Calcium channel blockers and Alzheimer's disease

Alzheimer＇s disease is characterized by two pathological hallmarks： amyloid plaques and neurofibrillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer＇s disease. Calcium channel blockers are effective therapeutics for treating Alzheimer＇s disease. This review provides an overview of the current research of calcium channel blockers involved in Alzheimer＇s disease theraov.

Antineoplastic Effect of Calcium Channel Blocker-Verapamil and 5-Fluorouracil Intraperitoneal Chemotherapy on Hepatocarcinoma-Bearing Rats

Objective To study the antineoplastic effect of the calcium channel blocker verapamil and 5-fluorouracil intraperitoneal chemotherapy on hepatocarcinoma-bearing rats,and examine the action between calcium channel blockers and cytotoxic drugs. Methods We adopted the method of subcapsular implantation of carcinoma tissues of walker-256 in the left liver lobe as a model of liver carcinoma-bearing rats.All experimental animals were divided into four groups.On the sixth day post implantation,in group A (control group) 6ml of saline was injected intraperitoneally once a day for 3 days.In group B(single chemotherapy group) 6ml of 5-Fu 75 mg/kg was injected intraperitoneally once a day for 3 days.In group C(combination of treatment group)both 5-Fu(75mg/kg) and verapamil (25mg/kg) were administered simultaneously as in A and B.In group D(simple verapamil group)only 6ml of verapamil(25mg/kg)was administered as above. Results Compared with groups A, B and D,The volume of cancer and the contents of liver cancer DNA and protein were significantly reduced.The rates of inhibiting cancer(89.9% in group C and 35.4% in group B)were significantly increased in groupC. Group C had significantly long survival time compared to groups A, B and D(P<0.05).By light microscopy, a number of focal necroses were found in cancer tissue in group C.Conclusion Calcium channel blockers can enhance the antineoplastic effect of 5-Fu intraperitonea chemotherapy to liver cancer;The use of verapamil can not increase the toxicity of 5-Fu.

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.

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.

ORIGINAL ARTICLES CALCIUM CHANNEL BLOCKERS IN CIRRHOTIC PATIENTS WITH PORTAL HYPERTENSION

Four calcium channel blockers, i.e. nifedipine, verapamil, cinnarizine and tetrandrine are currently available and used widely in treating cardiovascular diseases. To confirm the effects, if any, of calcium channel blockers on cirrhotic patients with portal hypertension, a study was performed on esophageal variceal pressure and rebleeding rate of esophageal varices after 2 years by using calcium channel blocker in 321 patients from some 23 hospitals. The results demonstrated that the calcium channel blockers could significantly reduce the esophageal variceal pressure and the portal blood flow in cirrhotic patients with portal hypertension. The proportion of patients with no recurrent gastrointestinal bleeding after 2 years medication of tetrandrine was 87.9% in tetrandrine group, significantly higher than those in the other 4 groups (P<0.05). It is suggested that tetrandrine should be more effective for cirrhotic patients with portal hypertension in preventing recurrent variceal bleeding.

Adjuvant role of a T-type calcium channel blocker, TTA-A2, in lung cancer treatment with paclitaxel

Aim:Chemoresistance is a prevalent issue in cancer treatment.Paclitaxel(PTX)is a microtubule-binding anticancer drug used in various cancer treatments.However,cancer cells often show chemoresistance against PTX with the help of P-glycoprotein(Pgp)-a drug efflux pump.It has also been observed that overexpressed T-type calcium channels(TTCCs)maintain calcium homeostasis in cancer cells,and calcium has a role in chemoresistance.Therefore,the aim of this study was to test the adjuvant role of TTA-A2,a TTCC blocker,in enhancing the anticancer effect of PTX on the A549 lung adenocarcinoma cell line.Methods:Morphology assay,calcium imaging assay,clonogenic assay,apoptosis assay,and real-time polymerase chain reaction(real-time PCR)were performed to find the adjuvant role of TTA-A2.Samples were treated with PTX at 10 nM concentration and TTA-A2 at 50 and 100 nM concentrations.PTX and TTA-A2 were used in the combination treatment at 10 and 100 nM concentrations,respectively.Results:Immunocytochemistry confirmed the expression of TTCC in A549 cells.Morphology assay showed altered morphology of A549 cells.The adjuvant role of TTA-A2 was observed in the calcium imaging assay in spheroids,in the clonogenic assay in monolayers,and in the apoptosis assay in both cultures.With real-time PCR,it was observed that,even though cells express the mRNA of Pgp,it is non-significant upon treatment with PTX and TTA-A2.Conclusion:TTA-A2 can be used as an adjuvant to reduce chemoresistance in cancer cells as well as to enhance the anticancer effect of the standard anticancer drug PTX.Being a potent TTCC inhibitor,TTA-A2 may also enhance the anticancer effects of other anticancer drugs.

Effect of Calcium Ionophore and Calcium Channel Blockers on Immediate Hypersensitivity Reactions

The release of mediators from mast cells is a model for cell secretion and is an in-vitro index for immediate hypersensitivity reactions. Calcium influx is generally accepted to be the primary biochemicalevent in mast cell activation.We studied the effect of the calcium ionophore A 23187 and calcium channelblockers,nifedipine and verapamil, in triggering the activation of rat peritoneal mast cells.At suitableconcentration nifedipine and verapamil have had the inhibition effect in the IgE-dependent roaction.

Calcium channel blockers improve prognosis of patients with coronavirus disease 2019 and hypertension

Background:Hypertension is considered an important risk factor for the coronavirus disease 2019(COVID-19).The commonly anti-hypertensive drugs are the renin-angiotensin-aldosterone system(RAAS)inhibitors,calcium channel blockers(CCBs),and beta-blockers.The association between commonly used anti-hypertensive medications and the clinical outcome of COVID-19 patients with hypertension has not been well studied.Methods:We conducted a retrospective cohort study that included all patients admitted with COVID-19 to Huo Shen Shan Hospital and Guanggu District of the Maternal and Child Health Hospital of Hubei Province,Wuhan,China.Clinical and laboratory characteristics were extracted from electronic medical records.Hypertension and anti-hypertensive treatment were confirmed by medical history and clinical records.The primary clinical endpoint was all-cause mortality.Secondary endpoints included the rates of patients in common wards transferred to the intensive care unit and hospital stay duration.Logistic regression was used to explore the risk factors associated with mortality and prognosis.Propensity score matching was used to balance the confounders between different anti-hypertensive treatments.Kaplan-Meier curves were used to compare the cumulative recovery rate.Log-rank tests were performed to test for differences in Kaplan-Meier curves between different groups.Results:Among 4569 hospitalized patients with COVID-19,31.7%(1449/4569)had a history of hypertension.There were significant differences in mortality rates between hypertensive patients with CCBs(7/359)and those without(21/359)(1.95%vs.5.85%,risk ratio[RR]:0.32,95% confidence interval[CI]:0.13–0.76,χ^(2)=7.61,P=0.0058).After matching for confounders,the mortality rates were similar between the RAAS inhibitor(4/236)and non-RAAS inhibitor(9/236)cohorts(1.69% vs.3.81%,RR:0.43,95% CI:0.13–1.43,χ^(2)=1.98,P=0.1596).Hypertensive patients with beta-blockers(13/340)showed no statistical difference in mortality compared with those without(11/340)(3.82% vs.3.24%,RR:1.19,95% CI:0.53–2.69,χ^(2)=0.17,P=0.6777).Conclusions:In our study,we did not find any positive or negative effects of RAAS inhibitors or beta-blockers in COVID-19 patients with hypertension,while CCBs could improve prognosis.

Inhibition of calcium channel blocker associated with lowering C-reactive protein level in rupture of abdominal aortic aneurysm

Background As to abdominal aortic aneurysm （AAA） disease, our major challenge faced in clinical practice is effective drug therapies to prevent rupture of AAA. At present, there wasn’t definite evidence that other drugs had a role in inhibiting AAA rupture except for beta blocker. In our study, we evaluated the role of calcium channel blocker （CCB） played in prevention of AAA rupture. Methods A total of 460 subjects with AAA, aged 29 to 89 years, at least twice admitted into our hospital from January 2000 to April 2010. All of them accepted ultrasound examination for scanning abdominal aortic aneurysm at each admission period. Results Our results revealed that AAA patients suffered from rupture took little CCB and beta-blockers. Treatment with CCB or beta blocker was negatively related to risk of rupture of abdominal aortic aneurysm, and drugs such as statins, angiotensin II receptor blocker （ARB） or angiotensin-converting enzyme inhibitor （ACEI） hadn’t positive or negative effect on AAA. C reactive protein level was lower in patients with taking CCB than those without CCB. Conclusions CCB therapy was negatively related to AAA rupture, and possibly was another kind of drug for.

Applying Theoretical Approach for Predicting the Selective Calcium Channel Blockers Pharmacological Parameter by Biopartitioning Micellar Chromatography

为预言口头的药的 biopartitioning micellar 层析(BMC ) 的实用性尖锐毒性和明显的 bioavailability 被表明。一个对数的模型(一个 LD50 模型) 和第二个顺序多项式模型(明显的 bioavailability 模型) 用选择的钙隧道 blockers 的保留数据被获得了预言混合物的药理学性质。BMC 的使用简单，可再现并且能在药发现过程期间关于尖锐毒性和新混合物的运输性质提供关键信息。

Argemone mexicana extract alleviates gastrointestinal disorders by stimulating muscarinic receptors and blocking voltage-gated L-type calcium channels

Objective:To investigate the pharmacological potential of Argemone mexicana in treating constipation and emesis by using in vitro and in vivo models.Methods:The spasmogenic and spasmolytic effects were evaluated on isolated rabbit jejunum fragments loaded in a tissue organ bath.The response was recorded with an isotonic transducer attached with Power Lab Data Acquisition System.The laxative and antiemetic activities were assessed in BALB-c mice and poultry chicks challenged with carbamylcholine and copper sulphate stimulated emesis,respectively.Results:The total phenolic and total flavonoids contents of the extract were(267.75±5.77)mg GAE/g and(73.86±6.01)mg QE/g,respectively.Argemone mexicana extract exerted spasmogenic effect on isolated rabbit jejunum segments with an EC_(50)value of 0.016 mg/m L,which was blocked by atropine(0.3μM).Argemone mexicana extract exerted spasmolytic effect in atropine treated jejunum fragments with an EC_(50)value of 2.185 mg/mL.Furthermore,Argemone mexicana extract relaxed potassium(80 mM)-induced contractions(EC_(50):9.07 mg/mL),similar to a standard drug verapamil.The calcium channel blocker activity was confirmed by a rightward shift of concentration-response curve of calcium in the presence of Argemone mexicana extract(1-5 mg/mL)and verapamil(0.1-1μM).In addition,the extract increased the distance travelled by a charcoal in the gastrointestinal tract and exhibited antiemetic effect on copper sulphate induced emesis in chicks.Conclusions:Argemone mexicana shows cholinergic agonist and calcium channel blocker activities,as well as antiemetic effect.It may be used as a potential agent for treating gastrointestinal disorders.

Calcium Signaling is Involved in Negative Phototropism of Rice Seminal Roots

Calcium ions （Ca2＋） act as an intracellular second messenger and affect nearly all aspects of cellular life. They are functioned by interacting with polar auxin transport, and the negative phototropism of plant roots is caused by the transport of auxin from the irradiated side to the shaded side of the roots. To clarify the role of calcium signaling in the modulation of rice root negative phototropism, as well as the relationship between polar auxin transport and calcium signaling, calcium signaling reagents were used to treat rice seminal roots which were cultivated in hydroculture and unilaterally illuminated at an intensity of 100-200 pmol/（m2.s） for 24 h. Negative phototropism curvature and growth rate of rice roots were both promoted by exogenous CaCI2 lower than 100 pmol/L, but inhibited by calcium channel blockers （verapamil and LaCI3）, calcineurin inhibitor （chlorpromazine, CPZ）, and polar auxin transport inhibitor （N-l-naphthylphthalamic acid, NPA）. Roots stopped growing and negative phototropism disappeared when the concentrations increased to 100 pmol/L verapamil, 12.500 ~Jmol/L LaCI3, 60 pmol/L CPZ, and 6 pmol/L NPA. Moreover, 100 pmol/L CaCI2 could relieve the inhibition of LaCI3, verapamil and NPA. The enhanced negative phototropism curvature was caused by the transportation of more auxin from the irradiated side to the shaded side in the presence of exogenous Ca2＋. Calcium signaling plays a key role as a second messenger in the process of light signal regulation of rice root growth and negative phototropism.

钙通道阻滞剂1,4-二氢吡啶类药物的绿色合成

心脏及心脑血管疾病是发达国家人群的第一死因,也是中国人死亡的首位原因.L-型钙通道是目前临床上主要使用选择性钙通道阻滞剂1,4-二氢吡啶类药物.文章研究了在非均相催化剂离子交换树脂Amberlyst 15的催化以及无溶剂条件下,高效的合成了钙通道阻滞剂1,4-二氢吡啶类药物.该反应体系具有原料便宜、反应时间短、操作及后处理简单、催化剂可回收利用、反应可放大等优良特点.

钙通道阻滞剂对未破裂颅内动脉瘤影响的研究进展

未破裂的颅内动脉瘤是一颗埋在患者体内的定时炸弹,这类患者往往伴有高血压病。除去多数研究已证实的促破裂危险因素以外,复杂的血流动力学、炎症因素以及未控制的高血压也增加了其破裂风险。作为临床常用的抗高血压药物,钙通道阻滞剂被发现在促破裂进程中可以发挥保护作用,但也有研究发现了不同甚至矛盾的结果。本文就动脉瘤破裂的危险因素、钙通道阻滞剂使用对瘤体破裂的影响以及发挥的双重效应作一综述。

钙离子通道阻滞剂在慢性疼痛患者中临床应用的研究进展

现代医学将疼痛列为继呼吸、脉搏、血压、体温后的第五生命体征,足见其在人体健康中的重要性。慢性疼痛是指超过正常愈合时间(一般指3个月)持续存在的自觉疼痛感,相对于急性疼痛而言,慢性疼痛一般会涉及生理或神经系统,并可能会影响身体的多个方面。由于受到发病机制复杂、个体差异大以及神经可塑性等因素的影响,慢性疼痛的治疗难度相对较大。药物治疗是慢性疼痛管理中的常用手段,关于药物的选择或配伍也一直是临床研究的热点。本文综述了钙离子通道阻滞剂在慢性疼痛中的应用,旨在为疾病的治疗提供参考。

Effects of 2-APB on Store-operated Ca^(2+) Channel Currents of Hepatocytes after Hepatic Ischemia/Reperfusion Injury in Rats

The effects of hepatic ischemia/reperfusion (I/R) injuries on hepatocellular viability and store-operated calcium current (Isoc) in isolated rat hepatocytes and the effects of 2-APB on store-operated calcium current (Isoc) in isolated rat hepatocytes after hepatic ischemia/reperfusion injuries were studied. Hepatic ischemia and reperfusion injury model was established and whole cell patch-clamp techniques were used to investigate the effects of 2-APB on Isoc. The results showed that ischemia/reperfusion injuries could significantly reduce hepatocellular viability and further increase Isoc in hepatocytes and 2-APB (20, 40, 60, 80, 100 μmol/L) produced a concentration-dependent decrease of Isoc with IC 50 value of 64.63±10.56 μmol/L (n=8). It was concluded that ischemia/reperfusion injuries could reduce hepatocellular viability, probably through increased Isoc in hepatocytes and 2-APB had a protective effect on ischemia/reperfusion-induced liver injury, probably though inhibiting Isoc.

Pharmacological Investigation of Voltage-dependent Ca^(2+) Channels in Human Ejaculatory Sperm in vitro

The types of the voltage-dependent calcium channels （VDCCs） in human ejaculatory sperm and the effects of calcium channel blocker （CCB） on human sperm motility parameters in vitro were investigated. The human sperm motility parameters in vitro in response to the pharmacological agents nifedipine （NIF, inhibitor of L-type VDCC） and ω-conotoxin （GVIA, inhibitor of N-type VDCC） were compared and analyzed statistically. The results showed that NIF （1, 5, 10 μmol/L） could not only significantly affect human sperm＇s shape but also spermatozoa motility after incubated at least 10 rain in vitro （P〈0.001）. GVIA （0.1, 0.5 and 1 μmol/L） could just only significantly affect human sperm＇s progressive motility （a %＋b %） after incubated for 20 min in vitro （P〈0.01）, but they both could not significantly affect spermic abnormality rate. It is suggested that L-type VDCC, non L-type VDCCs and isoform of L-type VDCC exist in the cell membrane of human sperm solely or together, and they participate in the spermic physiological processes especially the spermic motility.

Effects of Tetrandrine on Cytosolic Free Calcium in Cultured Bovine Aortic Smooth Muscle Cells

利用Ｆｕｒａ２技术和ＡＲＣＭＭＩＣ阳离子系统研究了粉防己碱对传代培养牛主动脉血管平滑肌细胞内游离钙的影响。粉防己碱（１～１００μｍｏｌ·Ｌ－１）不影响血管平滑肌细胞的静息钙，但在有胞外钙存在时，对高钾，５羟色胺，ＡＴＰ，血管紧张素Ｉ，去甲肾上腺素引起的胞内钙升高有抑制作用；在无胞外钙存在时，粉防己碱对苯肾上腺素引起的胞内钙升高也有一定的抑制作用。粉防己碱对高钾升高内钙的抑制作用呈剂量依赖性，ＩＣ５０值为９．２（９５％可信限：５．７～１４．９）μｍｏｌ·Ｌ－１。上述结果提示粉防己碱对血管平滑肌细胞的电压依赖性钙通道和受体调控性钙通道均有阻滞作用，对受体调控性钙通道阻滞作用主要表现为阻滞钙离子内流。

The effect of calcium-antagonist on Bcl-2 and Bax mRNA expression following ischemic brain injury

AIM:In order to explore whether the member of Bcl-2 gene family,for example,B cl-2 and Bax,are induced after cerebral ischemia,and whether expression of gene s can be modulated by calcium-antagonist.METHODS:The rat cerebral ischemic mode ls were made by Nagasawa and Zea Longa improvement method,by occluding left midd le cerebral artery;the expression of Bcl-2 and Bax mRNA were measured by RT-PC R method.RESULTS:After administration of nimodipine, Bcl-2 mRNA was up-regulat ed in the hippocampus at 6 and 24 h after ischemia,while Bax mRNA was down-regu lated at 6 and 24h after ischemia.CONCLUSION:Calcium-antagonist can up-regulat e Bcl-2 mRNA and down-regulate Bax mRNA.Increasing the ratio of Bcl-2 and Bax mRNA may contribute to the anti-apoptic effect of nimodipine.