Yamamura H, Nagano N, Hirano M, Muraki K, Watanabe M, Imaizumi Y
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
J Pharmacol Exp Ther. 1999 Oct;291(1):140-6.
The effects of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor and an antioxidant, on membrane currents were examined in single smooth muscle cells isolated from porcine coronary artery. Spontaneous transient outward currents (STOCs) recorded at -30 mV were markedly enhanced by NDGA (>/=10 microM). Pretreatment with caffeine and ryanodine abolished STOCs and reduced NDGA-induced increase in outward current at -30 mV by approximately 60%. NDGA showed dual action on an outward current elicited by step depolarization from -60 to 0 mV: inhibition and enhancement at concentrations of 3 and >/=10 microM, respectively. In the presence of Cd(2+), the inhibition of outward current by NDGA disappeared and the enhancement remained. NDGA inhibited both the voltage-dependent Ca(2+) channel current (IC(50) = 2.5 microM) and the delayed rectifier K(+) current (IC(50) = 9.8 microM). The NDGA-induced enhancement of STOCs and outward currents on depolarization was abolished by 100 nM iberiotoxin but was not affected by glibenclamide or apamin. Under current clamp mode, 30 microM NDGA significantly hyperpolarized myocytes. The application of lipoxygenase inhibitors (caffeic acid and esculetin), a cyclooxygenase inhibitor (indomethacin), antioxidants (ascorbic acid and erythorbic acid), and structural-related compounds of NDGA (catechol and dopamine) did not enhance K(+) currents. These results indicate that the opening of the large conductance Ca(2+)-dependent K(+) channel by NDGA, which is independent of its lipoxygenase inhibition or antioxidant effect, results in membrane hyperpolarization.
在从猪冠状动脉分离的单个平滑肌细胞中，研究了脂氧合酶抑制剂及抗氧化剂去甲二氢愈创木酸（NDGA）对膜电流的影响。在-30 mV记录的自发性瞬时外向电流（STOCs）可被NDGA（≥10 μM）显著增强。用咖啡因和ryanodine预处理可消除STOCs，并使NDGA诱导的-30 mV外向电流增加减少约60%。NDGA对从-60 mV至0 mV的阶跃去极化所引发的外向电流具有双重作用：在浓度为3 μM和≥10 μM时分别表现为抑制和增强。在Cd(2+)存在的情况下，NDGA对外向电流的抑制作用消失而增强作用仍存在。NDGA抑制电压依赖性Ca(2+)通道电流（IC(50)=2.5 μM）和延迟整流K(+)电流（IC(50)=9.8 μM）。NDGA诱导的STOCs增强及去极化时的外向电流增强可被100 nM埃博毒素消除，但不受格列本脲或阿帕明影响。在电流钳模式下，30 μM NDGA使心肌细胞显著超极化。应用脂氧合酶抑制剂（咖啡酸和七叶亭）、环氧化酶抑制剂（吲哚美辛）、抗氧化剂（抗坏血酸和异抗坏血酸）以及NDGA的结构相关化合物（儿茶酚和多巴胺）均未增强K(+)电流。这些结果表明，NDGA通过打开大电导Ca(2+)依赖性K(+)通道导致膜超极化，这一作用与其脂氧合酶抑制或抗氧化作用无关。
