Acute alterations in murine neuromuscular transmission following exposure to a nonparalytic dose of dithiobiuret.
Treatment of rats for 5 to 6 days with dithiobiuret (DTB, 1 mg/kg/day, ip) causes a flaccid, ascending neuromuscular weakness which is associated with a decreased end-plate potential (EPP) amplitude, quantal content, miniature end-plate potential (MEPP) frequency, and prolongation of MEPP and EPP rise and decay times. Whereas small daily doses of DTB reliably cause this paresis, a single large dose, approximating the LD50, and far in excess of the cumulative dose given chronically to induce paralysis, causes no apparent muscle weakness. It was of interest to determine whether subtle changes in neuromuscular transmission are produced by DTB under dosing conditions in which gross muscle weakness is not apparent. As such the present study had two goals: first, to determine whether a single large dose of DTB (25 mg/kg, ip) altered neuromuscular transmission at times when the animal did not exhibit paresis; and second, to determine whether bath application of DTB, at concentrations approximating those in the animal following a single large dose, altered junctional transmission at early exposure times. EPPs and MEPPs were recorded, from hemidiaphragms taken 1, 4, 8, or 24 hr following treatment of rats with a single dose of DTB or vehicle or from untreated rats which were exposed to 200 microM or 1.85 mM DTB by bath application. One hour after a single large dose of DTB, EPP amplitude and MEPP frequency and amplitude were all decreased. Rise and decay times for MEPPs were prolonged in muscles taken 4 hr after treatment. By 4, 8, and 24 hr after treatment, EPP amplitude, MEPP amplitude, and MEPP frequency returned toward control levels. Bath application of DTB initially increased EPP amplitude, MEPP amplitude, and MEPP frequency; however, with continued exposure EPP amplitude decreased to below control levels. Block of EPPs occurred after approximately 10 or 37 min of exposure to 1.85 mM or 200 microM DTB, respectively. MEPP frequency also decreased with continued exposure to DTB, yet remained above control levels for the duration of DTB exposure. Bath application of DTB caused a slowing of decay times of MEPPs similar to that observed following in vivo exposure. These results demonstrate that a single large dose of DTB initially induces neuromuscular effects similar to those observed in rats paralyzed following chronic treatment with DTB but these effects, with the exception of effects on rise and decay times of synaptic potentials, tend to reverse by 24 hr following exposure.(ABSTRACT TRUNCATED AT 400 WORDS)
Spitsbergen
J M
JM
Department of Pharmacology/Toxicology, Michigan State University, East Lansing 48824.
Atchison
W D
WD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008839:Microelectrodes; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D013890:Thiourea; C007540:2,4-dithiobiuret