Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which prolonged administration of ACTH causes a decrease in aldosterone secretion were studied in the rat. After 6 days of treatment with ACTH (2 U/day), blood corticosterone was elevated and plasma aldosterone was decreased in rats maintained on either a normal or low sodium diet. PRA was also decreased, probably secondary to increased sodium and/or fluid retention. In collagenase-dispersed glomerulosa cells from adrenals of ACTH-treated rats, angiotensin II receptors were markedly decreased, as were the in vitro aldosterone responses to angiotensin II, ACTH, 8-bromo-cAMP, and potassium. However, the production of deoxycorticosterone and precursor steroids was increased, indicating the presence of a block in the late aldosterone biosynthetic pathway. Measurement of the activity of biosynthetic enzymes of the steroidogenic pathway in isolated mitochondria revealed an 80% increase in side-chain cleavage enzyme in both glomerulosa and fasciculata mitochondria from ACTH-treated rats. Although ACTH injection also increased 11-hydroxylase activity in the fasciculata zone, this enzyme was reduced by 50% in capsular mitochondria. The 18-hydroxylase activity in adrenal capsular mitochondria was markedly decreased by ACTH treatment in both normal and sodium-restricted animals. The importance of ACTH-induced steroidogenesis in the development of altered glomerulosa cell function was indicated by the ability of aminoglutethimide to prevent the inhibitory effects of ACTH on angiotensin II receptors and PRA. It is likely that the observed inhibition of the renin-angiotensin system is responsible for the decrease in angiotensin II receptors and 18-hydroxylase, since both are highly dependent on the trophic effect of angiotensin II. The specific lesions produced in adrenal glomerulosa cells by long term ACTH treatment include decreased levels of angiotensin II receptors, 11-hydroxylase, and 18-hydroxylase. These changes are secondary to the suppression of renin-angiotensin activity and are responsible for the impaired aldosterone secretion that results from prolonged treatment with ACTH. (Endocrinology 108: 522, 1981)
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PMID:Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin. 625 54

The sites of action of aldosterone (A) along the tubule of rabbit kidney were studied by autoradiographic localization of mineralocorticoid-binding sites on microdissected tubular segments. Kidney pyramids were incubated at 30 degrees C for 1 h in a collagenase solution with [3H]aldosterone at a concentration of 1.5 X 10(-9) M with and without an excess unlabeled A. Tubular segments were then microdissected and transferred onto dry film; fixation and staining were done only after exposure of the film 4 mo later in order to avoid diffusion. Specific nuclear labeling was 19.0 +/- 1.3 silver grains/100 micrometers2 in distal convoluted tubules (n = 28) and 21.0 +/- 1.8 in cortical collecting ducts (n = 18). No difference between these two structures was observed (P greater than 0.1, paired t test, n = 15). No specific binding was found in the proximal tubule (0.5 +/- 0.4, n = 17). In the thick ascending limb of Henle's loop, the labeling was low (3.9 +/- 0.9, n = 16). We conclude that, in the rabbit kidney, nuclear mineralocorticoid-binding sites, presumably receptors, are present in the distal and cortical collecting tubule.
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PMID:Aldosterone binding along the rabbit nephron: an autoradiographic study on isolated tubules. 625 52

The steroidogenic properties of a glycoprotein fraction (urinary ASF), isolated from normal human urine, were studied in collagenase-dispersed rabbit adrenal capsular cells in 1) define the requirements for its steroidogenic activity, and 2) assess its site and mode of action. When incubated with adrenal cell suspension at 37 degrees C for 2 hours, urinary ASF induced dose-related increases in both aldosterone and corticosterone production. However, urinary ASF was less potent (ED50 = 10(-9) M) than either angiotensin II (ED50 = 8 x 10(-11) M) or ACTH (ED50 = 4 x 10(-11) M). Increases in cyclic AMP accompanized the steroidogenic response to ACTH but not to either urinary ASF or AII. Deprivation of potassium in incubation media or the addition of ouabain (1 mM) during incubation completely inhibited the steroidogenic response to either urinary ASF, ACTH, or AII. Like ACTH and AII, urinary ASF increased conversion of corticosterone to aldosterone. Specific competitive antagonist of AII (Sar1, Thr8, AII) and ACTH ([I1e9]ACTH1-24) did not prevent the ASF-induced increase in aldosterone production. These results suggest that urinary ASF is readily distinguishable from ACTH. Although it shares similar steroidogenic properties with AII, the inability of AII antagonist to block its effects suggests that it acts at a separate receptor site.
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PMID:Steroidogenic characteristics of a new aldosterone-stimulating factor (ASF) isolated from normal human urine. 626 51

To investigate the role of non-ACTH pituitary peptides on steroidogenesis, we studied the effects of synthetic beta-lipotropin, beta-melanotropin, and beta-endorphin on aldosterone and corticosterone stimulation using rat adrenal collagenase-dispersed capsular and decapsular cells. beta-lipotropin induced a significant aldosterone stimulation in a dose-dependent fashion (10 nM-1 muM). beta-endorphin, which is the carboxyterminal fragment of beta-lipotropin, did not stimulate aldosterone production at the doses used (3 nM-6 muM). beta-melanotropin, which is the middle fragment of beta-lipotropin, showed comparable effects on aldosterone stimulation. beta-lipotropin and beta-melanotropin did not affect corticosterone production in decapsular cells. Although ACTH(1-24) caused a significant increase in cyclic AMP production in capsular cells in a dose-dependent fashion (1 nM-1 muM), beta-lipotropin and beta-melanotropin did not induce an increase in cyclic AMP production at the doses used (1 nM-1 muM). The beta-melanotropin analogue (glycine[Gly](10)-beta-melanotropin) inhibited aldosterone production induced by beta-lipotropin or beta-melanotropin, but did not inhibit aldosterone production induced by ACTH(1-24) or angiotensin II. Corticotropin-inhibiting peptide (ACTH(7-38)) inhibited not only ACTH(1-24) action but also beta-lipotropin or beta-melanotropin action; however it did not affect angiotensin II-induced aldosterone production. (saralasin [Sar](1); alanine [Ala](8))-Angiotensin II inhibited the actions of beta-lipotropin and beta-melanotropin as well as angiotensin II. These results indicate that (a) beta-lipotropin and beta-melanotropin cause a significant stimulation of aldosterone production in capsular cells, (b) beta-lipotropin and beta-melanotropin have a preferential effect on zona glomerulosa cells, (c) beta-melanotropin contains the active peptide core necessary for aldosterone stimulation, (d) the effects of these peptides on aldosterone production may be independent of cyclic AMP, and (e) the receptors for beta-lipotropin or beta-melanotropin may be different from those for ACTH or angiotensin II.
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PMID:Effects of beta-lipotropin and beta-lipotropin-derived peptides on aldosterone production in the rat adrenal gland. 626 63

The site of action in the steroidogenic pathway of aldosterone stimulating factor (ASF), isolated from human urine, was studied in collagenase-dispersed rabbit adrenal capsular cells and compared with those of beta-lipotropin (beta-LPH), angiotensin II (A II) and adrenocorticotropic hormone (ACTH). When incubated with adrenal cell suspension at 37 degrees C for 2 hours, ASF, beta-LPH and ACTH induced dose-related increases in aldosterone production. ASF was less potent (ED50 = 10(-9) M) than ACTH but was more potent than beta-LPH. When ASF was added to the incubation with low dose of A II or ACTH, its effect on aldosterone production was additive, while no additional effect of ASF on aldosterone production was obtained in the presence of high dose of A II or ACTH. ASF increased the conversion of corticosterone to aldosterone like ACTH and beta-LPH. We have reported that ASF is a true aldosterone secretagogue and readily distinguishable from ACTH, A II and beta-LPH. The present study suggests ASF shares a common rate-limiting final pathway of steroidogenesis, which may be the step between corticosterone to aldosterone, with ACTH, A II and beta-LPH.
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PMID:Regulation of aldosterone secretion by a new aldosterone stimulating factor. 628 86

Metoclopramide, a dopaminergic antagonist, has consistently elevated plasma aldosterone levels in vivo. To determine whether this was a direct action of metoclopramide on adrenal steroidogenesis, we examined the response of collagenase-dispersed rat adrenal glomerulosa cells to metoclopramide in vitro. The effect of increasing concentrations of metoclopramide (3 X 10(-10) to 3 X 10(-4) M) on basal as well as angiotensin II (2.4 X 10(-10) to 2.4 X 10(-8) M)-, ACTH (3.5 X 10(-11) M)- and potassium (5.9 meq/liter)-stimulated aldosterone production was evaluated. Metoclopramide caused a dose-related decrease in basal and stimulated aldosterone production (P less than 0.01). In addition, metoclopramide also blocked basal and stimulated corticosterone production (P less than 0.01). This was not due to an irreversible toxic effect, since glomerulosa cells preincubated with 3 X 10(-4) M metoclopramide excluded trypan blue dye and responded to ACTH stimulation. Sodium metabisulfite, an antioxidant present in the metoclopramide preparation, did not contribute to the metoclopramide effect. These results indicate that metoclopramide is an aldosterone antagonist in vitro, contrary to reported data obtained in vivo. Thus, metoclopramide may be a partial dopaminergic agonist: in vitro where dopamine levels are negligible, it is an agonist, whereas in vivo where dopamine concentrations are greater, it is an antagonist.
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PMID:Metoclopramide inhibits aldosterone biosynthesis in vitro. 628 68

Metoclopramide (MCP), a dopaminergic antagonist, increases the levels of plasma aldosterone in man and sheep. The present studies were designed to determine how MCP exerts this effect. In in vitro studies using collagenase-dispersed rabbit adrenal zona glomerulosa cells, MCP (10(-4) M) failed to increase aldosterone biosynthesis and had no effect on the dose-related increases induced by angiotensin II (AII) or ACTH. Dopamine (10(-5) M) had no effect on the AII- or ACTH-induced aldosterone responses of these cells. Aldosterone production of cells pretreated with dopamine and stimulated by AII or ACTH was unaltered by the addition of MCP. Bolus intraarterial injections of MCP increased plasma aldosterone significantly; however, this response was completely abolished by concomitant administration of L-dopa. Chronic im administration of MCP produced significant elevations of plasma aldosterone that were associated with increases in adrenal weight and in the adrenal weight to body weight ratio. Glomerulosa cells isolated from these adrenal glands had normal basal aldosterone production and exhibited enhanced sensitivity to AII but normal responses to ACTH. These results suggest that MCP is devoid of intrinsic steroidogenic activity and that it increases aldosterone production by antagonizing a tonic inhibitory dopaminergic mechanism that leads to enhanced aldosterone production. This enhanced aldosterone production is mediated in part by increased adrenocortical sensitivity to AII.
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PMID:In vitro and in vivo evidence for an indirect mechanism mediating enhanced aldosterone secretion by metoclopramide. 629 Jan 89

The finding that incubation of rat adrenal capsules (largely zona glomerulosa) with trypsin reproducibly releases aldosterone and 18-hydroxycorticosterone (18-OH-B) from tightly protein-bound tissue stores leads to the hypothesis that the secretion of these steroids may be under the control of endogenous proteases. Rat adrenal capsule whole tissue and collagenase-dispersed cells were incubated under conditions of stimulation by (1-24)ACTH (10(-7) mol/l), potassium (8.4 X 10(-3) mol/l) or dibutyryl cyclic AMP (dbcAMP) (10(-4) mol/l) with the addition in some flasks of one of the following protease inhibitors at the appropriate concentration for their known actions: N alpha-p-tosyl-L-arginine methyl ester (TAME; 10(-2) mol/l), 2-nitro-4-carboxyphenyl-N,N'-diphenylcarbamate (NCDC; 2 X 10(-6) mol/l), N alpha-benzoyl-L-arginine (BA; 10(-2) mol/l), p-nitrophenyl-N alpha-benzyloxycarbonyl-L-lysinate (CBZ-NL; 2 X 10(-6) mol/l) and soybean trypsin inhibitor (STI; 1 mg/ml). The (1-24)ACTH-stimulated steroid output in dispersed cells was not affected by NCDC, BA or CBZ-NL. However, all of the inhibitors except STI produced selective effects on aldosterone and 18-OH-B production by whole capsule tissue under certain conditions. Thus TAME and NCDC significantly inhibited the dbcAMP-stimulated production of these two steroids (aldosterone values decreased from 328 +/- 35 to 128 +/- 15 and 157 +/- 32 ng/gland pair respectively) and furthermore NCDC elicited the same effect in potassium- or ACTH-stimulated whole tissue (e.g. in K+-stimulated tissue aldosterone decreased from 79 +/- 15 to 40 +/- 7 ng/gland pair). The reverse effect was shown by BA and CBZ-NL in potassium-stimulated whole tissue, and yields of aldosterone and 18-OH-B were significantly enhanced (aldosterone increased from 79 +/- 15 ng/pair to 151 +/- 14 ng in the presence of BA). The high molecular weight inhibitor STI had no effect on potassium-stimulated whole tissue, but enhanced the yield of extractable aldosterone from 9.7 +/- 1.7 to 16.9 +/- 2.3 ng/pair when added to incubations of a cytosol preparation. The results suggest that endogenous proteases in rat adrenal whole capsule tissue play specific roles in the control of aldosterone and 18-OH-B secretion. Some (type 1) whose action is mimicked by trypsin, are inhibited by TAME and NCDC and appear to be involved in the release of these two steroids from their tight (apparently covalent) binding to protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Serine proteases selectively control the output of 18-hydroxycorticosterone and aldosterone in stimulated zona glomerulosa tissue of the rat adrenal. 631 38

The effect of sodium deficiency on the adrenal sensitivity to beta MSH was studied using collagenase-dispersed rat adrenal cells from rats maintained on a normal sodium or a sodium-deficient diet for 2 weeks. In the cells prepared from adrenals of rats fed a normal sodium diet, angiotensin II (AII) and ACTH caused a dose-dependent increase in aldosterone production by glomerulosa cells at a threshold concentration of 10(-10) M and induced a maximal response at 10(-8) M. beta MSH also stimulated aldosterone production at a threshold of 10(-8) M and a maximum at 10(-6) M. However, in the cells from sodium-depleted rats, the threshold for AII was 10(-11) M and the maximum was 10(-8) M, while the threshold for ACTH and beta MSH was 10(-10) M. The shift to the left of the dose-response curve for beta MSH during sodium depletion was greater than that for AII or ACTH. The aldosterone levels obtained with maximal doses of beta MSH and AII were similar during sodium depletion. Sodium depletion did not affect the corticosterone response of decapsular cells to all three stimulators. In conclusion, sodium deficiency enhances the sensitivity of the adrenal glomerulosa cells to beta MSH, causing significant stimulation of aldosterone production by doses of beta MSH within the physiological range. These data suggest that beta MSH or peptides containing beta MSH may play a role in the regulation of aldosterone secretion during sodium deficiency in the rat.
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PMID:Effect of sodium deficiency on beta-melanocyte-stimulating hormone stimulation of aldosterone in isolated rat adrenal cells. 631 43

The dopamine antagonist metoclopramide (MCP) has been shown to acutely stimulate aldosterone secretion in vivo. To determine whether a dopaminergic mechanism is involved in the regulation of aldosterone secretion, we examined the effect of minipump infusion of MCP (iv) and/or angiotensin II (AII;sc) upon plasma aldosterone, adrenal capsular AII receptors, and 18-hydroxylase activity in rats maintained on high sodium intake. During normal sodium intake, plasma aldosterone was elevated from 8.3 +/- 1.3 to 35.4 +/- 3.2 ng/dl after 2-day infusion of a nonnatriuretic dose of AII (25 ng/min) and to 15.0 +/- 1.8 ng/dl after the infusion of 1.2 micrograms/min MCP. AII receptors were unchanged by MCP infusion, and rose from 1014 +/- 98 to 1638 +/- 98 fmol/mg after AII infusion. During high sodium intake, the infusion of either AII or MCP alone produced no change in plasma aldosterone or AII receptors. However, after simultaneous infusion of AII and MCP, plasma aldosterone rose from 4.5 +/- 1.2 to 32.5 +/- 2.7 ng/dl, AII receptors increased from 969 +/- 35 to 1607 +/- 280 fmol/mg, and 18-hydroxylase activity, measured as the conversion of corticosterone to aldosterone by isolated mitochondria, rose from 29.5 +/- 1.67 to 40.6 +/- 2.9 pmol/mg . min. These adrenal responses induced by the combined treatment with AII and MCP were similar to the effects of AII infusion during normal sodium intake, indicating that MCP exerts a permissive action upon the trophic effects of AII on the adrenal cell during high sodium intake. These actions of MCP were completely abolished by the simultaneous infusion of dopamine (2 micrograms/min), suggesting that the effects of MCP on adrenal function are due to its dopaminergic antagonist properties. In collagenase-dispersed adrenal glomerulosa cells, only supraphysiological concentrations of dopamine in the incubation medium (10-100 microns) inhibited basal, AII-stimulated, and ACTH-stimulated aldosterone production, and these inhibitory effects were not reversed by high concentrations of MCP. Also, MCP itself inhibited both basal and stimulated aldosterone production. These results suggest that the stimulatory actions of MCP in vivo are exerted through liberation of other local regulators, rather than directly upon the adrenal glomerulosa cell. These findings have defined a mechanism by which the primary regulatory action of AII upon aldosterone secretion can be modulated during high sodium intake by dopaminergic inhibition of adrenal glomerulosa function.
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PMID:Dopaminergic modulation of aldosterone secretion in the rat. 631 44


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