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Inositol phosphate release and steroidogenesis in rat adrenal glomerulosa cells. Comparison of the effects of endothelin, angiotensin II and vasopressin.

ABSTRACT: Endothelin has steroidogenic activity in adrenal glomerulosa cells, as do two other vasoconstrictor peptides, angiotensin II and vasopressin. The steroidogenic activities of angiotensin II and vasopressin are probably mediated via the phosphatidylinositol-turnover pathway and associated changes in cytosolic Ca2+ concentration. Endothelin caused a steroidogenic response, which was small compared with that to angiotensin II and quantitatively similar to the vasopressin response. Cytosolic free Ca2+ responses were similarly higher to angiotensin II than to either of the other two peptides. However, total inositol phosphate responses to endothelin and angiotensin II were similar when these were measured over 20 min, and were quantitatively greater than the vasopressin response. A detailed study has been made of the phosphatidylinositol-turnover response to endothelin in comparison with responses to angiotensin II and vasopressin. Each of the three peptides produced a rapid and transient rise in Ins(1,4,5)P3 (max. 5-15 s), followed by a slow sustained rise. Ins(1,4,5)P3 was metabolized by both dephosphorylation and phosphorylation pathways, but the relative importance of the two metabolic pathways was different under stimulation by each of the three peptides. These findings show that adrenal glomerulosa cells can distinguish between the stimulation of phosphatidylinositol turnover by three different effectors. These differences in the pathway may be associated with the observed different steroidogenic and Ca2+ responses to the three peptides.

SUBMITTER: Woodcock EA

PROVIDER: S-EPMC1149633 | biostudies-other | 1990 Nov

REPOSITORIES: biostudies-other

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Specific vasopressin binding to rat adrenal glomerulosa cells. Relationship to inositol lipid breakdown.

Project description:Cells from the zona glomerulosa of rat adrenals were isolated and maintained for 3 days in primary culture. Specific vasopressin binding was determined by using [3H]vasopressin. [3H]Vasopressin binding was time-dependent (half-time of about 2 min for 6 nM free ligand) and reversible on addition of unlabelled vasopressin (80% dissociation within 30 min). Dose-dependent [3H]vasopressin binding at equilibrium indicated that vasopressin interacted with two populations of sites: high-affinity sites (dissociation constant, Kd = 1.8 nM; maximal binding capacity = 10 fmol/10(6) cells) and low-affinity sites. Vasopressin increased the cellular content of labelled inositol mono-, bis- and tris-phosphate in cells prelabelled with myo-[3H]inositol. The vasopressin concentration eliciting half-maximal inositol phosphate accumulation was very close to the Kd value for vasopressin binding to high-affinity sites. Competition experiments using agonists and antagonists with enhanced selectivity for previously characterized vasopressin receptors indicated that vasopressin receptors from rat glomerulosa cells are V1 receptors of the vascular or hepatic subtype. The detected specific vasopressin-binding sites might represent the specific receptors mediating the mitogenic and steroidogenic effects of vasopressin on glomerulosa cells from rat adrenals.

| S-EPMC1146669 | biostudies-other

Cholera-toxin and corticotropin modulation of inositol phosphate accumulation induced by vasopressin and angiotensin II in rat glomerulosa cells.

Project description:Vasopressin (VP) and angiotensin II (AT II) stimulate the production of inositol phosphates (IP) in rat glomerulosa cells. Guanosine 5'-[gamma-thio]triphosphate (GTP[S]), but not VP or AT II, stimulates IP production in a myo-[3H]inositol-prelabelled glomerulosa-cell membrane preparation. In combination with GTP[S], these hormones potentiate the response to GTP[S], indicating the existence of a G-protein involved in the coupling of the VP and AT II receptor with the phospholipase C. ADP-ribosylation with pertussis toxin (IAP) revealed the specific labelling of a single molecule of 41 kDa. No significant inhibition of VP- or AT II-stimulated IP accumulation was detected in intact cells when the whole 41 kDa molecule was endogenously ADP-ribosylated by IAP treatment. On the contrary, when glomerulosa cells were infected with cholera toxin (CT), both the VP- and AT II-stimulated IP accumulations were inhibited in a dose-dependent manner. Yet these effects were partial even at high concentrations of CT, and could not be related to the ADP-ribosylation of 'alpha s' molecules. Similarly, when the cells were infected with 1 microgram of CT/ml, the specific binding of VP and AT II decreased by 50-60%. Such results may signify that the treatment primarily affects the densities of the hormone receptors. When glomerulosa cells were incubated for 15 h in the presence of 10 nM-corticotropin (ACTH), a condition in which the intracellular concentration of cyclic AMP was increased 3-fold, the maximum IP response to 0.1 microM-VP or -AT II was decreased by 50%. When similar experiments were carried out only after a 15 min incubation period with the same concentration of ACTH, the increase in cyclic AMP was more pronounced, but no inhibition of hormone-induced IP accumulation was observed. Altogether, these results may suggest that CT exerts its action on the VP- or AT II-sensitive phospholipase C systems via a prolonged increase in intracellular cyclic AMP.

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H.p.l.c. analysis of inositol monophosphate isomers formed on angiotensin II stimulation of rat adrenal glomerulosa cells.

Project description:[3H]Inositol-prelabelled isolated rat adrenal glomerulosa cells were stimulated with 25 nM-AII ([Asp1, Ile5]-angiotensin II) in the presence of 10 mM-Li+, and the resulting inositol monophosphate isomers were separated successfully by using a recently developed h.p.l.c. methodology. Two major peaks of radioactivity were detected which showed the same retention characteristics on h.p.l.c. as inositol 4-phosphate and inositol 1-phosphate and which increased 5-fold and 8-fold respectively on stimulation with AII. In addition, a relatively small peak with the retention characteristics of inositol 1:2-cyclic phosphate was seen to undergo a 1.5-fold increase on stimulation. This was not considered sufficient to suggest that cyclic phosphoinositols were a major product of AII-stimulated phosphoinositide turnover. No peaks of radioactive material were detected in the regions expected for inositol 2-phosphate (an acid hydrolysis product of inositol 1:2-cyclic phosphate) or inositol 5-phosphate. These results establish the identity of the major inositol phosphate products in AII-stimulated glomerulosa cells and confirm and extend the previous observations of Balla, Baukal, Guillemette, Morgan & Catt [(1986) Proc. Natl. Acad. Sci. 83, 9323-9327].

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Adenosine 3':5'-cyclic monophosphate production and steroidogenesis by isolated rat adrenal glomerulosa cells. Effects of angiotensin II and [Sar 1,Ala 8]angiotensin II.

Project description:Angiotensin II effects on cyclic AMP production and steroid output were studied in a sensitive preparation of isolated rat adrenal glomerulosa cells. With increasing concentrations of angiotensin II logarithmic dose-response curves for aldosterone and cyclic AMP production were similar. The minimum effective dose (0.2nm) for stimulation of aldosterone production also significantly (P<0.001) increased cyclic AMP output. For both aldosterone and cyclic AMP production, the peptide hormone concentration eliciting maximal response (0.2mum) and the ED(50) (median effective dose) values (1nm) were the same; this is consistent with cyclic AMP acting as an intracellular mediator for angiotensin II-stimulated aldosterone production by glomerulosa cells. The angiotensin II antagonist [Sar(1),Ala(8)]angiotensin II inhibited angiotensin II-stimulated corticosterone and aldosterone production in these cells. An equimolar concentration of antagonist halved the response to 20nm-angiotensin II, and complete inhibition was observed with 0.2mum-antagonist. In contrast, [Sar(1),Ala(8)]angiotensin II had no effect on maximally stimulated steroidogenesis induced by serotonin and a raised extracellular K(+) concentration. Increasing concentrations of [Sar(1),Ala(8)]angiotensin II alone decreased corticosterone and aldosterone outputs significantly (P<0.05) at concentrations of 20nm and 2nm of antagonist respectively. A significant (P<0.001) decrease in cyclic AMP production occurred with 2mum antagonist and this was comparable with the decrease in aldosterone production. It is concluded that [Sar(1),Ala(8)]angiotensin II can independently affect glomerulosa-cell steroidogenesis, possibly by modulating adenylate cyclase activity.

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Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin.

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Cytoplasmic Ca2+ signalling and reduction of mitochondrial pyridine nucleotides in adrenal glomerulosa cells in response to K+, angiotensin II and vasopressin.

Project description:We have examined the mitochondrial formation of NAD(P)H in rat adrenal glomerulosa cells. A short-term elevation of the K+ concentration from 3.6 to 8.4 mM induced a reversible increase in the formation of reduced pyridine nucleotides. Potassium applied after the addition of rotenone had no further effect, confirming that the redox signal was of mitochondrial origin. Inhibition of aldosterone synthesis by aminoglutethimide in K+-stimulated cells decreased the rate of decay of the NAD(P)H signal upon the termination of stimulation, indicating that the NADPH formed was consumed in aldosterone synthesis. When the NAD(P)H signal was measured simultaneously with the cytoplasmic free Ca2+ concentration ([Ca2+]i), elevation of the K+ concentration to 6.6 or 8.4 mM induced parallel increases in [Ca2+]i and NAD(P)H formation. The rates of increase and decrease of NAD(P)H were lower than for [Ca2+]i, confirming that the redox signal was secondary to the Ca2+ signal. Angiotensin II (100 pM-1 nM) induced an oscillatory NAD(P)H signal which usually returned to a lower baseline concentration, while a sustained signal with superimposed oscillations was observed at higher concentrations. Simultaneous measurements showed that NAD(P)H levels followed the [Ca2+]i pattern evoked by angiotensin II. Vasopressin (100 nM) also induced parallel oscillations of [Ca2+]i and NAD(P)H. A sustained rise in the extramitochondrial Ca2+ concentration to 1 microM induced a sustained elevation of the intramitochondrial Ca2+ concentration in permeabilized cells, as measured with rhod-2. A sustained rise in [Ca2+]i evoked by long-term stimulation with 8.4 mM K+ or 2.5 nM angiotensin II resulted in sustained NAD(P)H production. These Ca2+-dependent changes in the mitochondrial redox state support the biological response, i.e. aldosterone secretion by glomerulosa cells.

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| S-EPMC1131452 | biostudies-other

Monogenic Disorders of Adrenal Steroidogenesis.

Project description:Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.

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