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  • Na channels  (2)
  • Bufo marinus  (1)
  • Cl− secretion  (1)
  • Diuretics  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Structure-activity relationship of amiloride analogs as blockers of epithelial Na channels: II. Side-chain modifications (1987)
    Springer
    The journal of membrane biology 95 (1987), S. 171-185 
    Details
    ISSN: 1432-1424
    Keywords: amiloride ; analogs ; blocking kinetics ; structure-activity relationship ; Na channels ; frog skin ; fluctuation analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The overall on- and off-rate constants for blockage of epithelial Na channels by amiloride analogs were estimated by noise analysis of the stationary Na current traversing frog skin epithelium. The (2-position) side chain structure of amiloride was varied in order to obtain structure/rate constant relationships. (1) Hydrophobic chain elongations (benzamil and related compounds of high blocking potency) increase the stability of the blocking complex (lowered off-rate), explained by attachment of the added phenyl moiety to a hydrophobic area near the site of side chain interaction with the channel protein. (2) Some other chain modifications show that the on-rate, which is smaller than a diffusion-limited rate, varies with side chain structure. In several cases this effect is not attributable to steric hindrance on encounter, and implies that the side chain interacts briefly with the channel protein (encounter complex) before the main blocking position of the molecule is attained. The encounter complex must be labile since the overall rate constants of blockage are not concentration-dependent. (3) In two cases, changes at the 2-position side chain and at other ring ligands, with known effects on the blocking rate constants, could be combined in one analog. The rate constants of blocking by the resulting compounds indicate that the structural changes have additive effects in terms of activation energies. (4) Along with other observations (voltage dependence of the rate constants and competition with the transported Na ion), these results suggest a blocking process of at least two steps. It appears that initially the 2-position side chain invades the outward-facing channel entrance, establishing a labile complex. Then the molecule is either released completely (no block) or the 6-ligand of the pyrazine ring gains access to its receptor counterpart, thus establishing the blocking complex, the lifetime of which is strongly determined by the electronegativity of the 6-ligand.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01869162
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  • 2
    Electronic Resource
    Electronic Resource
    Amiloride inhibits the vasopressin-induced increase in epithelial water permeability (1990)
    Springer
    Pflügers Archiv 417 (1990), S. 200-206 
    Details
    ISSN: 1432-2013
    Keywords: Toad bladder ; Toad skin ; Water transport ; Hydrosmotic response ; Cyclic adenosine monophosphate ; Serosal hypertonicity ; Na+-free media ; Bufo marinus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The vasopressin (VP)-induced increase in water permeability in high-resistance, amphibian epithelia is not altered by the abolition of net Na+ flux caused by amiloride added to the apical bathing medium. In this work we looked at the effects on water transport of amiloride added to the serosal medium at a concentration (10−3 M) known to inhibit Na+/H + exchange. In urinary bladders of Bufo marinus, amiloride partially blocked the hydrosmotic response to VP. A similar inhibition was found with cyclic adenosine 5′-monophosphate (cAMP) or serosal hypertonicity. We hypothesized that this effect of amiloride could be due to an inhibition of Na+/H+ and/or Na+/Ca2+ antiporters present in the epithelial basolateral membrane and looked at the effects of the diuretic in Na+-free media. A similar degree of inhibition of water flow was still found, thus showing that amiloride acts on a cell target other than the antiporters. In toad skin, amiloride did not inhibit the hydrosmotic response to VP and to isoproterenol; however the response to high K+ was significantly reduced. Among the amiloride cell targets described so far, adenylate cyclase and protein kinase A appear to be the best candidates to explain the inhibition of the hydrosmotic response reported here. Direct measurements of intracellular cAMP are needed however to substantiate this hypothesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00370700
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  • 3
    Electronic Resource
    Electronic Resource
    Chloride transport activation by plasma osmolarity during rapid adaptation to high salinity of Fundulus heteroclitus (1995)
    Springer
    The journal of membrane biology 143 (1995), S. 207-217 
    Details
    ISSN: 1432-1424
    Keywords: Gill chloride cell ; Cl− secretion ; Fundulus heteroclitus ; Cell volume regulation ; Na+/H+ exchanger ; Cl−/HCO 3 − exchanger
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Transition from low salt water to sea water of the euryhaline fish, Fundulus heteroclitus, involves a rapid signal that induces salt secretion by the gill chloride cells. An increase of 65 mOsm in plasma osmolarity was found during the transition. The isolated, chloridecell-rich opercular epithelium of sea-water-adapted Fundulus exposed to 50 mOsm mannitol on the basolateral side showed a 100% increase in chloride secretion, which was inhibited by bumetanide 10−4 m and 10−4 m DPC (N-Phenylanthranilic acid). No effect of these drugs was found on apical side exposure. A Na+/H+ exchanger, demonstrated by NH4Cl exposure, was inhibited by amiloride and its analogues and stimulated by IBMX, phorbol esters, and epithelial growth factor (EGF). Inhibition of the Na+/H+ exchanger blocks the chloride secretion increase due to basolateral hypertonicity. A Cl−/HCO 3 − exchanger was also found in the chloride cells, inhibited by 10−4 m DIDS but not involved in the hyperosmotic response. Ca2+ concentration in the medium was critical for the stimulation of Cl− secretion to occur. Chloride cell volume shrinks in response to hypertonicity of the basolateral side in sea-water-adapted operculi; no effect was found on the apical side. Freshwater-adapted fish chloride cells show increased water permeability of the apical side. It is concluded that the rapid signal for adaptation to higher salinities is an increased tonicity of the plasma that induces chloride cell shrinkage, increased chloride secretion with activation of the Na+K+2Cl− cotransporter, the Na+/H+ exchanger and opening of Cl− channels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00233449
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  • 4
    Electronic Resource
    Electronic Resource
    Structure-activity relationship of amiloride analogs as blockers of epithelial Na channels: I. Pyrazine-ring modifications (1985)
    Springer
    The journal of membrane biology 83 (1985), S. 45-56 
    Details
    ISSN: 1432-1424
    Keywords: amiloride ; blocking kinetics ; structure-activity relationship ; Na channels ; frog skin ; fluctuation analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The overall on-and off-rate constants for blocking epithelial Na channels by amiloride analogs were estimated by noise analysis of frog skin epithelium. The substituents at position-5 and −6 of the pyrazine ring of amiloride were varied in order to obtain the structure/rate constant relationship. (1) The off-rate constant increases with halo-substitutions at position-6 in the order Cl〈Br〈I〈F〈H. Substitution of Cl by H lowers the standard free energy of activation of the off-step by 2.3 kcal mol−1. The on-rate constant is not affected. Apparently the substituent at ring position-6 controls the duration of attachment in the blocking position. pK a considerations show that the duration is longer when the 6-substituent is more negatively polarized. We suggest that this substituent binds to the receptor by virtue of its electronegativity. (2) In contrast, replacement of the adjacent 5-amino group (electron donor) by H or Cl affects both the on-rate and the off-rate. The dual effect may be explained by a decrease of the electronic charge at more remote parts of the molecule (on-rate decrease), as well as at the 6-position (off-rate increase). Apparently the 5-amino group stabilizes the blocking position by increasing the electron density on the 6-ligand.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01868737
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  • 5
    Electronic Resource
    Electronic Resource
    The significance of the relative effects of loop diuretics and anti-brain edema agents on the Na+, K+, Cl− cotransport system and the Cl−/NaCO 3 − anion exchanger (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 202-209 
    Details
    ISSN: 1432-1912
    Keywords: Biological transport ; Diuretics ; Brain injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 3-Amino-5-sulfamoylbenzoic acids and several series of (aryloxy)alkanoic acids were evaluated for their inhibitory effects on two human erythrocyte ion transport systems — the Na+, K+ cotransport system and the DIDS-sensitive anion carrier. Several classic loop diuretics, including the (aryloxy)alkanoic acid-ethacrynic acid and several 3-amino-5-sulfamoylbenzoic acids, like bumetanide and furosemide, displayed relatively strong inhibitory activity versus the cotransport system with relatively weaker action versus the anion carrier. Furthermore, diuretic potency correlated with cotransport inhibitory potency. Another class of (aryloxy)alkanoic acids, namely the [(2,3-dihydro-1 H-inden-5-yl)oxy]acetic acids, such as indacrinone and MK-473, which exhibit less potent loop dacrinone and MK-473, which exhibit less potent loop diuretic activity, were less potent cotransport inhibitors and more effective inhibitors of the anion carrier. Still other (aryloxy)alkanoic acids, with little saliuretic activity, namely a sub-class of [(2,3-dihydro-1 H-inden-5-yl)oxy]alkanoic acids and a series of [(2,3,9,9a-tetrahydro-1 H-fluoren-7-yl)oxy]acetic acids displayed little or no inhibitory action on the cotransport system but enhanced inhibitory action on the anion carrier. Most interestingly, the relative anion carrier inhibitory potency correlated well with the relative inhibitory activity of each compound on bicarbonate-stimulated cell swelling in cat cerebrocortical slices.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505823
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