			Home About us Contact

Transient Outward Current (transient + outward_current)

Distribution by Scientific Domains

Medical Sciences	90%

Selected Abstracts

Chromanol 293B Inhibits Slowly Activating Delayed Rectifier and Transient Outward Currents in Canine Left Ventricular Myocytes

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2001
Ph.D., ZHUO-QIAN SUN M.D.
Chromanol 293B on Ionic Currents.Introduction: Drugs that selectively inhibit the slowly activating component of the delayed rectifier potassium current (IKs) are being considered as possible antiarrhythmic agents, because they produce more prolongation of action potential duration at fast rates with less transmural dispersion of repolarization compared with blockers of the rapidly activating component (IKr). Although the chromanol derivative chromanol 293B has been shown to be relatively selective in blocking IKs in some species, its selectivity is far from established. Methods and Results: The present study uses whole-cell, patch-clamp technique to examine the selectivity of this compound for inhibition of IKs in comparison with other repolarizing ionic currents, such as IKr, inward rectifier potassium current (IK1), transient outward current (Ito), and L-type calcium current (ICa-L) in canine left ventricular mid-myocardial and endocardial cells. Chromanol 293B blocked IKs with an IC50 of 1.8 ,M and Ito with an IC50 of 38 ,M. Concentrations as high as 30 ,M did not affect IK1, IKr, or ICa-L. Higher concentrations of chromanol 293B (100 ,M) caused a slight, but statistically insignificant, inhibition of IKr. Conclusion: Our results indicate that chromanol 293B is a relatively selective blocker of IKs in canine left ventricular myocytes. [source]

A slowly inactivating sodium current (INa2) in the plateau range in canine cardiac Purkinje single cells

EXPERIMENTAL PHYSIOLOGY, Issue 1 2007
Mario Vassalle
The action potential of Purkinje fibres is markedly shortened by tetrodotoxin, suggesting the possibility that a slowly inactivating sodium current might flow during the plateau. The aim of the present experiments was to investigate, in canine cardiac Purkinje single cells by means of a whole cell patch clamp technique, whether a sodium current slowly inactivates at less negative potentials and (if so) some of its distinctive characteristics. The results showed that a 500 ms depolarizing step from a holding potential of ,90 mV to ,50 mV induced the fast inward current INa (labelled here INa1). With steps to ,40 mV or less negative values, a slowly decaying component (tentatively labelled here INa2) appeared, which peaked at ,30 to ,20 mV and decayed slowly and incompletely during the 500 ms steps. The INa2 was present also during steps to ,10 mV, but then the transient outward current (Ito) appeared. When the holding potential (Vh) was decreased to ,60 to ,50 mV, INa2 disappeared even if a small INa1 might still be present. Tetrodotoxin (30 ,m), lignocaine (100 ,m) and cadmium (0.2 mm; but not manganese, 1 mm) blocked INa2. During fast depolarizing ramps, the rapid inactivation of INa1 was followed by a negative slope region. During repolarizing ramps, a region of positive slope was present, whereas INa1 was absent. At less negative values of Vh, the amplitude of the negative and positive slopes became gradually smaller. Gradually faster ramps increased the magnitude of the negative slope, and tetrodotoxin (30 ,m) reduced or abolished it. Thus, Purkinje cells have a slowly decaying inward current owing to Na+ entry (INa2) that is different in several ways from the fast INa1 and that appears important for the duration of the plateau. [source]

Repolarization Abnormality in Idiopathic Ventricular Fibrillation:

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2004
Assessment Using 24-Hour QT-RR, QaT-RR Relationships
Introduction: We evaluated the characteristics of QT-RR and QaT (apex of T wave)-RR relationships in patients with idiopathic ventricular fibrillation (IVF) compared with control subjects. We hypothesized that IVF patients have unique repolarization dynamics related to a reduced fast Na current and a prominent transient outward current. Methods and Results: The study group consisted of 9 men (age 47 ± 10 years) with IVF (6 with Brugada type and 3 with non-Brugada type) who had experienced nocturnal episodes of VF. The control group consisted of 28 healthy age-matched men (age 44 ± 12 years). The relationships between QT and RR intervals and between QaT and RR intervals were analyzed from 24-hour Holter ECG data using an automatic measurement system. Both QT and QaT at RR intervals of 0.6, 1.0, and 1.2 seconds were determined from QT-RR and QaT-RR linear regression lines. Both QT-RR and QaT-RR slopes were lower in the IVF group than in the control group (QT-RR: 0.092 ± 0.023 vs 0.137 ± 0.031, P < 0.001; QaT-RR: 0.109 ± 0.025 vs 0.153 ± 0.028, P < 0.001). QT at an RR interval of 0.6 second did not differ between two groups, but QT at RR intervals of either 1.0 or 1.2 seconds was significantly shorter in the IVF group than in the control group (RR 1.0 s: 0.384 ± 0.018 vs 0.399 ± 0.017, P < 0.05; RR 1.2 s: 0.402 ± 0.019 vs 0.426 ± 0.020, P < 0.01). QaT at RR intervals of either 1.0 or 1.2 seconds also was shorter in the IVF group (RR 1.0 s: 0.289 ± 0.022 vs 0.312 ± 0.021, P < 0.01; RR 1.2 s: 0.311 ± 0.024 vs 0.343 ± 0.024, P < 0.01). In four patients, oral administration of disopyramide (300 mg/day) was effective in suppressing VF episodes and increased slopes of QT-RR and QaT-RR relationships. Conclusion: IVF patients had lower slopes of QT-RR and QaT-RR regression lines and impaired prolongation of QT and QaT at longer RR intervals compared with control subjects. These unique repolarization dynamics may be related to the frequent occurrence of VF episodes at night. (J Cardiovasc Electrophysiol, Vol. 15, pp. 59-63, January 2004) [source]

Chromanol 293B Inhibits Slowly Activating Delayed Rectifier and Transient Outward Currents in Canine Left Ventricular Myocytes

Modulation of cardiac ionic homeostasis by 3-iodothyronamine

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009
Sandra Ghelardoni
Abstract 3-iodothyronamine (T1AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect. In the isolated rat heart 20,25 ,M T1AM decreased cardiac contractility, but oxygen consumption and glucose uptake were either unchanged or disproportionately high when compared to mechanical work. In adult rat cardiomyocytes acute exposure to 20 ,M T1AM decreased the amplitude and duration of the calcium transient. In patch clamped cardiomyocytes sarcolemmal calcium current density was unchanged while current facilitation by membrane depolarization was abolished consistent with reduced sarcoplasmic reticulum (SR) calcium release. In addition, T1AM decreased transient outward current (Ito) and IK1 background current. SR studies involving 20 ,M T1AM revealed a significant decrease in ryanodine binding due to reduced Bmax, no significant change in the rate constant of calcium-induced calcium release, a significant increase in calcium leak measured under conditions promoting channel closure, and no effect on oxalate-supported calcium uptake. Based on these observations we conclude T1AM affects calcium and potassium homeostasis and suggest its negative inotropic action is due to a diminished pool of SR calcium as a result of increased diastolic leak through the ryanodine receptor, while increased action potential duration is accounted for by inhibition of Ito and IK1 currents. [source]

Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2003
Erika Hanada
ABSTRACT Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10,100 ,m) and erythromycin (100 ,m) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 ,m) and Ito (IC50 = 20.9 + 0.13 ,m) while erythromycin reduced IK (IC50 = 60.1 + 0.29 ,m) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration. [source]

Influence of Extracellular K+ Concentrations on Quinidine-induced K+ Current Inhibition in Rat Ventricular Myocytes

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2000
MICHIKO HIROTA
Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (IK), the transient outward current (Ito), and the inward rectifier potassium current (IK1), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on IK, Ito, and IK1 were evaluated under both normal ([K+]o = 5.4 mM) and hypokalaemic ([K+]o = 3.5 mM) conditions. In contrast to both IK and Ito, which were barely influenced by changes in [K+]o, IK1 was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both IK and Ito in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+]o. The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 ,M (IK), and 17.6 and 17.3 ,M (Ito). Although higher concentrations of quinidine were required to inhibit IK1, the inhibitory potency of quinidine was also found to be insensitive to changes in [K+]o. Thus, in rats, the inhibitory potency of quinidine for the K+ current-types IK, Ito and IK1 is barely influenced by changes in [K+]o. These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalaemia does not affect IK or Ito, it can inhibit IK1 and can result in QT prolongation in-vivo. [source]

A Metabolic Mechanism For Cardiac K+ Channel Remodelling

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002
George J Rozanski
SUMMARY 1. Electrical remodelling of the ventricle is a common pathogenic feature of cardiovascular disease states that lead to heart failure. Experimental data suggest this change in electrophysiological phenotype is largely due to downregulation of K+ channels involved in repolarization of the action potential. 2. Voltage-clamp studies of the transient outward current (Ito) in diabetic cardiomyopathy support a metabolic mechanism for K+ channel downregulation. In particular, Ito density is significantly increased in diabetic rat isolated ventricular myocytes treated in vitro with insulin or agents that activate pyruvate dehydrogenase. Recent data suggest this mechanism is not limited to diabetic conditions, because metabolic stimuli that upregulate Ito in diabetic rat myocytes act similarly in non- diabetic models of heart failure. 3. Depressed Ito channel activity is also reversed by experimental conditions that increase myocyte levels of reduced glutathione, indicating that oxidative stress is involved in electrical remodelling. Moreover, upregulation of Ito density by activators of glucose utilization is blocked by inhibitors of glutathione metabolism, supporting the premise that there is a functional link between glucose utilization and the glutathione system. 4. Electrophysiological studies of diabetic and non-diabetic disease conditions affecting the heart suggest Ito channels are regulated by a redox-sensitive mechanism, where glucose utilization plays an essential role in maintaining a normally reduced state of the myocyte. This hypothesis has implications for clinical approaches aimed at reversing pathogenic electrical remodelling in a variety of cardiovascular disease states. [source]

Endothelin-1 Modulates the Arrhythmogenic Activity of Pulmonary Veins

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 3 2008
AMEYA R. UDYAVAR M.D.
Objective: Endothelin-1 has important cardiovascular effects and is activated during atrial fibrillation. Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. The aim of this study was to evaluate whether endothelin-1 affects PV arrhythmogenic activity. Methods: Conventional microelectrodes were used to record the action potentials (APs) and contractility in isolated rabbit PV tissue specimens before and after the administration of endothelin-1 (0.1, 1, 10 nM). The ionic currents of isolated PV cardiomyocytes were investigated before and after the administration of endothelin-1 (10 nM) through whole-cell patch clamps. Results: In the tissue preparation, endothelin-1 (1, 10 nM) concentration dependently shortened the AP duration and decreased the PV firing rates. Endothelin-1 (10 nM) decreased the resting membrane potential. Endothelin-1 (0.1, 1, 10 nM) decreased the contractility and increased the resting diastolic tension. In single PV cardiomyocytes, endothelin-1 (10 nM) decreased the PV firing rates from 2.7 ± 1.0 Hz to 0.8 ± 0.5 Hz (n = 16). BQ-485 (100 ,M, endothelin-1 type A receptor blocker) reversed and prevented the chrono-inhibitory effects of endothelin-1 (10 nM). Endothelin-1 (10 nM) reduced the L-type calcium currents, transient outward currents, delayed rectifier currents, transient inward currents, and sodium,calcium exchanger currents in the PV cardiomyocytes with and without pacemaker activity. Endothelin-1 (10 nM) increased the inward rectifier potassium current, hyperpolarization-induced pacemaker current, and the sustained outward potassium current in PV cardiomyocytes with and without pacemaker activity. Conclusion: Endothelin-1 may have an antiarrhythmic potential through its direct electrophysiological effects on the PV cardiomyocytes and its action on multiple ionic currents. [source]

Multiple effects of mefenamic acid on K+ currents in smooth muscle cells from pig proximal urethra

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2003
N Teramoto
The effects of mefenamic acid on both membrane potential and K+ currents in pig urethral myocytes were investigated using patch-clamp techniques (conventional whole-cell, cell-attached, outside-out and inside-out configuration). In the current-clamp mode, mefenamic acid caused a concentration-dependent hyperpolarization, which was inhibited by preapplication of 1 ,M glibenclamide. In the voltage-clamp mode, mefenamic acid induced an outward current that was blocked by glibenclamide even in the presence of iberiotoxin (IbTX, 300 nM) at ,50 mV. ATP-sensitive K+ channels (KATP channels) could be activated in the same patch by mefenamic acid and levcromakalim, with the same unitary amplitude and the similar opening gating at ,50 mV in cell-attached configuration. In outside-out recording, external application of mefenamic acid activated intracellular Ca2+ -activated IbTX-sensitive large-conductance K+ channels (BKCa channels). Mefenamic acid (30 ,M) activated spontaneous transient outward currents (STOCs). In contrast, mefenamic acid (100 ,M) increased sustained outward currents, diminishing the activity of STOCs. Over the whole voltage range, mefenamic acid caused opposite effects on the membrane currents in the absence and presence of 5 ,M glibenclamide. In the presence of 10 mM 4-aminopyridine (4-AP), mefenamic acid only increased the outward currents. These results indicate that mefenamic acid increases the channel activities of two distinct types of K+ channels (i.e. BKCa channels and KATP channels) and decreased 4-AP-sensitive K+ channels in pig urethral myocytes. British Journal of Pharmacology (2003) 140, 1341,1350. doi:10.1038/sj.bjp.0705524 [source]

Electrophysiological effects of endothelin-1 and their relationship to contraction in rat renal arterial smooth muscle

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000
Luisa C Betts
The electophysiological effects of endothelin-1 (ET-1) and their relationship to contraction remain unclear in the renal circulation. Using endotheliumdenuded arteries from the main branch of the renal artery proximal to the kidney of the rat, we have examined its effects on tension and conducted parallel patch-clamp measurements using freshly isolated smooth muscle cells from this tissue. Pharmacological experiments revealed that ET-1 produced constriction of renal arteries dependent on the influx of extracellular Ca2+, mediated solely through ETA receptor stimulation. Current-clamp experiments revealed that renal arterial myocytes had a resting membrane potential of ,32 mV, with the majority of cells exhibiting spontaneous transient hyperpolarizations (STHPs). Application of ET-1 produced depolarization and in those cells exhibiting STHPs, either caused their inhibition or made them occur regularly. Under voltage-clamp conditions cells were observed to exhibit spontaneous transient outward currents (STOCs) inhibited by iberiotoxin. Application of voltage-ramps revealed an outward current activated at ,,30 mV, sensitive to both 4-AP and TEA. Taken together these results suggest that renal arterial myocytes possess both delayed rectifying K+ (KV) and Ca2+ -activated K+ (BKCa) channels. Under voltage-clamp, ET-1 attenuated the outward current and reduced the magnitude and incidence of STOCs: effects mediated solely as a consequence of ETA receptor stimulation. Thus, in conclusion, activation of ETA receptors by ET-1 causes inhibition of KV and BKCa channel activity, which could promote and/or maintain membrane depolarization. This effect is likely to favour L-type Ca2+ channel activity providing an influx pathway for extracellular Ca2+ essential for contraction. British Journal of Pharmacology (2000) 130, 787,796; doi:10.1038/sj.bjp.0703377 [source]