In vitro neuromuscular effects of valproic acid.
The contribution of the anticonvulsant agent, valproic acid, to the interaction between neuromuscular blockers and anticonvulsants remains unclear. Therefore, this study was undertaken to examine the acute neuromuscular effects of valproic acid and its potential for interaction with neuromuscular blocking drugs. Phrenic nerve-hemidiaphragm preparations from rats were mounted in modified Krebs buffer, maintained at 37 degrees C and aerated with a 5% carbon dioxide-95% oxygen gas mixture. Phrenic nerves were stimulated with 0.1 Hz supramaximal pulses of 0.2-ms duration and the elicited tension of the hemidiaphragm was recorded in seven preparations in the presence of valproic acid 100, 500 and 1000 mumol litre-1. In another six preparations, neuromuscular transmission was blocked completely with the non-depolarizing blocker tubocurarine 3 mumol litre-1 and the hemidiaphragm muscle was stimulated directly (2 Hz and 2 ms duration). The effect of the anticholinesterase drug, neostigmine, on an established block induced by valproic acid 1000 mumol litre-1 was also evaluated in five phrenic nerve stimulated preparations. The effect of valproic acid 100, 500 or 1000 mumol litre-1 on suxamethonium- or atracurium-induced neuromuscular block was also evaluated. Valproic acid produced a mean of 29.7 (SEM 1.7)% and 24.7 (1.7) % block of indirectly or directly elicited muscle twitches. The concentration of valproic acid that caused half maximal paralysis did not differ between indirect (460 (59) mumol litre-1) and direct (329 (35) mumol litre-1) stimulation. Neostigmine 1-3 mumol litre-1 failed to significantly alter the block of 19.8% induced by valproic acid 1000 mumol litre-1. Valproic acid 100, 500 or 1000 mumol litre-1 did not alter the concentrations of suxamethonium or atracurium needed to produce paralysis. These findings suggest that valproic acid does not produce significant block at the rat neuromuscular junction. The partial block that is produced is caused predominantly by a direct inhibitory effect on the muscle itself.
Nguyen
A
A
Department of Pharmacy, University of Sydney, NSW, Australia.
Ramzan
I
I
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001279:Atracurium / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066298:In Vitro Techniques; D008297:Male; D009388:Neostigmine / Q000494:pharmacology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013390:Succinylcholine / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D002800:Cholinesterase Inhibitors; D009467:Neuromuscular Depolarizing Agents; D003473:Neuromuscular Nondepolarizing Agents; D001279:Atracurium; D009388:Neostigmine; D014635:Valproic Acid; D013390:Succinylcholine