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Prediction of inhibition of the sodium ion - Proton antiporter by benzoylguanidine derivatives from molecular structure

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JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES 2000年第3期40卷 753-761页

作者： Kauffman, GW Jurs, PC Penn State Univ Dept Chem University Pk PA 16802 USA

The use of quantitative structure-activity relationships to predict IC50 values of 113 potential Na+/H+ antiporter inhibitors is reported. Multiple linear regression and computational neural networks (CNNs) are used to develop models using a set of information-rich descriptors. The descriptors encode information about topology, geometry, electronics, and combination hybrids. A five-descriptor CNN model with root-mean-square (rms) errors of 0.278 log units for the training set and 0.377 log units for the prediction set was developed. Examination of data set subclasses showed that systematic structural variations were also well-encoded resulting in 100% accuracy of prediction trends. An experiment involving a committee of five CNNs was also performed to examine the effect of network output averaging. This showed improved results decreasing the training and cross-validation set rms error to 0.228 log units and the prediction set rms error to 0.296 log units.

关键词：胍类/化学胍类/药理学分子结构钠氢反向转运物/拮抗剂和抑制剂动物兔

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Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na⁺/H⁺ exchanger

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BLOOD 2000年第4期95卷 1427-1434页

作者： Rich, IN Worthington-White, D Garden, OA Musk, P Palmetto Richland Mem Hosp S Columbia Canc Ctr Div Transplantat Med Columbia SC 29203 USA

The Na+/H+ exchanger isoform 1 (NHE1) is primarily responsible for the regulation of intracellular pH (pH(i)), It is a ubiquitous, amiloride-sensitive, growth factor-activatable exchanger whose role has been implicated in cell-cycle regulation, apoptosis, and neoplasia, Here we demonstrate that leukemic cell lines and peripheral blood from primary patient leukemic samples exhibit a constitutively and statistically higher pH(i) than normal hematopoietic tissue, We then show that a direct correlation exists between pH(i) and cell-cycle status of normal hematopoietic and leukemic cells, Advantage was taken of this relationship by treating leukemic cells with the Na+/H+ exchanger inhibitor, 5-(N, N-hexamethylene) amiloride (HMA), which decreases the pH(i) and induces apoptosis, By incubating patient leukemic cells in vitro with pharmacologic doses of HMA for up to 5 hours, we show, using flow cytometry and fluorescent ratio imaging microscopy, that when the pH(i) decreases, apoptosis-measured by annexin-V and TUNEL methodologies-rapidly increases so that more than 90% of the leukemic cells are killed, The differential sensitivity exhibited between normal and leukemic cells allows consideration of NHE1 inhibitors as potential antileukemic agents. (C) 2000 by The American Society of Hematology.

关键词：阿米洛利/类似物和衍生物阿米洛利/药理学抗肿瘤药/药理学细胞凋亡/药物作用细胞凋亡/生理学氢离子浓度 K562细胞白血病/病理学白血病/病理生理学淋巴细胞/细胞学淋巴细胞/药物作用淋巴细胞/免疫学小鼠近交NOD 小鼠 SCID 钠氢反向转运物/拮抗剂和抑制剂十四酰佛波乙酯/药理学移植异种肿瘤细胞培养的成年人动物人类小鼠

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Interferon-γ, bacterial lipopolysaccharide, and tumor necrosis factor-α induce CD11a mRNA and protein via Na⁺/H⁺ exchange and protein kinase C dependent mechanisms in tissue macrophages

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第2期257卷 635-641页

作者： Shackelford, RE Duke Univ Med Ctr Dept Pathol Durham NC 27709 USA

Previously CD11a or leukocyte function-associated antigen alpha-1 was found to be induced at the surface protein level in thioglycolate-elicited peritoneal macrophages by bacterial lipopolysaccharide and interferon-gamma. To investigate this induction further, Northern blotting and enzyme-linked immunosorbent assays were used to examine the role of second messengers in CD11a gene product induction by these agents. Here I report that CD11a RNA and cell surface protein induced by bacterial lipopolysaccharide and tumor necrosis factor-alpha are sensitive to inhibition of protein kinase C, while insensitive to inhibition of Na+/H+ exchange. CD11a induction by interferon-gamma conversely is sensitive to inhibition of Na+/H+ exchange and insensitive to inhibition of protein kinase C. These observations indicate that CD11a may be induced by multiple and separate second messenger systems in primary macrophages. (C) 1999 Academic Press.

关键词：阿米洛利/类似物和衍生物阿米洛利/药理学细胞膜/药物作用细胞膜/代谢细胞培养的剂量效应关系药物干扰素Ⅱ型/拮抗剂和抑制剂干扰素Ⅱ型/药理学脂多糖类/药理学淋巴细胞功能相关抗原1/遗传学淋巴细胞功能相关抗原1/代谢巨噬细胞腹膜/药物作用巨噬细胞腹膜/代谢小鼠近交C57BL 蛋白激酶C/拮抗剂和抑制剂蛋白激酶C/代谢 RNA 信使/代谢受体 IgG/遗传学第二信使系统/药物作用钠氢反向转运物/拮抗剂和抑制剂钠氢反向转运物/代谢星状孢子素/药理学十四酰佛波乙酯/药理学硫乙醇酸盐类/药理学时间因素反式激活(遗传学)/药物作用肿瘤坏死因子α/药理学动物小鼠

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Adenosine inhibits the transfected Na⁺-H⁺ exchanger NHE3 in Xenopus laevis renal epithelial cells (A6/C1)

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第3期515卷 829-842页

作者： Di Sole, F Casavola, V Mastroberardino, L Verrey, F Moe, OW Burckhardt, G Murer, H Helmle-Kolb, C Univ Gottingen Dept Physiol & Pathophysiol Div Vegetat Physiol & Pathophysiol D-37073 Gottingen Germany Univ Bari Inst Gen Physiol I-70126 Bari Italy Univ Zurich Inst Physiol CH-8057 Zurich Switzerland Univ Texas SW Med Ctr Dept Internal Med Div Nephrol Dallas TX 75235 USA

1. Adenosine influences the vectorial transport. of Na+ and HCO3- across kidney epithelial cells. However, its action on effector proteins, such as the Na+-H+ exchanger NHE3, an epithelial brush border isoform of the Na+-H+ exchanger (NHE) gene family: is not yet defined, 2. The present study was conducted in Xenopus laevis distal nephron A6 epithelia which express both an apical adenosine receptor of the A(1) type (coupled to protein kinase C (PKC)) and a basolateral receptor of the A(2) type (coupled to protein kinase A (PKA)). The untransfected A6 cell line expresses a single NHE type (XNHE) which is restricted to the basolateral membrane and which is activated by PKA. 3. A6 cell lines were generated which express exogenous rat NHE3. Measurements of side-specific pH(i) recovery from acid loads in the presence of HOE694 (an inhibitor with differential potency towards individual NHE isoforms) detected an apical resistant Na+-H+ exchange only in transfected cell lines. The sensitivity of the basolateral NHE to HOE694 was unchanged, suggesting that exogenous NHE3 was restricted to the apical membrane. 4. Stimulation of the apical A(1) receptor with N-6-cyclopentyladenosine (CPA) inhibited both epical NHE3 and basolateral;XNHE. These effects were mimicked by the addition of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and partially prevented by the PKC inhibitor calphostin C which also blocked the effect of PMA. 5. Stimulation of the basolateral A(2) receptor with CPA inhibited apical NHE3 and stimulated basolateral XNHE. These effects were mimicked by 8-bromo-cAMP and partially prevented by the PKA inhibitor H89 which entirely blocked the effect of 8-bromo-cAMP. 6. In conclusion, CPA inhibits rat NHE3 expressed apically in A6 epithelia via both the apical PKC-coupled A(1) and the basolateral PKA-coupled A(2) adenosine receptors.

关键词：腺苷/药理学细胞系细胞膜/药物作用细胞膜/生理学环AMP依赖性蛋白激酶类/代谢酶抑制剂/药理学上皮细胞/药物作用上皮细胞/生理学胍类/药理学氢离子浓度肾单位/生理学蛋白激酶C/代谢季胺类化合物/药理学受体嘌呤能P1/遗传学受体嘌呤能P1/生理学重组蛋白质类/拮抗剂和抑制剂重组蛋白质类/生物合成逆转录聚合酶链反应钠/代谢钠氢反向转运物/拮抗剂和抑制剂钠氢反向转运物/遗传学钠氢反向转运物/生理学砜类/药理学转染爪蟾光滑动物大鼠

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Inhibition of Na⁺-H⁺ exchange impairs receptor-mediated albumin endocytosis in renal proximal tubule-derived epithelial cells from opossum

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第3期520卷 709-721页

作者： Gekle, M Drumm, K Mildenberger, S Freudinger, R Gassner, B Silbernagl, S Univ Wurzburg Inst Physiol D-97070 Wurzburg Germany

1. Receptor-mediated endocytosis is an important mechanism for transport of macromolecules and regulation of cell-surface receptor expression. In renal proximal tubules, receptor-mediated endocytosis mediates the reabsorption of filtered albumin. acidification of the endocytic compartments is essential because it interferes with ligand-receptor dissociation, vesicle trafficking, fusion events and coat formation. 2. Here we show that the activity of Na+-H+ exchanger isoform 3 (NHE3) is important for proper receptor-mediated endocytosis of albumin and endosomal pH homeostasis in a renal proximal tubular cell line (opossum kidney cells) which expresses NHE3 only 3. Depending on their inhibitory potency with respect to NHE3 and their lipophilicity, the NHE inhibitors EIPA, amiloride and HOE694 differentially reduced albumin endocytosis. The hydrophilic inhibitor HOE642 had no effect. 4. Inhibition of NHE3 led to an alkalinization of early endosomes and to an acidification of the cytoplasm, indicating that Na+-H+ exchange contributes to the acidification of the early endosomal compartment due to the existence of a sufficient Na+ gradient across the endosomal membrane. 5. Exclusive acidification of the cytoplasm with propionic acid or by removal of Na+ induced a significantly smaller reduction in endocytosis than that induced by inhibition of Na+-H+ exchange. 6. Analysis of the inhibitory profiles indicates that in early endosomes and endocytic vesicles NHE3 is of major importance, whereas plasma membrane NHE3 plays a minor role. 7. Thus, NHE3-mediated acidification along the first part of the endocytic pathway plays an important role in receptor-mediated endocytosis. Furthermore, the involvement of NHE3 offers new ways to explain the regulation of receptor-mediated endocytosis.

关键词：阿米洛利/类似物和衍生物阿米洛利/药理学结合部位/药物作用细胞膜/代谢胞质溶胶/药物作用胞质溶胶/代谢胞吞作用/药物作用胞吞作用/生理学内颗粒/药物作用内颗粒/代谢上皮细胞/生理学胍类/药理学氢离子浓度/药物作用肾小管近端/细胞学肾小管近端/生理学溶酶体/药物作用溶酶体/代谢负鼠丙酸盐类/药理学受体细胞表面/生理学血清白蛋白/代谢钠/代谢钠氢反向转运物/拮抗剂和抑制剂砜类/药理学动物

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Endothelin receptor pathway in human left ventricular myocytes: Relation to contractility

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ANNALS OF THORACIC SURGERY 2000年第3期69卷 711-715页

作者： Goldberg, AT Bond, BR Mukherjee, R New, RB Zellner, JL Crawford, FA Spinale, FG Med Univ S Carolina Div Cardiothorac Surg Charleston SC 29403 USA

Background. Increased synthesis and release of the potent bioactive peptide endothelin-l (ET-1) occurs during and after cardiac surgery. However, the cellular and molecular basis for the effects of ET-1 on human left ventricular (LV) myocyte contractility remains unknown. Methods. LV myocyte contractility was examined from myocardial biopsies taken from patients (n = 30) undergoing elective coronary artery bypass. LV myocytes (n = 997, > 30/patient) were isolated using microtrituration and contractility examined by videomicroscopy at baseline and after ET-1 exposure (200 pmol/L). In additional studies, myocytes were pretreated to inhibit either protein kinase C (PKC) (chelerythrine, 1 mu mol/L), the sodium/hydrogen (Na/H) exchanger (EIPA, 1 mu mol/L), both PKC and the Na/H exchanger, or the ETA receptor (BQ-123, 1 mu mol/L), followed with ET-1 exposure. Results. Basal myocyte shortening increased 37.8 +/- 6.3% with ET-1 (p < 0.05). Na/H exchanger, PKC, and dual inhibition all eliminated the effects of ET-1. Furthermore, ETA inhibition demonstrated that ET-1 effects on myocyte contractility were mediated through the ETA receptor subtype. Conclusions. ET-1 directly influences human LV myocyte contractility, which is mediated through the ETA receptor and requires intracellular activation of PKC and stimulation of the Na/H exchanger. (C) 2000 by The Society of Thoracic Surgeons.

关键词：细胞培养的心室/细胞学心肌收缩/生理学蛋白激酶C/拮抗剂和抑制剂受体内皮缩血管肽/生理学钠氢反向转运物/拮抗剂和抑制剂人类中年人

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