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 N.N.-diethylamino)octyl-3,4,5-trimethoxybenzoate] , a putative calcium antagonist, on directly and indirectly evoked iso metric twitches, tetanic contractions and potassium- and caffeine-indu ced contractures, were investigated in the mouse isolated phrenic nerv e-hemidiaphragm preparation. In the lowest concentration tested (10(-6 ) M), TMB-8 produced an augmentation of both directly and indirectly i nduced twitches. In higher concentrations (10(-5)-3 x 10(-5) M), this augmentation was followed by twitch reduction. In the highest concentr ations (10(-4) M-3 x 10(-4) M), only twitch reduction in a concentrati on-dependent manner was observed. TMB-8 also depressed both directly a nd indirectly induced tetanic contractions. However, the drug was more effective in depressing neurotransmission than in reducing muscle con tractility. Elevated Ca2+ (4-8 mM) or 3,4-diaminopyridine (10(-4) M) p roduced a good reversal of neuromuscular blockade but this effect was transient. Pretreatment with 4 mM Ca2+ had no significant effect on th e time required to produce a 50 % or a 90 % inhibition of directly or indirectly induced twitches. However, 8 mM Ca2+ significantly prolonge d the inhibitory effects of TMB-8 on indirectly, but not directly indu ced twitches. On the other hand, neostigmine (3 mu M appeared to haste n the blockade of transmission. Submaximal potassium-induced contractu res were markedly depressed while caffeine-induced contractures were o nly 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 transm embrane Ca2+ movement, a depression of postsynaptic acetylcholine rece ptor sensitivity, and a decreased mobilization of sequestered calcium from the sarcoplasmic reticulum.