title: Antagonism of dithiobiuret toxicity in rats.
abstract: 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.
mesh_terms: D015082:2,2'-Dipyridyl / Q000494:pharmacology*; D000818:Animals; D003543:Cysteamine / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology*; D008297:Male; D009468:Neuromuscular Diseases / Q000139:chemically induced* / Q000517:prevention & control; D010396:Penicillamine / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D013890:Thiourea / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D011725:Pyridines; D015082:2,2'-Dipyridyl; D003543:Cysteamine; D004050:Ditiocarb; D004492:Edetic Acid; D010396:Penicillamine; D013890:Thiourea; C007540:2,4-dithiobiuret; D004221:Disulfiram