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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Stimulation of early gene expression by angiotensin II in bovine adrenal glomerulosa cells: roles of calcium and protein kinase C. 133 25

The role of AII receptors subtypes, AT1 and AT2, in the regulation of aldosterone secretion was studied in adrenal glomerulosa cells and membranes from rats on normal and low sodium intake, using AII receptor subtype-specific antagonists. In adrenal glomerulosa cells, more than 90% of the receptors were AT1 and there was a good correlation between the potencies of the antagonists to inhibit ligand binding, and AII-stimulated aldosterone production and inositol phosphate formation. The inhibition of basal and ACTH-stimulated cAMP by AII was also abolished by the AT1, but not the AT2, antagonist. Sodium restriction for 6 days increased both receptor subtypes in the same proportion, but only the AT1 antagonist inhibited AII-stimulated aldosterone production. The data demonstrate that AT1 receptor mediates the regulatory actions of AII in the adrenal zona glomerulosa.
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PMID:Role of angiotensin II receptor subtypes on the regulation of aldosterone secretion in the adrenal glomerulosa zone in the rat. 133 30

Regulation of the gene expression of type-1 angiotensin II receptor (AT1) by treatment with manidipine, a calcium channel blocker, or delapril, an angiotensin converting enzyme inhibitor, for one week was assessed in the adrenal gland, heart, kidney, and brain from spontaneously hypertensive rats (SHR). Tissue AT1 receptor messenger RNA (mRNA) content was measured by reverse transcriptase-polymerase chain reaction. Treatment with manidipine (3 mg/kg/day) or delapril (30 mg/kg/day) lowered systolic blood pressure (SBP) significantly (p < 0.01) (delta SBP; -73 mmHg or -67 mmHg, respectively). Although delapril markedly increased plasma renin activity (PRA), manidipine did not alter PRA. AT1 receptor mRNA content in the adrenal gland was significantly (p < 0.01) decreased by treatment with manidipine or delapril. In contrast, cardiac AT1 receptor mRNA content was significantly (p < 0.01) increased by treatment with either agent. There was no significant change in renal and brain AT1 receptor mRNA contents. These findings suggest that although the expression of AT1 receptor gene depends on the circulating renin-angiotensin system (RAS), it is regulated independently in a tissue-specific manner via the local RAS in each tissue of SHR.
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PMID:Regulation of the gene expression of type-1 angiotensin II receptor in spontaneously hypertensive rats. 134 80

Angiotensin II (ANG II), as a single factor, induces proliferation in a cultured murine mesangial cell line (MMC). This study was undertaken to evaluate a possible influence of atrial natriuretic peptide (ANP) on this ANG II-induced proliferation. ANP (10(-7) M) for 2 min significantly increased intracellular cGMP levels in MMC. This increase in cGMP was totally abolished when cells were preincubated for 5 min with 10(-7) M ANG II. Stimulation of intracellular cGMP formation by sodium nitroprusside was also decreased in the presence of ANG II. The ANG II-mediated inhibition of ANP-stimulated intracellular cGMP levels was blocked by Dupont 753, suggesting signal transduction through ANG II receptors of the AT1 class. ANP (10(-7) M) for 24 h completely abolished the ANG II-induced proliferation in MMC. However, 10(-7) M ANP had no significant effect on mitogenesis induced by platelet-derived growth factor or epidermal growth factor. Furthermore, ANP reduced the ANG II-stimulated expression of the proliferating cell nuclear antigen, a cofactor of polymerase delta that is active in the S-phase of the cell cycle. The addition of 10(-3) M N-monobutyryl-guanosine 3':5'-cyclic monophosphate or 8-bromo-guanosine 3':5'-cyclic monophosphate also blocked the ANG II-induced proliferation. ANP (10(-7)) M for 24 h had no significant influence on the expression (number and dissociation constant) of ANG II receptors as determined by binding assays. These results suggest that, besides the previously shown vasoconstrictive and vasodilating effects, complex interactions between ANG II and ANP exist that can modulate mesangial cell growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II-induced proliferation of cultured murine mesangial cells: inhibitory role of atrial natriuretic peptide. 136 89

Angiotensin II (AII) is a major regulator of cardiovascular function and fluid homeostasis. Recently, the cDNA for an AII receptor (AT1) was cloned from rat smooth muscle and bovine adrenal. To search for AII receptor subtypes, we amplified rat adrenal cortex cDNA by PCR using primers based on the AT1 receptor. The product was distinct from the AT1 receptor as indicated by restriction enzyme analysis and DNA sequencing. A full-length cDNA clone (2.2 kilobase pairs) encoding a novel AII receptor (AT3) was obtained by screening an adrenal cortex library. The AT3 cDNA encodes a Mr 40,959 protein with 95% amino acid identity to the rat smooth muscle receptor, but the overall nucleotide similarity is 71% due to low homology in the 5'- (58%) and 3'- (62%) untranslated regions. Expressed AT3 receptors in Xenopus oocytes and COS-7 cells mediate agonist-induced Ca2+ mobilization but are pharmacologically distinct from the AT1 receptors. AT3 mRNA is most abundant in the adrenal cortex and pituitary and differs from AT1 mRNA in its tissue distribution. The structural features of the AT3 receptor, including two additional potential phosphorylation sites for protein kinase C, could be related to the distinctive binding properties of the adrenal and vascular receptors and to their differential regulation during altered sodium intake.
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PMID:Cloning and expression of a novel angiotensin II receptor subtype. 137 2

The human angiotensin II (AII) type 1a receptor gene and its upstream control sequence has been cloned from a human leukocyte genomic library. The promoter element CAAT and TATA sequences were found at -602 and -538, respectively, upstream from the translational initiation site. The deduced protein sequence is homologous to rat and bovine AT1a receptors (94.7% and 95.3% identity). The expressed gene exhibited high-affinity AII and Dup753 binding and was functionally coupled to inositol phosphate turnover. Northern analysis of human tissues showed AT1 receptor mRNA expression in placenta, lung, heart, liver, and kidney. Using 5' untranslated and coding sequence as probes in a Southern blot analysis, it was established that another AT1 subtype exists in the human genome.
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PMID:Cloning, expression, and characterization of a gene encoding the human angiotensin II type 1A receptor. 137 23

To examine whether the subpopulation of the rat type 1 angiotensin II (AII) receptor (AT1A) couples with a single or multiple signal transduction pathways, we constructed Chinese hamster ovary (CHO) cell lines producing the recombinant receptor. The expressed AT1A receptor exhibits typical pharmacological characteristics of the AT1 receptor, known to mediate the main physiological function of AII. Addition of AII to the CHO cells induced a rapid, transient increase in intracellular free Ca2+ concentrations ([Ca2+]i) followed by a lower, sustained phase. Nicardipine, a blocker of voltage-dependent L-type Ca2+ channels, attenuated the transient [Ca2+]i response and abolished the sustained phase. The transient phase was also reduced dose-dependently by the phospholipase C inhibitor neomycin. Furthermore, AII inhibited forskolin-evoked cAMP accumulation. These data suggest, although another subpopulation named AT1B is present, that the rat AT1A receptor can independently couple with all three signal transduction pathways known to be induced by AII: i.e., i) activation of phospholipase C resulting in InsP3 generation with a subsequent release of intracellularly stored Ca2+, ii) activation of dihydropyridine-sensitive voltage-dependent Ca2+ channels, and iii) inhibition of adenylate cyclase activity.
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PMID:The rat angiotensin II AT1A receptor couples with three different signal transduction pathways. 137 99

A simplified and sensitive method for measuring expression levels of type-1 angiotensin II (AT1) receptor subtypes, AT1A and AT1B, was established. The two receptor cDNAs were co-amplified and measured by polymerase chain reaction using primers based on the corresponding receptor subtype genes. Both AT1A and AT1B mRNAs were widely expressed in the rat tissues including adrenal gland, kidney, heart, aorta, lung, liver, testis, pituitary gland, cerebrum and cerebellum. AT1A mRNA was predominantly expressed in the rat tissues examined except adrenal gland and pituitary gland where AT1B mRNA was predominantly expressed. Sodium depletion did not change mRNA levels of AT1A and AT1B in the all tissues. However, both AT1A and AT1B mRNA levels in the heart and aorta were down-regulated by treatment with AT1 specific antagonist, TCV 116. In contrast, AT1B mRNA in the adrenal gland was mainly reduced by the treatment. These results suggest that the expression level of AT1B mRNA in the adrenal gland depends on the activity of the renin-angiotensin-aldosterone system (RAAS) and both receptor subtypes mediate contraction and hypertrophy of the smooth and cardiac muscles via the RAAS.
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PMID:Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat. 138 88

Two new nonpeptide angiotensin II (AII) receptor antagonists, 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl ] biphenyl-2-carboxylic acid (BIBS 39) and 2-n-butyl-1-[4-(6-carboxy-2,5-dichlorobenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222) were characterized in radioligand binding assays, and in vitro and in vivo experiments. BIBS 39 displaced [125I] AII from its specific binding sites with a K(i) value of 29 +/- 7 nM for the AII subtype I (AT1) receptor and a K(i) value of 480 +/- 110 nM for the AII subtype 2 (AT2) receptor. BIBS 222 showed a K(i) value of 20 +/- 7 nM for the AT1 subtype and a K(i) value of 730 +/- 170 nM for the AT2 subtype. Thus BIBS 39 was 17 times more selective for the AT1 subtype and BIBS 222 37 times. Both compounds were specific for AII receptors as they did not show high affinity for other receptors. BIBS 39 shifted the AII concentration-contractile response curves in isolated rabbit aorta to the right in a parallel fashion. A pA2 value of 8.14 +/- 0.08 and a slope of 1.06 +/- 0.07 were calculated. BIBS 222 caused nonparallel shifts to the right and reduced the maximal response induced by AII by about 25%. A KB value of 9.01 (+/- 3.22) x 10(-8) M was determined. At 10(-5) M, neither compounds altered the contractile responses to noradrenaline and KCl. In pithed rats, BIBS 39 dose dependently shifted the dose-response curve of AII to the right without affecting the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of BIBS 39 and BIBS 222: two new nonpeptide angiotensin II receptor antagonists. 139 34

Recently several novel nonpeptide antagonists of angiotensin II (Ang II) have been identified. One of these, losartan potassium (formerly DuP 753) was developed as an orally active and highly selective antagonist for Ang II. As it is inhibited by sulfhydryl agents, it is specific for the AT1 receptor subtype. Since Ang II has both central and peripheral effects, we investigated whether losartan, given p.o. chronically, crosses the blood-brain barrier. The effects of chronic administration of losartan orally (p.o.) at 3 mg/kg per day for three days on the dipsogenic and pressor responses to a pre-established dose of Ang II i.v.t. (50 ng) were studied. Three series of experiments were carried out using conscious normotensive Sprague-Dawley rats. The rats were injected with Ang II intraventricularly (i.v.t.) before and after treatment of losartan p.o. and blood pressure and drinking responses measured. The experiments established that 3 mg/kg losartan p.o. for 3 days antagonized pressor effects of Ang II intravenously (i.v.), but did not antagonize the pressor or drinking effects of Ang II i.v.t. Daily water intake significantly increased with chronic losartan p.o.. Since chronic administration of losartan p.o. was able to block the effects of Ang II i.v. but had no effect on Ang II i.v.t. we conclude that losartan potassium does not readily cross the blood-brain barrier using this dose regimen.
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PMID:Losartan potassium, a nonpeptide antagonist of angiotensin II, chronically administered p.o. does not readily cross the blood-brain barrier. 139 42


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