Göthert M, Molderings G J
Institut für Pharmakologie und Toxikologie, Rheinische Friedrich Wilhelms-Universität Bonn, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Dec;356(6):860-3. doi: 10.1007/pl00005130.
Segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone were used to determine the effects of mibefradil, omega-conotoxin (omega-CTx) GVIA and nifedipine on tritium overflow evoked by transmural electrical stimulation. Mibefradil (which predominantly blocks T-type, and at lower potency also N-type, Ca2+ channels) at concentrations of 0.3-3 microM reduced the electrically evoked tritium overflow in a reversible and concentration-dependent manner (IC50%: 1 microM), whereas 0.1-10 microM nifedipine (a selective blocker of L-type channels) was ineffective. The evoked tritium overflow was almost abolished by 0.2 microM omega-CTx GVIA (a selective blocker of N-type channels). It is concluded that noradrenaline release from cardiac sympathetic nerves is triggered by Ca2+-influx via N-type, but not L-type, Ca2+ channels and that the inhibitory effect of mibefradil at clinically relevant concentrations on noradrenaline release is probably due to its blocking action on N-type Ca2+ channels. This property of mibefradil is unique among the therapeutically applied Ca2+ channel blockers and may contribute to the slight negative chronotropic effect of the drug in vivo.
将预先用[3H]去甲肾上腺素孵育并在含有地昔帕明和皮质酮的生理盐溶液中灌流的人右心耳节段用于确定米贝拉地尔、ω-芋螺毒素（ω-CTx）GVIA和硝苯地平对经壁电刺激诱发的氚溢出的影响。米贝拉地尔（主要阻断T型，低浓度时也阻断N型钙通道）在0.3 - 3 microM浓度下以可逆和浓度依赖性方式降低电诱发的氚溢出（IC50%：1 microM），而0.1 - 10 microM硝苯地平（L型通道的选择性阻断剂）无效。0.2 microM ω-CTx GVIA（N型通道的选择性阻断剂）几乎完全消除了诱发的氚溢出。结论是，心脏交感神经释放去甲肾上腺素是由通过N型而非L型钙通道的Ca2+内流触发的，米贝拉地尔在临床相关浓度下对去甲肾上腺素释放的抑制作用可能是由于其对N型钙通道的阻断作用。米贝拉地尔的这一特性在治疗应用的钙通道阻滞剂中是独特的，可能导致该药物在体内产生轻微的负性变时作用。
