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中华内科杂志 1986年第10期25卷 626-629页

作者：陈修湖南医学院药理教研室

钙拮抗剂(又称钙通道阻滞剂)的发展是近二十年心血管药物研究的一大突破,不但有重大的实用价值,也对研究钙离子和钙通道等生物医学基本问题有极大的促进作用。近年发展迅速,现结合1986年2月第12届国际心脏研究大会"Fleckenstein讨... 详细信息

钙拮抗剂(又称钙通道阻滞剂)的发展是近二十年心血管药物研究的一大突破,不但有重大的实用价值,也对研究钙离子和钙通道等生物医学基本问题有极大的促进作用。近年发展迅速,现结合1986年2月第12届国际心脏研究大会"Fleckenstein讨论会"的内容简要介绍如下。

关键词：钙通道阻滞药/药理学离子通道/药物作用

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不同剂量的钙离子通道拮抗剂对面神经损害的保护作用(英文)

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中国临床康复 2005年第17期9卷 210-211页

作者：唐金荣龚洁侯熙德苏建华徐长中王颖丁新生南京医科大学第一附属医院神经科江苏省南京市210029

背景:应用Ca2+通道拮抗剂对周围神经损害保护作用的实验研究较多,但在临床应用中其剂量大小对受损神经保护作用的效果差异尚需探讨。目的:应用不同剂量Ca2+通道拮抗剂氟桂利嗪治疗面神经麻痹(简称面瘫),观察治疗1个月后电生理学量化评... 详细信息

背景:应用Ca2+通道拮抗剂对周围神经损害保护作用的实验研究较多,但在临床应用中其剂量大小对受损神经保护作用的效果差异尚需探讨。目的:应用不同剂量Ca2+通道拮抗剂氟桂利嗪治疗面神经麻痹(简称面瘫),观察治疗1个月后电生理学量化评估结果。设计:随机分组,空白对照,随访1个月。单位:南京医科大学第一附属医院神经科。对象:1999-11/2001-05南京医科大学第一附属医院神经内科门诊面瘫患者35例,男19例,女16例,年龄16～58岁,病程≤3d,未经过任何治疗且瘫痪均为完全性。采用随机抽样方法将初诊患者分为对照组12例、治疗Ⅰ组10例,治疗Ⅱ组13例。方法:对照组采用基础治疗,强的松1mg/(kg·d),1次/d,晨服,最大剂量≤60mg/d,每隔5d减半量,1个疗程15d,甲钴胺口服500μg,3次/d。呋喃硫胺口服25mg,3次/d。超短波理疗,1次/d,治疗15d。共治疗1个疗程。治疗Ⅰ组和治疗Ⅱ组在此基础上进行Ca2+通道拮抗剂治疗:治疗Ⅰ组:氟桂利嗪5mg,1次/晚,治疗Ⅱ组:氟桂利嗪10mg,1次/晚。治疗前及治疗后1个月分别检测各组患者的Blink反射潜伏期及波幅的变化。主要观察指标:各组患者治疗1个月后Blink反射潜伏期和波幅。结果:按意向处理分析,35例患者均进入结果分析。①治疗前3组患者Blink反射均呈现面瘫侧传出型阻断,R1,R2均消失。

关键词：面神经麻痹钙通道阻滞药/药理学钙通道阻滞药/投药和剂量

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Inhibition of calcium release-activated calcium current by Rac/Cdc42-inactivating clostridial cytotoxins in RBL cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第25期275卷 18732-18738页

作者： Djouder, N Prepens, U Aktories, K Cavalié, A Univ Freiburg Inst Pharmakol & Toxikol D-79104 Freiburg Germany Univ Saarland Inst Pharmakol & Toxikol D-66421 Homburg Germany

Using large clostridial cytotoxins as tools, the role of Rho GTPases in activation of RBL 2H3 hm1 cells was studied. Clostridium difficile toxin B, which glucosylates Rho, Rac, and Cdc42 and Clostridium sordellii lethal toxin, which glucosylates Rac and Cdc42 but not Rho, inhibited the release of hexosaminidase from RBL cells mediated by the high affinity antigen receptor (Fc epsilon RI). Additionally, toxin B and lethal toxin inhibited the intracellular Ca2+ mobilization induced by Fc epsilon RI-stimulation and thapsigargin, mainly by reducing the influx of extracellular Ca2+. In patch clamp recordings, toxin B and lethal toxin inhibited the calcium release-activated calcium current by about 45%. Calcium release-activated calcium current, the receptor-stimulated Ca2+ influx, and secretion were inhibited neither by the Rho-ADP-ribosylating C3-fusion toxin C2IN-C3 nor by the actin-ADP-ribosylating Clostridium botulinum C2 toxin. The data indicate that Rac and Cdc42 but not Rho are not only involved in late exocytosis events but are also involved in Ca2+ mobilization most likely by regulating the Ca2+ influx through calcium release-activated calcium channels activated via Fc epsilon RI receptor in RBL cells.

关键词：肉毒毒素类/药理学钙/代谢钙通道阻滞药/药理学钙通道/药物作用钙通道/代谢蛋白质丝氨酸苏氨酸激酶/拮抗剂和抑制剂蛋白质丝氨酸苏氨酸激酶/代谢肿瘤细胞培养的动物大鼠

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Na⁺/Ca²⁺ exchange facilitates Ca²⁺-dependent activation of endothelial nitric-oxide synthase

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第41期274卷 29529-29535页

作者： Teubl, M Groschner, K Kohlwein, SD Mayer, B Schmidt, K Karl Franzens Univ Graz Inst Pharmakol & Toxikol A-8010 Graz Austria Graz Univ Technol Inst Biochem & Lebensmittelchem A-8010 Graz Austria

Recent evidence suggests the expression of a Na+/ Ca2+ exchanger (NCX) in vascular endothelial cells, To elucidate the functional role of endothelial NCX, we studied Ca2+ signaling and Ca2+-dependent activation of endothelial nitric-oxide synthase (eNOS) at normal, physiological Na+ gradients and after loading of endothelial cells with Na+ ions using the ionophore monensin. Monensin-induced Na+ loading markedly reduced Ca2+ entry and, thus, steady-state levels of intracellular free Ca2+ ([Ca2+](i)) in thapsigargin-stimulated endothelial cells due to membrane depolarization. Despite this reduction of overall [Ca2+](i), Ca2+-dependent activation of eNOS was facilitated as indicated by a pronounced leftward shift of the Ca2+ concentration response curve in monensin-treated cells. This facilitation of Ca2+-dependent activation of eNOS was strictly dependent on the presence of Na+ ions during treatment of the cells with monensin, Na+-induced facilitation of eNOS activation was not due to a direct effect of Na+ ions on the Ca2+ sensitivity of the enzyme. Moreover, the effect of Na+ was not related to Na+ entry-induced membrane depolarization or suppression of Ca2+ entry, since neither elevation of extracellular K+ nor the Ca2+ entry blocker 1-(beta-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) mimicked the effects of Na+ loading. The effects of monensin were completely blocked by 3',4'-dichlorobenzamil, a potent and selective inhibitor of NCX, whereas the structural analog amiloride, which barely affects Na+/Ca2+ exchange, was ineffective. Consistent with a pivotal role of Na+/Ca2+ exchange in Ca2+-dependent activation of eNOS, an NCX protein was detected in caveolin-rich membrane fractions containing both eNOS and caveolin-1. These results demonstrate for the first time a crucial role of cellular Na+ gradients in regulation of eNOS activity and suggest that a tight functional interaction between endothelial NCX and eNOS may tak

关键词：阿米洛利/药理学缓激肽/药理学钙/药理学钙通道阻滞药/药理学窖蛋白1 细胞质膜微囊蛋白细胞培养的瓜氨酸/代谢内皮血管酶激活/药物作用荧光抗体技术 Fura-2/化学咪唑类/药理学膜蛋白质类/代谢莫能星/药理学一氧化氮合酶/代谢钠/药理学钠钙交换蛋白/代谢猪动物

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Changes of plasma L-arginine levels in spontaneously hypertensive rats under induced hypotension

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BIOMEDICAL CHROMATOGRAPHY 1999年第1期13卷 27-32页

作者： Prados, P Matsunaga, H Mori, T Santa, T Fukushima, T Homma, H Kasai, C Imai, K Univ Tokyo Grad Sch Pharmaceut Sci Bunkyo Ku Tokyo 1130033 Japan Yamanouchi Seiyaku Co Ltd Pharmacol Res Lab Tsukuba Ibaraki 3050841 Japan

Nicardipine, a dihydropyridine type calcium channel blocker, was infused at two flow-rates into spontaneously hypertensive (SH) and control normotensive Wistar-Kyoto (WKY) rats (young, 6-week-old and adult, 23-week-old, n = 5) under pentobarbital anesthesia, to cause hypotension. Mean arterial blood pressure and the concentrations of plasma amino acids and norepinephrine (NE) were measured before infusion and at each step of the infusion. The reduction in blood pressure caused by nicardipine induced a decrease in plasma L-arginine concentration in both young and adult SH rats, this effect being larger in adult rats. There was no significant change in plasma levels of L-arginine in age-matched WKY rats. The concentration of other amino acids did not change in both rat strains. On the contrary, there was an increase in plasma NE concentration in both SH and WKY rats after infusion with nicardipine. Plasma L-arginine concentration showed a good inverse correlation with the logarithm of plasma NE concentration in SH and WKY rats and the correlation was expressed as Y = -alpha log(X) + m (Y, plasma L-arginine concentration (nmol/mL);X, plasma NE concentration (pmol/mL);alpha, a slope;and m, an intercept). alpha, 43.0 and 4.35 for 23-week-old SH and WKY rats, respectively, and 17.0 and 4.0 for 6-week-old SH and WKY rats, respectively. The present data together with previous data suggest a direct noradrenergic stimulation of the synthesis of nitric oxide (NO) from L-arginine. The findings also indicate an impairment of the L-arginine metabolism or pools in SH rats compared with WKY rats. The deficiency of L-arginine increases with the age of SH rats and could be related to the development and maintenance of hypertension due to inefficient production of NO. Copyright (C) 1999 John Wiley & Sons, Ltd.

关键词：抗高血压药/药理学精氨酸/血液钙通道阻滞药/药理学高血压/血液低血压/血液低血压/化学诱导尼卡地平/药理学去甲肾上腺素/血液大鼠近交SHR 大鼠近交WKY 动物男(雄)性大鼠

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Intracellular calcium dynamics during photolysis

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JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME 1998年第5期120卷 570-578页

作者： Busch, NA Reiken, SR Toner, M Yarmush, ML Massachusetts Gen Hosp Ctr Engn Med Lab Surg Sci & Engn Boston MA 02114 USA Shriners Burns Hosp Boston MA 02114 USA Harvard Univ Sch Med Boston MA 02114 USA

The objective of this investigation was to gain a deeper understanding of the intracellular events that precede photolysis of cells. A model system, consisting of malignant melanoma cells pretreated,vith the calcium sensitive fluorescent dye, Fluo-3, was used to examine the intracellular calcium dynamics in single-cell photolysis experiments. Exposure of the cells to 632 nm laser light in the presence of photosensitizer, tin chlorin e6, resulted in a rise in intracellular calcium. The increase in intracellular calcium,was blocked using a variety of calcium channel blocking agents, including verapamil, nifedipine, and nickel. Treatment with the channel blockers was also effective in either decreasing or eliminating cell death despite the presence of lethal doses of photosensitizer and irradiation. These results show that intracellular calcium rises prior to plasma membrane lysis, and that this early rise in intracellular calcium is necessary for membrane rupture.

关键词：苯胺化合物/药代动力学钙/代谢钙通道阻滞药/药理学钙通道/药物作用钙通道/辐射效应钙信号/药物作用钙信号/辐射效应黑色素瘤金属卟啉类/药理学镍/药理学硝苯地平/药理学光化学疗法光解光敏感药/药理学光谱法质量基质辅助激光解吸电离时间因素肿瘤细胞培养的/辐射效应维拉帕米/药理学呫吨类/药代动力学人类

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Synthesis, bioactivity, and cloning of the L-type calcium channel blocker ω-conotoxin TxVII

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BIOCHEMISTRY 1999年第39期38卷 12876-12884页

作者： Sasaki, T Feng, ZP Scott, R Grigoriev, N Syed, NI Fainzilber, M Sato, K Mitsubishi Kasei Inst Life Sci Tokyo 1948511 Japan Univ Calgary Fac Med Div Resp Med Dept Anat & Med Physiol Calgary AB T2N 4N1 Canada Weizmann Inst Sci Dept Biol Chem IL-76100 Rehovot Israel

omega-Conotoxin TxVII is the first conotoxin reported to block L-type currents. In contrast to other omega-conotoxins, its sequence is characterized by net negative charge and high hydrophobicity, although it retains the omega-conotoxin cysteine framework. In order to obtain structural information and to supply material for further characterization of its biological function, we synthesized TxVII and determined its disulfide bond pairings. Because a linear precursor with free SH groups showed a strong tendency to aggregate and to polymerize, we examined many different conditions for air oxidation and concluded that a mixture of cationic buffer and hydrophobic solvent was the most effective for the folding of TxVII. Synthetic TxVII was shown to suppress the slowly inactivating voltage-dependent calcium current in cultured Lymnaea RPeD1 neurons and furthermore to suppress synaptic transmission between these neurons and their follower cells. In contrast, TxVII did not block calcium flux through L-type channels in PC12 cells, suggesting a phyletic or subtype specificity in this channel family. Disulfide bond pairings of TxVII and its isomers were determined by enzymatic fragmentation in combination with chemical synthesis, thus revealing that TxVII has the same disulfide bond pattern as other omega-conotoxins. Furthermore, the CD spectrum of TxVII is similar to those of omega-conotoxins MVIIA and MVIIC. The precursor sequence of TxVII was determined by cDNA cloning and shown to be closest to that of delta-conotoxin TxVIA, a sodium channel inactivation inhibitor. Thus TxVII conserves the structural fold of other omega-conotoxins, and the TxVIA/TxVII branch of this family reveals the versatility of its structural scaffold, allowing evolution of structurally related peptides to target different channels.

关键词：氨基酸序列碱基序列钙通道阻滞药/化学合成钙通道阻滞药/药理学色谱法高压液相圆二色性克隆分子 DNA 互补二硫化物类/化学椎实螺属分子序列数据肽类/化学合成肽类/遗传学肽类/药理学种系发生蛋白质结构二级序列同源性氨基酸 ω蜗牛毒素类动物

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Differences in gonadotropin-releasing hormone-induced calcium signaling between melatonin-sensitive and melatonin-insensitive neonatal rat gonadotrophs

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ENDOCRINOLOGY 2000年第3期141卷 1017-1026页

作者： Zemková, H Vanecek, J Acad Sci Czech Republic Inst Physiol CR-14220 Prague 4 Czech Republic

The sensitivity of GnRH-stimulated calcium signaling to melatonin, in a subpopulation of neonatal gonadotrophs, is supposed to be attributable to melatonin receptors. However, it is not yet known whether the intracellular pathway for GnRH action in melatonin-sensitive cells is the same as in melatonin-insensitive cells. By monitoring intracellular Ca2+ changes as an outward current carried through apamin-sensitive Ca2+-activated K+ channels, we compared GnRH-induced calcium responses in these two subpopulations of neonatal gonadotrophs. GnRH induced various oscillatory, as well as nonoscillatory, responses in both cell types that was not related to melatonin sensitivity. Melatonin-sensitive GnRH-induced responses could be clearly distinguished according to the pharmacological properties of their latency. The latency increased in zero extracellular Ca2+ or with the addition of nifedipine, staurosporine, and ryanodine. This effect was only rarely observed in melatonin-insensitive cells. This indicates that there are two pathways for initiation of GnRH-induced calcium signaling in neonatal gonadotrophs. The first pathway is mediated by inositol 1,4,5,-trisphosphate production, whereas the second involves extracellular calcium entry through voltage-dependent L-type Ca2+ channels, protein kinase C activation, and Ca2+ release from a ryanodine-sensitive store, which may coactivate Ca2+ release from an inositol 1,4,5,-trisphosphate-sensitive store. Only the second mechanism is accessible to inhibition by melatonin.

关键词：动物新生/生理学抗氧化剂/药理学蜂毒明肽/药理学钙/生理学钙通道阻滞药/药理学钙信号/药物作用电生理学酶抑制剂/药理学促性腺素释放激素/药理学褪黑激素/药理学膜电位/药物作用硝苯地平/药理学膜片钳术磷酸二酯酶抑制剂/药理学垂体/细胞学垂体/药物作用垂体/代谢钾通道/药物作用兰尼碱/药理学星状孢子素/药理学动物女(雌)性大鼠

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Block of voltage-dependent calcium channels by aliphatic monoamines

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BIOPHYSICAL JOURNAL 2000年第1期79卷 260-270页

作者： Beedle, AM Zamponi, GW Univ Calgary Dept Pharmacol & Therapeut Calgary AB T2N 4N1 Canada

We have recently identified farnesol, an intermediate in the mevalonate pathway, as a potent endogenous modulator and blocker of N-type calcium channels (Roullet, J. B., R. L. Spaetgens, T. Burlingame, and G. W. Zamponi. 1999. J. Biol Chem. 274:25439-25446). Here, we investigate the action of structurally related compounds on various types of voltage-dependent Ca2+ channels transiently expressed in human embryonic kidney cells. 1-Dodecanol, despite sharing the 12-carbon backbone and headgroup of farnesol, exhibited a significantly lower blocking affinity for N-type Ca2+ channels. Among several additional 12-carbon compounds tested, dodecylamine (DDA) mediated the highest affinity inhibition of N-type channels, indicating that the functional headgroup is a critical determinant of blocking affinity. This inhibition was concentration-dependent and relatively non-discriminatory among N-, L-, P/Q-, and R-Ca2+ channel subtypes. However, whereas L-type channels exhibited predominantly resting channel block, the non-L-type isoforms showed substantial rapid open channel block manifested by a speeding of the apparent time course of current decay and block of the inactivated state. Consistent with these findings, we observed significant frequency-dependence of block and dependence on external Ba2+ concentration for N-type, but not L-type, channels. We also systematically investigated the drug structural requirements for N-type channel inhibition. Blocking affinity varied with carbon chain length and showed a clear maximum at C12 and C13, with shorter and longer molecules producing progressively weaker peak current block. Overall, our data indicate that aliphatic monoamines may constitute a novel class of potent inhibitors of voltage-dependent Ca2+ channels, with block being governed by rigid structural requirements and channel-specific state dependencies.

关键词：乙酸盐类/药理学烷烃类/药理学胺类/药理学钡/药理学钙通道阻滞药/药理学钙通道/药物作用钙通道/代谢致癌物/药理学细胞系十二醇/药理学剂量效应关系药物法尼醇/类似物和衍生物法尼醇/药理学肾/细胞学肾/药物作用肾/代谢膜片钳术构效关系表面活性剂/药理学转染动物人类大鼠

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Effect of ω-conotoxin GVIA on noradrenaline release from postganglionic sympathetic neurones in rabbit aorta

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PHARMACOLOGY & TOXICOLOGY 2000年第1期86卷 30-35页

作者： Nedergaard, OA Odense Univ Sch Med Dept Pharmacol DK-5000 Odense C Denmark

The aim of the present work was to examine the effect of the selective N-type calcium blocking agent omega-conotoxin GVIA on stimulation-evoked release of noradrenaline from sympathetic nerves in rabbit isolated aorta with regard to stimulation frequency, extracellular Ca2+ concentration, and transmitter uptake. Rings of rabbit isolated aorta were preloaded with (-)-H-3-noradrenaline and the fractional H-3-overflow evoked by electrical-field stimulation was determined by liquid scintillation spectrometry. omega-Conotoxin GVIA (3 x 10(-10) - 3 x 10(-8) M) did not alter the spontaneous H-3-outflow omega-Conotoxin GVIA (3 x 10(-10) - 3 x 10(-8) M) caused a slowly developing reduction of stimulation-evoked H-3-overflow at 1 and 30 Hz. The Emax for the omega-conotoxin-induced inhibition was less (70%) at 30 Hz than that (96%) seen at 1 Hz. Short-term incubation with omega-conotoxin GVIA caused a subsequent steady-state inhibition. The inhibitory action of omega-conotoxin GVIA (3 x 10(-10) - 3 x 10(-9) M) was inversely related to the extracellular Ca2+ concentration (6.5 X 10(-4) - 2.7 x 10(-3) M). Cocaine (3 x 10(-5) M) plus corticosterone (4 x 10(-5) M), neuronal and extraneuronal uptake inhibitors, respectively, did not alter the inhibitory effect of omega-conotoxin GVIA (3 x 10(-9) M) on H-3-overflow evoked by stimulation at a frequency of either 1 or 30 Hz. It is concluded that omega-conotoxin GVIA acts on prejunctional N-type calcium channels to inhibit stimulation-evoked noradrenaline release from sympathetic neurone terminals in rabbit aorta. At a high frequency, another subtype calcium channel may possibly be involved. The action of omega-conotoxin GVIA is independent of neuronal and extraneuronal uptake mechanisms for noradrenaline, but dependent on the amount of Ca2+ to be transported across the neurilemma from the extracellular space into the neurone.

关键词：主动脉胸/神经支配钙/代谢钙/生理学钙通道阻滞药/药理学钙通道 L型/生理学可卡因/药理学皮质酮/药理学剂量效应关系药物电刺激神经元/药物作用神经元/分泌神经递质摄取抑制药/药理学去甲肾上腺素/分泌交感神经纤维节后/药物作用交感神经纤维节后/分泌氚 ω蜗牛毒素GVIA/药理学动物女(雌)性男(雄)性兔

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