Hirano T, Mori T, Kido M, Toide K, Ohura M, Fujiki H, Orito K, Yoshida K, Ikezono K, Sumida T, Nakayama N, Yabuuchi Y
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan.
Fundam Clin Pharmacol. 1999;13(6):650-5. doi: 10.1111/j.1472-8206.1999.tb00376.x.
Pranidipine is an optically-active 1,4-dihydropyridine (DHP) voltage-dependent L-type calcium channel inhibitor. Certain enantiomeric pairs display opposite effects, i.e., inhibition and activation of the calcium channel while others exhibit the same qualitative actions. We investigated pranidipine, a new DHP, using a paradigm of vascular smooth muscle reactivity. In isolated rat aorta, depolarized with 80 mM KCl, both isomers of pranidipine caused a right-ward shift of the concentration-contraction curves for extracellular Ca2+. The apparent pA2, values of the S-isomer and R-isomer were 10.03 and 8.36, respectively, providing evidence that the calcium channel blocking action of the S-isomer was 50 times more potent than that of the R-isomer. Antihypertensive actions of these two isomers studied in pentobarbital-anaesthetized spontaneously hypertensive rats, revealed that the S-isomer, at doses of 3-30 microg/kg i.v. decreased blood pressure in a dose-dependent manner, while the R-isomer had no effect on blood pressure at those doses. We conclude that the pair of enantiomers of pranidipine qualitatively display the same Ca2+ channel blocking action and that neither isomer exhibits Bay K 8644-like activation. Pranidipine may be useful in studies on the architecture of the DHP receptor 'pocket'.
普拉地平是一种具有光学活性的1,4-二氢吡啶（DHP）电压依赖性L型钙通道抑制剂。某些对映体对表现出相反的作用，即对钙通道的抑制和激活，而其他对映体对则表现出相同的定性作用。我们使用血管平滑肌反应性范式研究了一种新型DHP——普拉地平。在分离的大鼠主动脉中，用80 mM KCl去极化后，普拉地平的两种异构体均使细胞外Ca2+的浓度-收缩曲线向右移动。S-异构体和R-异构体的表观pA2值分别为10.03和8.36，这表明S-异构体的钙通道阻断作用比R-异构体强50倍。在戊巴比妥麻醉的自发性高血压大鼠中研究这两种异构体的降压作用，结果显示，静脉注射剂量为3-30μg/kg的S-异构体可使血压呈剂量依赖性降低，而在这些剂量下R-异构体对血压没有影响。我们得出结论，普拉地平的这对对映体在定性上表现出相同的Ca2+通道阻断作用，且两种异构体均未表现出类似Bay K 8644的激活作用。普拉地平可能有助于研究DHP受体“口袋”的结构。
