scholarly journals Dual Mechanisms of Cardiac Action Potential Prolongation by 4-Oxo-Nonenal Increasing the Risk of Arrhythmia; Late Na+ Current Induction and hERG K+ Channel Inhibition

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1139
Author(s):  
Seong-Woo Choi ◽  
Ming-Zhe Yin ◽  
Na-Kyeong Park ◽  
Joo-Han Woo ◽  
Sung-Joon Kim
Keyword(s):  
Action Potential ◽  
Simulation Analysis ◽  
K Channel ◽  
Delayed Rectifier ◽  
Lipid Peroxidation Product ◽  
Na Current ◽  
Channel Inhibition ◽  
Arrhythmogenic Effect ◽  
Peroxidation Product ◽  
Channel Currents

4-Oxo-nonenal (4-ONE) is an endogenous lipid peroxidation product that is more reactive than 4-hydroxy-nonenal (4-HNE). We previously reported the arrhythmic potential of 4-HNE by suppression of cardiac human Ether-a-go-go Related Gene (hERG) K+ channels with prolonged action potential duration (APD) in cardiomyocytes. Here, we illustrate the higher arrhythmic risk of 4-ONE by modulating the cardiac hNaV1.5 channel currents (INaV). Although the peak amplitude of INaV was not significantly changed by 4-ONE up to 10 μM, the rate of INaV inactivation was slowed, and the late Na+ current (INaL) became larger by 10 μM 4-ONE. The chemical modification of specific residues in hNaV1.5 by 4-ONE was identified using MS-fingerprinting analysis. In addition to the changes in INaV, 4-ONE decreased the delayed rectifier K+ channel currents including the hERG current. The L-type Ca2+ channel current was decreased, whereas its inactivation was slowed by 4-ONE. The APD prolongation by 10 μM of 4-ONE was more prominent than that by 100 μM of 4-HNE. In the computational in silico cardiomyocyte simulation analysis, the changes of INaL by 4-ONE significantly exacerbated the risk of arrhythmia exhibited by the TdP marker, qNet. Our study suggests an arrhythmogenic effect of 4-ONE on cardiac ion channels, especially hNaV1.5.

scholarly journals Second-Generation Histamine H1 Receptor Antagonists Suppress Delayed Rectifier K+-Channel Currents in Murine Thymocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Kazutomo Saito ◽  
Nozomu Abe ◽  
Hiroaki Toyama ◽  
Yutaka Ejima ◽  
Masanori Yamauchi ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Second Generation ◽  
Membrane Capacitance ◽  
K Channel ◽  
Delayed Rectifier ◽  
Cell Recording ◽  
Voltage Dependent ◽  
Proliferation Of Lymphocytes ◽  
First Time ◽  
Channel Currents

Background/Aims. Voltage-dependent potassium channels (Kv1.3) are predominantly expressed in lymphocyte plasma membranes. These channels are critical for the activation and proliferation of lymphocytes. Since second-generation antihistamines are lipophilic and exert immunomodulatory effects, they are thought to affect the lymphocyte Kv1.3-channel currents. Methods. Using the patch-clamp whole-cell recording technique in murine thymocytes, we tested the effects of second-generation antihistamines, such as cetirizine, fexofenadine, azelastine, and terfenadine, on the channel currents and the membrane capacitance. Results. These drugs suppressed the peak and the pulse-end currents of the channels, although the effects of azelastine and terfenadine on the peak currents were more marked than those of cetirizine and fexofenadine. Both azelastine and terfenadine significantly lowered the membrane capacitance. Since these drugs did not affect the process of endocytosis in lymphocytes, they were thought to have interacted directly with the plasma membranes. Conclusions. Our study revealed for the first time that second-generation antihistamines, including cetirizine, fexofenadine, azelastine, and terfenadine, exert suppressive effects on lymphocyte Kv1.3-channels. The efficacy of these drugs may be related to their immunomodulatory mechanisms that reduce the synthesis of inflammatory cytokine.

scholarly journals Permeation, selectivity, and blockade of the Ca2+-activated potassium channel of the guinea pig taenia coli myocyte.

1989 ◽  
Vol 94 (5) ◽  
pp. 849-862 ◽  
Author(s):  
S L Hu ◽  
Y Yamamoto ◽  
C Y Kao
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Single Channel ◽  
K Channel ◽  
Delayed Rectifier ◽  
Dependent Manner ◽  
Taenia Coli ◽  
Excitable Membranes ◽  
Voltage Dependent ◽  
Permeation Properties

The permeation properties of the 147-pS Ca2+-activated K+ channel of the taenia coli myocytes are similar to those of the delayed rectifier channel in other excitable membranes. It has a selectivity sequence of K+ 1.0 greater than Rb+ 0.65 greater than NH4+ 0.50. Na+, Cs+, Li+, and TEA+ (tetraethylammonium) are impermeant. Internal Na+ blocks K+ channel in a strongly voltage-dependent manner with an equivalent valence (zd) of 1.20. Blockade by internal Cs+ and TEA+ is less voltage dependent, with d of 0.61 and 0.13, and half-blockage concentrations of 88 and 31 mM, respectively. External TEA+ is about 100 times more effective in blocking the K+ channel. All these findings suggest that the 147-pS Ca2+-activated K+ channel in the taenia myocytes, which functions physiologically like the delayed rectifier, is the single-channel basis of the repolarizing current in an action potential.

Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits

2006 ◽  
Vol 291 (3) ◽  
pp. H1446-H1455 ◽  
Author(s):  
Yiqiang Zhang ◽  
Jiening Xiao ◽  
Huizhen Wang ◽  
Xiaobin Luo ◽  
Jingxiong Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Rabbit Model ◽  
Clinical Problem ◽  
Qt Prolongation ◽  
Dependent Diabetes Mellitus ◽  
K Channel ◽  
Delayed Rectifier ◽  
Diabetic Patients ◽  
Qtc Interval

Abnormal QT prolongation (QT-P) in diabetic patients has become a nonnegligible clinical problem and has attracted increasing attention from basic scientists, because it increases the risk of lethal ventricular arrhythmias. Correction of QT-P may be an important measure in minimizing sudden cardiac death in diabetic patients. Here we report the efficacy of insulin in preventing QT-P and the associated arrhythmias and the mechanisms underlying the effects in a rabbit model of type 1 insulin-dependent diabetes mellitus (IDDM). The heart rate-corrected QT (QTc) interval and action potential duration were considerably prolonged, with frequent ventricular tachycardias. The rapid delayed rectifier K+ current ( IKr) was markedly reduced in IDDM hearts, and hyperglycemia depressed the function of the human ether-a-go-go-related gene (HERG), which conducts IKr. The impairment was primarily ascribed to the enhanced oxidative damage to the myocardium, as indicated by the increased intracellular level of reactive oxygen species and simultaneously decreased endogenous antioxidant reserve and by the increased lipid peroxidation and protein oxidation. Moreover, IDDM or hyperglycemia resulted in downregulation of HERG protein level. Insulin restored the depressed IKr/HERG and prevented QTc/action potential duration prolongation and the associated arrhythmias, and the beneficial actions of insulin are partially due to its antioxidant ability. Our study represents the first documentation of oxidative stress as the major metabolic mechanism for HERG K+ dysfunction, which causes diabetic QT-P, and suggests IKr/HERG as a potential therapeutic target for treatment of the disorder.

scholarly journals Differential effects of ginsenoside metabolites on slowly activating delayed rectifier K+and KCNQ1 K+channel currents

2013 ◽  
Vol 37 (3) ◽  
pp. 324-331
Author(s):  
Sun-Hye Choi ◽  
Byung-Hwan Lee ◽  
Hyeon-Joong Kim ◽  
Seok-Won Jung ◽  
Sung-Hee Hwang ◽  
...  
Keyword(s):  
K Channel ◽  
Delayed Rectifier ◽  
Differential Effects ◽  
Channel Currents

Characterization of single non-inactivating potassium channels in primary neuronal cultures of Drosophila

1989 ◽  
Vol 145 (1) ◽  
pp. 173-184
Author(s):  
D. Yamamoto ◽  
N. Suzuki
Keyword(s):  
Time Distribution ◽  
Single Channel ◽  
K Channel ◽  
Delayed Rectifier ◽  
Neuronal Cultures ◽  
Patch Clamp Technique ◽  
Primary Neuronal Cultures ◽  
Single Channel Currents ◽  
Channel Currents ◽  
Cytoplasmic Side

Permeability and gating properties of single, non-inactivating, K+ channel currents in cultured Drosophila neurons were studied using the gigaohm-seal patch-clamp technique. The non-inactivating K+ currents were activated by depolarizing the membrane to −30 mV or to more positive potentials. The slope conductance of the channel was estimated to be 17.6 +/− 3.70 pS when the cytoplasmic side of the inside-out membrane patch was perfused with solutions containing 145 mmoll-1 K+. The single-channel conductance was temperature-sensitive, with a Q10 of 1.44 between 10 and 20 degrees C. Single-channel currents could be recorded when the cytoplasmic K+ was replaced with NH4+, Rb+ or Na+, but not with Cs+. The conductance ratio of the channel for these cations was: K+ (1) greater than NH4+(0.53) greater than Rb+ (0.47) greater than Na+ (0.44). Tetraethylammonium (TEA+) ions applied at a concentration of 10 mmoll-1 to the cytoplasmic side of the membrane increased the frequency of ‘blank’ traces which contained no channel openings during repetitive depolarization. In addition, single-channel amplitude was reduced by about 20%. The open-time distribution was fitted by a single exponential function, whereas the closed-time distribution required a three-exponential fit. Permeability and gating properties of single, non-inactivating K+ channel currents in neurons of eag, a mutant which has defects in the delayed rectifier K+ channel, were indistinguishable from those recorded from wild-type neurons.

Mechanisms Underlying the QT Interval–prolonging Effects of Sevoflurane and Its Interactions with Other QT-prolonging Drugs

2006 ◽  
Vol 104 (5) ◽  
pp. 1015-1022 ◽  
Author(s):  
Jiesheng Kang ◽  
William P. Reynolds ◽  
Xiao-Liang Chen ◽  
Junzhi Ji ◽  
Hongge Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Antiarrhythmic Drugs ◽  
Ventricular Repolarization ◽  
K Channel ◽  
Na Channel ◽  
Ca Channel ◽  
Class Iii ◽  
K Channels ◽  
Channel Currents

Background Sevoflurane prolongs ventricular repolarization in patients, but the mechanisms are not fully characterized. The effects of sevoflurane on many cloned human cardiac ion channels have not been studied, and the interactions between sevoflurane and other drugs that prolong cardiac repolarization have not been detailed. Methods The effects of sevoflurane on action potentials and L-type Ca channels in guinea pig myocytes were examined. Sevoflurane's effects on cloned human cardiac K channels and the cloned human cardiac Na channel were studied. The consequences of combining sevoflurane and the class III antiarrhythmic drugs sotalol or dofetilide on action potential duration were also examined. Results Sevoflurane produced an increase in action potential duration at concentrations of 0.3-1 mm. Contrary to most drugs that delay ventricular repolarization, sevoflurane was without effect on the human ether-a-go-go-related gene cardiac potassium channel but instead produced a reduction in KvLQT1/minK K channel currents and inhibited the Kv4.3 K channel by speeding its apparent rate of inactivation. Sevoflurane had little effect on Na and Ca channel currents at concentrations of 1 mm or less. When the authors coadministered sevoflurane with sotalol or dofetilide, synergistic effects on repolarization were observed, resulting in large increases in action potential duration (up to 66%). Conclusion Prolonged ventricular repolarization observed with administration of sevoflurane results from inhibition of KvLQT1/minK and Kv4.3 cardiac K channels. Combining sevoflurane with class III antiarrhythmic drugs results in supra-additive effects on action potential duration. The results indicate that sevoflurane, when administered with this class of drug, could result in excessive delays in ventricular repolarization. The results suggest the need for further clinical studies.

scholarly journals Ionic currents and ion channels of lobster olfactory receptor neurons.

1989 ◽  
Vol 94 (6) ◽  
pp. 1085-1099 ◽  
Author(s):  
T S McClintock ◽  
B W Ache
Keyword(s):  
Ion Channels ◽  
Olfactory Receptor ◽  
Ionic Currents ◽  
K Channel ◽  
Delayed Rectifier ◽  
Na Current ◽  
Cl Channel ◽  
Inward Currents ◽  
K Current ◽  
K Currents

The role of the soma of spiny lobster olfactory receptor cells in generating odor-evoked electrical signals was investigated by studying the ion channels and macroscopic currents of the soma. Four ionic currents; a tetrodotoxin-sensitive Na+ current, a Ca++ current, a Ca(++)-activated K+ current, and a delayed rectifier K+ current, were isolated by application of specific blocking agents. The Na+ and Ca++ currents began to activate at -40 to -30 mV, while the K+ currents began to activate at -30 to -20 mV. The size of the Na+ current was related to the presence of a remnant of a neurite, presumably an axon, and not to the size of the soma. No voltage-dependent inward currents were observed at potentials below those activating the Na+ current, suggesting that receptor potentials spread passively through the soma to generate action potentials in the axon of this cell. Steady-state inactivation of the Na+ current was half-maximal at -40 mV. Recovery from inactivation was a single exponential function that was half-maximal at 1.7 ms at room temperature. The K+ currents were much larger than the inward currents and probably underlie the outward rectification observed in this cell. The delayed rectifier K+ current was reduced by GTP-gamma-S and AIF-4, agents which activate GTP-binding proteins. The channels described were a 215-pS Ca(++)-activated K+ channel, a 9.7-pS delayed rectifier K+ channel, and a 35-pS voltage-independent Cl- channel. The Cl- channel provides a constant leak conductance that may be important in stabilizing the membrane potential of the cell.

Benidipine persistently inhibits delayed rectifier K+-channel currents in murine thymocytes

2012 ◽  
Vol 35 (1) ◽  
pp. 28-33 ◽  
Author(s):  
Itsuro Kazama ◽  
Yoshio Maruyama ◽  
Mitsunobu Matsubara
Keyword(s):  
K Channel ◽  
Delayed Rectifier ◽  
Channel Currents

Suppression of Potassium Conductance by Droperidol Has Influence on Excitability of Spinal Sensory Neurons

2001 ◽  
Vol 94 (2) ◽  
pp. 280-289 ◽  
Author(s):  
Andrea Olschewski ◽  
Gunter Hempelmann ◽  
Werner Vogel ◽  
Boris V. Safronov
Keyword(s):  
Action Potential ◽  
Dorsal Horn ◽  
Sensory Neurons ◽  
K Channel ◽  
Delayed Rectifier ◽  
Membrane Excitability ◽  
Patch Clamp Technique ◽  
K Channels ◽  
Dorsal Horn Neurons ◽  
Drug Concentrations

Background During spinal and epidural anesthesia with opioids, droperidol is added to prevent nausea and vomiting. The mechanisms of its action on spinal sensory neurons are not well understood. It was previously shown that droperidol selectively blocks a fast component of the Na+ current. The authors studied the action of droperidol on voltage-gated K+ channels and its effect on membrane excitability in spinal dorsal horn neurons of the rat. Methods Using a combination of the patch-clamp technique and the "entire soma isolation" method, the action of droperidol on fast-inactivating A-type and delayed-rectifier K+ channels was investigated. Current-clamp recordings from intact sensory neurons in spinal cord slices were performed to study the functional meaning of K+ channel block for neuronal excitability. Results Droperidol blocked delayed-rectifier K+ currents in isolated somata of dorsal horn neurons with a half-maximum inhibiting concentration of 20.6 microm. The A-type K+ current was insensitive to up to 100 microm droperidol. At droperidol concentrations insufficient for suppression of an action potential, the block of delayed-rectifier K+ channels led to an increase in action potential duration and, as a consequence, to lowering of the discharge frequency in the neuron. Conclusions Droperidol blocks delayed-rectifier K+ channels in a concentration range close to that for suppression of Na+ channels. The block of delayed-rectifier K+ channels by droperidol enhances the suppression of activity in spinal sensory neurons at drug concentrations insufficient for complete conduction block.

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