Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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)
 ...
PMID:Acute alterations in murine neuromuscular transmission following exposure to a nonparalytic dose of dithiobiuret. 215 19

Daily treatment of rats with 2,4-dithiobiuret (DTB, 1 mg/kg/day, ip) causes a flaccid neuromuscular weakness first observable in the hindlimbs after 5-6 days of treatment. With continued exposure, neuromuscular weakness appears to encompass the other muscles of the body; death is presumed to result from paralysis of respiratory muscles. The purpose of the present study was to investigate the early effects on neuromuscular transmission which precede neuromuscular weakness caused by DTB, particularly as they relate to the apparent differential muscle sensitivity, using conventional intracellular microelectrode recording techniques. Experiments were conducted using the hemidiaphragm muscle isolated from male rats treated for 7-8 days, with 1 mg/kg/day DTB ip, a regimen which resulted in hindlimb, but not diaphragmatic paralysis, or with 0.9% NaCl (1 ml/kg/day) as control. Analysis of quantal content of end plate potentials (EPPs) from hemidiaphragms of DTB-treated rats indicated no difference from control. Exposure of hemidiaphragm preparations from DTB-paralyzed rats to solutions containing elevated Mg2+ and lowered Ca2+ concentrations (6 and 1 mM, respectively) resulted in a decreased quantal content of the EPP compared to that of similarly treated control preparations. When miniature EPPs (MEPPs) were evoked from nerve terminals by elevating [K+]e, in the presence of 6 mM Mg2+ and 1 mM Ca2+, the mean peak frequency evoked by K(+)-induced depolarization was reduced in the DTB-treated group; however, the time at which peak frequency was attained was the same for the control and DTB-treated group. Mean MEPP amplitude but not resting MEPP frequency was altered in the presence of high [Mg2+] for diaphragms of the DTB-treated group. Neither MEPP amplitude nor frequency was altered in diaphragms exposed to normal concentrations of Ca and Mg. Prolongation of rise and decay times of MEPPs occurred from end plates of DTB-treated rats irrespective of whether low [Ca2+]/high [Mg2+] solutions were used. However, these effects were more pronounced when low [Ca2+]/high [Mg2+] solutions were used. Diaphragm-derived end plates of the DTB-treated group were also characterized frequently by the presence of very large amplitude MEPPs with prolonged decay times. The overall percentage of the total population of MEPPs which these abnormal MEPPs made up in the DTB-treated rats was increased dramatically by exposure to low [Ca2+]/high [Mg2+] solutions. Thus, differential muscle sensitivity occurs during paralysis induced by chronic DTB treatment, with the diaphragm being somewhat more resistant than hindlimbs to neuromuscular weakness.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Reduced safety factor for neuromuscular transmission and abnormal quantal secretion precede neuromuscular weakness induced by dithiobiuret. 217 53

Daily treatment of rats with 2,4-dithiobiuret (DTB, 1 mg/kg/day i.p.) produces a flaccid neuromuscular weakness first observed in the hindlimbs after 5 to 6 days of treatment. This condition is characterized by diminished contractile strength following single shock and tetanic stimulation of the motor nerve, but no effect on contractions evoked by direct muscle stimulation, indicating an apparent impairment of motor axon conduction, junctional transmission or both. The purpose of the present study was to investigate further the neuromuscular depression caused by DTB using conventional intracellular microelectrode recording techniques. All experiments were conducted using the extensor digitorum longus muscle isolated from male rats treated for 6 to 7 days with 1 mg/kg/day i.p. of DTB or with 0.9% NaCl (1 ml/kg/day) as control. End-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) were recorded from single junctions of DTB-poisoned or NaCl-treated paired controls. Muscles were transected ("cut muscle") to prevent contraction after peroneal nerve stimulation. EPP amplitude was decreased at the time of observable muscle weakness in DTB-treated rats. Endplate resting membrane potential was not affected. Decreased EPP amplitude was associated with a decrease in mean quantal content. Quantal content was depressed to an equivalent extent in DTB-treated rats when stimulus frequency was increased from 0.5 to 2, 5, 25 and 50 Hz. However, as the stimulus frequency was increased, preparations from DTB-treated rats were characterized by failures of nerve impulses to elicit an EPP.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Alterations of spontaneous and evoked release of acetylcholine during dithiobiuret-induced neuromuscular weakness. 249 75

Daily administration of dithiobiuret (DTB, 1 mg/kg X 6 days, ip) produced delayed onset muscle weakness in rats as indicated by failure in a treadmill test. In nerve-muscle preparations from DTB-intoxicated rats neuromuscular toxicity was manifested as contractile fatigue during tetanic nerve stimulation. As muscle weakness developed, feed intake decreased and the animals lost body weight. Water intake was not altered during this time, but urine output was increased concomitant with the development of muscle weakness and resulted in a state of negative water balance. Daily administration of d-penicillamine (d-PEN) antagonized DTB-induced treadmill failure in a dose-dependent fashion. A daily dose of d-PEN (1 mMol/kg, ip) that completely antagonized treadmill failure also antagonized the contractile fatigue, reduced feed intake, weight loss and negative water balance caused by DTB administration. In rats already intoxicated with DTB, initiating daily d-PEN treatment or discontinuing further DTB administration, caused the animals to recover normal treadmill performance after a latent period of five days. A single dose of d-PEN (1 mMol/kg, iv) was not effective in reversing treadmill failure or contractile fatigue in rats already intoxicated with DTB. Thus, continuous daily administration of d-PEN was necessary for it to be effective. A single dose of d-PEN (1 m Mol/kg, ip) administered one hr after [14C]-DTB (1 mg/kg, ip) did not affect the plasma and tissue concentrations of DTB-derived radioactivity or their corresponding elimination kinetics. Cumulative urinary and fecal excretion of DTB-derived radioactivity were also unaffected by d-PEN administration as were the relative proportions of DTB and two of its metabolites, monothiobiuret and thiuret, in urine. Other agents that produced dose-dependent antagonism of DTB toxicity were diethyldithiocarbamate, disulfiram, cysteamine and 2,2'-dipyridyl. Considering the chemical and biological properties of DTB and its antagonists, a mechanism of antagonism involving an alteration of the thiol-disulfide and/or divalent metal cation status of motor axon terminals is postulated.
 ...
PMID:Antagonism of dithiobiuret toxicity in rats. 301 25