结肠缺血再灌注损伤及乳酸盐和黄嘌呤氧化酶的测定

选择Ｓｐｒａｇｕｅ Ｄａｗｌｅｙ大鼠，建立右半结肠缺血再灌注动物模型。以组织中Ｅｖｅｎ蓝含量为指标，观察右半结肠缺血再灌注损伤。测定静脉血中乳酸盐浓度和结肠组织黄嘌呤氧化酶的活性。结果提示：右半结肠缺血时间越长，缺血再灌注损伤就越严重。造成损伤的主要原因包括缺血期间乳酸酸中毒，再灌注后的黄嘌呤氧化酶活性增加，氧自由基的大量生成。     

克霉唑抗大鼠肝缺血再灌注损伤机制研究

目的 研究孕烷X受体(pregnane Xreceptor,PXR)介导克霉唑抗大鼠肝缺血再灌注损伤作用及其机制.方法 SD大鼠随机分成4组,分别为假手术组、缺血再灌注组、克霉唑低剂量组和克霉唑高剂量组.以谷丙转氨酶(ALT)、谷草转氨酶(AST)、乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(G...     

克霉唑抗大鼠肝缺血再灌注损伤机制研究

目的研究孕烷X受体(pregnane X receptor,PXR)介导克霉唑抗大鼠肝缺血再灌注损伤作用及其机制。方法 SD大鼠随机分成4组,分别为假手术组、缺血再灌注组、克霉唑低剂量组和克霉唑高剂量组。以谷丙转氨酶(ALT)、谷草转氨酶(AST)、乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MDA)含量及热休克蛋白70(HSP70)蛋白表达等为观察指标,用终浓度分别为25 mg/kg和50 mg/kg的克霉唑预处理大鼠5 d,5 h后观察其对肝缺血再灌注损伤的作用。结果 PXR特异性强诱导剂克霉唑,与假手术组比,能明显诱导CYP3A1基因表达,表现为ALT、AST和LDH显著降低(P<0.05),且呈剂量依赖性,SOD和GSH-Px活性分别升高,MDA显著降低,对抗氧自由基ROS损伤,上调HSP70表达(P<0.05),表现出强大的抗缺血再灌注损伤作用。结论克霉唑预具有较好抗肝缺血再灌注损伤的保护作用,其机制可能在PXR介导下,拮抗ROS损伤及内源性保护蛋白HSP70表达上调有关。     

肝缺血再灌注脂质过氧化损伤及维生素C的保护作用

目的探讨维生素C(VitC)预防及治疗肝缺血再灌注脂质过氧化损伤的作用。方法制备家兔肝缺血再灌注模型 ,检测血浆及肝组织脂质过氧化产物丙二醛(MDA)和维生素E(VitE) ,动态观察肝形态学变化 ,并应用0.25g·kg-1VitC防治脂质过氧化损伤。结果肝缺血再灌注期间 ,MDA明显增高 ,VitE显著下降 ,肝形态学发生异常变化 ;缺血前及再灌注时应用VitC ,血、肝MDA均显著低于对照组 (P<0.01) ,VitE均明显高于对照组(P<0.01) ,肝形态学异常改变明显减轻。结论0.25g·kg-1VitC能抑制或减轻肝缺血再灌注脂质过氧化损伤。     

丹参抗脑缺氧缺血／再灌注损伤机制的实验研究进展

丹参在临床治疗上广泛应用于心、脑、肝缺血／再灌注损伤的保护、调节免疫应答、抗感染等。其已知的脂溶性成分有丹参酮Ⅰ、丹参酮Ⅱ-A、丹参酮Ⅱ-B等，具有清除自由基、抗炎和钙离子拮抗作用；水溶性成分有儿茶酚、丹参酚和丹参素等，具有抗氧化、改善微循环及抗凝等作用。近年来，丹参在脑缺氧缺血／再灌注损伤的神经保护作用机制     

钙离子在肝缺血再灌注损伤中的作用及丹参的抗损伤作用

通过肝左后叶和中叶组织缺血再灌注损伤模型，观察大白鼠在肝组织缺血４５ｍｉｎ和肝组织缺血４５ｍｉｎ后再灌注６０ｍｉｎ时的肝组织钙离子、血清中谷丙转氨酸的变化及肝病理结构、超微结构的改变。并在此基础上探讨了丹参的抗损伤作用，尤其是它的钙拮抗作用。     

NO在缺血再灌注损伤中的作用

1 NO的基本特性及作用 1980年Furchgott和Zawadzki报告内皮细胞(endothelial cell,EC)可产生一种因子,作用于平滑肌引起血管扩张,并命名为内皮源性舒张因子(endothelial derived relaxing factor,EDRF),进一步的研究表明EDRF就是一氧化氮(nitric oxide,NO)。基础状态下,EC可分别通过NADPH、Ca~(2+)/钙调素依赖的NO合成酶使L-精氨酸(Larginine,L-Arg)氨基端胍基脱氨氧化生成NO和L-瓜氨酸(L-citrulline,L-Cit),并在乙酰胆碱、缓激肽、A_(23187)等作用下通过增加细胞内钙离子浓度进一步增加NO的合成和释放。 EDRF的扩血管作用可能是通过平滑肌细胞(SMC)内环磷酸鸟苷酸(cGMP)含量增加来介导的,即EC释放EDRF,后者弥散到SMC,激活鸟苷酸环化酶,使细胞内cGMP含量升高,再经蛋白激酶G引起蛋白质磷酸化,介导平滑肌的松弛反应。外源性NO合成酶抑制剂N~G-monomethyl-L-arginine(L-NMMA)、N~G-nitro-L-arginine-methylester(L-NAME)可抑制NO的合成和释放,引起平滑肌收缩,补充合成NO所需的底物L-Arg或给予体内生理条件下自发特异形成NO的NO供体——硝普     

再灌注早期渐增灌注压力对缺血再灌注心肌保护作用的实验研究

目的 探讨心肌缺血后再灌注时渐增灌注压力是否具有与标准心肌缺血后处理相同的心肌保护用以及其机制.方法 观察持续缓慢升高灌注压力对缺血再灌注后心肌的冠脉流出液中cTnI含量及冠脉流量、心肌细胞超微结构变化的影响以及P-Akt的表达.结果 持续缓慢升压组能有效促进缺血再灌注心脏的冠脉流量恢复,冠脉流出液中cTnI含量减少,P-Akt高表达,同时电镜观察显示细胞超微损伤亦减轻.结论 持续缓慢升高灌注压力对离体缺血再灌注心脏具有保护作用,PI3K/Akt/GSK-3β通路可能是其心肌保护作用的信号传导通路之一.     

一氧化氮在肝脏缺血再灌注损伤中作用的实验研究

缺血再灌注（I／R）损伤临床上常见,本实验通过观察肝脏I／R前后亚硝酸盐含量及一氧化氮合成酶（NOS）活性的变化,以探讨NO在肝脏I／R损伤中的作用。材料与方法一、动物：雌性SD大鼠27只,体重150～2009,南京军区总医院实验动物中心提供,随机分为（l）假手术组;（2）缺血再灌注组;（3）L一精氨酸（L—Arg）组,每组9只。二、模型：大鼠禁食12／J‘时,戊巴比经30mg／kg腹腔麻醉,开腹暴露肛门部,假手术组仅作肛门部血管分离而不阻断,其他均以无损伤微动脉夹夹闭肝蒂,断流40分钟后再灌注60分钟。L－Arg组在再灌注时静脉推注…     

T型钙通道阻滞剂的临床应用进展

T型钙通道是一种低电压钙通道,在体内分布广泛,参与多种生理过程。T型钙通道阻滞剂是目前关注较多的一种新型钙通道阻滞剂,除具备与传统钙通道阻滞剂相似的降压作用外,还具有如降低心肌自律性、抗心肌重塑、保护肾功能、抗交感神经等药理作用。对T型钙通道阻滞剂的药理作用、药物相互作用与不良反应等研究进展进行综述,从而了解T型钙通道阻滞剂在临床实践中的应用现状,探索和开发其在临床实践中的新使用价值。     

Analgesic actions of the N-type voltage-dependent calcium channel blockers

OBJECTIVE The participation of N-type voltage-dependence calcium channel(N-VDCC) in pain transmission has been proved,and the analgesia of N-VDCC blokcers has also been confirmed.The aim of this study was to obtain the small molecular N-VDCC blockers with oral analgesic activity and tho investigate the characteristics of its analgesia.METHODS Taken NMED-160 and ZC88 as leading compounds,a series of candidates of non-peptide N-VDCC blockers were synthesized.The inhibition of these chemicals to N-VDCC currents was tseted by using two-electrode voltage-clamp technique,and the oral analgesic activity was detected by using the model of chronic construction injury of sciatic nerve(CCI) in rats,a classic model of neuropathic pain.Among these compounds,D304 was selected to further investigate its analgesic action by using a variety of acute and chronic pain models.RESULTS Among these compounds we synthesized,eight compounds displayed high activity of inhibiting N-VDCC currents,and D214 and D304,showed strong oral analgesic activity in the rat CCI model.According to these results,D304 was selected to further study its analgesic action.In the mouse 55℃ hot-plate model,D304 given by oral route(10,30,100 mg·kg-1) failed to observed significant analgesia,suggesting that D304 had no effect on the thermal-stimulated acute pain.In the rat formalin-induced persistent pain model,D304 administered orally(10,30,100 mg·kg-1) dose-dependently inhibited formalin-induced pain in phaseⅡ,rather than in phaseⅠ,with equivalent intensity of analgesia to positive control of NMED-160.In the rat complete Freund adjuvant-induced chronic inflammatory pain model,D304(10,30,100 mg·kg-1,po) dose-dependently inhibited mechanical-stimulated allodynia and thermal-stimulated hyperalgesia,and its analgesic strength was equal to or even slightly stronger than that of NMED-160.In the two classical peripheral neuropathic pain models-the rat CCI model and the rat diabetic peripheral neuropathic pain model,D304(10,30,100 mg·kg-1,po) dose-dependently inhibited mechanical-stimulated allodynia and thermal-stimulated hyperalgesia,and its analgesic strength was slightly stronger than that of NMED-160 or gabapentin.The preliminary safety evaluation showed that the LD50 of D304(po) was 570 mg·kg-1,and therapeutic index was about 10.CONCLUSIONTaken together,we designed and synthesized a series of samll molecular N-VDCC blockers with oral analgesic activity.Among these compounds,D304 had no significant analgesia to acute pain,but showed strong oral analgesic activity to persistent and chronic pain,especially to chronic inflammatory pain and neuropathic pain.This findings set up a foundation for the further research and development of samll molecular N-VDCC blockers with oral analgesic activity.     

Efficacy of calcium channel blockers as maintenance therapy for asthma

AIMS: Previous bronchoprovocation studies indicate that nifedipine attenuates airway responsiveness to several stimuli whereas diltiazem has no effect. The aim of this study was to determine whether such studies predict the efficacy of calcium channel blockers as maintenance therapy for persistent asthma. METHODS: Twenty-one otherwise healthy adults with persistent asthma, mean age 25 years, completed treatment with maximum tolerated doses of placebo (P), nifedipine (N), and diltiazem (D) in a double-blind, randomized, three-treatment, three-period, crossover manner, each for 4 weeks. Frequency and severity of asthmatic symptoms were recorded twice daily, as well as peak expiratory flow and frequency of 'prn' use of inhaled terbutaline. Blood pressure, heart rate, P-R interval of the ECG and spirometry were measured biweekly. At the end of each treatment, airway responsiveness to exercise was measured. RESULTS: The mean (s.e. mean)% of days with wheeze was 69plus minus7% during P, 75plus minus6% during N and 72plus minus6% during D (P=0.7). FEV1 was 79plus minus2% of predicted during P, 81plus minus2% during N and 79plus minus2% during D (P=0.6). The decrease in FEV1 after exercise was 32plus minus4% during P, 32plus minus5% during N and 27plus minus4% during D (P=0.5). Heart rate was elevated during N (P=0.0002) whereas P-R interval was prolonged during D (P=0.0001). CONCLUSIONS: Maintenance therapy with calcium channel blockers, at doses that produce cardiovascular effects, do not suppress the signs and symptoms of persistent asthma. Previous bronchoprovocation studies did not predict these results.     

Recent patents on calcium channel blockers: emphasis on CNS diseases

Introduction: Altered homeostasis of cell calcium movement is a central stage in multiple diseases of CNS. This explains the great therapeutic interest in blockers for the various subtypes of voltage-activated calcium channels (VACCs) expressed in neurons. Mitigation of Ca²⁺ entry excess elicited by those blockers may restore the altered synaptic transmission, synaptic plasticity and gene expression to normal parameters, ending the enhanced neuronal vulnerability.

Areas covered: This review summarize 23 patents on ligands for L-, N- or T-type channels, claimed to have potential therapeutic interest in epilepsy, pain, migraine and neurodegenerative diseases.

Expert opinion: Collections of compounds are generally screened in cell lines expressing a given subtype of VACCs. IC₅₀ to block such channels are often, but not always, provided. In few instances, compounds exhibiting the highest potency in in vitro experiments are also tested in animal models of pain, behavior, epilepsy or Alzheimer’s disease. Attempts to develop selectivity for a given VACC subtype with non-peptidic organic ligands have so far failed. Due to their wide tissue expression, such selectivity is crucial for minimizing possible side effects. However, the few data reported by patents does not allow prediction of selectivity of the new compounds in many cases.     

钙通道阻滞剂对大鼠肝细胞钙释放激活的钙电流的影响(英文)

目的:研究钙通道拮抗剂对大鼠肝细胞钙释放激活的钙电流(I_(CRAC))的影响,方法:应用全细胞膜片箝技术。结果:I_(CRAC)的电流峰值是(-0.41±0.09)nA(n=15),反转电位约为0 mV,维拉帕米(Ver),地尔硫(艹卓)(Dil)和硝苯地平(Nif)显著降低I_(CRAC),不影响它的反转电位,Ver 5 μmol·L~(-1)的抑制率是40％±12％(n=3),Ver 50 μmol·L~(-1)使,CRAC的幅值从(-0.49±0.12)nA降到(-0.20±0.09)nA(n=5,P<0.01),抑制率为57％±15％,Dil和Nif 50 μmol·L~(-1)分别从(-0.43±0.10)nA(n=5),(-0.32±0.08)nA(n=5)降到(-0.29±0.07)nA(P<0.01),(-0.27±0.08)nA(P<0.01),抑制率分别为31％±11％,19％±7％,I_(CRAC)的幅值大小依赖细胞外钙浓度。I_(CRAC)在含台氏液1.8 mmol·L~(-1)中电流幅值为(-0.21±0.08)nA(n=3,P<0.01),结论:这三种钙通道拮抗剂有效抑制,I_(CRAC)并且通过抑制I~(CRAC)减少肝细胞钙超载。     

Transdermal delivery of calcium channel blockers for hypertension

Introduction: Calcium channel blockers are a very important class of antihypertensive drugs. Most calcium channel blockers (CCBs) exhibiting low oral bioavailability are required to be taken more than once a day due to their short half-lives which result in poor patient compliance. There is an ineluctable requirement for improved drug-delivery devices for CCBs because of the quantum of their utilization and shortcoming associated with their conventional dosage forms.

Areas covered: There have been worthwhile research endeavors worldwide to investigate the skin permeation and to develop transdermal formulations of various categories of CCBs. This review explores the investigations on the feasibility and applicability of systemic delivery of various CCBs via skin.

Expert opinion: Transdermal delivery of CCBs has been particularly acknowledged as a potential drug-delivery route in the therapy of hypertension. Several overtures have been made to enhance delivery of these drugs via skin barrier. There have been remarkable research endeavors worldwide to investigate the skin permeation and to develop transdermal systems of various CCBs. Persistent advancement in this area holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.     

钙通道阻滞药与心肌顿抑

心肌顿抑是指短暂缺血后可逆性心肌收缩功能异常 ,是再灌注损伤的一种形式 ,临床上常出现该现象。钙通道阻滞药是心血管疾病常用药物 ,目前大量研究证明可以抑制心肌顿抑。本文综述了钙通道阻滞药治疗心肌顿抑的实验证据、理论基础以及在临床心肌顿抑中的应用等问题     

L-型钙通道阻断剂对曲马多镇痛作用的影响

目的　研究L 型钙通道阻断剂对曲马多镇痛作用的影响。方法　选用小鼠热板实验和醋酸扭体实验作为评价方法。腹腔注射曲马多观察该药在不同模型中的镇痛作用。维拉帕米 ,尼莫地平或硝苯地平分别与阈下剂量曲马多合用 ,观察这 3种L 型钙通道阻断剂对曲马多镇痛作用的影响。结果　热板实验中 ,曲马多 (10 ,2 0 ,4 0mg·kg-1)剂量依赖性地延长小鼠舔后足或跳跃的潜伏期 ;维拉帕米可增强曲马多的镇痛作用。醋酸扭体实验中 ,曲马多 (2 ,5 ,10mg·kg-1)显著减少小鼠扭体反应的次数 ;维拉帕米、尼莫地平和硝苯地平均可剂量依赖性地增强曲马多的镇痛作用。结论　L 型钙通道阻断剂维拉帕米、尼莫地平和硝苯地平对曲马多的镇痛作用有一定的增强作用。L 型钙通道介导的胞外钙内流可能参与了曲马多的镇痛机制     

Combination of calcium channel blockers and β-adrenoceptor blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers

AIMS: The combination of calcium channel blockers and beta-adrenoceptor blockers is more effective for the treatment of exercise-induced angina pectoris than beta-adrenoceptor blocker monotherapy. As ischaemia in exercise-induced angina is preceded by increase in heart rate, calcium channel blockers with negative chronotropic properties may perform better for this purpose than nonchronotropic compounds. METHODS: A 335 patient double-blind parallel-group study comparing 14 day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and mibefradil 50 and 100 mg added to baseline beta-adrenoceptor blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. RESULTS: Although none of the calcium channel blockers improved duration of exercise or amount of workload, all significantly delayed onset of 1 mm ST-segment depression on ETT (P<0.001 for any treatment vs baseline). In addition, mibefradil, both low and high dose treatment, produced the longest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively, P<0. 003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly correlated with the reduction in rate pressure product (RPP). Serious symptoms of dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19 patients on mibefradil withdrew from trial. CONCLUSIONS: Calcium channel blockers with negative chronotropic properties provide greater delay of ischaemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness attenuates this benefit.