Effects of TMB-8, a putative calcium antagonist, on neuromuscular transmission and muscle contractility in the mouse phrenic nerve-hemidiaphragm preparation.
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.
Singh
Y N
YN
College of Pharmacy, South Dakota State University, Brookings 57007-0099.
Lamberty
M A
MA
Johnson
A
A
Adam
T J
TJ
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects; D004594:Electrophysiology; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D013742:Tetanus
D002121:Calcium Channel Blockers; D009466:Neuromuscular Blocking Agents; D002110:Caffeine; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D011188:Potassium