Effects of aconitine on neurotransmitter release in the rat neuromuscular junction.
Aconitine (ACO), A Na+ channel activator, induces depolarization in skeletal muscle and blocks neuromuscular transmission. We investigated the effects of ACO on neurotransmitter release in the rat isolated phrenic nerve-diaphragm preparation at 24 +/- 1 degrees C. ACO inhibited the twitch responses to nerve stimulation but did not affect direct muscle contractions. ACO, without causing excessive membrane depolarization, increased the frequency of miniature end-plate potential (MEPP)s, but did not alter their amplitude or time course. The increase in MEPP frequency started about 60, 30 and 15 min after the application of 6, 20 and 60 microM ACO, respectively. MEPP frequency reached its maximum (250-400 sec-1), within 10-15 min after it began to increase. ACO, without altering direct muscle action potentials decreased the amplitude and blocked end-plate potential (EPP)s and nerve action potential (NAP)s simultaneously, before the increase in MEPP frequency became evident. ACO did not increase MEPP frequency in Ca(2+)-free media. Prior application of tetrodotoxin (1 microM) inhibited the ACO-induced MEPP frequency increase. Carbamazepine (120 microM) and amiloride (100 microM) did not completely inhibit the MEPP frequency increase but prolonged the latency. ACO-induced alterations in the neuromuscular transmission exhibited minimal recovery upon washing for 2-3 hr. These results indicate that ACO-induced neuromuscular blockade is mainly due to presynaptic mechanisms and can be explained by excessive presynaptic depolarization which leads to the blockade of NAPs and EPPs. Depolarization in turn increases intraterminal Ca2+ concentration and results in an excessive increase in MEPP frequency.
Department of Pharmacology, Hacettepe University, Faculty of Medicine, Ankara, Turkey.
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Onur
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Bozdagi
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Ayata
D000157:Aconitine / Q000494:pharmacology*; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D018377:Neurotransmitter Agents; D002220:Carbamazepine; D000157:Aconitine