Interaction of lipopolysaccharide endotoxin produced from Escherichia coli with D-tubocurarine at the nicotinic2 receptor and adenosine 3':5' cyclic monophosphate during physiological contraction in skeletal muscle.
In this report the murine model of endotoxicosis was used to evaluate hyposensitivity to the neuromuscular relaxant D-tubocurarine (dTC). This hyposensitivity was expressed in terms of a decreased potency to dTC. A rightward shift of the dose-response curve due to endotoxin was observed. Mice were subjected to cumulative intraperitoneal doses of Escherichia coli endotoxin over a 2-wk period. The interaction between endotoxin and dTC was examined during an acute (1 wk) and chronic (2 wk) period of endotoxicosis. Muscle twitch analyses were performed and samples of gastrocnemius muscle were assayed for adenosine 3':5' cyclic monophosphate (cAMP) by [125I]radioimmunoassay. A parallel shift in the dose-response curve occurred in the endotoxin group subjected to doses corresponding to one-third the dose evoking 50% lethality for 2 wk. Both skeletal muscle tension and cAMP levels decreased as cumulative endotoxin doses increased. A relationship between decreasing cAMP levels and increasing dTC and effective dose required to achieve 50% muscle paralysis values was thought to be evoked by the agonistic activity of E. coli endotoxin leading to desensitizing of adenylate cyclase. The perturbations of the classical second messenger cAMP system by endotoxin may be responsible for skeletal muscle dysfunction observed in immunocompromised patients.
Tomera
J F
JF
Clinical Pharmacology Laboratory, Shriners Burns Institute, MA 02114, USA.
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004926:Escherichia coli; D016014:Linear Models; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003473:Neuromuscular Nondepolarizing Agents / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014403:Tubocurarine / Q000633:toxicity*
D008070:Lipopolysaccharides; D003473:Neuromuscular Nondepolarizing Agents; D011978:Receptors, Nicotinic; D000242:Cyclic AMP; D014403:Tubocurarine