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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated the effects of the calcium channel blockers nifedipine (a dihydropyridine) and verapamil (a papaverine derivative), on aldosterone production utilizing isolation of the early and late phases of aldosterone biosynthesis. Pregnenolone production (the early phase of aldosterone biosynthesis) was assessed in trilostane-treated bovine glomerulosa cells, used to inhibit the conversion of pregnenolone onwards to aldosterone. Conversion of exogenous corticosterone to aldosterone, an index of late phase activity, was assessed using aminoglutethimide to inhibit endogenous aldosterone production. Low concentrations of nifedipine, 10(-11)-10(-9) M, stimulated basal total aldosterone biosynthesis by enhancing the late phase although the early phase was inhibited. In the presence of 12 mM potassium (K+), which is less effective in stimulating aldosterone production than lower K+ concentrations, aldosterone production was enhanced by nifedipine, 10(-8) M, by an effect on the late phase. At K+ 6 and 8 mM, nifedipine, 10(-4) M, inhibited the early phase. Nifedipine 10(-5) inhibited angiotensin II (AII)-stimulated total aldosterone biosynthesis by independent effects on the early and late phases. Verapamil, 10(-4) M, inhibited total and early phase aldosterone production at K+, 4 mM and inhibited both phases at K+, 8 mM, stimulation was not observed using verapamil. Verapamil, 10(-4) M, also inhibited AII-stimulated aldosterone production. Basal and AII-stimulated pregnenolone production were inhibited by verapamil, 10(-4) M (basal) and 10(-6) M (AII-stimulated). These studies using nifedipine have revealed subtle calcium-dependent mechanisms involved in the tonic inhibition of activity in the late phase of aldosterone biosynthesis and the reversal of the inhibitory effect of high K+ concentrations also on the late phase. In addition, the data reported indicate that both AII and K+ independently enhance activity in the early and late phases of aldosterone production by calcium-dependent mechanisms.
J Steroid Biochem Mol Biol 1992 Jul
PMID:Evidence for a tonic inhibitory role of nifedipine-sensitive calcium channels in aldosterone biosynthesis. 132 60

The intracellular mechanisms of action of alpha-MSH in rat adrenocortical cells were examined. When rat adrenal capsule (largely glomerulosa) cells were stimulated with a range of concentrations of alpha-MSH there was significant stimulation of aldosterone secretion at 10(-10) mol/l, although cyclic AMP was not increased until high concentrations of alpha-MSH were used (10(-6) mol/l and above). However, cells incubated with ACTH showed an increase in aldosterone secretion at 10(-11) mol/l and levels of cyclic AMP were elevated at 10(-9) mol ACTH/l. When rat adrenal whole capsules were incubated with alpha-MSH, membrane-bound protein kinase C (PKC) activity was increased and cytosolic enzyme activity decreased, showing PKC activation. Stimulation with angiotensin II also induced translocation of PKC activity, but ACTH did not. When [3H]inositol-loaded glomerulosa cells were stimulated with alpha-MSH there was significant generation of [3H]inositol trisphosphate (IP3) at concentrations of alpha-MSH which stimulated secretion of aldosterone. Significantly increased levels of [3H]IP3 were also measured when loaded cells were exposed to angiotensin II. ACTH did not cause any significant stimulation of [3H]IP3 production at any concentration used. These results indicate that activation of PKC and phospholipase C is important in modulating the steroidogenic effect of alpha-MSH.
J Mol Endocrinol 1992 Aug
PMID:Studies on the intracellular mechanism of action of alpha-melanocyte-stimulating hormone on rat adrenal zona glomerulosa. 132 51

The adrenal glomerulosa cell is a major site of action of angiotensin II (AII), which binds to AT1 receptors to stimulate phosphoinositide hydrolysis and Ca2+ mobilization, and the subsequent production of aldosterone. All also influences adrenal growth and proliferation and promotes thymidine incorporation in adrenocortical cells. In primary cultures of bovine glomerulosa cells, AII was found to induce the expression of several early growth response genes (c-fos, c-jun, JunB, and Krox 24). This effect of AII was dose-dependent and was blocked by [Sar1,IIe8] AII and the nonpeptide antagonist DuP 753, indicating that it is mediated by the AT1 subtype of the AII receptor. ACTH, which elevates cAMP in glomerulosa cells, was a relatively weak inducer of c-fos expression but was as potent as AII in stimulating the expression of JunB. ACTH did not further enhance the maximal effect of AII on c-fos expression. The role of the AII-induced cytoplasmic Ca2+ increase in generating the c-fos response was suggested by the ability of the Ca2+ ionophore ionomycin to induce c-fos expression. However, mobilization of intracellular Ca2+ by the Ca2+ ATPase inhibitor thapsigargin, as well as the stimulation of Ca2+ influx by depolarization with potassium, were less potent stimuli of c-fos expression. Omission of Ca2+ from the extracellular medium, which abolishes the plateau phase of the AII-induced Ca2+ signal without affecting the early increase due to Ca2+ mobilization, enhanced the early phase of the AII-induced c-fos response, indicating that Ca2+ also has an inhibitory effect on the early gene response. Activation of protein kinase C by phorbol 12-myristate, 13-acetate (PMA) also stimulated c-fos expression, but the combination of PMA and ionomycin did not further increase the c-fos response. Inhibition of protein kinase C by staurosporine, or its depletion by prolonged exposure to PMA, prevented the c-fos response to PMA but only partially inhibited the response to AII, suggesting the involvement of other factors in stimulus-transcription coupling from the AT1 receptor.
Mol Endocrinol 1992 Nov
PMID:Stimulation of early gene expression by angiotensin II in bovine adrenal glomerulosa cells: roles of calcium and protein kinase C. 133 25

Results of previous studies indicated that insulin at levels comparable to those in humans during hyperinsulinemia decreased ACTH-stimulated cortisol and androstenedione secretion by bovine adrenal fasciculata-reticularis cells in primary culture. In the present studies this inhibitory action was examined further by comparing the effects of insulin on ACTH-stimulated corticosteroid secretion with its effects on 8-(4-chlorophenylthio)-cAMP (cpt-cAMP), forskolin- and [5val]angiotensin II (Ang II)-stimulated corticosteroid secretion. Effects on corticosteroid secretion were correlated with effects on cAMP accumulation and rates of cAMP production. Monolayers were incubated for 24 h in the absence or presence of each agonist alone or in combination with insulin. Insulin (1.7 x 10(-9) or 17.5 x 10(-9) M) caused about a 50% decrease in cortisol and androstenedione secretion in response to ACTH (10(-11) or 10(-8) M). Insulin also decreased ACTH-stimulated aldosterone secretion by cultured glomerulosa cells. Cpt-cAMP (10(-4) or 10(-3) M)-stimulated increases in cortisol and androstenedione secretion were inhibited by insulin, but to a lesser extent than those in response to ACTH. The inhibition of cpt-cAMP-stimulated steroid secretion was not related to increased degradation of the cyclic nucleotide. Increases in cortisol and androstenedione secretion caused by a submaximal concentration (10(-6) M) of forskolin were decreased 50-70% by insulin. In contrast, insulin failed to significantly affect cortisol or androstenedione secretion caused by a maximal concentration (10(-5) M) of forskolin. The secretory responses to Ang II (10(-8) M) were also unaffected by insulin. The effect of insulin to inhibit ACTH-stimulated steroid secretion was accompanied by a reduction in cAMP accumulation as well as an apparent inhibition of adenylate cyclase activation. These data indicate that the effect of insulin to attenuate ACTH-stimulated corticosteroid secretion results from both an inhibition of ACTH-stimulated adenylate cyclase activity and an antagonism of the intracellular actions of cAMP.
J Steroid Biochem Mol Biol 1992 Jan
PMID:Mechanisms of insulin inhibition of ACTH-stimulated steroid secretion by cultured bovine adrenocortical cells. 137 Sep 6

Stimulation of aldosterone synthesis by angiotensin II (AII) is associated with depolarization of the cell membrane. Since the potential difference of adrenocortical cells is dependent on membrane permeability to potassium ions, the effects of agents which hyperpolarize the cell (by increasing permeability to K+) on the control of aldosterone synthesis were investigated further. Basal and AII-stimulated aldosterone synthesis was increased by 20-70% in cells incubated with 1 or 10 nM of the potassium ionophore valinomycin; higher concentrations markedly inhibited AII-stimulated synthesis. Cromakalim, a potential antihypertensive drug which facilitates the opening of K+ channels in smooth muscle cells, stimulated basal aldosterone synthesis at 2 microM but had no effect at 40 microM. AII-stimulated aldosterone synthesis was not affected by cromakalim except at 40 microM, which was inhibitory. The inhibitory effects of cromakalim, unlike those of valinomycin, were not reversible. Aldosterone synthesis from added hydroxycholesterol and pregnenolone (but not from deoxycorticosterone and corticosterone) was significantly inhibited by 40 microM cromakalim. Potassium efflux from cells preloaded with 43K was unaffected by low concentrations of valinomycin, but was markedly increased by concentrations which inhibited AII-stimulated aldosterone production. Small decreases and increases in 43K efflux, caused by 1 and 40 microM cromakalim respectively, corresponded with increases and decreases in basal aldosterone production; cromakalim did not affect 43K efflux from AII-stimulated cells. We suggest that increasing adrenocortical cell membrane permeability to K+ reduces steroidogenesis, but that valinomycin and cromakalim have other actions which complicate the relationship between 43K efflux and aldosterone production. Cromakalim appears to inhibit 21-hydroxylase activity in the biosynthetic pathway and may also affect 3 beta-hydroxysteroid dehydrogenase activity.
J Mol Endocrinol 1992 Oct
PMID:Membrane permeability to K+ and the control of aldosterone synthesis: effects of valinomycin and cromakalim in bovine adrenocortical cells. 141 87

[3H]L-158,809, a new potent and AT1-selective nonpeptide angiotensin II receptor antagonist, bound saturably and reversibly to rat adrenal membranes. Scatchard and Hill plot analyses indicated a single class of high affinity (Kd = 0.66 nM) binding sites. The relative potencies of various angiotensin II-related peptide and nonpeptide antagonists in displacing [3H]L-158,809 binding correlated with their potencies in displacing the binding of 125I-Sar1,Ile8-angiotensin II to adrenal AT1 receptors. [3H]L-158,809 binding to adrenal membranes was not affected by addition of guanosine-5'-(beta,gamma-imido)triphosphate or various pharmacological agents known to interact with other common peptide and nonpeptide receptor systems. The potencies of angiotensin II receptor agonists, but not antagonists, in inhibiting specific [3H]L-158,809 binding were decreased in the presence of guanosine-5'-(beta,gamma-imido)triphosphate. Specific [3H]L-158,809 binding was also observed in rat liver and kidney. Collectively, the data indicate that [3H]L-158,809 represents a new, potent, nonpeptide, antagonist radioligand suitable for the study of angiotensin II AT1 receptors.
Mol Pharmacol 1992 Dec
PMID:Characterization of the binding of [3H]L-158,809: a new potent and selective nonpeptide angiotensin II receptor (AT1) antagonist radioligand. 148 Jan 33

In cultured bovine adrenal glomerulosa cells, diacylglycerol content remains elevated for up to 75 min following the removal of angiotensin II. This maintained increase could provide a mechanism by which angiotensin II pretreatment may prime cells to secrete aldosterone in response to the calcium channel agonist Bay K 8644. In the present study we find that carbachol failed both to produce this persistent diacylglycerol elevation and to exert a priming effect. In addition, because carbachol was also a less potent activator of phospholipase D than angiotensin II, our results implicate phospholipase D in the maintained increase in diacylglycerol content observed following stimulation with and removal of angiotensin II. Carbachol also elicited changes in the radiolabeled levels of both myristate- and arachidonate-containing diacylglycerol. However, the rapid decline in diacylglycerol content following carbachol removal resembled the rapid fall in arachidonate-diacylglycerol; we therefore proposed that the diacylglycerol species generated with carbachol stimulation contains predominantly arachidonic acid. In summary, our results suggest that prolonged elevations in diacylglycerol content following removal of hormones such as angiotensin II, as well as the identity of the diacylglycerol species itself, may be important in the regulation of cellular responses.
Mol Cell Endocrinol 1992 Jul
PMID:Signal transduction mechanisms involved in carbachol-induced aldosterone secretion from bovine adrenal glomerulosa cells. 151 82

The peptide angiotensin II (AngII) has been reported to stimulate phosphoinositide-specific phospholipase C (PLC) activity in the murine neuroblastoma cell line N1E-115. In the present study, polyclonal antibodies raised against a PLC isoenzyme, PLC-alpha, reacted with a 60-kDa protein present in both membrane and cytosolic fractions of differentiated N1E-115 cells. In order to examine the possible association of PLC-alpha with cell surface AngII receptors (AngII-Rs), membranes from differentiated N1E-115 cells were solubilized, using the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). CHAPS (1%) solubilized AngII-Rs, from N1E-115 cells, that maintained their high affinity for agonists. Gel filtration analysis of the solubilized membranes revealed that the majority of the specific binding of 125I-AngII eluted as a large protein complex with a molecular mass of 380 kDa and that agonist binding was partially reduced by guanosine-5'-O-(3-thio)triphosphate (GTP gamma S), within this complex. CHAPS also effectively solubilized immunoreactive PLC-alpha, from N1E-115 cell membranes, that was similarly present within the 380-kDa AngII-binding complex. Anti-PLC-alpha antisera immunoprecipitated approximately 16% of the total phosphatidylinositol-4,5-bisphosphate-specific PLC activity in the 1% CHAPS extract and 40% of cytosolic PLC activity. Moreover, a 60-kDa 35S-Trans S-labeled protein, comigrating with immunoreactive PLC-alpha, was immunoprecipitated from the 1% CHAPS extract by the antisera. In addition, anti-PLC-alpha antisera immunoprecipitated approximately 20% of solubilized AngII-Rs prebound with 125I-AngII but failed to precipitate receptors prebound with the antagonist 125I-Sarc1,Ile8-AngII. The anti-PLC-alpha antisera also immunoprecipitated AngII-Rs when intact membranes were labeled with 125I-AngII before solubilization in 1% CHAPS, suggesting that the AngII-R interaction with PLC-alpha was not the result of detergent-promoted protein-protein interaction. On the other hand, monoclonal antibodies against another PLC isozyme, PLC-gamma, did not precipitate AngII-Rs in solubilized N1E-115 membranes. Finally, the formation of the immunoprecipitated AngII-R-PLC-alpha complex was disrupted by the nonhydrolyzable guanine nucleotide analog GTP gamma S, suggesting that the interaction between AngII-Rs and PLC-alpha is likely to involve a heterotrimeric guanine nucleotide-binding protein in neuron-like cells.
Mol Pharmacol 1992 Aug
PMID:Association of solubilized angiotensin II receptors with phospholipase C-alpha in murine neuroblastoma NIE-115 cells. 151 21

Using tritiated-thymidine incorporation as a measure of cell growth, interleukin-1 beta stimulated the growth of bovine zona fasciculata/reticularis adrenocortical cells after 72 h in primary culture. Within the range of 10-1000 pg/ml, interleukin-1 beta produced over 40% of angiotensin II-stimulated [3H]thymidine incorporation (P less than 0.005 compared with basal for 10 pg/ml and 1000 pg/ml; P less than 0.05 for 100 pg/ml; two-tailed unpaired Student's t-test). Interleukin-1 beta did not directly stimulate cortisol secretion. By stimulating adrenocortical growth, the increase in interleukin-1 during fever provides a potential mechanism for chronically raising glucocorticoid output. This study is the first demonstration of a long-term effect involving interleukin-1 beta on the adrenal cortex.
J Mol Endocrinol 1992 Apr
PMID:Interleukin-1 beta stimulates growth of adrenocortical cells in primary culture. 151 17

The angiotensinogen gene encodes the precursor protein for the potent vasoconstrictor angiotensin II. Although the gene is expressed in several tissues, the liver is the major source of circulating protein. In previous in-vivo studies we have found that a mini-gene containing 750 bp of 5'-flanking sequence is transcribed in a manner which largely parallels the expression of the endogenous gene. In this report, we characterized conserved elements in the promoter region, in order to determine their role in the transcription of the angiotensinogen gene. Constructs fused to the chloramphenicol acetyl transferase (CAT) reporter gene were transfected into hepatocarcinoma Hep G2 cells as well as into nonhepatic cell lines. We found that 5'-deletion mutant constructs, containing sequences from +25 to -90 bp and -321 to -750 bp, were each able to activate transcription. These constructs contain the TATA box and core promoter sequences, including an Sp1-binding site, and two glucocorticoid responsive elements respectively. In the non-hepatic cell lines, HeLa and Jeg-3, we found that the constructs were transcribed at a much lower rate when compared with the expression of a plasmid containing the Rous sarcoma virus long terminal repeat fused to the CAT gene. Constructs which included sequence 5' to -244 were oestrogen inducible. An element which is conserved between rodent and human angiotensinogen promoters is contained within a sequence which is oestrogen responsive, while another binds the liver-enriched transcriptional activator hepatocyte nuclear factor 1. However, the role of this transactivator in the transcription of angiotensinogen remains uncertain.
J Mol Endocrinol 1992 Aug
PMID:The function of conserved elements in the promoter of the mouse angiotensinogen gene. 151 23


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