胍丁胺抑制兔房室结细胞的自发活动(英文)

目的:研究胍丁胺(Agm)对兔房室结细胞自发活动的影响及其作用机制.方法:应用玻璃微电极方法.结果:Agm不仅剂量依赖地抑制兔房室结细胞自发活动的V_(max),APA和VDD,RSF;而且延长APD_(90);idazoxan能明显抑制Agm的作用;而L-NAME不能影响Agm的作用;提高灌流液中的Ca~(2 )浓度可对抗Agm的作用;ATP-敏感性钾通道开放剂(lemakalim)可拮抗Agm延长APD_(90)的作用.结论:Agm对房室结细胞自发活动的抑制作用由咪唑啉受体和/或肾上腺素α_2-受体介导,并与Ca~(2 )内流和K~ 外流减少有关.     

植物性雌激素金雀异黄素对家兔窦房结起搏细胞的电生理效应

目的:研究植物性雌激素金雀异黄素(genistein,GST)对家兔窦房结起搏细胞的电生理效应及其作用机制.方法:应用经典玻璃微电极方法.结果:GST(10-150μmol/L)不仅以剂量依赖性方式抑制窦房结起搏细胞的零相最大上升速度(V_(max)),舒张期除极速度(VDD),起搏放电频率(RPF)和动作电位幅度(APA),而且延长复极化90％时间(APD_(90)).提高灌流液中钙离子浓度以及应用L型钙通道开放剂Bay K8644(0.5μmol/L)均可逆转GST对起搏细胞的上述电生理效应,但NO合酶阻断剂L-NAME(1 mmol/L)对GST的效应并无影响.结论:GST对家兔窦房结具有负性变时作用,并可延长复极化时程.这些效应可能与其抑制钙离子内流及钾离子外流有关.     

辣椒素对家兔窦房结起搏细胞的电生理效应

目的:研究辣椒素对离体家兔窦房结起搏细胞的电生理效应及其作用机制。方法:应用经典玻璃微电极方法。结果:辣椒素(10 μmol/L)使窦房结起搏细胞的零相最大上升速度(V_(max))由(2.4±0.5)V/s降至(1.7±0.2)V/s(P<0.05);舒张期除极速度(VDD)由(91±34)mV/s降至(70±30)mV/s(P<0.01);起搏放电频率(RPF)由(186±14)beat/min降至(162±10)beat/min(P<0.01);最大舒张电位(MDP)绝对值由(49±3)mV降至(44±2)mV(P<0.01);动作电位幅度(APA)由(55±4)mV降至(49±4)mV(P<0.05)。复极化90％时间(APD_(90))则由(149±21)ms延长至(167±27)ms(P<0.01)。应用辣椒素受体阻断剂钌红(10 μmol/L)对辣椒素的上述电生理效应无影响。提高灌流液中钙离子浓度(5 mmol/L)以及应用L型钙通道开放剂Bay-K-8644(0.5μmol/L)均可抑制辣椒素对起搏细胞的电生理效应。β-肾上腺素能受体激动剂异丙肾上腺素(20 nmol/L)可逆转辣椒素所引起的除极化时间延长和MDP的降低。结论:辣椒素对家兔窦房结细胞有负性变时作用,这些效应可能与其抑制钙离子内流及/或钾离子外流有关,而非由辣椒素受体介导。     

内源性腺苷和K_(ATP)通道介导缺氧窦房结起搏细胞的电生理效应(英文)

目的:观察腺苷脱氨酶(ADase),8-苯茶碱(8-PT)和格列苯脲(Gli)在豚鼠缺氧窦房结起搏细胞的电生理效应.方法:以充有100％氮和无糖的K-H液灌流豚鼠窦房结20 min引起其缺氧.用玻璃微电极技术记录起搏细胞的MDP,APA,APD_(90),V_(max),RPF和VDD等动作电位参数.结果:缺氧增加起搏细胞APA,MDP和V_(max),但减小VDD和RPF.Adase 10 U·L~(-1),8-PT 0.1 μmol·L~(-1)和Gli10 μmol·L~(-1)明显缓解缺氧引起的电生理效应. 结论:内源性腺苷和KATp通道在缺氧所致窦房结起搏细胞电生理效应中起重要作用.     

白藜芦醇对家兔窦房结起搏细胞的电生理效应(英文)

目的为探讨白藜芦醇是否能成为抗心律失常药,研究了其对窦房结起搏细胞的电生理效应。方法应用细胞内微电极方法记录家兔窦房结起搏细胞的动作电位。结果白藜芦醇(30~120μmol.L-1)显著降低窦房结起搏细胞的动作电位幅度、零相最大上升速率(Vmax)、舒张期除极速率和起搏放电频率。而对最大舒张期电位和90%复极化的时间无明显作用。预先应用L型钙通道开放剂Bay-K-8644(0.5μmol.L-1)灌流窦房结10 min可阻断白藜芦醇(60μmol.L-1)对起搏细胞的上述电生理效应。而应用超极化激活电流阻断剂氯化铯(2 mmol.L-1)加钾通道阻断剂四乙铵(20 mmol.L-1)或应用一氧化氮(NO)合酶阻断剂-LNAME(0.5 mmol.L-1)灌流窦房结标本10min对白藜芦醇(60μmol.L-1)的电生理效应没有明显影响。结论白藜芦醇能抑制家兔窦房结起搏细胞的自发活动,此效应可能与其通过非NO依赖性途径抑制钙离子内流有关。     

异紫堇啡碱对家兔窦房结及豚鼠心室肌动作电位的作用

用细胞内固定微电极技术观察了异紫堇啡碱(isocorydine)对家兔窦房结电活动、豚鼠心室肌动作电位及Ba~(2+)诱发的豚鼠心室肌自发电活动的作用。结果表明,异紫堇啡碱能使窦房结细胞APA,SP_0,SP_4减小、APD_(90)延长、自律性降低。3 μM异紫堇啡碱能使心室肌细胞的APD_(50),APD_(90)和ERP延长,300μM异紫堇啡碱则使心室肌细胞APD_(50)和APD_(90)缩短,但不缩短ERP,使ERP相对延长。300μM异紫茧啡碱亦能明显抑制Ba~(2+)诱发的心室肌自发电活动。     

腺苷三磷酸通过P1受体影响兔窦房结起搏细胞电生理活动(英文)

目的:研究腺苷三磷酸(ATP)对兔离体窦房结起搏细胞动作电位的作用,分析相关受体。方法:利用细胞内微电极技术记录兔离体窦房结细胞跨膜电位。结果:ATP 0.1-3.0mmol/L浓度依赖性减慢窦房结自发搏动速率16％-43％,降低舒张期除极速率33％-67％,增大动作电位幅值6％9％,加快最大除极速率30％-76％,APD_(50)和APD_(90)分别缩短7％-12％和6.3％-9％,等浓度ATP、腺苷二磷酸(ADP)和腺苷(Ado)的效应相比时,各组间无显著性差异,尿苷三磷酸(UTP)和α,β-meATP对动作电位各参数均无影响,P1受体拮抗剂氨茶碱(0.1mmol/L)显著拮抗ATP和Ado的作用(P<0.05),且拮抗程度相同,P2受体拮抗剂反应兰2 (0.05mmol/L)不影响ATP的作用(P<0.05)。结论:兔窦房结不存在功能性P2X,和P2Y_2受体,ATP对兔窦房结的作用主要通过其降解产物Ado,由P1受体介导而发挥。     

莫索尼定对兔窦房结起搏细胞的电生理效应(英文)

目的　研究莫索尼定 (Mox)对窦房结起搏细胞是否具有电生理作用及其相关受体以探讨Mox治疗实验性心律不齐的机理。方法　利用细胞内微电极技术记录窦房结细胞AP。结果　Mox(0 .3～ 3mmol·L- 1)浓度依赖性地降低AP的舒张期除极速率 (VDD) ,减慢自发搏动速率 (RPF) ,延长AP复极达 5 0 %及 90 %的时程 (APD50 和APD90 )。 1和 3mmol·L- 1Mox还明显增大最大舒张电位 (MDP)的绝对值。预先灌流α2 受体拮抗剂育亨宾 (1.0 μmol·L- 1,2 0min)取消Mox降低VDD ,延长APD50 和APD90 的作用 ;拮抗较低浓度Mox降低RPF和增大MDP的作用。育亨宾处理标本后 ,Mox显著增加AP幅度和最大除极速率。结论　Mox延长兔窦房结起搏细胞动作电位APD50 和APD90 以及降低VDD的作用主要由α2 受体中介。Mox增大MDP绝对值和减慢RPF的作用则与α2 受体部分相关     

磷酸羟基喹哌对豚鼠心室肌和家兔窦房结细胞慢反应电活动的影响

为进一步研究HPQP抗心律失常的机理,本实验采用细胞内固定微电极技术,观察到该药在30μmol/L可降低高钾除极化心肌动作电位APA和V_(max);对V_(max)呈频率依赖性抑制作用;抑制钡诱发的心室肌自发电活动;对家兔窦房结优势起搏细胞的V_(max)和APA均有抑制,延长APD_(50)和APD_(100),降低四相除极斜率。以上结果均表明该药对钙通道有阻滞作用。     

植物性雌激素金雀异黄素对人心房肌的电生理效应

目的:研究植物性雌激素金雀异黄素(genistein,GST)对人心房肌的电生理效应及其作用机制.方法:应用经典玻璃微电极方法.结果:GST(10-100μmol/L)抑制人心房肌纤维的舒张期(4相)除极化速率(VDD)和起搏细胞放电频(RPF),此外,GST(100 μmol/L)缩短APD_(90).应用L型钙通道开放剂BayK8644(0.5 μmol/L)可拮抗GST对人心房肌纤维的上述电生理效应,但NO合酶阻断剂L-NAME(1 mmol/L)对GST的效应并无影响.结论:GST对人心房肌具有负性变时作用,并可缩短复极化时程.这些效应可能与其抑制钙离子内流有关.     

Interaction of hydrogen sulfide with ion channels

1. Hydrogen sulfide (H₂S) is a signalling gasotransmitter. It targets different ion channels and receptors, and fulfils its various roles in modulating the functions of different systems. However, the interaction of H₂S with different types of ion channels and underlying molecular mechanisms has not been reviewed systematically. 2. H₂S is the first identified endogenous gaseous opener of ATP‐sensitive K⁺ channels in vascular smooth muscle cells. Through the activation of ATP‐sensitive K⁺ channels, H₂S lowers blood pressure, protects the heart from ischemia and reperfusion injury, inhibits insulin secretion in pancreatic β cells, and exerts anti‐inflammatory, anti‐nociceptive and anti‐apoptotic effects. 3. H₂S inhibited L‐type Ca²⁺ channels in cardiomyocytes but stimulated the same channels in neurons, thus regulating intracellular Ca²⁺ levels. H₂S activated small and medium conductance K_Ca channels but its effect on BK_Ca channels has not been consistent. 4. H₂S‐induced hyperalgesia and pro‐nociception seems to be related to the sensitization of both T‐type Ca²⁺ channels and TRPV₁ channels. The activation of TRPV₁ and TRPA₁ by H₂S is believed to result in contraction of nonvascular smooth muscles and increased colonic mucosal Cl^? secretion. 5. The activation of Cl^? channel by H₂S has been shown as a protective mechanism for neurons from oxytosis. H₂S also potentiates N‐methyl‐d ‐aspartic acid receptor‐mediated currents that are involved in regulating synaptic plasticity for learning and memory. 6. Given the important modulatory effects of H₂S on different ion channels, many cellular functions and disease conditions related to homeostatic control of ion fluxes across cell membrane should be re‐evaluated.     

The real life of voltage-gated K channels: more than model behaviour

The past ten years have provided an embarrassment of riches for those interested in cloned voltage-gated K⁺ (Kv) channels. Details of their physiology and pharmacology in expression systems, and their precise cellular location abound, making them excellent targets for pharmacologists. However, there is still a considerable and important gap in our knowledge between the behaviour of expressed Kv channels and K⁺ currents in vivo. In this review Brian Robertson focuses on a few of the recent developments in the field of Kv channels, namely modulation of their behaviour by accessory subunits, their control, and localization of identified Kv subunits.     

An assessment of the present and future roles of non-ligand gated ion channel modulators as CNS therapeutics

Few approved drugs have, as their primary known mechanism of action, modulation of non-ligand gated ion channels. However, these proteins are important regulators of neuronal function through their control of sodium, potassium, calcium and chloride flux, and are ideal candidates as drug discovery targets. Recent progress in the molecular biology and pharmacology of ion channels suggests that many will be associated with specific pharmacological profiles that will include both activators and inhibitors. Ion channels, through their regulation by G-proteins, are a major component of the final common pathway of many drugs acting at classical neuronal receptors. Thus, targeting of the ion channels themselves may confer different profiles of efficacy and specificity to drug action in the brain and spinal cord. Three areas for drug discovery are profiled that the authors consider prime targets for ion channel based therapies, anticonvulsant drugs, cognition enhancing drugs and drugs for improving neurone survival following ischaemia.     

罗哌卡因对豚鼠心室肌细胞钠电流、钙电流和钾电流的影响

目的:研究罗哌卡因(Rop)对豚鼠心室肌细胞钠电流(Ⅰ_(Na))、L-型钙电流(Ⅰ_(Ca-L)、内向整流钾电流(Ⅰ_(Kl)及延迟整流钾电流(I_K)的影响.方法:全细胞膜片箝技术.结果:罗哌卡因10,50与100μmol/L使Ⅰ_(Na)的峰电流分别减小8.3％、33.3 ％和62.5％(P<0.01),使失活时间常数分别延长8.2％、24.7％和64.1％(P<0.05);罗哌卡因50与100μmol/L使Ⅰ_(Ca-L)的峰电流分别减小7.6％和22.5％(P<0.05),使慢失活时间常数分别延长15.5％和33.0％(P<0.01);罗哌卡因50与100μmol/L对Ⅰ_(Kl)和Ⅰ_K的峰电流无明显影响.结论:罗哌卡因抑制Ⅰ_(Na)和Ⅰ_(Ca-L),可能与其心脏毒性作用有关.     

Pharmacological activation and inhibition of Slack (Slo2.2) channels

The Slack (Sequence like a calcium-activated K channel) (Slo2.2) gene is abundantly expressed in the mammalian brain and encodes a sodium-activated K+ (KNa) channel. Although the specific roles of Slack channel subunits in neurons remain to be identified, they may play a role in the adaptation of firing rate and in protection against ischemic injury. In the present study, we have generated a stable cell line expressing the Slack channel, and have analyzed the pharmacological properties of these channels in these cells and in Xenopus oocytes. Two known blockers of KNa channels, bepridil and quinidine, inhibited Slack currents in a concentration-dependent manner and decreased channel activity in excised membrane patches. The inhibition by bepridil was potent, with an IC50 of 1.0 microM for inhibition of Slack currents in HEK cells. In contrast, bithionol was found to be a robust activator of Slack currents. When applied to the extracellular face of excised patches, bithionol rapidly induced a reversible increase in channel opening, suggesting that it acts on Slack channels relatively directly. These data establish an important early characterization of agents that modulate Slack channels, a process essential for the experimental manipulation of Slack currents in neurons.     

高血压发展过程中脑血管平滑肌细胞离子通道的变化

脑血管重构是高血压发展过程中最重要的病理生理改变,由此引起的脑卒中更日益危害人类的健康。在高血压发展过程中,脑血管平滑肌细胞上分布的多种离子通道,如钾钙、氯等均发生变化,导致细胞内离子浓度异常,在脑血管重构的发生发展过程中发挥了重要作用。     

Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy

Importance of the field: The human genome encodes at least 40 distinct voltage-gated potassium channel subtypes, which vary in regional expression, pharmacological and biophysical properties. Voltage-dependent potassium (Kv) channels help orchestrate many of the physiological and pathophysiological processes that promote and sometimes hinder the healthy functioning of our bodies.

Areas covered in this review: This review summarizes patent and scientific literature reports from the past decade highlighting the opportunities that Kv channels offer for the development of new therapeutic interventions for a wide variety of disorders.

What the reader will gain: The reader will gain an insight from an analysis of the associations of different Kv family members with disease processes, summary and evaluation of the development of therapeutically relevant pharmacological modulators of these channels, particularly focusing on proprietary agents being developed.

Take home message: Development of new drugs that target Kv channels continue to be of great interest but is proving to be challenging. Nevertheless, opportunities for Kv channel modulators to have an impact on a wide range of disorders in the future remain an exciting prospect.     

Functional and pharmacological properties of human and rat NaV1.8 channels

The aim of this work is to characterise the functional properties of human and rat Na_V1.8 channels and to investigate the action of anti-nociceptive agents. Na_V1.8 α-subunits were expressed in mammalian sensory neuron-derived ND7/23 cells, and sodium currents were recorded using whole-cell patch clamp. The current-voltage curves for activation were similar for human and rat Na_V1.8 channels. However, for inactivation, human Na_V1.8 showed more hyperpolarised voltage-dependence than for the rat channel, faster development of inactivation, slower recovery from the fast component of inactivation, and faster recovery from the slow component. Thus, this would imply that the human channel is more inactivated at normal resting potentials. Compounds 227c89, A-803467, V102862, ralfinamide and tetracaine all showed greater affinity for the inactivated state than for the resting state. Compounds A-803467 and V102862 were the most potent, and A-803467 showed greater inactivated state affinity for human than for rat channels. Surprisingly, during recovery from inactivation, an increase in current was observed for V102862 and A-803467, probably due to disinhibition of resting block. Rather than the use-dependent inhibition normally seen with inactivated state blockers, for A-803467 this disinhibition led to an increase in current during repetitive stimulation, while V102862 showed less inhibition than otherwise expected at lower frequencies. Thus the data supports the suggestion that, while both V102862 and A-803467 are potent inhibitors of Na_V1.8, the compound V102862, rather than A-803467, may be useful as an analgesic where physiological firing frequencies are higher.     

Arachidonic acid and ion channels: an update

Arachidonic acid (AA), a polyunsaturated fatty acid with four double bonds, has multiple actions on living cells. Many of these effects are mediated by an action of AA or its metabolites on ion channels. During the last 10 years, new types of ion channels, transient receptor potential (TRP) channels, store-operated calcium entry (SOCE) channels and non-SOCE channels have been studied. This review summarizes our current knowledge about the effects of AA on TRP and non-SOCE channels as well as classical ion channels. It aims to distinguish between effects of AA itself and effects of AA metabolites. Lipid mediators are of clinical interest because some of them (for example, leukotrienes) play a role in various diseases, others (such as prostaglandins) are targets for pharmacological therapeutic intervention.