Singh Y N, Lamberty M A, Johnson A, Adam T J
College of Pharmacy, South Dakota State University, Brookings 57007-0099.
Arch Int Pharmacodyn Ther. 1994 May-Jun;327(3):363-74.
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.
研究了一种假定的钙拮抗剂TMB - 8 [8 -（N，N - 二乙氨基）辛基 - 3,4,5 - 三甲氧基苯甲酸酯]对小鼠离体膈神经 - 半膈肌标本直接和间接诱发的等长收缩、强直收缩以及钾离子和咖啡因诱导的挛缩的影响。在测试的最低浓度（10^(-6) M）下，TMB - 8使直接和间接诱发的收缩增强。在较高浓度（10^(-5) - 3×10^(-5) M）时，这种增强之后是收缩减弱。在最高浓度（10^(-4) M - 3×10^(-4) M）时，仅观察到以浓度依赖方式的收缩减弱。TMB - 8还抑制直接和间接诱发的强直收缩。然而，该药物在抑制神经传递方面比降低肌肉收缩力更有效。升高的Ca2 +（4 - 8 mM）或3,4 - 二氨基吡啶（10^(-4) M）可使神经肌肉阻滞得到良好逆转，但这种作用是短暂的。用4 mM Ca2 +预处理对产生50%或90%抑制直接或间接诱发收缩所需的时间没有显著影响。然而，8 mM Ca2 +显著延长了TMB - 8对间接诱发但非直接诱发收缩的抑制作用。另一方面，新斯的明（3 microM）似乎加速了传递阻滞。在测试的浓度范围（10^(-5) - 3×10^(-4) M）内，亚最大钾离子诱导的挛缩明显受到抑制，而咖啡因诱导的挛缩仅略有抑制。这些结果与以下假设一致：TMB - 8通过减少跨膜Ca2 +移动、降低突触后乙酰胆碱受体敏感性以及减少从肌浆网中释放的钙的动员来抑制骨骼肌收缩力。
