Library

X
feed icon rss

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • Electronic Resource  (4)
  • Chloride channels  (2)
  • Excitability  (2)
  • 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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 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
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Aging and chloride channel regulation in rat fast-twitch muscle fibres (1994)
    Springer
    Pflügers Archiv 427 (1994), S. 80-85 
    Details
    ISSN: 1432-2013
    Keywords: Rat skeletal muscle ; Aging ; Chloride channels ; Phorbol esters ; Protein kinases ; Cholera toxin ; G protein pathways ; Calcium ionophore A23187
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract By the use of pharmacological tools, we tested the hypothesis that age-related alterations in the regulatory pathways of chloride channels might contribute to the lowered chloride conductance (G Cl) found in skeletal muscle of aged rats. The restingG Cl of extensor digitorum longus (EDL) muscles from adult rats either young (3–4 months old) or aged (29 months old) was measured by means of computerized intracellular microelectrode recordings. In EDL muscle from 3 to 4-month-old rats, 4-β-phorbol 12,13-dibutyrate (4-β-PDB), a direct activator of protein kinase C (PKC), decreasedG Cl in a concentration-dependent manner. The same effect was exerted by cholera toxin. The effects of both the phorbol ester and cholera toxin were inhibited by staurosporine, thus indicating that either direct or indirect (via G protein) activation of PKC accounts for the decrease ofG Cl. An increase of cytosolic Ca2+ by the ionophore A23187 also significantly decreasedG Cl by 25%. In EDL muscles from aged rats, 4-β-PDB was 20-fold more potent in blockingG Cl than in muscles from younger controls, and the ionophore blockedG Cl by 40%. On the other hand, cholera toxin was ineffective. Our findings support the hypothesis that in fast-twitch muscle the regulation of chloride channels by PKC and Ca2+ is a target of the aging process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00585945
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Pharmacological block of chloride channels of developing rat skeletal muscle affects the differentiation of specific contractile properties (1990)
    Springer
    Pflügers Archiv 416 (1990), S. 17-21 
    Details
    ISSN: 1432-2013
    Keywords: Rat skeletal muscle ; Development ; Chloride channels ; Anthracene 9-carboxylic acid ; Contractile properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A specific chloride channel blocker, anthracene 9-carboxylic acid was locally applied for 8–9 days on the extensor digitorum longus muscle of 7–8-day-old rats. The effects of chronic anthracene 9-carboxylic acid treatment on muscle development, were evaluated in vitro on the electrical properties with intracelluar microelectrodes and in vivo on the contractile parameters by recording isometric concentractions. Our data show that the treatment prevented the normal development of chloride conductance so that by 15 days of age it was 45% lower in fibers of the treated muscles when compared to age-related control fibers. Potassium conductance was not significantly changed by the treatment. In vivo the anthracene-9-carboxylic acid-treated muscles were slower to contract and relax; having a 20% slower time to peak twitch force and time of half relaxation. These muscles were also 32% less fatiguable with respect to the controls. Moreover, in most of the treated muscles tetanic contractions during high-frequency stimulation were not maintained. The block of chloride channels in developing striated fibers appears to affect the differentiation of specific properties of fast skeletal muscle such as the speed of contraction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00370216
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...