profile of the 5-HT4 receptor in the frog adrenal gland is very similar to those recently characterized in the brain and peripheral organs of mammals. It thus appears that the frog adrenal gland is a valuable model for the investigation of the biochemical characteristics and mode of action of novel 5-HT4 receptor ligands.
European Journal of Pharmacology 11/1994; · 2.52 Impact Factor
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ABSTRACT: In order to determine the role of intermediate filaments in adrenal steroidogenesis, we have studied the effect of IDPN (β-β'iminodipropionitrile), an intermediate filaments perturbing agent, on corticosteroid secretion by frog interrenal glands in virto. A 6-h administration of IDPN (10−3M) did not affect the spontaneous release of corticosterone and aldosterone. While IDPN did not alter the response of adrenal fragments to ACTH, the drug caused a marked decrease in angiotensin II-induced stimulation of corticosterone and aldosterone production. These results indicate that, in contrast to microfilaments, which play an important role in spontaneous steroidogenesis, intermediate filaments are not required for basal corticosteroid secretion but are involved in the mechanism of action of angiotensin in frog adrenocortical cells.
Journal of Steroid Biochemistry 02/1988;
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ABSTRACT: The involvement of short-lived proteins in the steroidogenic action of corticotropic peptides has been investigated in vitro by means of a Perifusion technique using frog adrenal glands. Graded concentrations of cycloheximide (10−7 M to 10−5 M) led to a dose-related inhibition of corticosterone and aldosterone production. The Perifusion model gives detailed information on the kinetics of the inhibitory effect of cycloheximide. This effect was rapidly observed (the lag period was about 15 min), maximum inhibition being obtained 25 min after the end of administration of the protein synthesis inhibitor. Whatever the concentration of cycloheximide, corticosteroid output returned to basal values 2 h after the onset of cycloheximide infusion. Stimulation of steroidogenesis by ACTH and angiotensin II was totally inhibited by cycloheximide (10−6 M) indicating that the synthesis of a labile protein was required for the adrenal response to corticotropic peptides. In addition, the stimulatory effect of cAMP and PGE1, which are considered to be the second messengers of ACTH and angiotensin II in amphibian interrenal gland, was blocked by cycloheximide. Taken together, these data suggest that a labile protein is involved in an early step of corticosteroid biosynthesis in the frog.
Journal of Steroid Biochemistry 08/1986;
