Itogawa E, Kurosawa H, Yabana H, Murata S
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Eur J Pharmacol. 1996 Dec 19;317(2-3):401-6. doi: 10.1016/s0014-2999(96)00758-3.
The protective effect of l-cis-diltiazem, the stereoisomer of d-cis-diltiazem, was studied against the veratridine-induced hypercontracture of rat myocytes. Veratridine increased both [Na+]i and [Ca2+]i, but did not cause hypercontracture in the absence of extracellular Ca2+. Both l-cis-diltiazem (0.1-10 microM) and d-cis-diltiazem (10-30 microM) inhibited the hypercontracture and the increase in [Ca2+]i in a concentration-dependent manner. However, l-cis-diltiazem did not exert a negative inotropic effect in K+ (20 mM)-depolarized rat papillary muscles even at a dose of 10 microM. As seen in the case of tetrodotoxin, l-cis-diltiazem and d-cis-diltiazem also suppressed the increase in [Na+]i. The results show that l-cis-diltiazem prevents the veratridine-induced hypercontracture of myocytes by suppression of the [Ca2+]i increase. The attenuation of the [Ca2+]i increase by l-cis-diltiazem was not dependent on inhibition of Ca2+ channels, but was partly due to inhibition of excessive Na+ entry via veratridine-modified Na+ channels.
研究了d - 顺式地尔硫䓬的立体异构体l - 顺式地尔硫䓬对藜芦碱诱导的大鼠心肌细胞超收缩的保护作用。藜芦碱可使细胞内钠离子浓度（[Na⁺]i）和钙离子浓度（[Ca²⁺]i）升高，但在无细胞外钙离子的情况下不会引起超收缩。l - 顺式地尔硫䓬（0.1 - 10 μM）和d - 顺式地尔硫䓬（10 - 30 μM）均以浓度依赖性方式抑制超收缩和[Ca²⁺]i升高。然而，即使在10 μM剂量下，l - 顺式地尔硫䓬对钾离子（20 mM）去极化的大鼠乳头肌也未产生负性肌力作用。如同在河豚毒素的情况中所见，l - 顺式地尔硫䓬和d - 顺式地尔硫䓬也能抑制[Na⁺]i升高。结果表明，l - 顺式地尔硫䓬通过抑制[Ca²⁺]i升高来预防藜芦碱诱导的心肌细胞超收缩。l - 顺式地尔硫䓬对[Ca²⁺]i升高的减弱作用并非依赖于对钙通道的抑制，而是部分归因于对通过藜芦碱修饰的钠通道的过量钠离子内流的抑制。
