肥厚心肌细胞钠通道电流

目的 探讨自发高血压大鼠(SHR)肥厚心肌钠通道电流的动态演变规律及与左心室肥厚的关系.方法 采用全细胞膜片钳技术记录10、24和34周龄SHR左心室心肌钠通道电流及膜电容,同时测定大鼠动脉收缩压和左心室质量指数,以10周龄Wistar大鼠为对照组.结果 (1)SHR的左心室质量指数及膜电容明显大于Wistar大鼠(P＜0.01).在SHR中,各组大鼠的膜电容和左心室质量指数具有明显差别(P＜0.01).(2)10周龄和24周龄SHR肥厚心肌钠通道电流密度与10周龄Wistar大鼠比较无明显变化(P＞0.05);34周龄SHR肥厚心肌钠通道电流密度＞10周龄Wistar大鼠[(-18.3±1.9 )pA/pF vs (-15.3±2.0)pA/pF,P＜0.05).(3)钠通道电流密度与左心室质量指数呈正相关关系(r=0.879, P＜0.01).结论 左心室肥厚越明显,钠通道电流密度越升高.     

自发高血压大鼠左心室心肌瞬时外向钾通道电流的动态变化

目的探讨自发高血压大鼠左心室心肌瞬时外向钾通道电流(transient outward potassium channel current,ITO)的动态演变规律及与左心室肥厚的关系。方法采用全细胞膜片钳技术记录10、24和34周龄自发高血压大鼠左心室心肌瞬时外向钾通道电流及膜电容,同时测定各组大鼠动脉收缩压和左心室质量指数。对照组为10周龄Wistar大鼠。结果①各组自发高血压大鼠的左心室质量指数及膜电容明显大于Wistar大鼠(P<0.01)。自发高血压大鼠膜电容和左心室质量指数组间差异有统计学意义(P<0.01);②10、24和34周龄组肥厚心肌ITO分别为(15.0±0.4)pA/pF,(13.9±0.9)pA/pF和(11.3±1.0)pA/pF,均小于对照组(16.3±0.8)pA/pF(P<0.05);③ITO与左心室质量指数呈负相关(r=-0.96,P<0.01),左心室质量指数是影响ITO密度的主要因素(β=0.91,P<0.01)。结论各周龄自发高血压大鼠左心室心肌出现肥厚;肥厚心肌ITO降低,且左心室肥厚越明显ITO越低。     

自发高血压大鼠肥厚心肌L型钙通道电流变化及与左室肥厚的关系

目的探讨自发高血压大鼠肥厚心肌L型钙通道电流的动态演变规律及与左室肥厚的关系。方法采用全细胞膜片钳技术记录10,24和34周龄组(n均为10)自发高血压大鼠左室心肌L型钙通道电流(ICa-L)及膜电容(MC),同时测定大鼠动脉收缩压(SBP)和左室质量指数(LVMI),以10周龄Wistar大鼠为对照组(n=10)。结果①自发高血压大鼠的LVMI及MC明显大于对照组(P<0.01)。在自发高血压大鼠中,各周龄组的MC和LVMI具有明显差别(P<0.01)。②10周龄组ICa-L电流密度明显大于对照组(-7.2±0.9pA/pFvs-5.7±0.6pA/pF,P<0.05),34周龄组ICa-L电流密度明显小于对照组(-4.2±0.3pA/pFvs-5.7±0.6pA/pF,P<0.05)。③ICa-L电流密度与LVMI呈负相关关系(r=-0.95,P<0.01),同时LVMI和大鼠周龄是影响ICa-L电流密度的主要因素(P<0.01)。结论左室肥厚越明显,ICa-L电流密度越降低。     

自发性高血压大鼠左心室肌细胞动作电位延长的离子机制

目的:研究自发性高血压大鼠(SHR)左心室肌细胞动作电位时程延长的膜离子流基础.方法:应用酶解方法分离获得正常血压Wistar大鼠和SHR的左心室肌细胞,采用玻璃微电极技术记录动作电位,膜片钳全细胞记录膜离子流,对比正常心室肌细胞和肥大心室肌细胞间动作电位及膜离子流差别.结果:(1)SHR和Wistar大鼠的心脏/体重比分别为5.66±0.46 mg/g和3.7±0.29 mg/g (P<0.001) ,细胞平均膜电容分别为280.68±67.98 pF 和189.94±56.59 pF(P<0.05).提示SHR 心脏肥厚、心肌细胞增大;(2)SHR动作电位APD50和APD90较Wistar大鼠明显延长(21.33±1.56 ms vs 14.91±2.95 ms,P<0.001; 164.6±74 ms vs 93.27±10.59 ms,P<0.00 1),说明SHR心室肌细胞存在复极延迟;(3)SHR的平均ICa-L幅值显著大于Wistar大鼠,分别为1944±466.8 pA和1136±33.3 pA(P<0.001),电流密度二者间无差异(6.932±1.7 1 pA/pF vs 6.19±2.85 pA/pF) ,但SHR的慢失活时间常数明显延长(56.01±13.36 ms vs 43.63±17.89 ms,P<0.001);(4)S HR的Ik1内向电流密度显著小于Wistar大鼠(11.3±2.26 pA/pF vs 14.33 pA/pF,P<0.05),外向电流密度二者间差异无显著性(2.36±0.86 pA/pF vs 2.96±1.27 pA/pF);(5)SHR的Ik密度与Wista r大鼠间无差别(12.38±5.46 pA/pF vs 11.86±3.59 pA/pF);(6)SHR的Ito密度显著地低于Wistar 大鼠(+70 mV时, 8.21±6.64 pA/pF vs 19.16±6.17 pA/pF, P<0.001).但通道的激活和失活时间常数二者无差异,提示Ito的降低可能仅是通道数减少所致.结论:SHR左心室肌细胞动作电位时程延长系外向复极钾流(Ito、Ik1)减小和慢钙通道失活时间常数延长所致.     

辛伐他汀逆转左室肥厚的作用与抑癌基因PTEN表达的关系

目的观察辛伐他汀逆转自发性高血压大鼠(SHR)左心室肥厚(LVH)的作用及其与抑癌基因第10号染色体缺失的张力蛋白同源区(PTEN)表达的关系。方法16只雄性8周龄SHR测量体重和收缩压后,随机分为SHR治疗组和SHR对照组,分别给予辛伐他汀和安慰剂灌胃治疗,性别、年龄、数量匹配的Wistar大鼠给予安慰剂治疗作为正常对照组,疗程10周,观察辛伐他汀对大鼠收缩压和左心室重量/体重比值(LVW/BW)的影响,采用逆转录聚合酶链式反应(RTPCR)和蛋白免疫印迹法(Westernblot)检测辛伐他汀对心肌组织PTEN表达的影响。结果(1)治疗前两组SHR收缩压无显著差异(P>0.05),均高于Wistar正常对照组大鼠(P<0.01);给予辛伐他汀后,SHR治疗组收缩压(217.3±8.5)mmHg较SHR对照组(220.8±9.9)mmHg略有降低,但无统计学意义(P>0.05),且两组SHR收缩压仍高于Wistar正常对照组大鼠(126.0±5.8)mmHg,差异非常显著(P<0.01)。(2)SHR对照组大鼠的LVM/BW(4.10±0.13)mg/g明显高于Wistar正常对照组(3.04±0.12)mg/g,并有统计学意义(P<0.01),而SHR辛伐他汀治疗组的LVM/BW(3.73±0.08)mg/g较SHR对照组明显下降(P<0.01)。(3)SHR对照组大鼠心肌组织PTEN的mRNA表达水平(0.36±0.04)低于Wistar正常对照组(0.87±0.05),差异非常显著(P<0.01),SHR治疗组大鼠的PTENmRNA表达水平(0.60±0.05)较SHR对照组显著升高,并有统计学意义(P<0.01)。(4)Wistar正常对照组、SHR对照组和SHR治疗组大鼠心肌组织PTEN蛋白表达水平分别为50.53±2.92、24.65±3.89和40.32±4.04,其中SHR对照组明显低于Wistar正常对照组(P<0.01),SHR治疗组则较SHR对照组显著升高(P<0.01)。结论辛伐他汀能够逆转SHR的LVH,其机制可能与PTEN表达水平增加有关。     

ERK表达及活化在自发性高血压大鼠心肌肥厚中作用的研究

目的　以SHR大鼠作为自发性高血压动物模型 ,研究ERK表达及活化在高血压并发左心室肥厚 (LVH)中的作用。方法　SHR大鼠按年龄分为 8周、16周和 2 4周三组 ,以Wistar大鼠作为对照。ERK表达及活性定量测定采用WesternBlot方法。结果　SHR左室质量指数与磷酸化ERK水平正相关。 2 4周龄SHR大鼠基础ERK表达水平较 8周龄和 16周龄减少 ,亦明显低于同龄Wistar大鼠 (P =0 0 0 3) ;SHR大鼠ERK活化程度高于同龄Wistar大鼠 ,随年龄增加 ,SHR磷酸化ERK表达量增加。结论　ERK的活化参与高血压心肌肥厚的发病。     

氯通道阻滞剂尼氟灭酸对肥厚心肌心室有效不应期及心室颤动阈值的疗效

背景 肥厚心肌离子通道的重塑容易发生恶性室性心律失常,钙激活氯通道的改变起着重要的作用,尼氟灭酸(NFA)是常用的钙激活氯通道的阻滞剂.目的 不同剂量NFA对左室肥厚心肌心室有效不应期及心室颤动阈值的影响.方法 32只10周龄雄性自发性高血压大鼠(SHR)随机分成非NFA处理组及3个NFA不同剂量(0.01,0.1,1.0 μmol/kg.iv)处理组,每组8只,取8只雄性Wistar大鼠作为对照组,分别测定各组大鼠心率、动脉收缩压、心室有效不应期、心室颤动阈值及左室质量指数.结果 1)SHR左室质量指数明显大于Wistar大鼠(P＜0.01);2)NFA非处理组的心室颤动阈值明显小于对照组[(15.0±1.2)mA vs(26.4±1.5)mA,P＜0.01);3)NFA浓度越大延长左室肥厚心肌的心室有效不应期越明显,提高左室肥厚心肌的心室颤动阈值越明显(P＜0.05),呈浓度依赖趋势;4)心室有效不应期与心室颤动阈值正相关,NFA的3个不同处理剂量与心室有效不应期或心室颤动阈值正相关.结论 NFA可以延长左室肥厚心肌的心室有效不应期,提高左室肥厚心肌的心室颤动阈值.     

ERK表达及活化在自发性高血压大鼠心肌肥厚中作用的研究

目的以SHR大鼠作为自发性高血压动物模型,研究ERK表达及活化在高血压并发左心室肥厚(LVH)中的作用.方法 SHR大鼠按年龄分为8周、16周和24周三组,以Wistar大鼠作为对照.ERK表达及活性定量测定采用Western Blot方法.结果 SHR左室质量指数与磷酸化ERK水平正相关.24周龄SHR大鼠基础ERK 表达水平较8周龄和16周龄减少,亦明显低于同龄Wistar大鼠(P=0.003);SHR大鼠ERK活化程度高于同龄Wistar大鼠,随年龄增加,SHR磷酸化ERK表达量增加.结论 ERK的活化参与高血压心肌肥厚的发病.     

辛伐他汀逆转左室肥厚的作用与抑癌基因PTEN表达的关系

目的观察辛伐他汀逆转自发性高血压大鼠(SHR)左心室肥厚(LVH)的作用及其与抑癌基因-第10号染色体缺失的张力蛋白同源区(PTEN)表达的关系.方法16只雄性8周龄SHR测量体重和收缩压后,随机分为SHR治疗组和SHR对照组,分别给予辛伐他汀和安慰剂灌胃治疗,性别、年龄、数量匹配的Wistar大鼠给予安慰剂治疗作为正常对照组,疗程10周,观察辛伐他汀对大鼠收缩压和左心室重量/体重比值(LVW/BW)的影响,采用逆转录聚合酶链式反应(RT-PCR)和蛋白免疫印迹法(Westernblot)检测辛伐他汀对心肌组织PTEN表达的影响.结果(1)治疗前两组SHR收缩压无显著差异(P＞0.05),均高于Wistar正常对照组大鼠(P＜0.01);给予辛伐他汀后,SHR治疗组收缩压(217.3±8.5)mmHg较SHR对照组(220.8±9.9)mm Hg略有降低,但无统计学意义(P＞0.05),且两组SHR收缩压仍高于Wistar正常对照组大鼠(126.0±5.8)mm Hg,差异非常显著(P＜0.01).(2)SHR对照组大鼠的LVM/BW(4.10±0.13)mg/g明显高于Wistar正常对照组(3.04±0.12)mg/g,并有统计学意义(P＜0.01),而SHR辛伐他汀治疗组的LVM/BW(3.73±0.08)mg/g较SHR对照组明显下降(P＜0.01).(3)SHR对照组大鼠心肌组织PTEN的mRNA表达水平(0.36±0.04)低于Wistar正常对照组(0.87±0.05),差异非常显著(P＜0.01),SHR治疗组大鼠的PTEN mRNA表达水平(0.60±0.05)较SHR对照组显著升高,并有统计学意义(P＜0.01).(4)Wistar正常对照组、SHR对照组和SHR治疗组大鼠心肌组织PTEN蛋白表达水平分别为50.53±2.92、24.65±3.89和40.32±4.04,其中SHR对照组明显低于Wistar正常对照组(P＜0.01),SHR治疗组则较SHR对照组显著升高(P＜0.01).结论辛伐他汀能够逆转SHR的LVH,其机制可能与PTEN表达水平增加有关.     

阿托伐他汀对自发性高血压大鼠心肌组织p21表达的影响及其意义

目的:观察阿托伐他汀(ATV)对自发性高血压大鼠(SHR)心肌组织中p21表达的影响,探讨其改善心肌肥厚的可能机制。方法:将16只8周龄SHR随机分为2组(n=8):ATV药物干预组(ATV组)与SHR模型对照组(SHR组),并以8只同周龄Wistar-Kyoto大鼠作为正常对照组(WKY组)。ATV组用ATV 50 mg/(kg·d)灌胃,SHR组与WKY组采用等容量蒸馏水每日同时灌胃。每隔2周测1次血压。10周后,观察大鼠血脂、心肌肥厚指标、p21 mRNA及其蛋白表达的改变。结果:干预10周后,ATV组及SHR组血脂、血压无明显差异。ATV组左室质量指数低于SHR组(P<0.01)。ATV组p21mRNA及蛋白的表达明显高于SHR组(P<0.01)。心肌组织p21mRNA的表达与全心质量与体质量比(HW/BW)呈负相关(r=-0.709,P<0.01),与左室质量与体质量比(LVW/BW)呈负相关(r=-0.665,P<0.01)。结论:ATV可上调SHR肥厚心肌组织中p21的表达,可有效改善左室肥厚。     

Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites

Selective ion conduction across ion channel pores is central to cellular physiology. To understand the underlying principles of ion selectivity in tetrameric cation channels, we engineered a set of cation channel pores based on the nonselective NaK channel and determined their structures to high resolution. These structures showcase an ensemble of selectivity filters with a various number of contiguous ion binding sites ranging from 2 to 4, with each individual site maintaining a geometry and ligand environment virtually identical to that of equivalent sites in K(+) channel selectivity filters. Combined with single channel electrophysiology, we show that only the channel with four ion binding sites is K(+) selective, whereas those with two or three are nonselective and permeate Na(+) and K(+) equally well. These observations strongly suggest that the number of contiguous ion binding sites in a single file is the key determinant of the channel's selectivity properties and the presence of four sites in K(+) channels is essential for highly selective and efficient permeation of K(+) ions.     

Autonomic Regulation of Voltage-Gated Cardiac Ion Channels

Altering voltage-gated ion channel currents, by changing channel number or voltage-dependent kinetics, regulates the propagation of action potentials along the plasma membrane of individual cells and from one cell to its neighbors. Functional increases in the number of cardiac sodium channels (Na_V1.5) at the myocardial sarcolemma are accomplished by the regulation of caveolae by β adrenergically stimulated G-proteins. We demonstrate that Na_V1.5, Ca_V1.2a, and K_V1.5 channels specifically localize to isolated caveolar membranes, and to punctate regions of the sarcolemma labeled with caveolin-3. In addition, we show that Na_V1.5, Ca_V1.2a, and K_V1.5 channel antibodies label the same subpopulation of isolated caveolae. Plasma membrane sheet assays demonstrate that Na_V1.5, Ca_V1.2a, and K_V1.5 cluster with caveolin-3. This may have interesting implications for the way in which adrenergic pathways alter the cardiac action potential morphology and the velocity of the excitatory wave.     

Structure and regulation of L-type calcium channels a current assessment of the properties and roles of channel subunits

L-type Ca channels are complex heteromultimeric proteins that play important roles in the cardiovascular system. Recent studies have revealed new insights into how the pore-forming ₁ subunits interact with accessory subunits to produce functional Ca channels. The function of L-type Ca channels is often regulated by receptor-mediated signal transduction events that are thought to result in the phosphorylation of proteins that comprise the Ca channels. Although the molecular events underlying phosphorylation based regulation have been intensely investigated with the use of electrophysiological approaches, surprisingly few details are known about the biochemical events involved, and many questions remain unanswered. © 1996, Elsevier Science Inc. (Trends Cardiovasc Med 1996;6:265–273).     

Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium

The inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) is an intracellular Ca(2+) release channel, and its opening is controlled by IP(3) and Ca(2+). A single IP(3) binding site and multiple Ca(2+) binding sites exist on single subunits, but the precise nature of the interplay between these two ligands in regulating biphasic dependence of channel activity on cytosolic Ca(2+) is unknown. In this study, we visualized conformational changes in IP(3)R evoked by various concentrations of ligands by using the FRET between two fluorescent proteins fused to the N terminus of individual subunits. IP(3) and Ca(2+) have opposite effects on the FRET signal change, but the combined effect of these ligands is not a simple summative response. The bell-shaped Ca(2+) dependence of FRET efficiency was observed after the subtraction of the component corresponding to the FRET change evoked by Ca(2+) alone from the FRET changes evoked by both ligands together. A mutant IP(3)R containing a single amino acid substitution at K508, which is critical for IP(3) binding, did not exhibit this bell-shaped Ca(2+) dependence of the subtracted FRET efficiency. Mutation at E2100, which is known as a Ca(2+) sensor, resulted in ～10-fold reduction in the Ca(2+) dependence of the subtracted signal. These results suggest that the subtracted FRET signal reflects IP(3)R activity. We propose a five-state model, which implements a dual-ligand competition response without complex allosteric regulation of Ca(2+) binding affinity, as the mechanism underlying the IP(3)-dependent regulation of the bell-shaped relationship between the IP(3)R activity and cytosolic Ca(2+).     

Molecular structure of an open human KATP channel

K_ATP channels are metabolic sensors that translate intracellular ATP/ADP balance into membrane excitability. The molecular composition of K_ATP includes an inward-rectifier potassium channel (Kir) and an ABC transporter–like sulfonylurea receptor (SUR). Although structures of K_ATP have been determined in many conformations, in all cases, the pore in Kir is closed. Here, we describe human pancreatic K_ATP (hK_ATP) structures with an open pore at 3.1- to 4.0-Å resolution using single-particle cryo-electron microscopy (cryo-EM). Pore opening is associated with coordinated structural changes within the ATP-binding site and the channel gate in Kir. Conformational changes in SUR are also observed, resulting in an area reduction of contact surfaces between SUR and Kir. We also observe that pancreatic hK_ATP exhibits the unique (among inward-rectifier channels) property of PIP₂-independent opening, which appears to be correlated with a docked cytoplasmic domain in the absence of PIP₂.

K _ATP, a K⁺ channel that is gated by intracellular ATP and ADP (1–7), functions in many different cells including pancreatic β-cells (6), heart (8), skeletal muscle (9), smooth muscle (10), and neurons (11). By regulating K⁺ permeability as a function of cytoplasmic ATP and ADP concentrations, K_ATP links membrane electrical excitability to a cell’s energy budget (1). In pancreatic β-cells, this K_ATP-mediated link couples insulin secretion to serum glucose concentration (5, 6, 12–16). K_ATP is thus a pharmacological target for the treatment of type II diabetes (17–19).K_ATP consists of an inward-rectifier potassium channel (Kir) surrounded by four sulphonylurea receptors (SUR) that belong to the ABC transporter family (20–23) (Fig. 1A). Kir, a tetramer with four identical subunits, contains an ATP-binding site on the cytoplasmic domain (CTD) of each subunit (24–26). This site binds ATP with higher affinity than ADP (27). When ATP binds, pore closure is favored and thus the ATP site on Kir is referred to as inhibitory (1, 24). Each SUR subunit contains two adenosine nucleotide binding sites nestled in between two nucleotide binding domains (NBDs) (28, 29). These sites are formed when the NBDs engage each other (a process called dimerization) (28, 30, 31). One site, termed the degenerate site because it is incapable of mediating ATP hydrolysis, binds both ATP and ADP. The other, termed the consensus site, mediates ATP hydrolysis and favors ADP binding. Notably, and in contrast to most ABC transporters, Mg^2+-ADP alone is sufficient to dimerize the NBDs (32)—and when dimerization occurs, pore opening is favored (27). The opposing influence of ATP and ADP is central to the regulation of K_ATP gating in cells (1).Open in a separate windowFig. 1.Functional validation of purified human K_ATP (hKir6.2-hSUR1). (A) Locations of inhibitory (red) and activating (green) ATP and ADP in K_ATP. Kir subunit is colored in blue, and SUR subunit is colored in yellow. In all recordings, the membranes do not contain PIP₂. A total of 2 mM MgCl₂ was included in recording buffers. Currents are plotted according to physiological conventions such that inward current is negative. (B) Representative single-channel recording of reconstituted WT hK_ATP at two membrane voltages. Current levels for closed and one and two simultaneously opened channels are labeled as C, O1, and O2. (C) WT hK_ATP was activated by C8-PIP₂ and inhibited by ATP. Although not shown in the figure, ATP inhibition also occurs in the absence of PIP₂. (D) Locations of C166 (purple spheres) and G334 (cyan spheres) in the structural model of WT hKir6.2. Inhibitory ATP is colored in red. (E) hK_ATP (G334D_Kir) was activated by both ATP and ADP. (F) Representative single-channel recording of hK_ATP (C166S_Kir). Current levels for closed and one opened channel are labeled as C and O1. (G) Representative single-channel recording of hK_ATP (C166S_Kir, G334D_Kir). Current levels for closed and one to three simultaneously opened channels are labeled as C, O1, O2, and O3.Even though many molecular structures of K_ATP have been determined (32–39), we still cannot explain how ATP and ADP regulate the gate. All of the structures show the same closed conformation (32–39), so we cannot correlate conformational changes near the binding sites with those near the gate. In this paper, we describe a method for expressing and isolating a human pancreatic K_ATP (hK_ATP) complex composed of independent polypeptides. We show that hK_ATP channels in a reconstituted system exhibit physiological and pharmacological properties similar to those in cells. Then, through mutagenic alteration of the inhibitory ATP-binding site and a gate residue, we produce hK_ATP that exhibits high open probability and no ATP inhibition. Using single-particle cryo-electron miscroscopy (cryo-EM), we characterize hK_ATP with an open pore. From this structure, we correlate protein conformational changes that connect the ATP and ADP regulatory sites to the gate.     

心肌缺血预适应中的离子通道

缺血预适应调动机体内源性抗损伤能力，保护缺血缺氧的组织细胞，是近年来心血管领域研究的热点之一。本该对心肌缺血预适应中的离子通道、三磷酸腺苷敏感性钾通道（KATP通道）、L-型钙道道（L-Ca^2 通道）、体积调节性氯通道（Cl vol通道）的特性、作用及其机制作一综述。     

ATP-sensitive potassium channels and myocardial ischemia: Why do they open?

Summary There is evidence that the ATP-sensitive potassium channel opens, at least during the early stages of myocardial ischemia, despite relatively high ATP levels. Thus, channel opening may partially contribute to potassium efflux and accumulation of extracellular potassium, but probably much more profoundly to electrical abnormalities associated with ischemia, including the development of lethal arrhythmias. Several factors are discussed that may promote a significant open-channel probability of the channel, in spite of relatively high levels of ATP. It is argued that, even with a very low open probability, the magnitude of total membrane current carried by these channels may be substantial (comparable to other potassium currents) because of the high density and conductance of the ATP-sensitive potassium channel. Finally, it is shown how the ATP-sensitive potassium channel may play a role in various tissue types, ranging from the physiological to the pathophysiological. This potassium channel is therefore increasingly targeted for drug development and research.     

Endothelial‐smooth muscle cell interactions in the regulation of vascular tone in skeletal muscle

The SMCs of skeletal muscle arterioles are intricately sensitive to changes in membrane potential. Upon increasing luminal pressure, the SMCs depolarize, thereby opening VDCCs, which leads to contraction. Mechanisms that oppose this myogenic tone can involve voltage‐dependent and independent dilator pathways, and can be endothelium‐dependent or independent. Of particular interest are the pathways leading to hyperpolarization of SMCs, as these can potentially evoke both local and conducted dilation. This review focuses on three agonists that cause local and conducted dilation in skeletal muscle: ACh, ATP, and KCl. The mechanisms for the release of these agonists during motor nerve stimulation and/or hypoxia, and their actions to open either Ca²⁺‐activated K⁺ channels (K_Ca) or inwardly rectifying K⁺ channels (K_IR) are described. By causing local and conducted dilation, each agonist has the ability to improve skeletal muscle blood flow during exercise and ischemia.     

T-Type Calcium Channel Blockade in the Management of Chronic Ischemic Heart Disease

The T-Type calcium channel offers a new therapeutic target for teatment of patients with cardiovascular disease. Mibefradil, a T channel blocker, produces heart rate slowing and coronary vasodilatation but without the negative inotropic effect commonly seen when L-Type channel blockers are used. The present study shows Mibefradil prevents ischemic episodes that are and are not preceded by an increase in heart rate. Although Mibefradil has been withdrawn because of multiple drug interactions, new T-Type calcium channel blockers are under development.