EFFECT OF ELECTROACUPUNCTURE AND CALCIUM-CHANNEL INHIBITORS ON CYTOPLASMIC FREE CALCIUM CONCENTRATION OF MOUSE BRAIN CELLS

Objective: To study the effect of electroacupuncture (EA) and Verapamil and Nifedipine (calcium channel inhibitors) on free calcium concentrations of cells and intrasynaptosomes in hypothalamus (HT), periaqueductual grey matter (PAG) and hippocampus (HIP) of mice. Methods: The female ICR mice were randomly divided into control, EA, CaCl2 and CaCl2+EA groups (n=8 in each group). Pain threshold was detected by using radiation-heat irradiation-induced tail flick method. EA (8 Hz, a suitable stimulating strength, dense-sparse waves and duration of 30 min) was applied to“Shuigou” (水沟 GV 26) and “Chengjiang” (承浆CV 24). CaCl2 (10 μL, 0.2 μmol/L) was injected into the lateral cerebral ventricle of mice after EA. The concentrations of cytosolic free calcium ([Ca 2+]i) in HIP, PAG, HT cell suspension specimen and hippocampal intrasynaptosome suspension of mice were determined by the fluorescent calcium indicator Fura-2-AM and a spectrofluorometer. Results: During EA analgesia, the intracellular free [Ca 2+]i in HT and PAG specimens and intrsynaptosomal [Ca 2+]i of the 3 cerebral regions decreased considerably (P<0.05～0.01), but that in hippocampal cell suspension increased significantly (P<0.01) in comparison with control group. The concentrations of hippocampal intrasynaptosomal free [Ca 2+]i decreased significantly after adding Verapamil and Nifedipine to the extracted hippocampal intrasynaptosomal specimen. Microinjection of CaCl2 into lateral ventricle had no apparent influence on degree of analgesia (DA)% and intracellular and intrasynapsotomal [Ca 2+]i, but significantly lower DA% and reduce changes of cytosolic and intrasynaptosomal [Ca 2+]i induced by EA stimulation. Conclusion: Calcium ion in the neurons and intrasynaptosome of HT, PAG and HIP is involved in electroacupuncture analgesia.

Calcium channel blocker monotherapy versus combination with reninangiotensin system inhibitors on the development of new-onset diabetes mellitus in hypertensive Korean patients

Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.

Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitors

Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca^2＋ entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury site via an iPRECIO-@ pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery. In addition, all of the ion channel inhibitor treated rats were administered with calcium channel antagonist lomerizine hydrochloride. It is important to note that as a result of implantation of the particular pumps required for programmable delivery of therapeutics directly to the injury site, seromas occurred in a significant proportion of animals, indicating infection around the pumps in these animals. Improvements in visual function were observed only when treatment was delayed by 6 hours; phosphorylated Tau was reduced when treatment was delayed by 24 hours or 7 days. Improvements in structure of node/paranode of Ranvier and reductions in oxidative stress indicators were also only observed when treatment was delayed for 6 hours, 24 hours, or 7 days. Benefits of ion channel inhibitors were only observed with time-delayed treatment, suggesting that delayed therapy of Ca^2＋ ion channel inhibitors produces better neuroprotective effects on secondary degeneration, at least in the presence of seromas.

硝苯地平控释片联合盐酸贝那普利片治疗老年高血压临床效果的研究进展

随着社会与生活环境的不断改变,老年高血压的发病率也逐年攀升。硝苯地平控释片联合盐酸贝那普利片在老年高血压治疗方面受到普遍的关注以及重视,二者分别属于钙离子通道阻滞剂和血管紧张素转化酶抑制剂,发挥降压效果的机制也各不相同。对老年高血压患者联合应用上述两种药物进行治疗,可以发挥互相协同的降压效果,使患者的血压控制率得到明显提升,同时还能够有效地降低单一药物应用所导致的不良反应。本文综述近年在老年高血压患者的临床治疗过程中,联合应用硝苯地平控释片以及盐酸贝那普利片临床效果的研究进展。

跨膜蛋白16A及其抑制剂的研究进展

跨膜蛋白16A(TMEM16A)是一种具有电压依赖性的钙激活氯离子通道,广泛表达于癌细胞中。在多种癌症中,TMEM16A不仅可以调控癌细胞的增殖、侵袭和转移,还与癌症治疗的预后相关。近年来,TMEM16A以及TMEM16A抑制剂在癌症领域的相关研究不断深入。本文总结了近10年来的相关研究,旨在为今后TMEM16A抑制剂在癌症治疗中的临床应用提供新的治疗策略。

CALCIUM ANTAGONIST AND ENDOTHELIN IN THE ACUTE SPINAL INJURY

Objective Acute spinal injury(ASI) is a kind of disease commonly seen in the orthopedic department, with secondary pathological injury causing the delayed damage of tissue structure. This study is focused on finding the injury mechanism of endothelin and the relation with calcium in SCI, and developing an effective treatment of SCI through animal experiment for clinic application in the future. Methods ASI animal model with radioimmuological techniques are applied to examine the level of endothelin, and to flid the pathological changes under microscope and electron-microscope. Results The quantity of endothelin and calcium in the cell with 1, 4-dihydropyridine calcium channel inhibitor is decreased, as a result, depolarization was lightened. The mechanism delays the development of secondary injury significantly. Conclusion This type of treatment may be used in emergency for spinal cord injury ln order to protect the function and to gain much precious opportunity for spinal recovery and other treatment.

Effects of Ginkgo biloba extracts with mirodenafil on the relaxation of corpus cavernosal smooth muscle and the potassium channel activity of corporal smooth muscle cells

In this study, we investigated the effects of a combination of Ginkgo biloba extracts （GBE） and phosphodiesterase type 5 （PDE-5） inhibitors on the muscular tone of the corpus cavernosum and potassium channel activity of corporal smooth muscle cells. Strips of corpus cavernosum from male New Zealand white rabbits were mounted in organ baths for isometric tension studies. After contraction with 1 × 10^-5 mol I^-1 norepinephrine, GBE （0.01-1 mg ml^-1） and mirodenafil （0.01-100 nmol I^-1） were added together into the organ bath. In electrophysiological studies, whole-cell currents were recorded by the conventional patch-clamp technique in cultured smooth muscle cells of the human corpus cavernosum. The corpus cavemosum was relaxed in response to GBE in a dose-dependent manner （from 0.64%±8.35% at 0.01 mg ml^-1 to 52.28%±11.42% at 1 mg ml^-1）. After pre-treatment with 0.03 mg ml^-1 of GBE, the relaxant effects of mirodenafil were increased at all concentrations, After tetraethylammonium （TEA） （1 mmol I^-1） administration, the increased effects were inhibited （P〈0.01）. Extracellular administration of GBE increased the whole-cell K^＋ outward currents in a dose-dependent fashion. The increase of the outward current was inhibited by I mmol 1-1 TEA. These results suggest that GBE could increase the relaxant potency of mirodenafil even at a minimally effective dose. The K＋ flow through potassium channels might be one of the mechanisms involved in this synergistic relaxation.

钙调磷酸酶抑制剂致肾损伤的研究进展

钙调磷酸酶抑制剂(CNI)是一类应用广泛的免疫抑制剂,临床常用的有环孢素A和他克莫司。CNI通过抑制T细胞的活化、诱导T细胞凋亡及抑制多种免疫因子的表达等方式发挥免疫抑制作用,对系统性红斑狼疮、膜性肾病等自身免疫疾病有着显著的治疗效果。同时,CNI也存在致肾损伤的毒副作用。CNI可通过激活肾素-血管紧张素-醛固酮系统、破坏肾脏局部血管活性物质的平衡、促进氧化应激等多种方式对肾小球、肾小血管和肾小管及肾间质产生不同程度的损伤。尿视黄醇结合蛋白等生物标志物可能对早期检测CNI所致的肾损伤具有一定价值。钙离子通道拮抗剂则被认为是减轻CNI所致肾损伤的有效手段。本文旨在为应对CNI所致肾损伤提供理论依据和防治思路,促进临床中合理、安全地使用CNI。

Advances in Medical Treatment of Primary Aldosteronism

Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease

Background：Renin-angiotensin system inhibitor and calcium channel blocker （CCB） are widely used in controlling blood pressure （BP） in patients with chronic kidney disease （CKD）.We carried out a meta-analysis to compare the renoprotective effect of the combination of angiotensin-converting enzyme inhibitor （ACEI） or angiotensin receptor blocker （ARB） and CCB （i.e.,ACEI/ARB ＋ CCB） with ACEI/ ARB monotherapy in patients with hypertension and CKD.Methods：Publications were identified from PubMed,Embase,Medline,and Cochrane databases.Only randomized controlled trials （RCTs） of BP lowering treatment for patients with hypertension and CKD were considered.The outcomes of end-stage renal disease （ESRD）,cardiovascular events,BP,urinary protein measures,estimated glomerular filtration rate （GFR）,and adverse events were extracted.Results：Based on seven RCTs with 628 patients,ACEI/ARB ＋ CCB did not show additional benefit for the incidence of ESRD （risk ratio [RR] =0.84;95% confidence interval [CI]：0.52-1.33） and cardiovascular events （RR =0.58;95% CI：0.21-1.63） significantly,compared with ACEI/ARB monotherapy.There were no significant differences in change from baseline to the end points in diastolic BP （weighted mean difference [WMD] =-1.28 mmHg;95% CI：-3.18 to-0.62）,proteinuria （standard mean difference =-0.55;95% CI：-1.41 to-0.30）,GFR （WMD =-0.32 ml/min;95% CI：-1.53 to-0.89）,and occurrence of adverse events （RR =1.05;95% CI：0.72-1.53）.However,ACEI/ARB ＋ CCB showed a greater reduction in systolic BP （WMD =-4.46 mmHg;95% CI：-6.95 to-1.97）,compared with ACEI/ARB monotherapy.Conclusion：ACEI/ARB ＋ CCB had no additional renoprotective benefit beyond than what could be achieved with ACEI/ARB monotherapy.

不同种类降压药与骨质疏松症相关性研究进展

高血压和骨代谢在生理调节上有共同点,特定种类的降压药也可能影响骨密度或降低骨质疏松症相关骨折风险。虽然现有研究不足以明确哪类降压药对骨骼有益,但目前大部分研究支持血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂和β受体拮抗剂能够改善骨密度或降低骨折风险,袢利尿剂则增加骨折风险,而噻嗪类利尿剂和钙通道阻滞剂相关结论互相矛盾。基于高血压的高患病率及降压药的广泛使用,探讨不同种类降压药对骨骼的影响很重要。通过总结近年来关于不同种类降压药与骨质疏松症相关性研究,为易患骨质疏松症高危人群的高血压患者选择合适的降压药提供临床依据。

CCB及RAAS抑制剂降压治疗预防脑血管事件差异的真实世界研究

目的研究钙通道阻滞剂(CCB)及肾素-血管紧张素-醛固酮系统(RAAS)抑制剂降压治疗预防脑血管事件差异的真实世界。方法对915例高血压患者进行资料查看、筛选、分析,观察患者血压控制及终点事件发生情况,比较用药CCB、RAAS抑制剂对减少心脑血管事件效果的真实世界情况。结果随访时间2.0~6.5年,平均随访时间4.5年。915例高血压患者中,482例患者采用单一CCB治疗,433例患者采用单一RAAS抑制剂治疗。用药CCB患者收缩压降低幅度略大于用药RAAS抑制剂患者,舒张压降低幅度略小于用药RAAS抑制剂患者,但差异无统计学意义(P>0.05);随访至终点时,用药CCB患者脑卒中发生率为5.60%(27/482),低于用药RAAS抑制剂患者的6.47%(28/433),经R语言生存分析差异具有统计学意义(P=0.016<0.05)。用药CCB患者心肌梗死发生率为2.90%(14/482),高于用药RAAS抑制剂患者的2.31%(10/433),经R语言生存分析差异无统计学意义(P=0.920>0.05)。用药CCB患者总死亡率为4.56%(22/482),用药RAAS抑制剂患者总死亡率为4.62%(20/433),经R语言生存分析差异无统计学意义(P=0.872>0.05)。结论CCB降压治疗预防脑卒中的效果优于RAAS抑制剂,显示CCB对脑卒中的一级预防具有更多的优势。

宫缩抑制剂:钙通道阻滞剂的益处和风险

早产是造成婴儿发病率和死亡率增长的一个主要原因。各种宫缩抑制剂研究的目的是预防早产的发生,增加分娩时的胎龄,并预防与早产相关的并发症。本文旨在总结抗宫缩药的主要类别,并回顾与归纳相关研究资料。总结非甾体类消炎药、钙通道阻滞剂、硫酸镁和β2肾上腺素能受体激动剂的益处和风险。钙通道阻滞剂在延长妊娠期和降低新生儿发病率和死亡率方面有较好的疗效,并且不良反应也最小。宫缩抑制剂,尤其是钙通道阻滞剂,可能对孕妇及其婴儿有益。它们的使用应针对患者的具体情况具体分析,并与其他治疗策略结合使用。例如,使用糖皮质激素促进胎儿肺成熟或使用硫酸镁进行神经保护并转移到三级医疗中心救治。期望本研究可以促使妇产科医生、家庭医生能够更好地明确主要类别的宫缩抑制剂以及作用机制,并根据有关潜在益处和风险选择合适的宫缩抑制剂。

VASORELAXANT DITERPENES: FROM TRADITIONNAL MEDICINE TO NEW INHIBITORS OF VOLTAGE-DEPENDANT CALCIUM CHANNELS

Croton zambezicus Muell.Arg.(Euphorbiaceae)(Syn.C.amabilis Muell.Arg.,C.gratissimus Burch.)is a shrub or small tree reaching 10 m in height.The leaf decoction is used in Benin as anti-hypertensive,anti-microbial(urinary infections)and to treat fever associated with malaria.We analysed the in vitro and in vivo vasorelaxant activity

西洋参茎叶皂甙对兔主动脉条收缩反应的影响

西洋参茎叶皂甙１．２ｍｇ／ｍｌ对ＮＥ，ＫＣｌ，ＣａＣｌ２收缩兔主动脉条的量效曲线呈非竞争性拮抗，并能明显抑制ＮＥ引起的主动脉条依细胞内及细胞外Ｃａ２＋收缩。其作用性质与维拉帕米相似。

失血性休克引起大鼠肠系膜动脉平滑肌依钙K^+通道活动改变

在由股动脉放血制备的失血性休克大鼠模型急性分离的肠系膜动脉平滑肌细胞上 ,利用膜片箝单通道记录技术观察了血管平滑肌依钙K+通道 (BKCa)的活动。发现在对去甲肾上腺素 (NE)反应性增高的休克代偿期 ,BKCa的开放概率 (Po)和单位电导都显著较正常动物的低 ,Po 的改变主要是由通道的慢关闭时间常数 (τcs)增大引起关闭时间延长所致 ;而处于对NE反应性降低的休克失代偿期 ,BKCa的Po 和单位电导都高于正常动物 ,Po的变化也主要是τcs减小所致。

鞘内注射米贝地尔抑制慢性坐骨神经结扎大鼠机械痛敏和热痛敏

目的:观察脊髓水平T型钙通道阻滞剂米贝地尔(m ibefrad il)对坐骨神经慢性松结扎(CCI)大鼠机械和热痛阈的影响,探讨脊髓T型钙通道在伤害性信息传递中的作用。方法雄性SD大鼠48只,随机分为6组(n=8):假手术组(Sham),CCI组,CCI+生理盐水组,CCI+米贝地尔50μg、100μg、200μg组。CCI组和Sham组在术前、术后1 d、3 d、5 d、7 d、14 d、21d测定大鼠机械缩腿阈值(MWT)和热缩腿潜伏期(TWL);其余各组大鼠在手术前5天先进行鞘内置管,在术前测定基础MWT和TWL,CCI手术后5 d鞘内注射不同剂量的米贝地尔,测定给药前、给药后0.5 h、1 h、2 h、4h、8 h大鼠MWL和TWL。结果:CCI组从术后3 d开始直到本实验观察的术后21 d,MWT和TWL均明显降低,与Sham组相比具有显著性意义(P<0.01);CCI加生理盐水组大鼠在各个时间点上与给药前相比MWT和TWL无明显改变(P>0.05);CCI加米贝地尔各个剂量组大鼠在给药后MWT和TWL均逐渐增加,具有剂量依赖性,并随时间的延长又逐渐恢复到给药前水平,CCI+米贝地尔200μg在给药后1 h时作用最明显,与给药前和盐水组相比P<0.01,并一直持续到给药后4h。结论:鞘内注射米贝地尔能明显减轻慢性坐骨神经松结扎大鼠机械痛敏和热痛敏,提示T型钙通道在脊髓水平参与疼痛信息传递。

新型脑、心血管活性药——法舒地尔

法舒地尔是目前唯一临床可用的Rho激酶抑制剂暨新型细胞内Ca2+拮抗剂,能强效扩血管、保护缺血脑组织,临床主要用于蛛网膜下腔出血手术后脑血管痉挛、脑缺血等的防治。鉴于Rho蛋白／Rho激酶系统在细胞分子水平生命活动中的重要意义,近年来,对法舒地尔的研究不断深入,其脑、心血管系统保护作用尤其明了。该药更多的适应证已处于临床试验后期中,有望成为颇具前景的新型脑、心血管活性药物。

内皮祖细胞——抗动脉粥样硬化药物的新靶点

内皮祖细胞(endothelial progenitor cells,EPCs)是存在于骨髓、脐血和外周血的一种具有高增殖潜能的前体细胞,在一定条件下可诱导分化为成熟的血管内皮细胞。研究表明,EPCs可促进血管内皮修复和新生血管形成,其功能受损与动脉粥样硬化(atherosclerosis,AS)的发生和发展密切相关。因此,EPCs功能变化可作为心血管疾病的预测因子。大量研究证明,多种药物可通过调节EPCs功能进而起到抗AS的作用。本文综述EPCs在AS的作用及药物对EPCs功能的影响,探讨EPCs作为AS治疗手段和靶点的可行性及存在的问题。

胆固醇脂质体对兔胆道口平滑肌收缩性的影响

目的研究兔胆道口括约肌(sphincter of Oddi,SO)平滑肌细胞在胆固醇脂质体作用后收缩性的变化,探讨高胆固醇血症兔SO 动力异常的机制方法取纯种新西兰兔 SO 段,用Ⅱ型胶原酶消化获得单个平滑肌细胞,与胆崮醇/卵磷脂摩尔比为2:1和0.5:1的胆固醇脂质体(1g/L)分别孵育2 h 后,用不同浓度 KCl(9-24)nmol/L,乙酰胆碱(10^(12)～10^(-6))mol/L 作用于平滑肌细胞,激动剂作用后30s,加入丙烯醛固定,分别测量各组细胞的收缩百分比.结果兔 SO 平滑肌细胞平均长度为(143.7±12.3)μm,经胆固醇脂质体作用后平均长度无明显变化,对 KCl 和乙酰胆碱呈浓度依赖性收缩.KCl(18mmol/L)诱导最大收缩比为22.2%±0.7%,而2:1的胆固醇脂质体作用后收缩比为16.5%±0.6%(P<0.01);乙酰胆碱(10^(-7)mol/L)诱导最大收缩比为20.3%±1.4%,2:1的胆固醇脂质体作用后收缩比为16.5%±1.3%(P<0.05).摩尔比为0.5:1胆固醇脂质体作用后最大收缩比分别为21.3%±1.4%和19.2%±1.1%,同对照组相比无显著下降.结论兔 SO 平滑肌细胞经摩尔比2:1的胆固醇脂质体后起收缩性下降,推测这是高胆固醇血症可以导致兔 SO 的动力异常的机制.