伊伐布雷定在心血管疾病中的临床研究进展

伊伐布雷定为第一个特异性心脏起搏电流抑制剂,具有特异性降低心率的作用,其相关的动物实验及临床研究也在日益增多。大量临床研究表明,伊伐布雷定对冠心病、心力衰竭、心律失常、心肌梗死等有明确治疗效果。现对伊伐布雷定的药理机制及在心血管系统疾病中的临床应用进行综述。     

伊伐布雷定在快速性心律失常治疗中的研究进展

伊伐布雷定是一种新型减慢心率药物,对快速性心律失常有潜在的治疗作用。伊伐布雷定特异性地抑制起搏电流(If),降低窦房结节律,对不适当窦性心动过速及体位性心动过速综合征的治疗有一定的作用。伊伐布雷定能降低心肌细胞自发动作电位的频率,减慢房室结的传导速度,可能减少心房颤动的发生并且控制心室率,其临床疗效观察存在不一致性,其疗效有待观察。伊伐布雷定通过抑制超极化激活环核苷酸门控通道(HCN)通道介导的If增加,其可能减少室性心律失常的发生率,降低心室颤动阈值,其临床疗效有待验证。     

伊伐布雷定在心血管疾病应用中的研究进展

伊伐布雷定是目前唯一的特异性If电流通道阻滞剂,通过抑制窦房结P细胞动作电位4期If电流而达到减慢心率的作用.伊伐布雷定在减慢心率的同时不影响左心室收缩功能;治疗剂量范围内不影响PR间期、QRS间期及QTc;也不影响支气管平滑肌、糖脂代谢、血压.多项研究表明伊伐布雷定能明确改善冠心病、慢性心力衰竭等心血管疾病患者的临床症状及预后,且对窦性心动过速亦有疗效.     

伊伐布雷定增加心房颤动发生的可能机制及临床应用注意事项

伊伐布雷定在降低窦性心律下心力衰竭或冠心病患者的心室率方面有明显益处。但临床实践提示,伊伐布雷定的应用会增加非心房颤动(房颤)患者的房颤发生风险。基于相关临床和基础研究证据,本文将系统阐述伊伐布雷定增加房颤发生风险的可能机制,并为伊伐布雷定的临床应用提供注意事项。     

伊伐布雷定治疗心力衰竭的基础和临床研究进展

伊伐布雷定是高度特异性的If离子通道阻滞剂,通过抑制If电流降低窦房结节律,减慢心率,而对心内传导系统、心肌收缩力以及血流动力学无明显影响。很多基础和临床研究表明,伊伐布雷定能改善心力衰竭患者临床症状、提高生活质量、降低病死率及心血管事件发生率。     

伊伐布雷定在快速性心律失常中的应用

伊伐布雷定是一种特殊的起搏电流(If)抑制剂,可用于降低心率,并具有潜在的抗心律失常作用。伊伐布雷定能降低由If引起的细胞自律性以及抑制房室结的传导速度,具有潜在的预防与治疗心房颤动和控制心房颤动心室率的作用。伊伐布雷定抑制HCN通道和If,对室性心律失常有一定的治疗作用。伊伐布雷定可抑制窦房结内的If,降低窦房结节律,从而稳定心率。伊伐布雷定目前的治疗价值尚缺乏大规模临床研究的证据支持,还需进一步深入研究。     

伊伐布雷定临床应用进展

伊伐布雷定是临床用于心绞痛及心力衰竭患者稳定心率的药物,可减少患者心源性死亡的风险,并改善长期预后、提高生活质量。对合并哮喘、慢性阻塞性肺病以及其他β受体阻滞剂禁忌证的患者,可考虑使用伊伐布雷定。伊伐布雷定耐受性良好、不良反应少,但对快心室率异位心律无效。     

伊伐布雷定临床应用进展

伊伐布雷定是临床用于心绞痛及心力衰竭患者稳定心率的药物,可减少患者心源性死亡的风险,并改善长期预后、提高生活质量。对合并哮喘、慢性阻塞性肺病以及其他β受体阻滞剂禁忌证的患者,可考虑使用伊伐布雷定。伊伐布雷定耐受性良好、不良反应少,但对快心室率异位心律无效。     

伊伐布雷定治疗稳定性心绞痛的研究进展

心率增快是心血管疾病的重要危险因素,也是导致心绞痛发作的重要原因。伊伐布雷定是一种I(f)电流通道抑制剂,能有效减慢稳定性心绞痛患者心率,进而减低心肌耗氧量、改善临床症状、减少心绞痛发作次数。但目前关于伊伐布雷定能否改善稳定性心绞痛患者远期预后及提高患者生活质量等方面的研究仍存在争议。本文从伊伐布雷定作用机制、相关临床证据及不良反应等方面进行综述,以探讨伊伐布雷定治疗稳定性心绞痛的可行性。     

伊伐布雷定在冠心病患者中的应用进展

心率过快缩短心肌血流灌注时间,加剧心肌供氧不足和耗氧过多的不平衡,不利于冠心病患者的病情控制。伊伐布雷定可特异性减慢窦性心率,且对心肌收缩、房室传导、支气管平滑肌无影响,相比于β受体阻滞剂,在冠心病的应用具备一定的优势。现阶段临床研究表明,伊伐布雷定可降低稳定性冠心病患者心率,具有一定的抗心肌缺血、缓解胸痛的作用;对于合并慢性心力衰竭者,还可改善心室重构和远期临床转归;伊伐布雷定在急性冠状动脉综合征中可能具有潜在的临床应用价值,但其长期应用的安全性和有效性仍待观察和验证。     

原代培养乳鼠窦房结细胞肿胀激活氯电流的研究

目的 记录并研究乳鼠窦房结细胞肿胀激活氯电流的电生理学特征.方法 取培养乳鼠窦房结细胞,在不同干预条件下用全细胞膜片钳记录肿胀激活氯电流.结果 等渗溶液中细胞背景电流较小且稳定,低渗溶液诱导激活肿胀激活氯电流,该电流呈现较明显的外向整流特点,具有容积敏感性,可被细胞外高渗溶液刺激所抑制.氯通道阻断剂tamoxifen显著抑制肿胀激活氯电流.结论 培养乳鼠窦房结细胞存在肿胀激活氯电流.     

Determinants of gradient field-induced current in a pacemaker lead system in a magnetic resonance imaging environment

BACKGROUND: The determinants of low-frequency-induced current by magnetic resonance imaging (MRI) gradient fields in a pacemaker lead system are largely unknown. OBJECTIVE: The purpose of this study was to determine the magnitude of MRI low-frequency-induced current in an implanted pacemaker lead system and to investigate in vivo determinants of low-frequency-induced current in an animal model. METHODS: Six mongrel dogs underwent conventional single-chamber pacemaker implantation with a current recorder connected in series. Pulse generator (PG) was programmed to VOO 120 bpm with subthreshold output. MRI was performed in a 1.5-T scanner. Low-frequency-induced current was recorded during unipolar pacing, bipolar pacing, and bipolar pacing with the PG case electrically isolated from the pocket. In each mode, low-frequency-induced current was recorded with and without a large loop of additional lead connected in series. RESULTS: With a conventional implant, low-frequency-induced current was < or =0.5 mA in all three pacing modes. With five external loops, the magnitude of low-frequency-induced current increased to >30 mA, with consistent myocardial capture in unipolar and bipolar pacing. However, in bipolar pacing with the PG electrically isolated from the pocket, low-frequency-induced current decreased to <0.5 mA with no myocardial capture even with additional looped leads. CONCLUSION: Under conventional implant conditions, the magnitude of low-frequency-induced current is <0.5 mA and is unlikely to cause myocardial capture; however, arrhythmia induction cannot be excluded. With sufficient increase in effective loop area (additional looped leads), direct myocardial capture by the low-frequency-induced current is possible. In this study, breaking the return pathway by electrically isolating the PG case from the circuit abolished low-frequency-induced current.     

Calcium-activated chloride current in rabbit ventricular myocytes

We have used the whole-cell patch-clamp technique to examine the ionic basis for a transient outward current in rabbit ventricular myocytes. High concentrations of intracellular calcium buffer prevented the current, isoproterenol increased it, and cadmium, nisoldipine, ryanodine, or caffeine blocked it. These data are consistent with a current that is calcium activated, by the calcium transient that causes contraction. The current was not blocked by external 4-aminopyridine or tetraethylammonium, and it was still present if external potassium was omitted and internal potassium was replaced by cesium. The current was absent when intracellular and extracellular chloride concentrations were drastically reduced, even when intracellular and extracellular potassium concentrations were normal. The current was blocked by the anion transport blockers 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and responded to extracellular chloride changes as expected for a chloride current. We used SITS and DIDS to define the voltage dependence of the transient outward current. The current first appeared at voltages positive to the threshold of the calcium current and declined as voltage approached the calcium reversal potential. Tail-current experiments suggested that the current rectified strongly in the outward direction. We propose that the 4-aminopyridine-resistant transient outward current of rabbit ventricular myocytes is a calcium-activated chloride current.     

Serotonin modulates a specific potassium current in the sensory neurons that show presynaptic facilitation in Aplysia.

Serotonin exerts a long-lasting excitatory action on sensory neurons of Aplysia californica by decreasing outward K+ current. The depression of outward current delays repolarization of the action potential and extends the duration of Ca2+ influx into the presynaptic terminals, thereby contributing to the facilitation of transmitter release that underlies behavioral sensitization. We have extended the analysis of serotonin's action and find that it acts on a specific serotonin-sensitive K+ current (S current), which is different from the early K+ current (IA), the delayed K+ current (IK), the Ca2+-dependent K+ current (IC), and the muscarine-sensitive M current. The serotonin-sensitive current in these cells persists when IA and IK are reduced by conditioning depolarization or channel-blocking agents. The S current is not activated by intracellular injection of Ca2+, nor is it affected by substitution of Ba2+ for Ca2+, a treatment that reduces IC. Moreover, intracellular injection of cyclic AMP exerts an effect indistinguishable from that of serotonin. This observation and the insensitivity of the current to Ba2+ distinguishes the S current from M current. S current is activated at the resting potential and does not inactivate with steady-state depolarization. It is active sufficiently early during an action potential to contribute to the repolarization of the action potential and therefore accounts for the physiological effects of serotonin.     

Channel-mediated calcium current in the heart

Summary Calcium ions play an important role in the regulation of heart functions. Calcium ions may enter or leave the myocardial cell through various mechanisms, including several exhange mechanisms and pumps. This review concentrates on the influx of calcium ions through channels in the sarcolemma, resulting in an electric current flow. The calcium current plays an important role in the maintenance of the action potential duration, in the generation of pacemaker activity, and in the initiation of contraction.The calcium current displays both activation and a subsequent inactivation when the membrane potential is changed in a stepwise fasion. Previously, the activation was thought to occur rather slowly, hence the name slow inward current. Recent evidence suggests that the calcium current occurs much faster and that two types of calcium currents might exist, differing in their selectivity to other ions and in their sensitivity to membrane potential and to drugs.The calcium current is modulated by several factors. Beta-adrenergic stimulation increases the calcium current by increasing the opening probability of the calcium channel. The effects of acetylcholine are less well described. There also exists a class of drugs, called calcium channel blockers (or calcium antagonists) that decrease the flow of calcium ions through calcium channels.It is not quite clear how the calcium current is changed during myocardial ischemia. Factors that may reduce the calcium current during ischemia are the increased extracellular potassium concentration, metabolic inhibition and a decreased ATP level, and acidosis. Raised levels of intracellular cAMP, however, should lead to an increased calcium current.     

Ionic Current in Sinoatrial Node Cells

Ionic Current in Sinoatrial Node Cells. In this article, we report our current understanding of ionic mechanisms of the spontaneous rhythm of the mammalian sinoatrial pacemaker cells obtained from whole-cell voltage clamp studies. Various ionic currents that underlie the pacemaker potential are discussed. Calcium (Ca) current, delayed-rectifier potassium (K) current, and hyperpolarization-activated inward current were found to be the major time-dependent currents responsible for the pacemaker depolarization. Together with these time-dependent currents, a time-independent background current may also contribute to generation of pacemaker activity.     

Membrane current changes induced by acetylstrophanthidin in cardiac Purkinje fibers

Voltage clamp experiments were carried out with short Purkinje fibers exposed to acetylstrophanthidin. A consistent change in membrane current was an appearance of a transient inward current on repolarization to the resting potential from the preceding depolarization, when preparations were treated with sufficient concentration of acetylstrophanthidin to cause the transient depolarization. This transient inward current displayed voltage- and time-dependence on the preceding depolarization, of which kinetics were different from the pacemaker K+ current. The transient inward current was easily blocked by manganese ions. The results indicated that acetylstrophanthidin induced the transient inward current which was the basis of the transient depolarization and the current might represent an abnormal state of the slow inward current possibly related to the altered internal Na+ and Ca++ concentrations.     

Inhibition of sodium pump by l-palmitoylcarnitine in single guinea-pig ventricular myocytes.

We reinvestigated the issue of whether l-palmitoylcarnitine inhibits the Na/K pump in the heart. The effects of l-palmitoylcarnitine or ouabain on the Na/K pump current were studied with the voltage-clamp technique in isolated guinea-pig ventricular myocytes. In myocytes bathed in Tyrode's solution, l-palmitoylcarnitine shifted the current-voltage relation inward at all potentials between -80 and 20 mV. the "U"-shaped difference current seen in l-palmitoylcarnitine was maximal at -30 mV and declined at potentials more positive and negative than this. Under conditions that minimized time-dependent currents, ouabain or l-palmitoylcarnitine shifted membrane current inward in the presence of 5.4 mM extracellular potassium. Reduction of extracellular potassium to 0 mM for 2 min also shifted membrane current inward. When extracellular potassium was returned to 5.4 mM, the intracellular sodium that had accumulated was extruded and a transient outward current was generated as a result of Na/K pump stimulation. Ouabain or l-palmitoylcarnitine reversibly suppressed this transient outward current and reduced the rate constant for the decline of this current. The ability of l-palmitoylcarnitine to imitate the actions of ouabain on membrane current and on the transient outward current indicates that this amphiphile inhibits the Na/K pump current in guinea-pig ventricular myocytes. This results is consistent with the suppression by l-palmitoylcarnitine of the activity of Na/K ATPase in cardiac sarcolemmal vesicles.     

Sensitivity of cough with capsaicin in smokers

In this study, effect of long term smoking on sensitivity of cough reflex was investigated. Healthy, current smoker male and female was evaluated by capsaicin cough challenge test and they were compared with healthy, non-smoker persons with similar age and gender, prospectively. In current smokers, there were 50 male and 39 female, in non-smoker control group, there were 20 male and 21 female. Mean and log C5 dosage in current smoker and non-smoker groups and mean and log C5 dosage in current smoker according to gender were calculated by using Mann-Whitney U-test. Results of capsaicin cough challenge test in current and non-smoker groups were evaluated by using Pearson Chi-Square test and Fisher's Exact test. In current smokers comparison of results of capsaicin cough challenge test with smoking history (age with first smoking, duration, pocket year and smoking per day) was evaluated by using Mann-Whitney U-test. Mean C5 and mean log C5 dosage were found decreased in current smokers when they were compared to control group (p< 0.00). In current smoker group mean C5 and mean log C5 dosage were found decreased in male (p< 0.002). When the results of capsaicin cough challenge test were compared between current smoker and control groups, sensitivity of cough reflex in concentration with 0.49, 0.98, 1.95, 3.9, 7.8, 15.6 microM was significantly decreased in current smoker group. Also there was a significant correlation between concentration with 0.98, 1.95, 3.9, 7.8, 15.6, 31.2 microM, and duration of smoking and pocket year of smoking. Also there was a correlation between concentration with 15.6, 31.2, 62.5, 125 microM and smoking per day. This results were correlated with hypothesis about inhibition of C-fibers with nicotin or decrease of C-fibers' sensitivity due to induction of neuropeptide wasting.     

New pharmacologic approaches in gastroesophageal reflux disease

This article highlights current and emerging pharmacological treatments for gastroesophageal reflux disease (GERD), opportunities for improving medical treatment, the extent to which improvements may be achieved with current therapy, and where new therapies may be required. These issues are discussed in the context of current thinking on the pathogenesis of GERD and its various manifestations and on the pharmacologic basis of current treatments.