UMLS:C0004135 - FACTA Search

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Query: UMLS:C0004135 (ATM)
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In this study we have investigated the effect of angiotensin-II (A-II) on cortisol production and 17 alpha-hydroxylase cytochrome P450 (P450(17 alpha)) expression in primary cultures of ovine adrenocortical cells and the A-II receptor subtypes that mediate these responses. While A-II alone had no stimulatory effect on cortisol secretion, it inhibited the cortisol response to ACTH (10(-8) M) in a dose-dependent manner (Ki, less than 0.1 nM; maximum inhibition, 60-80%). While prolonged treatment with ACTH (10(-8) M) increased the expression of P450(17 alpha), cotreatment with A-II (10(-8) M) also inhibited ACTH-stimulated expression, as determined by changes in mRNA, immunoreactive P450(17 alpha), and 17 alpha-hydroxylase activity. A study of the effects of the AT1 and AT2 receptor antagonists, DuP 753 and PD 123319, on binding of [125I]A-II to ovine adrenocortical cells showed that the A-II receptor population was predominantly of the AT1 subtype. The effects of A-II on inhibition of cortisol secretion in response to ACTH and the activation of phosphoinositidase-C in response to A-II alone were both fully antagonized by DuP 753, but not by PD 123319. Furthermore, the inhibitory effects of A-II on expression of P450(17 alpha), as measured at the levels of mRNA, immunoreactive protein, and enzyme activity, were reversed by DuP 753 (10(-5) M), but not PD 123319 (10(-5) M). We conclude that A-II has a potentially important role in the control of cortisol secretion and long term maintenance of P450(17 alpha) expression in the ovine adrenal cortex, and that the effects of A-II on both cortisol secretion and P450(17 alpha) expression are mediated through the AT1 receptor, which is coupled to phosphoinositidase-C.
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PMID:Angiotensin-II acts via the type 1 receptor to inhibit 17 alpha-hydroxylase cytochrome P450 expression in ovine adrenocortical cells. 131 75

Angiotensin-II (AII), a component of the renin-angiotensin system, is the major factor that regulates the formation of aldosterone in the adrenal cortex zona glomerulosa (ZG). The activity of this system is increased by an increase in potassium intake or a decrease in sodium intake. Using immunoblotting analysis, we determined whether these ions affect the expression of type 1 AII receptors (AT1) and compared the results thus obtained with the AT1 receptor mRNA levels. We also studied the interrelation among AII, AT1 receptors, cytochrome P450 aldosterone synthase (P450c18), and plasma aldosterone levels in rats fed a normal diet or a low sodium or high potassium diet with or without captopril, an inhibitor of angiotensin-converting enzyme, for 7 days. The effects of ions on the level of ACTH receptor mRNA were also analyzed. We found that a low sodium intake increased plasma aldosterone levels from 5.5 to 236 ng/dl and led to 2.3- and 3.7-fold increases in the levels of adrenal ZG AT1 receptor protein and AT1 receptor mRNA, whereas a 11.8-fold increase was found in the level of P450c18 mRNA. Captopril almost completely reversed these effects. We have shown that a high potassium intake increased plasma aldosterone levels to 25.9 ng/dl and also led to 1.84- and 1.95-fold increases in the level of ZG AT1 receptor protein and AT1 receptor mRNA, whereas the ZG P450c18 mRNA level was increased 3.5-fold. The plasma aldosterone level of animals fed a high diet of potassium and captopril was still higher than that in control animals at 16.6 ng/dl, and the levels of ZG AT1 receptor and P450c18 mRNAs were only slightly less than those of the high potassium groups, indicating that captopril did not efficiently block aldosterone formation under these conditions. ACTH receptor mRNA levels remain unaffected by either low sodium or high potassium intake. Collectively, these results indicate that the increased aldosterone secretion induced by low sodium or high potassium intake involves concomitant increases in AT1 receptor and P450c18 mRNAs, which are effectively translated into their respective proteins, and that the expression of both proteins is mediated in part by AII.
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PMID:Both low sodium and high potassium intake increase the level of adrenal angiotensin-II receptor type 1, but not that of adrenocorticotropin receptor. 750 36

While known to be a potent activator of phosphoinositidase C, angiotensin II (A-II) also causes a small but significant increase in cAMP production through the type 1 A-II (AT1) receptor in bovine adrenocortical cells (Mol Cell Endocrinol 81:33-41, 1991). We have carried out studies on primary cultures of fetal bovine adrenocortical cells to examine the effects of A-II on the expression of cytochrome P450 17 alpha-hydroxylase (P450c17), which is known to be regulated in a cAMP-dependent fashion. Prolonged treatment (48 h) of cells with A-II (10(-7) M) did not give rise to a detectable increase in P450c17 as measured by immunoblotting, although both A-II and the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA) attenuated the large increase in P450c17 induced by ACTH (10(-8) M). A-II alone (10(-7) M) however, caused a time-dependent increase in cAMP secretion, reaching 8-fold within 3 h. Prolonged treatment of cells with A-II also resulted in a 3-fold increase in P450c17 mRNA within 12 h (10(-7) M), and a dose-dependent increase in 17 alpha-hydroxylase activity within 48 h (16.4-fold max at 10(-7) M). The stimulatory actions of A-II alone (10(-7) M) on cAMP levels, P450c17 mRNA, and 17 alpha-hydroxylase activity were much smaller than in response to ACTH (10(-8) M), but were largely reproduced by TPA (10(-7) M), suggesting a role for protein kinase C in mediating these responses to A-II. These findings indirectly support the hypothesis that A-II alone can stimulate an increase in cAMP in adrenocortical cells. Such a stimulation of cAMP may then result in increased expression of steroidogenic enzymes, as we have shown is the case for P450c17 expression. However, A-II in the presence of ACTH appears to attenuate the ACTH-stimulated expression of P450c17.
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PMID:Angiotensin-II stimulates an increase in cAMP and expression of 17 alpha-hydroxylase cytochrome P450 in fetal bovine adrenocortical cells. 838 Oct 79

Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.
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PMID:Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. 865 89

The aim of the study was to investigate whether the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in the adrenal gland and to explore the mechanisms of this action. Twelve-week-old male Sprague-Dawley rats were studied: 22 rats were maintained on a regular diet; 27 and 22 rats received a low salt diet with and without treatment, respectively, with the angiotensin II (Ang II) AT1-subtype receptor antagonist losartan (10 mg/kg per day). A fraction of each group of rats underwent bilateral nephrectomy (n = 12, 15, and 10, respectively) and was killed 48 hours later. In an additional group of 24 (12 intact and 12 nephrectomized) rats, the effects of the Ang II AT2-subtype receptor antagonist PD123319 were investigated. In intact rats, plasma renin activity (PRA) and adrenal renin activity and expression were progressively raised by salt restriction and losartan, whereas aldosterone synthase mRNA and plasma aldosterone (PA) levels were increased by salt restriction and reduced by losartan. Forty-eight hours after nephrectomy, PRA fell to undetectable levels; in contrast, adrenal renin expression, assessed by semiquantitative reverse-transcriptase polymerase chain reaction (using GAPDH as a standard for gene expression), showed an 18-fold increase and was further increased after salt restriction and losartan (all P < .05). Also, adrenal renin activity was raised after nephrectomy and further increased after salt restriction (P < .05) and losartan. Cytochrome P450 aldosterone synthase expression in the adrenal cortex was stimulated by nephrectomy alone and by nephrectomy combined with low salt intake (P < .05), with consequent increases in PA concentrations. In losartan-treated salt-restricted nephrectomized rats, cytochrome P450 aldosterone synthase expression (P < .05 versus nephrectomy alone and nephrectomy plus salt restriction) and PA concentrations were diminished (P < .05) in spite of the observed increases of adrenal renin expression. The AT2-receptor antagonism did not significantly affect PRA, adrenal renin, and aldosterone biosynthesis and production in either intact or nephrectomized salt-restricted rats. These results demonstrate that the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in vivo. This action is mediated primarily via the Ang II AT1-subtype receptors.
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PMID:Role of tissue renin in the regulation of aldosterone biosynthesis in the adrenal cortex of nephrectomized rats. 935 60

Eprosartan is a nonpeptide angiotensin II receptor antagonist which has a high affinity for the AT1 receptor subtype. When administered at dosages of 400 to 800 mg/day (once or twice daily) for 13 weeks to patients with mild to moderate essential hypertension, eprosartan significantly reduced blood pressure compared with placebo. Eprosartan was at least as effective as enalapril 10 to 40 mg/day in a dose-titration study in patients with severe hypertension. Eprosartan is generally well tolerated; clinical trials have shown the drug to have a tolerability profile similar to that of placebo. As with other angiotensin II receptor antagonists, it does not cause cough. Eprosartan is not metabolised by the cytochrome P450 system and therefore has a low potential for drug interactions.
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PMID:Eprosartan. 958 67

1. We showed earlier that NO inhibition caused a left-shift and augmented Emax of the concentration-response curve of AT1-mediated (angiotensin II)-induced vasoconstrictions (AII-VC) in the rat kidney. The 0.01-0.1 nM AII-VC unmasked by the potentiating effect of NO inhibition, were sensitive not only to AT1 (L158809), but also to AT2 receptor (PD123319) antagonists. We now demonstrate the role of endothelium and eicosanoids in the NO-masked AT1/AT2-mediated component of the AII-VC in isolated indomethacin-perfused kidneys of the rat. 2. L-NAME increased 0.1 nM AII-VC 7.2 fold. Pretreatment of the kidneys with factor VIII antibody/complement or with the detergent CHAPS to damage endothelium, decreased carbachol-induced vasodilatation and blunted by 60 and 30% respectively, the enhancement of AII-VC during NO inhibition. 3. L-NAME also increased 3 microM noradrenaline (NA)-induced vasoconstriction (NA-VC) 8.1 fold. In contrast to AII-VC, endothelium damage was without effect on the enhancement of NA-VC by L-NAME, suggesting a dominant role of endothelium-derived NO in the enhancement of NA-VC. 4. During NO inhibition, ETYA (2 microM; an inhibitor of all arachidonic acid derived pathways) and alpha-naphtoflavone (10 microM; an inhibitor of the cytochrome P450 isozymes), decreased by 85% the 0.1 nM AII-VC. 5. In conclusion, during NO inhibition, the AT1-mediated constriction to low concentrations of AII, which is sensitive to AT2 antagonists, depends on intact endothelium, and can be blocked by inhibition of eicosanoid synthesis. The results suggest that the AII-mediated vasoconstriction through AT1 receptors is potentiated in the absence of NO, by the release of eicosanoids from the endothelium through AT2 receptors.
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PMID:AT2 antagonist-sensitive potentiation of angiotensin II-induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature. 969 80

The purpose of this study was to evaluate the effects of acute (a single injection) and chronic stimulation (twice daily injection for 9 days) by ACTH on changes occurring in the temporal expression of steroidogenic enzymes in the rat adrenal in vivo. Under acute ACTH stimulation, the level of steroidogenic acute regulatory protein (StAR) messenger RNA (mRNA) was increased within 0.5 h in both zona glomerulosa (ZG) and zona fasciculata-reticularis (ZFR), with maximal increases of 220-370% and 300-350% in the ZG and ZFR, respectively. Increases in the levels of StAR protein in homogenates were also found in the ZG (700%) and the ZFR (300%), but were delayed compared with those of their mRNA. Furthermore, the increase in mitochondrial StAR protein was concomitant with that in the homogenate, indicating that the entry of StAR into mitochondria might not be necessary to increase steroidogenesis during the early stimulatory phase. The levels of c-jun, c-fos, junB, and fosB mRNA in ZG and ZFR were also rapidly maximally elevated within 0.5-1 h after ACTH administration and fell to near control levels 5 h posttreatment. The levels of c-jun protein were already increased in both zones at 1 h, reached 200% at 3 h, and remained elevated 5 h post-ACTH treatment. The levels of c-Fos protein were maximally increased by 240% in both zones after 1 h and decreased thereafter to control values at 5 h. Few changes were observed in the adrenal protein contents of cholesterol side-chain cleavage cytochrome P450 (P450scc), cytochrome P450 11beta-hydroxylase (P450C11), cytochrome P450 21-hydroxylase (P450C21), and 3beta-hydroxysteroid dehydrogenase (3betaHSD). Under chronic stimulation by ACTH, we observed elevations in the levels of plasma corticosteroids and changes in the mRNA and protein levels of many adrenal steroidogenic enzymes in both zones. In the ZG, administration of ACTH for 9 days provoked an increase in the level of StAR mRNA (210-270%) and a decrease in the levels of 3betaHSD, cytochrome P450 aldosterone synthase (P450aldo), and AT1 receptor mRNA (by 40%, 70%, and 90%, respectively), whereas the levels of P450scc and P450C21 mRNA did not differ significantly from the control values. Western blotting analysis showed that the adrenal ZG protein levels of StAR and P450scc were increased (150%), 3betaHSD was not changed, and P450C21 was decreased by 70%. In the ZFR, the levels of P450scc and StAR mRNAs were increased (260% and 570-870%, respectively). The levels of 3betaHSD, P450C21, and P450C11 mRNA did not differ from control values in that zone. Western blotting analysis showed that the ZFR protein level of 3betaHSD was not changed, P450scc and P450C21 were decreased by 40% and 60%, respectively, and StAR was increased by 160%. Although c-fos and fosB mRNAs were undetectable after 9 days of chronic ACTH treatment, c-jun mRNA and its protein were still detectable, suggesting a basic role for this protooncogene in maintaining the integrity and function of the adrenal cortex. When dexamethasone was administered to rats for 5 days to inhibit their ACTH secretion, the mRNA levels of many steroidogenic enzymes were decreased, with the exception of StAR, 3betaHSD, and P450aldo. These results confirm the importance of physiological concentrations of ACTH in maintaining normal levels of adrenocortical enzymes and also indicate that in addition to ACTH, other factors are involved in controlling the expression of StAR, 3betaHSD, and P450aldo. In conclusion, we showed that ACTH acutely increases StAR mRNA followed, after a delay, by an increase in the level of StAR protein; this suggests that posttranslational modifications of the StAR precursor occurred during the early stimulatory phase and before the apparent translation of the newly formed mRNA. The rapid induction of protooncogenes suggests their participation in the action of ACTH to stimulate steroidogenesis. (ABSTRACT TRUNCATED)
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PMID:The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. 972 47

Angiotensin II is a key element in regulating the volume of extracellular liquid. It acts indirectly through aldosterone secretion by adrenals and directly on the renal tubule too: It regulates luminal Na+/H+ antiporters (NHE3 and possibly NHE2) after binding to membrane AT1 receptors located both on the basolateral and on the apical side of the cells. The main site of Ang II action is proximal tubule, mainly the S1 segment which has a high level of AT1 receptors. Circulating Ang II concentrations (10(-12) to 10(-10) M), increased NaCl, water and NaHCO3 reabsorption via NHE3 in the proximal tubule. There is also a synthesis of Ang II within the cells of proximal tubule, which is secreted within the lumen where the physiological concentration is stable 10(-8) M, i.e. 100 to 1000 times higher than the circulating concentration. Luminal ANG II originating from kidney has a physiological autocrine function on NaCl, water and probably NaHCO3 reabsorption, since inhibiting Ang II synthesis, by conversion enzyme inhibition, or effect, by AT1 receptor antagonists, induces a reduction of proximal tubule reabsorption. The stimulatory effects of circulating and intrarenal Ang II seem to be explained by protein kinase C stimulation and possibly by a reduction of cAMP production or by a stimulation of a non-receptor tyrosine kinase. When pharmacological doses of Ang II (> 10(-8) M) are applied in the peritubular or the luminal medium of isolated microperfused proximal tubule in vitro, a paradoxical inhibition of NHE3 was observed. These effects appear to involve arachidonic acid metabolites through the cytochrome P450 pathway and possibly a rise in cytosolic free Ca++. The physiological significance of these supraphysiological effects are unknown.
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PMID:[Effect of angiotensin ii on Na+/H+ exchangers of the renal tubule]. 985 78

Angiotensin II (Ang II) is an important regulator of the function of medullary thick ascending limb of loop of Henle (MTAL). Recent studies showed that changes in Ang II receptor expression occur and underlie changes in the function of proximal tubules during altered sodium intake. The present experiment was designed to determine (1) whether expression of the type 1 Ang II (AT1) receptor in the MTAL is regulated by altered sodium intake, and (2) the specific pathway(s) mediating sodium-induced AT1 expression in the MTAL. Wistar rats were fed a normal sodium (0.5%, NS), low sodium (0.07%, LS), or high sodium (4%, HS) diet for 2 weeks. Northern blot analysis and radioligand binding showed that in rats fed a normal sodium diet the rank of order for both AT1 mRNA expression and receptor density was outer medulla > cortex > inner medulla. Sodium restriction significantly increased both AT1 mRNA expression and receptor density in the outer medulla. In contrast, neither AT1 mRNA expression nor receptor density in the outer medulla was altered by sodium loading. Losartan treatment (3 mg/kg/per day by oral gavage for 2 weeks) prevented low sodium-induced upregulation of the AT1 receptor in the outer medulla, but it had no effect on AT1 expression in the outer medulla of rats fed a normal sodium diet. Highly purified suspensions of MTAL were isolated from rats fed a normal or low sodium diet. Low sodium intake significantly increased AT1 mRNA level by 184% and AT1 receptor density by 58% in MTALs. Primary cultures of MTAL cells were treated with PBS, Ang II (10(-8) M), and Ang II + 17 octadecynoic (17 ODYA, 10 microM). Ang II caused about 2-fold increase in AT1 mRNA levels, and this increase was diminished by about 30% by the addition of 17 ODYA. We conclude that (1) sodium restriction but not sodium loading increases AT1 receptor expression in the MTAL, (2) low sodium-induced upregulation of the AT1 receptor in the MTAL is Ang II-dependent, and (3) Ang II-induced upregulation of the AT1 receptor in the MTAL is mediated, at least in part, by cytochrome P450 pathways.
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PMID:Regulation of angiotensin II receptors in the medullary thick ascending limb. 1110 53

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