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)

Inhibitory effects of TCV-116 [(+-)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H- tetrazol-5- yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate], a novel angiotensin II AT1 subtype receptor antagonist, on the proliferation of vascular smooth muscle cells and the impairment of endothelium-dependent vascular relaxation were examined in the rat carotid balloon injury model. DNA content in the carotid artery was increased 3 days after carotid balloon injury and reached a plateau 14 days after the injury. Beneficial effects of TCV-116 in this model were examined 14 days after the injury. Oral administration of TCV-116 at 1 and 10 mg/kg/day significantly inhibited the increase in DNA content by 69 and 85%, respectively. Histological examination demonstrated that TCV-116 at 1 and 10 mg/kg significantly inhibited intimal thickening by 43 and 58%, respectively. Cilazapril (10 mg/kg/day p.o.) also inhibited intimal thickening by 48%. Contracting or relaxing vascular responses to phenylephrine or sodium nitroprusside did not differ between uninjured and injured arteries. However, acetylcholine-induced endothelium-dependent relaxation was greatly reduced in injured arteries; maximal relaxation was 6 +/- 2% (n = 17). TCV-116 at 1 and 10 mg/kg significantly ameliorated the impairment of vascular relaxation; maximal relaxation was 25 +/- 8 (n = 7) and 51 +/- 12% (n = 5), respectively. In uninjured arteries, L-NG-monomethyl arginine (300 microM), an inhibitor of endothelium-derived relaxing factor synthesis, inhibited acetylcholine (10 microM)-induced relaxation by 58 +/- 4% (n = 5). Scanning electron micrographs demonstrated that TCV-116 (10 mg/kg/day) enhanced restoration of endothelial cells in the carotid artery 14 days after injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TCV-116, a novel angiotensin II receptor antagonist, prevents intimal thickening and impairment of vascular function after carotid injury in rats. 837 Nov 64

The purpose of the present study was to identify the angiotensin II-receptor subtype involved in the enhancement of the amplitude of the phasic contractions by angiotensin II in the isolated rat portal vein preparation. At an extracellular Ca2+ concentration of 0.9 mmol/l and a K+ concentration of 4 mmol/l, angiotensin II induced concentration-dependent increases in the amplitude of the phasic contractions. The enhancement of phasic contraction amplitude caused by angiotensin II was not significantly altered by pretreatment of the rat portal vein with indomethacin 10(-5) mol/l or nitro-L-arginine 10(-4) mol/l, indicating that neither prostaglandins nor the endothelium derived-relaxing factor (NO) are involved. Losartan (DuP 753), a nonpeptide selective AT1-receptor antagonist, concentration-dependently shifted the concentration-response curve for the effect of angiotensin II on the amplitude of the contractions to the right, without reducing the maximal response (pA2 = 8.6, slope = 0.98), thus suggesting competitive antagonism at the level of AT1-receptors. By contrast, PD 123,177, a nonpeptide selective AT2-receptor antagonist, even at 10(-5) mol/l, caused no significant change of the phasic myogenic response to angiotensin II, indicating the absence of AT2-receptor involvement. Dithiothreitol, a disulfide-reducing agent which is known to inactivate AT1-receptors in various tissues, markedly inhibited (3 mmol/l) or even abolished (5 mmol/l) the contractile response of the rat portal vein to angiotensin II, supporting the conclusion that these receptors can be classified as AT1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the angiotensin II-receptor subtype in the longitudinal smooth muscle of the rat portal vein. 847 39

The present study was designed to investigate whether nitric oxide (NO) antagonizes angiotensin II (Ang II) in modulating the tubuloglomerular feedback (TGF) system. Maximum TGF responses were assessed by evaluating stop-flow pressure (SFP) responses to late proximal perfusion with artificial tubular fluid (40 nl/min). Peritubular capillary (PTC) infusion of 10(-3) M NG-L-arginine (NLA) at a rate of 20 nl/min, and infusion of 10(-7) and 10(-6) M Ang II at rates that did not decrease SFP under conditions of zero flow to the macula densa (resting SFP), augmented maximum SFP feedback responses to 12.0 +/- 1.7, 12.1 +/- 2.4 and 16.9 +/- 3.0 mm Hg, respectively (all P < 0.01 vs. control response). Combined PTC infusion of NLA and 10(-7) M Ang II at a rate of 20 nl/min resulted in decreases in resting SFP in 7 of the 12 nephrons studied. When the infusion rate was decreased to 15 +/- 3 nl/min, concomitant PTC infusion of NLA and 10(-7) M Ang II was associated with a tremendous increase in maximum TGF responses (23.8 +/- 3.9 mm Hg; P < 0.01 vs. responses during PTC NLA or Ang II) in the absence of a decrease in resting SFP. During AT1 receptor blockade using losartan, SFP feedback responses were attenuated to 1.6 +/- 0.6 mm Hg and PTC infusion of NLA only augmented TGF responses to 3.8 +/- 1.0 mm Hg. These results strongly suggest that local NO antagonizes Ang II with respect to the regulation of TGF responsiveness. Disruption of this balance by NO synthesis inhibition strongly potentiates TGF-independent and TGF-dependent actions of Ang II on the preglomerular vasculature.
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PMID:Nitric oxide antagonizes the actions of angiotensin II to enhance tubuloglomerular feedback responsiveness. 854 96

1. It has been recently reported that angiotensin II can enhance atrial natriuretic factor-stimulated cyclic GMP release from brain capillary endothelial cells and stimulate directly the release of cyclic GMP by Neuro 2a cells. A possible mechanism mediating such cyclic GMP release could be via the production of nitric oxide and the resultant stimulation of soluble guanylate cyclase. 2. The ability of angiotensin II, atrial natriuretic factor and c(4-23) atrial natriuretic factor to stimulate nitric oxide production was investigated in primary cultures of human proximal tubular cells. 3. Freshly prepared human proximal tubular cells were seeded onto 6-well plates and allowed to reach confluence. Cells were then incubated with incremental concentrations of either angiotensin II, atrial natriuretic factor or c(4-23) atrial natriuretic factor alone for 1, 4, 12 or 24h or in the presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Angiotensin II was also incubated with human proximal tubular cells in the presence of the AT1 and AT2 receptor antagonists DuP 753 and PD 123319. 4. Incubation of human proximal tubular cells with angiotensin II, atrial natriuretic factor or c(4-23) atrial natriuretic factor produced a dose- and time-dependent increase in nitric oxide production, which was inhibited in the presence of NG-monomethyl-L-arginine. A similar increase in nitric oxide production was observed after incubation with atrial natriuretic factor or c(4-23) atrial natriuretic factor. 5. The angiotensin-induced increase in nitric oxide production was not inhibited in the presence of either the angiotensin AT1 or AT2 receptor antagonists DuP 753 or PD 123319. 6. This study demonstrates that primary cultures of human proximal tubular cells can be stimulated to produce nitric oxide by both atrial natriuretic factor and angiotensin II. Furthermore, the atrial natriuretic factor-induced response appears to be mediated via the atrial natriuretic factor-C receptor, while the angiotensin II-induced response appears to be mediated by a novel, as yet unidentified, angiotensin II receptor.
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PMID:Atrial natriuretic factor and angiotensin II stimulate nitric oxide release from human proximal tubular cells. 854 68

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
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PMID:Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. 861 97

Wortmannin at nanomolar concentrations is a potent and specific inhibitor of phosphoinositide (PI) 3-kinase and has been used extensively to demonstrate the role of this enzyme in diverse signal transduction processes. At higher concentrations, wortmannin inhibits the ataxia telangiectasia gene (ATM)-related DNA-dependent protein kinase (DNA-PKcs). We report here the identification of the site of interaction of wortmannin on the catalytic subunit of PI 3-kinase, p110alpha. At physiological pH (6.5 to 8) wortmannin reacted specifically with p110alpha. Phosphatidylinositol-4,5-diphosphate, ATP, and ATP analogs [adenine and 5'-(4-fluorosulfonylbenzoyl)adenine] competed effectively with wortmannin, while substances containing nucleophilic amino acid side chain functions had no effect at the same concentrations. This suggests that the wortmannin target site is localized in proximity to the substrate-binding site and that residues involved in wortmannin binding have an increased nucleophilicity because of their protein environment. Proteolytic fragments of wortmannin-treated, recombinant p110alpha were mapped with anti-wortmannin and anti-p110alpha peptide antibodies, thus limiting the target site within a 10-kDa fragment, colocalizing with the ATP-binding site. Site-directed mutagenesis of all candidate residues within this region showed that only the conservative Lys-802-to-Arg mutation abolished wortmannin binding. Inhibition of PI 3-kinase occurs, therefore, by the formation of an enamine following the attack of Lys-802 on the furan ring (at C-20) of wortmannin. The Lys-802-to-Arg mutant was also unable to bind FSBA and was catalytically inactive in lipid and protein kinase assays, indicating a crucial role for Lys-802 in the phosphotransfer reaction. In contrast, an Arg-916-to-Pro mutation abolished the catalytic activity whereas covalent wortmannin binding remained intact. Our results provide the basis for the design of novel and specific inhibitors of an enzyme family, including PI kinases and ATM-related genes, that play a central role in many physiological processes.
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PMID:Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. 865 48

1. In the present study, the contractile effects of angiotensin III (AIII) and angiotensin IV (AIV) compared with those of angiotensin II (AII) were determined in rat aortic ring preparations. 2. All three peptides caused concentration-dependent contractions with similar maximal responses. AIII proved approximately 4 times less potent than AII, whereas AIV was about 1000 times less active than AII. 3. The selective AT1-receptor antagonist, losartan (10-300 nM) caused parallel rightward shifts of the concentration-response curves (CRC) for all three peptides. The Schild plot slopes for the effect of losartan on AIII curves were significantly lower than unity (P < 0.05). The selective AT2-receptor antagonist, PD123177 did not influence the CRCs for AII and AIV. However, the AIII curves were moderately shifted leftward in the presence of PD123177 (0.1 and 1 microM). 4. Destruction of the endothelium or incubation with the NO-synthesis inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (0.1 mM) significantly enhanced the contractile responses to all three peptides. 5. Tachyphylaxis was investigated by constructing a second CRC for all three peptides, after an interval of 1 h. The presence of endothelium significantly enhanced the development of tachyphylaxis to all three peptides. However, in endothelium-denuded preparations, the Emax value of the second curve elicited by AII was about 50%, compared with the first one, whereas for AIII and AIV Emax values were as high as 90% and 100%, respectively. 6. Our results indicate that both AIII and AIV are less potent but similarly efficacious vasoconstrictor agents compared with AII. Their contractile effects are also mediated by AT1-receptors and probably modulated by endothelium. Tachyphylaxis induced by AIII and AIV proved weaker than that for AII. Tachyphylaxis appears to be enhanced by the presence of an intact endothelium.
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PMID:Comparative effects of angiotensin II and its degradation products angiotensin III and angiotensin IV in rat aorta. 868 Jul 31

We report the detection of four new mutations in the ataxia telangiectasia gene (ATM). Reverse-transcribed RNA extracted from cultured cells was analysed for mutations by polymerase chain reaction amplifications and restriction endonuclease fingerprinting. Three deletions and a base substitution are described. The deletions reported here would result in severe disruptions of the ATM gene product by leading either to a protein truncation (a 4-bp deletion) or the loss of stretches of 53 and 58 amino acids (a 159-bp deletion and a 174-bp deletion, respectively); whereas the base substitution would lead to an amino acid change from a highly conserved glycine to an arginine residue.
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PMID:New mutations in the ataxia telangiectasia gene. 869 54

These experiments tested the hypothesis that hypertension caused by chronic inhibition of nitiric oxide synthase (NOS) is associated with augmented pressor responsiveness to angiotensin II (ANG II). Antagonism of ANG II AT1 receptors with losartan caused a greater fall in blood pressure (BP) in rats treated for 2 wk with the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) than in normotensive rats. The delayed time course of the decline in BP implicated the slow pressor effect (SPE) of ANG II in L-NAME hypertension. Further experiments showed that direct elicitation of the SPE by continuous low-dose (4 ng/min) intravenous infusion of ANG II in enalapril-treated rats resulted in a larger chronic increase in BP if NOS was inhibited. However, L-NAME alone also caused a significant increase in BP in enalapril-treated rats. The combined effect on BP of ANG II and L-NAME was merely additive. These results confirm that ANG II is involved in L-NAME hypertension. However, chronic pressor responsiveness to the peptide is not augmented by L-NAME.
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PMID:Role of ANG II in hypertension produced by chronic inhibition of nitric oxide synthase in conscious rats. 877 Jan 26

Renin-like activity (RLA), angiotensin I converting enzyme-like (ACELA), and kallikrein-like activity (KLA), activities of the key enzymes of renin-angiotensin and kallikrein-kinin systems, were sought in the kidney of the African lungfish Protopterus annectens during the aquatic phase. RLA, examined by RIA (using porcine angiotensinogen as substrate), was 0.38 +/- 0.05 ng angiotensin I/mg protein/hr. ACELA and KLA were investigated in assays spectrophotometrically. ACELA, measured at 37 and at 20 degrees , was, respectively, 1.55 +/- 0.55 and 0.61 +/- 0.23 nmol hippurate/min/mg protein. KLA was 7.34 +/- 0.93 mU/mg protein in the crude kidney extract and 31.05 +/- 7.50 mU/mg protein after electrophoretic purification. Renal kininogenase activity was inhibited by 100% by D-Phe-Phe-Arg-chloromethyl ketone (10 microM), 98% by phenylmethylsulfonyl fluoride (2 nM), and 91% by aprotinin (1000 kIU). The apparent molecular weight of the renal kininogenase on SDS-PAGE was 27,000 Da. Both the renal enzyme and the purified glandular kallikrein, used as a control, have the same mobility on polyacrylamide gel electrophoresis. Immunoreactivities toward angiotensin II and bradykinin were localized by double immunostaining in the same cells of the proximal tubules. Putative angiotensin II receptors were demonstrated immunohistochemically, in the supranuclear region of proximal tubular cells, using an antibody to the sequence between amino acids 225 and 237 of the mammalian AT1 receptor.
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PMID:The kallikrein-kinin and renin-angiotensin systems in the kidney of an African lungfish, Protopterus annectens. 881 41


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