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

The aim of this study was to evaluate the direct trophic effects of angiotensin II (AII) on rat vascular smooth muscle cells obtained from a single cellular isolate. Cell volume, protein synthesis, fibronectin (FN) release and FN-EIIIA+ mRNA isoform expression were analyzed in parallel. The effects of HR 720, a novel AT1 angiotensin receptor antagonist with some AT2 receptor affinity, were compared with those of selective AT1 antagonist EXP 3174. Both HR 720 and EXP 3174 inhibited in a concentration-dependent manner the maximum increase in cell volume induced by 10(-9) M Sar1-All (IC50 = 0.49 x 10(-9) M and 0.79 x 10(-9) M, respectively). Maximum [3H]leucine incorporation was also achieved at 10(-9) M All. HR 720 blocked the increase in protein synthesis with potency similar to EXP 3174; the respective IC50 values were 1.04 x 10(-9) M and 1.36 x 10(-9) M. All dose-dependently increased FN release, which was also equally inhibited by about 50% with both compounds at 10(-6) M. Furthermore, All enhanced FN-EIIIA+ mRNA in rat vascular smooth muscle cells (VSMC), which indicated a modulation of FN isoform expression which was inhibited by angiotensin II antagonists. In conclusion, All induced parallel and concentration-dependent increases in cell volume, protein synthesis, FN release and FN-EIIIA+ mRNA expression in vascular smooth muscle cells. These effects appeared to be essentially mediated by AT1 receptor stimulation as indicated by the equal inhibitory effects of HR 720 and EXP 3174.
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PMID:HR 720, a novel angiotensin receptor antagonist inhibits the angiotensin II-induced trophic effects, fibronectin release and fibronectin-EIIIA+ expression in rat aortic vascular smooth muscle cells in vitro. 899 27

Angiotensin-(1-7) is a novel peptide of the renin-angiotensin system that counteracts the pressor and proliferative responses to angiotensin II. We now report that cultured bovine aortic endothelial cells contain a saturable, high-affinity [125I]angiotensin-(1-7) binding site with an affinity of 19.3 +/- 10.7 nmol/L and a density of 1351 +/- 710 fmol/mg protein. Angiotensin-(1-7) competed at a second lower-affinity site, with an IC50 of 2.9 mumol/L. The high-affinity angiotensin II receptor antagonist sarcosine1-isoleucine8-angiotensin II blocked [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells at both a high- (IC50 = 1.3 nmol/L) and a low-affinity (IC50 = 6.2 mumol/L) binding site. In contrast, D-alanine7-angiotensin-(1-7) completely blocked [125I]angiotensin-(1-7) binding, with an IC50 of 19.8 nmol/L, suggesting that D-alanine7-angiotensin-(1-7) may selectively block responses to angiotensin-(1-7) in endothelial cells. Neither the AT1 antagonist losartan nor the AT2 antagonist PD 123319 exhibited significant competition for [125I]angiotensin-(1-7) binding to endothelial cells isolated from bovine aorta, in agreement with the absence of detectable mRNAs encoding typical angiotensin receptor subtypes 1 or 2 (AT1 or AT2). Angiotensin II also competed for [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells; however, the relative affinity was 13-fold lower than angiotensin-(1-7), suggesting a preference for angiotensin-(1-7) over angiotensin II. These results demonstrate that bovine aortic endothelial cells contain a unique non-AT1, non-AT2 angiotensin receptor that preferentially binds angiotensin-(1-7).
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PMID:Bovine aortic endothelial cells contain an angiotensin-(1-7) receptor. 903 32

In this study we determined the cardiovascular effects produced by microinjection of angiotensin peptides [Angiotensin-(1-7) and Angiotensin II] and angiotensin antagonists (losartan, L-158,809, CGP 42112A. Sar1-Thr8-Ang II, A-779) into the rostral ventrolateral medulla of freely moving rats. Microinjection of angiotensins (12.5-50 pmol) produced pressor responses associated to variable changes in heart rate, usually tachycardia. Unexpectedly, microinjection of both AT1 and AT2 ligands produced pressor effects at doses that did not change blood pressure in anesthetized rats. Conversely, microinjection of Sar1-Thr8-Ang II and the selective Ang-(1-7) antagonist, A-779, produced a small but significant decrease in MAP an HR. These findings suggest that angiotensins can influence the tonic activity of vasomotor neurons at the RVLM. As previously observed in anesthetized rats, our results further suggest a role for endogenous Ang-(1-7) at the RVLM. The pressor activity of the ligands for AT1 and AT2 angiotensin receptor subtypes at the RVLM, remains to be clarified.
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PMID:Cardiovascular effects produced by microinjection of angiotensins and angiotensin antagonists into the ventrolateral medulla of freely moving rats. 909 57

Angiotensin II is involved in blood pressure regulation, cell growth and angioneogenesis. The angiotensin receptors which mediate the intracellular effects of angiotensin II are expressed in numerous tissues and cell types. We studied the expression of angiotensin II receptors in cultured human skin fibroblasts derived from a skin biopsy. Angiotensin II binding characteristics were analyzed by radioligand binding assays. The DNA synthesis was assessed by [H]thymidine incorporation assays. Intracellular calcium concentrations were measured by fura-2 spectrofluorometry, and mRNA expression levels were analyzed by northern blot technology. Two distinct angiotensin receptors were detectable on human skin fibroblasts: the AT1 receptor with Kd = 1.0 +/- 0.7 nmol/l and Bmax = 17.9 +/- 0.9 fmol/mg protein, and an angiotensin(1-7) binding site with Kd = 26 +/- 6.6 nmol/l and Bmax = 80.4 +/- 3.5 fmol/mg protein, as shown by competition binding assays using selective angiotensin II receptor antagonists and the heptapeptide angiotensin(1-7). The angiotensin AT1 receptor mRNA was substantially expressed in human skin fibroblasts and was subjected to homologous downregulation. In human skin fibroblasts angiotensin II caused a profound increase in intracellular calcium which was blocked by angiotensin AT1 receptor antagonists such as Exp-3174. Furthermore, both angiotension II and angiotensin(1-7) led to increased DNA synthesis in human skin fibroblasts. In conclusion, cultured human skin fibroblasts express angiotensin AT1 receptors and a putatively new angiotensin receptor activated by angiotensin(1-7), both coupled to signaling pathways involved in DNA synthesis.
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PMID:Characterization of angiotensin receptors on human skin fibroblasts. 910 70

Our laboratory has previously reported the discovery of a unique angiotensin binding site (termed AT4) specific for angiotensin IV (AngIV) in cultured vascular endothelial and smooth muscle cells. The present investigation employed laser-Doppler flowmetry to examine the effect of angiotensin II (AngII) and AngIV stimulation of these receptors on cerebral microcirculation in anesthetized Sprague-Dawley rats. Internal carotid artery infusion of AngII at a low dose (0.1 pmol min-1) revealed a 23% reduction in cerebral blood flow (CBF), while the infusion of AngIV increased CBF in a dose-dependent fashion with the highest dose (100 pmol min-1) resulting in an elevation of 30%. In a second experiment separate groups of rats were pre-treated with the AT1 receptor subtype antagonist DuP 753 (Losartan), the AT2 receptor subtype antagonist PD123177, or a newly synthesized AT4 receptor subtype antagonist Divalinal-AngIV (Divalinal), followed by AngII or AngIV for the purpose of determining which angiotensin receptor subtype is responsible for mediating these AngII- and AngIV-induced responses. Pre-treatment with Losartan completely blocked subsequent AngII-induced reductions in CBF, while both PD123177 and Divalinal failed to inhibit this response. In contrast, significant increases in CBF were measured due to AngIV stimulation following pre-treatment with Losartan and PD 123177, while Divalinal abolished this AngIV-induced response. These results suggest that AngII and IV play opposite roles in cerebral microcirculation, i.e., the AT1 receptor subtype mediates AngII-induced reductions in CBF, while the AT4 receptor subtype regulates increases in CBF.
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PMID:Angiotensin II- and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes. 911 Mar 85

This study was undertaken to determine if changes in receptor density or affinity could account for the reduced vascular sensitivity to angiotensin II seen during pregnancy. Angiotensin receptor subtypes in the uterine arteries of non-pregnant, pregnant and postpartum ewes were investigated using saturation and competition receptor binding techniques with the specific receptor antagonists, losartan (DuP-753) and PD-123319 (S)1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenylacetyl )-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid, ditrifluoroacetate, monohydrate). Receptor density and affinity of total angiotensin receptors, as well as the angiotensin AT1 and AT2 receptor subtypes in uterine arteries were compared with those in the mesenteric artery and aorta. The uterine artery contains both AT1 and AT2 receptor subtypes, whereas the mesenteric artery and aorta contain primarily the AT1 receptor subtype. In uterine arteries from pregnant sheep, angiotensin receptor density was increased because AT2 receptors were increased. AT1 receptor density was not altered. This change was not seen in the aorta. In the uterine artery, receptor affinity for [Sar1,Ile8]angiotensin II decreased in mid-gestation (IC50 7.7 +/- 1.2 x 10(-9) M) compared with non-pregnant ewes (IC50 3.0 +/- 0.6 x 10(-9) M, P = 0.006), and there was decreased affinity of angiotensin AT1 receptors for losartan during pregnancy (IC50 2.8 +/- 1.0 x 10(-4) M) compared with non-pregnant ewes (IC50 2.2 +/- 1.3 x 10(-6) M, P = 0.025). Our results show changes in the density and affinity of the angiotensin receptor subtypes in the uterine artery which could explain its reduced responsiveness to circulating angiotensin II during pregnancy.
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PMID:Angiotensin receptor subtypes in the uterine artery during ovine pregnancy. 925 61

This study examined whether a regulatory mechanism exists for the angiotensin II receptor that is compatible with in vivo homeostatic need. Experiments were conducted under two different experimental stresses, (1) deletion of receptor protein and (2) chronic extracellular fluid (ECF) volume depletion. To circumvent potentially dampening intermediary feedback signals in vivo, any feedback gain was completely averted through genetic engineering. The coding exon of angiotensin type 1A (AT1A) receptor gene (Agtr1a) was targeting-replaced with a reporter gene, lacZ, so that the transcription of lacZ, instead of Agtr1a, is driven by the native Agtr1a promoter. ECF volume depletion by dietary sodium restriction enhanced Agtr1a gene expression in the adrenal gland of wild-type mice. However, although blood pressure fell in the homozygous targeted mice, Agtr1a gene expression remained unchanged in the adrenal, indicating that adrenal Agtr1a gene expression is regulated entirely through angiotensin receptor-ligand interactions. In the kidney, AT1A mRNA assessed by Northern blotting also did not change in AT1A null-mutated mice with or without sodium restriction. However, tissue examinations for lacZ mRNA and activities indicated that sodium restriction and receptor protein depletion result in dramatic up-regulation of Agtr1a gene expression within the renal arterioles, which can be nullified by an experimental normalization of blood pressure. No such change was observed in wild-type mice. This study demonstrates a presence within the resistance vessel of a blood pressure-sensitive mechanism for AT1 receptor regulation that opposes a down-regulatory influence of the ligand during ECF volume depletion.
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PMID:A novel in vivo mechanism for angiotensin type 1 receptor regulation. 926 89

The hypertrophy of renal proximal tubular cells occurs as an adaptive response to a variety of stimuli and may be involved with the progression of renal disease. Angiotensin II acting alone or in combination with other growth factors has been implicated in this process. The aims of this study were to identify the role of both angiotensin II and the angiotensin receptor subtypes in DNA synthesis and protein synthesis in human renal proximal tubular cells. Primary cultures of human renal proximal tubular cells were incubated with angiotensin II (10(-10) M, 10(-8) M, 10(-6) M) for 24 to 120 hours either alone or in combination with losartan, PD123319 or 8-bromo-cAMP. Incubation of human proximal tubular cells with angiotensin II (10(-10) M, 10(-8) M) induced a significant early increase in [3H]thymidine uptake by 19% and 56% (P < 0.01), respectively, and a later increase in total protein content by 30% (P < 0.01). The effect of angiotensin II upon DNA and protein synthesis was inhibited by 8-bromo-cAMP and losartan but not by PD 123319, indicating that the responses are mediated via the AT1 receptor and dependent upon the inhibition of adenylate cyclase.
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PMID:Selective antagonism of the AT1 receptor inhibits angiotensin II stimulated DNA and protein synthesis in primary cultures of human proximal tubular cells. 929 Nov 90

The pharmacological profile of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a novel non-peptide angiotensin AT1 receptor antagonist, was studied in vitro and in vivo. YM358 competed with [125I][Sar1, Ile8]angiotensin II for angiotensin AT1 receptors in rat liver membranes. YM358 displayed competitive kinetics and the pKi value was calculated as 8.79. In contrast, YM358 had little effect on the binding of [125I][Sar1, Ile8]angiotensin II to the angiotensin AT2 receptor in bovine cerebellum. In isolated rabbit aorta, YM358 produced a parallel rightward shift in the concentration-response curve for angiotensin II with a pA2 value of 8.82. YM358 had no effect on the contraction induced by KCl, norepinephrine, serotonin, histamine, prostaglandin F2alpha or endothelin-1 even at 10(-5) M. On the basis of pKi values in the binding assay and pA2 values in the isolated tissues, YM358 was approximately 3-10 times more potent than losartan in antagonizing angiotensin AT1 receptors. In pithed rats, intravenous administration of YM358 inhibited an increase in mean blood pressure induced by intravenous infusion of angiotensin II in a dose-dependent manner. In conscious normotensive rats, YM358 at 3-30 mg/kg p.o. inhibited the angiotensin II-induced pressor response in a dose-dependent manner. YM358 at 30 mg/kg caused maximum and complete inhibition 30 min after dosing, and inhibition lasted more than 24 h. These results demonstrate that YM358 is a potent, AT1-selective and competitive nonpeptide angiotensin receptor antagonist. Moreover, YM358 is both orally active and long-lasting. This pharmacological profile suggests that YM358 would be suitable for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.
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PMID:Pharmacological profile of YM358, a novel nonpeptide angiotensin AT1 receptor antagonist. 936 70

The acute vasodepressor effect of AT1 angiotensin receptor blockers losartan and CL329167 was compared in spontaneously hypertensive rats (SHR) pretreated and not pretreated with NG-monomethyl-L-arginine (LNMMA; 15 mg/kg i.v. bolus plus infusion at 10 mg/kg/h), an inhibitor of nitric oxide (NO) synthesis. The antihypertensive effect of losartan (30 mg/kg, i.v.) in SHR pretreated with LNMMA (-13 +/- 4 mmHg) was greatly diminished (P < 0.01) relative to the antihypertensive effect of losartan in SHR not pretreated with LNMMA (-44 +/- 8 mmHg). Similarly, the antihypertensive effect of CL329167 (5 mg/kg, i.v.) in SHR pretreated with LNMMA (-12 +/- 3 mmHg) was surpassed (P < 0.01) by the antihypertensive effect in SHR not pretreated with LNMMA. (-41 +/- 4 mmHg). However, pretreatment of SHR with LNMMA did not minimize the vasodepressor effect of prazosin, isoproterenol or sodium nitroprusside. The impairment in vasodepressor responsiveness to losartan in rats pretreated with LNMMA was not demonstrable in rats concurrently receiving sodium nitroprusside to correct for the loss of endogenous NO, or atrial natriuretic peptide which also increases vascular cGMP. These data suggest that a mechanism mediated by NO and/or cGMP is necessary for the full expression of the acute antihypertensive effect of AT1 angiotensin receptor blockers in SHR.
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PMID:Contribution of nitric oxide to the acute antihypertensive effect of blockers of AT1 angiotensin receptors in spontaneously hypertensive rats. 938 74


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