Frequency-dependent effect of verapamil on rat soleus muscle

Summary In the presence of verapamil (0.1 mM) rat soleus muscle fibers failed to generate action potentials with overshoots. In fibers with their V_m set to a local level of –90 mV, verapamil produces a gradual reduction in the amplitude of the repetitive action potentials; this effect is more pronounced at high rates of stimulation (100 Hz). Our results suggest a local anesthetic action of this drug that could contribute with its calcium channel blocking effect to the diminished mechanical tension observed in the presence of the drug.Acknowledgments. We thank A. Losavio and M. Stefanolo for technical assistance. This work was supported by grants from CONICET and SUBCYT, Buenos Aires, Argentina and Muscular Dystrophy Association, USA.     

维拉帕米对肺静脉急性电重构的影响

探讨维拉帕米对短阵快速剌激肺静脉后肺静脉有效不应期及有效不应期频率适应性的影响。对8条成年杂种犬采用自身前后对照的方法,第一部分实验:首先分别测量起搏周长(PCL)分别为300 ms、400 ms时肺静脉有效不应期(PV-ERP),接着以1:1起搏肺静脉的最快频率刺激肺静脉10 min,分别在刺激中止后即刻、5 min、10 min时重复测量PV-ERP。第二部分实验:完成上述实验后15 min给予维拉帕米,再次重复第一部分实验内容。结果:短阵快速刺激肺静脉可以引起PV-ERP明显缩短,PV-ERP频率适应性下降,即肺静脉发生了急性电重构,应用维拉帕米后虽然不能逆转上述改变,但是明显减小改变的程度。说明维拉帕米一定程度上抑制了肺静脉急性电重构的程度。     

钙拮抗剂异博定增强博来霉素A_5对人肝癌BEL-7402细胞的毒性作用

应用肿瘤细胞增殖抑制、克隆形成、流式细胞术,研究了钙拮抗剂异博定(Ver)与博来霉素A_5(BLM A_5)对人肝癌BEL-7402细胞的影响.结果表明:无细胞毒性作用的Ver(20μmol)增强BLM A_5对人肝癌BEL-7402细胞增殖抑制作用达4倍;100μmol Ver增强BLM A_5毒性达11倍;与BLM A_5单独作用比较,Ver使G_2M期细胞进一步增多.另外,提高胞外钙浓度能增加BLM A_2对人肝癌BEL-7402细胞的增殖抑制作用.     

Difference of the inhibitory action of verapamil on the positive inotropic effect of Ca2+ between spontaneously hypertensive and normotensive rat myocardium

Summary Verapamil, a calcium entry blocker, had a greater inhibitory effect on the positive inotropic effect of excess Ca²⁺ in SHR than in NWR, suggesting that the cardiac responsiveness to verapamil was enhanced in SHR.     

异博定增强平阳霉素对体外培养人喉癌细胞的毒性及机制

为探讨钙拮抗剂异博定是否能增强平阳霉素对人癌细胞的毒性,利用体外培养人喉癌细胞对二药单用和合用效果进行了比较研究.结果表明,非抑制浓度的异博定使平阳霉素的半抑制浓度显著下降;平阳霉素与异博定联合处理后,细胞存活率下降到单用平阳霉素的1/16～1/43;异博定能增强平阳霉素对人喉癌细胞的毒性,原因之一是异博定促进了细胞对平阳霉素的吸收,使药物在细胞内的积聚增加,但对该药外排无显著影响.     

P-糖蛋白抑制剂维拉帕米对龙血素A、B、C在大鼠体内药物动力学影响

研究灌胃给予大鼠龙血竭后，P糖蛋白抑制剂维拉帕米对其有效成分龙血素A、B、C在大鼠血浆中的药物动力学影响.将SD大鼠随机分为对照组和抑制剂组并单次给药，对照组灌胃给予大鼠5 g/kg龙血竭，抑制剂组联合给予大鼠维拉帕米（1 mg/kg）和龙血竭（5 g/kg）.收集两组相同系列时间的血浆样本，采用HPLC-MS/MS的方法对龙血素A、B、C在大鼠血浆中的浓度测进行检测，求算两组血浆样本药物动力学参数.与对照组相比，抑制剂组大鼠龙血素A、B、C的血药浓度-时间曲线下面积分别增加109.4%，78.5%，22.8%，血药峰浓度分别增加69.6%，115.0%，42.1%，龙血素A、B的达峰时间均延长、龙血素C的达峰时间无变化，三者的生物半衰期（T_0.5）均变小，说明P糖蛋白抑制剂能够引起龙血素A、B、C在大鼠体内的血浆药物动力学参数变化，龙血素A、B、C均有可能为P糖蛋白的潜在底物.      

平阳霉素与异博定联合应用对肺纤维化的影响

研究了平阳霉素与异博定联合应用对小白鼠肺纤维化的影响,结果表明,异博定与平阳霉素联合应用,肺内病变有一定程度减轻,肺内毛细血管数量增加,使肺内血运量增强,药物在肺内积累减少,从而减低肺的毒性.     

Reversal Efficacy of SDZ-PSC833 and Verapamil on Drug-Resistant Human Cervical Carcinoma Cells Line

This article discusses the characteristics of the drugresistant human cervical carcinoma cell line HeLa/MMC and investigates reversal effect of SDZ-PSC833（PSC833） and Verapamil （Ver） upon HeLa/MMC. Relative content of cell DNA detection, H3-TdR incorporation test and drug-resistance have been experimented, meanwhile a tumor transplant model in the nude mice for Hela/MMC has been established. Then the volume of cancer, tumor weight, curve line of growing up in tumor -bearing nude mouse and its morphological variation of carcinoma organism are observed to evaluate the reversal effect of PSC833 and VER. It has been found that： （1） Compared with HeLa cells,subline HeLaJ MMC Cells＇ drug-resistant capability against Mitomycin（MMC） or cisplatin（DDP） is as 5.02 folds or 2 folds as that of the former, respectively. The Hela/MMC cell line has characteristics of multi- drug resistance and stronger multiplication; （2） PSC833 and VER can reverse resistance of HeLa/MMC to Mitomycin in vivo.PSC833 will be a better candidate for reversing multidrug resistant than verapamil in clinic application.     

Acute effects of adrenergic agents on post-defibrillation arrest time in a cultured heart model

Possible drug interactions with electrical defibrillation were examined. We tested the hypothesis that adrenergic agents (epinephrine, norepinephrine, isoproterenol) and a calcium channel blocker (verapamil), when applied acutely, alter the duration of arrest following a defibrillator shock. A secondary hypothesis (based on observations) was that the drugs alter the occurrence of changes to normal rhythms following the shock. Dissociated heart cells from 10-day chicken embryos were cultured to form spherical aggregates and plated in petri dishes. In the experiments, the spheres were paced at 0.75 V/cm above contraction threshold, and a biphasic defibrillator shock was applied for 1 ms at 46 V/cm. The arrest time and occurrence of rhythm changes were recorded. The adrenergic agents shortened the duration of arrest following a defibrillator shock, while the calcium channel blocker lengthened the arrest time. Comparisons with the control proportion of double beats showed no significant change with the adrenergic agents and a decrease with verapamil.Received 19 August 2004; received after revision 8 October 2004; accepted 18 October 2004     

Pharmacological manipulation of L-carnitine transport into L6 cells with stable overexpression of human OCTN2

The high-affinity Na+-dependent carnitine transporter OCTN2 (SLC22A5) has a high renal expression and reabsorbs most filtered carnitine. To gain more insight into substrate specificity of OCTN2, we overexpressed hOCTN2 in L6 cells and characterized the structural requirements of substances acting as human OCTN2 (hOCTN2) inhibitors. A 1905-bp fragment containing the hOCTN2 complete coding sequence was introduced into the pWpiresGFP vector, and L6 cells were stably transduced using a lentiviral system. The transduced L6 cells revealed increased expression of hOCTN2 on the mRNA, protein and functional levels. Structural requirements for hOCTN2 inhibition were predicted in silico and investigated in vitro. Essential structural requirements for OCTN2 inhibition include a constantly positively charged nitrogen atom and a carboxyl, nitrile or ester group connected by a 2-4-atom linker. Our cell system is suitable for studying in vitro interactions with OCTN2, which can subsequently be investigated in vivo.