Effects of TMB-8, a putative calcium antagonist, on neuromuscular transmission and muscle contractility in the mouse phrenic nerve-hemidiaphragm preparation.

Abstract

The effects of TMB-8 [8-(N.N.-diethylamino)octyl-3,4,5-trimethoxybenzoate], a putative calcium antagonist, on directly and indirectly evoked isometric twitches, tetanic contractions and potassium- and caffeine-induced contractures, were investigated in the mouse isolated phrenic nerve-hemidiaphragm preparation. In the lowest concentration tested (10(-6) M), TMB-8 produced an augmentation of both directly and indirectly induced twitches. In higher concentrations (10(-5)-3 x 10(-5) M), this augmentation was followed by twitch reduction. In the highest concentrations (10(-4) M-3 x 10(-4) M), only twitch reduction in a concentration-dependent manner was observed. TMB-8 also depressed both directly and indirectly induced tetanic contractions. However, the drug was more effective in depressing neurotransmission than in reducing muscle contractility. Elevated Ca2+ (4-8 mM) or 3,4-diaminopyridine (10(-4) M) produced a good reversal of neuromuscular blockade but this effect was transient. Pretreatment with 4 mM Ca2+ had no significant effect on the time required to produce a 50% or a 90% inhibition of directly or indirectly induced twitches. However, 8 mM Ca2+ significantly prolonged the inhibitory effects of TMB-8 on indirectly, but not directly induced twitches. On the other hand, neostigmine (3 microM) appeared to hasten the blockade of transmission. Submaximal potassium-induced contractures were markedly depressed while caffeine-induced contractures were only slightly depressed by TMB-8 in the concentration range tested (10(-5)-3 x 10(-4) M). The results are consistent with the hypothesis that TMB-8 inhibits skeletal muscle contractility by a reduction in transmembrane Ca2+ movement, a depression of postsynaptic acetylcholine receptor sensitivity, and a decreased mobilization of sequestered calcium from the sarcoplasmic reticulum.

• Authors: Y N Singh, M A Lamberty, A Johnson, T J Adam
• Journal: Archives internationales de pharmacodynamie et de therapie (Arch Int Pharmacodyn Ther) 1994 May-Jun Vol. 327 Issue 3 Pg. 363-74 ISSN: 0003-9780 [Print] Belgium
• PMID: 7848017 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Neuromuscular Blocking Agents
• Caffeine
• 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate
• Gallic Acid
• Potassium

Topics

• Animals
• Caffeine (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Diaphragm (drug effects)
• Electrophysiology
• Gallic Acid (analogs & derivatives, pharmacology)
• Male
• Mice
• Muscle Contraction (drug effects)
• Neuromuscular Blocking Agents (pharmacology)
• Neuromuscular Junction (drug effects, physiology)
• Phrenic Nerve (drug effects, physiology)
• Potassium (pharmacology)
• Synaptic Transmission (drug effects)
• Tetanus