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

A number of different assay methods have been used to study repair of strand breaks in DNA after exposure of cells to ionizing radiation. Use of these methods indicates that fibroblasts from patients with ataxia telangiectasia (AT), a multiform genetic disease exhibiting high sensitivity to ionizing radiation, have a normal ability to repair strand breaks in DNA. All of these methods determine the extent of breakage of DNA and the resealing of these breaks but do not provide information on restoration of DNA configuration in the nucleus. In this report we have used a sensitive technique to investigate restoration of the 3-dimensional structure of DNA in AT lymphoblastoid cells after exposure to ionizing radiation. This technique provides a means of lysing cells using a high concentration of salt and a non-ionic detergent, giving rise to structures called nucleoids which contain nuclear RNA and DNA, are depleted in protein, and sediment in a manner characteristic of supercoiled DNA. We have shown that the degree of supercoiling is the same in control and AT lymphoblastoid cells using sedimentation in the presence of ethidium bromide. The extent of breakage after exposure of cells to gamma-radiation, and the rate of repair of these breaks are similar in both cell types. Rate of repair of strand breaks is dose dependent and the restructured rapidly sedimenting complex behaves similarly, on sucrose gradients containing ethidium bromide, to that extracted from unirradiated cells.
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PMID:Repair of strand breaks in superhelical DNA of ataxia telangiectasia lymphoblastoid cells. 727 97

[3H]Senktide, a highly selective tachykinin NK3 receptor agonist, was used to study tachykinin NK3 receptors of rat and guinea pig brain. Guinea pig brain membranes had a Kd of 3.9 +/- 0.5 nM and a Bmax of 42 fmol/mg. Dose-displacement experiments with neurokinins and selective tachykinin receptor agonists revealed the following order of potency: [MePhe7]neurokinin B > neurokinin B > substance P > neurokinin A. This order is typical for a tachykinin NK3 receptor. To further characterize the specificity of this receptor, the effects of unrelated compounds such as: bradykinin, angiotensin II, bombesin and their structural analogs were also evaluated on the binding of [3H]senktide. Unexpectedly, the angiotensin AT1 receptor antagonists, DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)bip hen yl-4-yl)methyl]imidazole potassium salt), L-158,809 (5,7-dimethyl-2-ethyl-3-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl) methyl]-3H-imidazo[4,5-beta]pyridine H2O) and EXP 3174 (2-n-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole- 5-carboxylic acid), inhibited the binding of [3H]senktide to its receptor in the guinea pig brain membranes with IC50 values of 18 microM, 25 microM and 50 microM, respectively. Similar effects were also observed with rat brain membranes. Angiotensin II, saralasin ([Sar1,Val5,Ala8]angiotensin II, a peptide angiotensin AT1 receptor antagonist) and PD 123,319 (1-[4-(dimethylamino)3-methylphenyl]methyl-5-(diphenylacetyl)-4,5, 6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid, a known non-peptide angiotensin AT2 receptor antagonist) did not inhibit the binding of [3H]senktide to either type of membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Non-peptide angiotensin receptor antagonists bind to tachykinin NK3 receptors of rat and guinea pig brain. 751 91

Since dietary salt loading enhances nitric oxide (NO) generation in the kidney, we investigated the hypothesis that changes in salt intake have specific effects on vascular resistance in the kidney mediated by the L-arginine-NO pathway. We contrasted changes in renal and hindquarter vascular resistances (RVR and HQVR) in anesthetized rats during intravenous infusions of graded doses of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Groups (N = 8 to 10) of rats were maintained on a high salt (HS) or low salt (LS) diet for two weeks. Compared to those on LS, rats on HS had a greater increase in mean arterial pressure (delta MAP; +32 +/- 4 vs. +22 +/- 3%; P = 0.05) and RVR (+160 +/- 17 vs. +83 +/- 10%; P < 0.005) and a greater fall in renal blood flow (delta RBF; -47 +/- 3 vs. -32 +/- 4%; P < 0.01); changes in HQVR were similar in the two groups. The enhanced RVR response to L-NAME in HS rats could not be ascribed to the higher renal perfusion pressure (RPP) since it persisted in rats whose RPP was controlled by adjustment of a suprarenal aortic clamp. Changes in RVR with an NO donor (SIN-1) were similar in HS and LS rats. L-NAME reduced plasma renin activity in both HS and LS rats. After inhibition of ACE with captopril, or of angiotensin II type I (AT1) receptor with losartan, the increase in RVR with L-NAME remained greater in HS than LS rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal vasoconstriction during inhibition of NO synthase: effects of dietary salt. 752 72

To identify specific interactions between either the tetrazole or carboxylate pharmacophores of non-peptide antagonists and the rat AT1 receptor, 6 basic residues were examined by site-directed mutagenesis. Three of the mutants (H183Q, H256Q, and H272Q) appeared to be like wild type. Lys102 and Arg167 mutants displayed reduced binding of the non-peptide antagonist losartan. Examination of their properties employing group-specific angiotensin II analogues indicated that their effects on binding were indirect. Interestingly, the affinity of losartan was not altered by a K199Q mutation, but the same mutation reduced the affinity of angiotensin II, the antagonist [Sar1,Ile8]angiotensin II, and several carboxylate analogues of losartan. An Ala199 substitution reduced the affinity of peptide analogues to a larger extent as compared to the affinity of losartan. Thus, the crucial acidic pharmacophores of angiotensin and losartan appear to occupy the same space within the receptor pocket, but the protonated amino group of Lys199 is not essential for binding the tetrazole anion. The binding of the tetrazole moiety with the AT1 receptor involves multiple contacts with residues such as Lys199 and His256 that constitute the same subsite of the ligand binding pocket. However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine-aromatic interaction.
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PMID:Tetrazole and carboxylate groups of angiotensin receptor antagonists bind to the same subsite by different mechanisms. 753 Jul 21

The selective biphenylimidazole and tetrahydroimidazopyridine antagonists exemplified by losartan (DuP 753) and PD 123319 have been shown to bind selectively to angiotensin AT1 and AT2 receptor subtypes, respectively. To characterize which subtypes of angiotensin II receptors are expressed in mammalian portal vein smooth muscle, we performed, using both membrane and strip preparations, [3H]angiotensin II binding experiments and then contraction experiments to investigate the functional relevance of these binding sites. Specific binding of [3H]angiotensin II was of high affinity, saturable and reversible. Specific binding of [3H]angiotensin II was completely displaced by angiotensin II and the peptide antagonist [Sar1,Ile8]angiotensin II. The inhibition of [3H]angiotensin II binding by losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl)- methyl]imidazole, potassium salt) and DuP 532 (2-n-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biph enyl-4-yl)- methyl]imidazole-5-carboxylic acid) was biphasic and LIGAND curve-fitting analysis revealed two populations of specific binding sites. One subpopulation represented 75% of the total binding and showed high affinity for angiotensin II, losartan and DuP 532, but low affinity for the peptide angiotensin AT2 receptor antagonist CGP 42112A (N-alpha-nicotinoyl-Tyr-Lys-[N-alpha-CBZ-Arg]-His-Pro-Ile-OH) and thus appeared identical to the cloned angiotensin AT1 receptor subtype. The remaining 25% of the sites showed nearly 1000-fold lower affinity for losartan, 6500-fold lower affinity for DuP 532 and high affinity for 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, difluoroacetate monohydrate) and CGP 42112A, with values of Ki in the same range (nM) as those found for losartan and DuP 532 at angiotensin AT1 binding sites. These sites appear to be angiotensin AT2 receptors. Only the angiotensin AT1 receptor subtype interacted with G-proteins, as indicated by the 80% inhibition of [3H]angiotensin II binding in the presence of guanosine 5'-O-(3-thiophosphate) or fluoroaluminates. Although the angiotensin II-induced contraction was completely inhibited by losartan with a pA2 value of 8.8, PD 123319 reduced the angiotensin II-induced contraction by 20-25%, indicating that both angiotensin AT1 and AT2 receptor subtypes are functional in portal vein smooth muscle.
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PMID:Angiotensin II receptor subtypes and contractile responses in portal vein smooth muscle. 755 78

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.
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PMID:Derivatives of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins as orally active angiotensin II receptor antagonists. 756 6

This paper describes the renal pharmacology of the novel, specific, non-peptide angiotensin AT1 receptor antagonist, GR138950 (1-[[3-bromo-2-[2-[[(trifluoromethyl) sulphonyl] amino] phenyl]-5-benzofuranyl] methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5- carboxamide). When administered to anaesthetised salt-replete dogs, GR138950 caused renal vasodilatation and significant increases in sodium and urine excretion. No change in glomerular filtration rate was observed indicating that the natriuresis was a consequence of inhibition of tubular sodium reabsorption. Qualitatively similar but less marked changes in renal function were observed in response to the angiotensin converting enzyme inhibitor, captopril, although in contrast to GR138950, captopril also caused a small but significant fall in mean blood pressure. Intra-renal artery infusion of exogenous angiotensin II resulted in dose-related renal vasoconstriction and decreases in urine excretion, sodium excretion, fractional excretion of sodium and glomerular filtration rate. These renal effects of angiotensin II were all markedly antagonised by GR138950. We conclude that GR138950 is an effective antagonist of the renal haemodynamic and excretory actions of endogenous and exogenous angiotensin II.
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PMID:Renal pharmacology of GR138950, a novel non-peptide angiotensin AT1 receptor antagonist. 758 86

The synthesis and pharmacological activity of new potent nonpeptide non-tetrazole angiotensin II (AII) receptor antagonists are described. These compounds are 4-thioimidazole derivatives linked on N1 to a biphenylsulfonyl fragment by a methylene spacer. Different acidic sulfonamides such as sulfonylureas 12, sulfonylcarbamates 15, sulfonylamides 16, and sulfonylsulfonamides 17 have been investigated as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activity were evaluated by AII receptor binding assay as well as by in vivo (i.v. and po) assays such as inhibition of the AII-induced pressor response in pithed rats. Most of the synthesized sulfonyl derivatives showed nanomolar affinity for the AT1 receptor subtype. The N-propylsulfonylurea 12d and the ethyl sulfonylcarbamate 15b as representative members of this series exhibited high oral activity in the pithed rat model with ID50 values of 0.38 and 0.4 mg/kg, respectively. Structure-activity relationships on the imidazole ring linked to the methylbiphenyl N-propylsulfonylurea fragment demonstrated similar features to those found in the corresponding tetrazole series. For both class of compounds, the linear butyl chain in position 2 and a carboxylic acid in position 5 were important for high in vitro and in vivo activity. In most cases, replacement of the carboxylic acid was detrimental to in vivo activity while maintaining the in vitro binding affinity. Introduction of a methylthio group in position 4 was found to enhance oral activity compared to compounds with chloro or other alkylthio, (polyfluoroalkyl)thio, and arylthio groups. 2-Butyl-4-(methylthio)-1-[[2'- [[[(propylamino)carbonyl]amino[sulfonyl](1,1'-biphenyl)-4- yl]methyl]-1-H-imidazole-5-carboxylic acid (12d) as the most promising example of the series was synthesized as its dipotassium salt (50, HR 720). This compound 50 inhibited the specific binding of [125I]-AII to rat liver membranes with an IC50 value of 0.48 nM. In vivo, 50 dose-dependently inhibited the AII-induced pressor response in normotensive pithed rats (ID50 = 0.11 mg/kg i.v. and 0.7 mg/kg po). In addition, this compound produced a marked and long-lasting decrease in blood pressure in high renin animal models and proved to be superior to the corresponding tetrazole 45 as well as to DuP 753 or its active metabolite EXP 3174. Compound 50 has been selected for in-depth investigations and is currently undergoing phase II clinical trials.
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PMID:Sulfonylureas and sulfonylcarbamates as new non-tetrazole angiotensin II receptor antagonists. Discovery of a highly potent orally active (imidazolylbiphenylyl)sulfonylurea (HR 720). 760 2

Cardiovascular responses after the central blockade of the brain angiotensin system with peptide or nonpeptide angiotensin II analogs in conscious, freely moving hypertensive Dahl salt-sensitive (DS/JR) rats were measured. Four-week-old animals were maintained on an 8% salt diet until experimentation at 7 weeks of age. At the time of experimentation, mean arterial pressures were 176 +/- 6 mm Hg. The i.c.v. administration of 20 micrograms of the peptide analog sarcosine1, threonine8-angiotensin II (sarthran) resulted in a significant bradycardic response (approximately 17% decrease in H.R. peaking at 8 min after injection) without a significant change in blood pressure. Central administration of the AT1 antagonist losartan (10 micrograms) or of the AT2 antagonist PD 123319 (10 micrograms) was without effect. The peptide and nonpeptide analogs differed in their ability to inhibit central angiotensin II (10 ng)-induced pressor and dipsogenic responses. PD 123319 (10 micrograms) had no effect on the pressor and dipsogenic responses, whereas losartan (10 micrograms) and sarthran (20 micrograms) inhibited both responses for 85 +/- 17 and 29 +/- 3 min, respectively. The effect of preblocking either the AT1 or the AT2 receptors on the sarthran-induced bradycardia was also determined. Preblocking with either losartan (10 micrograms) or PD 123319 (10 micrograms) inhibited the bradycardic response by approximately 45%, which suggests that both receptor subtypes are involved in the central cardiovascular responses in the DS/JR rat and that, because it was attenuated by pure antagonists, the response to sarthran may be mediated by its agonist actions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiovascular effects after the intracerebroventricular administration of peptide and nonpeptide angiotensin antagonists in Dahl salt-sensitive rats. 763 38

The identification of the AT1 and AT2 receptor subtypes has stimulated interest in developing balanced angiotensin II receptor antagonists. A series of 5-(3-amidopropanoyl)imidazoles has been prepared which possess balanced affinity for the AT1 and AT2 receptors. XR510 (1), 1-[[2'-[[(isopentoxycarbonyl)amino]sulfonyl]-3- fluoro(1,1'-biphenyl)-4-yl]methyl]-5-[3-(N-pyridin-3- ylbutanamido)propanoyl]-4-ethyl-2-propyl-1H-imidazole, potassium salt, exhibits subnanomolar affinity for both receptor sites. XR510 is very active in lowering blood pressure in renal hypertensive rats and furosemide-treated dogs following oral administration.
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PMID:Balanced AT1/AT2 receptor antagonists. 4. XR510 and related 5-(3-amidopropanoyl)imidazoles possessing equal affinity for the AT1 and AT2 receptors. 763 54


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