Uceda G, García A G, Guantes J M, Michelena P, Montiel C
Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Eur J Pharmacol. 1995 Mar 15;289(1):73-80. doi: 10.1016/0922-4106(95)90170-1.
This study was carried out to define the effects of various Ca2+ channel modulatory drugs on mitochondrial Ca2+ movements. Bovine adrenal medulla mitochondria took up Ca2+ at an initial rate of 6.8 nmol mg protein-1 5 s-1, with a Km of 15 microM and a Bmax of 30 nmol mg protein-1. At 30 microM, neither verapamil, diltiazem, nitrendipine nor Bay K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate] affected the initial rate of Ca2+ uptake. Ca(2+)-loaded mitochondria retained their Ca2+ contents in the presence of ruthenium red for at least 30 min. Cinnarizine and flunarizine, but not verapamil, diltiazem, isradipine, Bay K 8644 or nitrendipine, caused a fast and dramatic Na(+)-independent Ca2+ loss. Other Ca2+ channel antagonists assayed such as penfluridol, R56865 [N-[1-(4-(4-fluorophenoxy)butyl)]-4-piperidinyl-N-methyl-2- benzothiazolamine], lidoflazine, R87926 [(+)-(S)-4-(2-benzothiazolyl-methylamino)-alpha-[(3,4-difluorophenoxy ) methyl] 1 piperidine] and sabeluzole, also had a mitochondrial Ca2+ depleting effect which seemed to be directly related to their octanol/water partition coefficient. The Na(+)-dependent Ca2+ efflux from mitochondria was completely inhibited by diltiazem and greatly blocked by nitrendipine. Isradipine caused a moderate blockade and Bay K 8644 and verapamil had no effect. All these data open the possibility of developing novel Ca2+ channel antagonists having selective actions on plasmalemmal Ca2+ channels, and others with additional and different effects on mitochondrial Ca2+ transport.(ABSTRACT TRUNCATED AT 250 WORDS)
本研究旨在确定各种钙通道调节药物对线粒体钙转运的影响。牛肾上腺髓质线粒体摄取钙的初始速率为6.8 nmol mg蛋白⁻¹ 5 s⁻¹，米氏常数（Km）为15 μM，最大结合量（Bmax）为30 nmol mg蛋白⁻¹。在30 μM浓度下，维拉帕米、地尔硫䓬、尼群地平以及Bay K 8644 [甲基-1,4-二氢-2,6-二甲基-3-硝基-4-(2-三氟甲基苯基)-吡啶-5-羧酸盐]均不影响钙摄取的初始速率。负载钙的线粒体在钌红存在下至少30分钟内保持其钙含量。桂利嗪和氟桂利嗪可引起快速且显著的非钠依赖性钙流失，而维拉帕米、地尔硫䓬、伊拉地平、Bay K 8644或尼群地平则无此作用。所检测的其他钙通道拮抗剂，如五氟利多、R56865 [N-[1-(4-(4-氟苯氧基)丁基)]-4-哌啶基-N-甲基-2-苯并噻唑胺]、利多氟嗪、R87926 [(+)-(S)-4-(2-苯并噻唑基甲基氨基)-α-[(3,4-二氟苯氧基)甲基]哌啶]和沙贝鲁唑，也具有线粒体钙消耗作用，这似乎与其辛醇/水分配系数直接相关。地尔硫䓬完全抑制线粒体钠依赖性钙外流，尼群地平则显著阻断该过程。伊拉地平引起中度阻断，Bay K 8644和维拉帕米无作用。所有这些数据为开发对质膜钙通道具有选择性作用的新型钙通道拮抗剂以及对线粒体钙转运具有额外不同作用的其他拮抗剂提供了可能性。（摘要截短于250字）
