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  • 1
    Electronic Resource
    Electronic Resource
    Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 352 (1995), S. 653-661 
    Details
    ISSN: 1432-1912
    Keywords: Key words Sodium channel ; Excitability ; Skeletal muscle ; Enantiomers ; Mexiletine ; Tocainide ; Use-dependent block ; Myotonia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of the enantiomers of mexiletine were tested on sodium currents of frog skeletal muscle fibers recorded by means of the three vaseline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-(−) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses from the holding potential of −100 mV to −20 mV, with an IC50 of 43.9±1 μM, whereas the corresponding S-(+) enantiomer produced the same effects at about twofold higher concentrations. A similar stereoselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-(−) and S-(+) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behaviour led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([IC50S-(+)]/[IC50R(−)]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h∞) , suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-(−) vs. S-(+) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential was observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-(−) isomers were more potent than the S-(+) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during state-dependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-(−) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171325
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  • 2
    Electronic Resource
    Electronic Resource
    Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 352 (1995), S. 653-661 
    Details
    ISSN: 1432-1912
    Keywords: Sodium channel ; Excitability ; Skeletal muscle ; Enantiomers ; Mexiletine ; Tocainide ; Use-dependent block ; Myotoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the enantiomers of mexiletine were tested on sodium currents of frog skeletal muscle fibers recorded by means of the three vaseline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-( − ) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses from the holding potential of − 100 mV to − 20 mV, with an IC50 of 43.9 ± 1 μM, whereas the corresponding S-( + ) enantiomer produced the same effects at about twofold higher concentrations. A similar stereoselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-( − ) and S-( + ) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behaviour led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([IC50S-( + )]/[IC50R( − )]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h∞) , suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-( − ) vs. S-( + ) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential was observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-( − ) isomers were more potent than the S-( + ) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during statedependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-( − ) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171325
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Effects of taurine analogues on chloride channel conductance of rat skeletal muscle fibers: a structure-activity relationship investigation (1994)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 349 (1994), S. 416-421 
    Details
    ISSN: 1432-1912
    Keywords: Skeletal muscle ; Chloride channel conductance ; Taurine binding site ; Taurine analogues ; Structure-activity relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rat skeletal muscle, taurine was proposed to interact with a low affinity binding site on sarcolemmal phospholipids near chloride channel, increasing chloride conductance (GCI). In an attempt to evaluate the structure-activity relationship between taurine and its binding site, a series of N-azacycloalkenyl analogues of taurine (A: N-(1′aza-cyclopenten-2′yl)-2-aminoethane sulfonic acid; B: N-(1′-aza-cyclopenten-2′-yl)-2-aminoethane sulfonic acid; C: N-(1′aza-cyclopenten-2′-yl)-3-amino-propane sulfonic acid; D: N-(1′aza-cyclopenten-2′-yl)-3-aminopropane sulfonic acid) have been synthetized and tested in vitro on rat extensor digitorum longus (EDL) muscle. In spite of the presence of a bulky and lipophilic 5 or 7 membered heterocycle linked to the taurine amino group, analogues A and B determined an increase of GCI, although less potently than taurine. Also 3-aminopropane sulfonic acid (homotaurine), tested in comparison, showed less activity in increasing GCI with respect to taurine, probably for the increased distance between charged groups. Taurine analogues C and D, which differ from compounds A and B for an additional methylene group, showed much lower activity in increasing GCI. It has been reported that guanidinoethane sulfonate (GES) displaces taurine from the low affinity site on sarcolemma by only 7%. This compound, characterized by lower charge density on the guanidinium cationic head, applied in vitro on EDL muscle, show reduced taurine-like activity in increasing GCl. Our results support the hypothesis that the effect of taurine on muscle GCI is due to a specific binding on a low affinity site on sarcolemma and that charge delocalization reduces the binding probability more than the substitution of the primary amino group or the increased distance between charged groups.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00170889
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Chloride channels of skeletal muscle from developing, adult and aged rats are differently affected by enantiomers of 2-(p-chlorophenoxy) propionic acid (1992)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 346 (1992), S. 601-606 
    Details
    ISSN: 1432-1912
    Keywords: Skeletal muscle ; Chloride channel ; Postnatal development ; Aging ; Pharmacological characterization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Enantiomers of 2-(p-chlorophenoxy) propionic acid, compounds acting specifically on chloride channels of adult rat skeletal muscles, have been tested on extensor digitorum longus (EDL) muscle of developing and aged rats, in an attempt to characterize the chloride channels responsible for the low chloride conductance (GC1) found in the above physiological situations. The S-(−) enantiomer, which produces a concentration-dependent inhibition of GC1 in the adult EDL, is less effective in inhibiting GC1 of EDL of either 2–3 weeks or 29 months old rats, particularly at low concentrations. The R-(+) isomer, which in the adult enhances GC1 at low concentrations and blocks it at concentrations higher than 10 μM, lacks inhibitory action, enhancing GC1 in both developing and aged EDL. At 30–40 days of age both the enantiomers produce almost the same effects exerted in adulthood. From these data we hypothesize that the low GC1 found in EDL of developing and aged rats might be due not only to a lower number of conductive channels but also to the presence of a mixed population of isoforms of chloride channels having different pharmacological properties.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168731
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    Paper (German National Licenses)
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