Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

2006 ◽  
Vol 291 (2) ◽  
pp. H570-H580 ◽  
Author(s):  
Ling Xiao ◽  
Liming Zhang ◽  
Wei Han ◽  
Zhiguo Wang ◽  
Stanley Nattel
Keyword(s):  
Sex Differences ◽  
Action Potentials ◽  
Ionic Current ◽  
Ionic Currents ◽  
Left Ventricular ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Qt Intervals ◽  
Whole Cell Patch Clamp ◽  
Ventricular Cells

The female sex is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that sex differences in repolarization may be associated with differential transmural ion-current distribution. Whole cell patch-clamp and current-clamp were used to study ionic currents and action potentials (APs) in isolated canine left ventricular cells from epicardium, midmyocardium, and endocardium. No sex differences in AP duration (APD) were found in cells from epicardium versus endocardium. In midmyocardium, APD was significantly longer in female dogs (e.g., at 1 Hz, female vs. male: 288 ± 21 vs. 237 ± 8 ms; P < 0.05), resulting in greater transmural APD heterogeneity in females. No sex differences in inward rectifier K+ current ( IK1) were observed. Transient outward K+ current ( Ito) densities in epicardium and midmyocardium also showed no sex differences. In endocardium, female dogs had significantly smaller Ito (e.g., at +30 mV, female vs. male: 2.5 ± 0.2 vs. 3.5 ± 0.3 pA/pF; P < 0.05). Rapid delayed-rectifier K+ current ( IKr) density and activation voltage-dependence showed no sex differences. Female dogs had significantly larger slow delayed-rectifier K+ current ( IKs) in epicardium and endocardium (e.g., at +40 mV; tail densities, female vs. male; epicardium: 1.3 ± 0.1 vs. 0.8 ± 0.1 pA/pF; P < 0.001; endocardium: 1.2 ± 0.1 vs. 0.7 ± 0.1 pA/pF; P < 0.05), but there were no sex differences in midmyocardial IKs. Female dogs had larger L-type Ca2+ current ( ICa,L) densities in all layers than male dogs (e.g., at −20 mV, female vs. male, epicardium: −4.2 ± 0.4 vs. −3.2 ± 0.2 pA/pF; midmyocardium: −4.5 ± 0.5 vs. −3.3 ± 0.3 pA/pF; endocarium: −4.5 ± 0.4 vs. −3.2 ± 0.3 pA/pF; P < 0.05 for each). We conclude that there are sex-based transmural differences in ionic currents that may underlie sex differences in transmural cardiac repolarization.

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

2002 ◽  
Vol 283 (3) ◽  
pp. H1031-H1041 ◽  
Author(s):  
Gui-Rong Li ◽  
Chu-Pak Lau ◽  
Anique Ducharme ◽  
Jean-Claude Tardif ◽  
Stanley Nattel
Keyword(s):  
Left Ventricle ◽  
Action Potential ◽  
Action Potentials ◽  
Slow Component ◽  
Ionic Current ◽  
Ionic Currents ◽  
Cell Types ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Early Afterdepolarizations

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K+ current ( I K1) was homogeneously reduced by ∼41% (at −60 mV) in the three cell types. Transient outward K+ current ( I to1) was decreased by 43–45% at +30 mV, and the slow component of the delayed rectifier K+ current ( I Ks) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K+ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I K1, I to1, and I Ks increases APD and favors occurrence of EADs.

scholarly journals The electrophysiological effects of cannabidiol on action potentials and transmembrane potassium currents in rabbit and dog cardiac ventricular preparations

2021 ◽  
Author(s):  
Leila Topal ◽  
Muhammad Naveed ◽  
Péter Orvos ◽  
Bence Pászti ◽  
János Prorok ◽  
...  
Keyword(s):  
Side Effects ◽  
Action Potentials ◽  
Oral Intake ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiovascular Side Effects ◽  
Channel Inhibition ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

AbstractCannabis use is associated with known cardiovascular side effects such as cardiac arrhythmias or even sudden cardiac death. The mechanisms behind these adverse effects are unknown. The aim of the present work was to study the cellular cardiac electrophysiological effects of cannabidiol (CBD) on action potentials and several transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations. CBD increased action potential duration (APD) significantly in both rabbit (from 211.7 ± 11.2. to 224.6 ± 11.4 ms, n = 8) and dog (from 215.2 ± 9.0 to 231.7 ± 4.7 ms, n = 6) ventricular papillary muscle at 5 µM concentration. CBD decreased IKr, IKs and Ito (only in dog) significantly with corresponding estimated EC50 values of 4.9, 3.1 and 5 µM, respectively, without changing IK1. Although the EC50 value of CBD was found to be higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that potassium channel inhibition by lengthening cardiac repolarization might have a role in the possible proarrhythmic side effects of cannabinoids in situations where CBD metabolism and/or the repolarization reserve is impaired.

Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes

1988 ◽  
Vol 254 (6) ◽  
pp. H1157-H1166 ◽  
Author(s):  
J. A. Wasserstrom ◽  
J. J. Salata
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Detectable Effect ◽  
Na Channel ◽  
Na Current ◽  
Voltage Range ◽  
Purkinje Fibers ◽  
Ventricular Cells

We studied the effects of tetrodotoxin (TTX) and lidocaine on transmembrane action potentials and ionic currents in dog isolated ventricular myocytes. TTX (0.1-1 x 10(-5) M) and lidocaine (0.5-2 x 10(-5) M) decreased action potential duration, but only TTX decreased the maximum rate of depolarization (Vmax). Both TTX (1-2 x 10(-5) M) and lidocaine (2-5 x 10(-5) M) blocked a slowly inactivating toward current in the plateau voltage range. The voltage- and time-dependent characteristics of this current are virtually identical to those described in Purkinje fibers for the slowly inactivating inward Na+ current. In addition, TTX abolished the outward shift in net current at plateau potentials caused by lidocaine alone. Lidocaine had no detectable effect on the slow inward Ca2+ current and the inward K+ current rectifier, Ia. Our results indicate that 1) there is a slowly inactivating inward Na+ current in ventricular cells similar in time, voltage, and TTX sensitivity to that described in Purkinje fibers; 2) both TTX and lidocaine shorten ventricular action potentials by reducing this slowly inactivating Na+ current; 3) lidocaine has no additional actions on other ionic currents that contribute to its ability to abbreviate ventricular action potentials; and 4) although both agents shorten the action potential by the same mechanism, only TTX reduces Vmax. This last point suggests that TTX produces tonic block of Na+ current, whereas lidocaine may produce state-dependent Na+ channel block, namely, blockade of Na+ current only after Na+ channels have already been opened (inactivated-state block).

scholarly journals Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

2020 ◽  
Vol 21 (5) ◽  
pp. 1672 ◽  
Author(s):  
Wei-Ting Chang ◽  
Ping-Yen Liu ◽  
Kaisen Lee ◽  
Yin-Hsun Feng ◽  
Sheng-Nan Wu
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Ionic Current ◽  
Small Animal ◽  
Ionic Currents ◽  
Neonatal Rat ◽  
Delayed Rectifier ◽  
Qtc Prolongation ◽  
The Impact

Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na+ and K+ currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K+ current (IK(S)) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of IK(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of IK(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from IK(S) deactivation. As rapid repetitive stimuli, the IK(S) amplitude decreased; however; the LAP-induced inhibition of IK(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K+ and voltage-gated Na+ current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals.

Ionic Currents Underlying Fast Action Potentials in the Obliquely Striated Muscle Cells of the Octopus Arm

2002 ◽  
Vol 88 (6) ◽  
pp. 3386-3397 ◽  
Author(s):  
Dan Rokni ◽  
Binyamin Hochner
Keyword(s):  
Time Constant ◽  
Action Potentials ◽  
Striated Muscle ◽  
Muscle Cells ◽  
Ionic Currents ◽  
Delayed Rectifier ◽  
Inactivation Kinetics ◽  
Activation Kinetics ◽  
Voltage Dependent ◽  
Neuromuscular Systems

The octopus arm provides a unique model for neuromuscular systems of flexible appendages. We previously reported the electrical compactness of the arm muscle cells and their rich excitable properties ranging from fast oscillations to overshooting action potentials. Here we characterize the voltage-activated ionic currents in the muscle cell membrane. We found three depolarization-activated ionic currents: 1) a high-voltage-activated L-type Ca2+ current, which began activating at approximately −35 mV, was eliminated when Ca2+ was substituted by Mg2+, was blocked by nifedipine, and showed Ca2+-dependent inactivation. This current had very rapid activation kinetics (peaked within milliseconds) and slow inactivation kinetics (τ in the order of 50 ms). 2) A delayed rectifier K+ current that was totally blocked by 10 mM TEA and partially blocked by 10 mM 4-aminopyridine (4AP). This current exhibited relatively slow activation kinetics (τ in the order of 15 ms) and inactivated only partially with a time constant of ∼150 ms. And 3) a transient A-type K+ current that was totally blocked by 10 mM 4AP and was partially blocked by 10 mM TEA. This current exhibited very fast activation kinetics (peaked within milliseconds) and inactivated with a time constant in the order of 60 ms. Inactivation of the A-type current was almost complete at −40 mV. No voltage-dependent Na+ current was found in these cells. The octopus arm muscle cells generate fast (∼3 ms) overshooting spikes in physiological conditions that are carried by a slowly inactivating L-type Ca2+ current.

Discrepant effects of heart failure on electrophysiological property in right ventricular outflow tract and left ventricular outflow tract cardiomyocytes

2017 ◽  
Vol 131 (12) ◽  
pp. 1317-1327 ◽  
Author(s):  
Yen-Yu Lu ◽  
Chen-Chuan Cheng ◽  
Chin-Feng Tsai ◽  
Yung-Kuo Lin ◽  
Ting-I Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Action Potential ◽  
Ventricular Arrhythmias ◽  
Ionic Currents ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Left Ventricular Outflow

Ventricular arrhythmias commonly arise from the right (RVOT) and left ventricular outflow tracts (LVOT) in patients without structural heart disease. Heart failure (HF) significantly increases the risk of ventricular arrhythmias. The regional differences and how HF affects the electrophysiological characteristics of RVOT and LVOT cardiomyocytes remain unclear. The whole-cell patch-clamp technique was used to investigate the action potentials and ionic currents in isolated single RVOT and LVOT cardiomyocytes from control rabbits and rabbits with HF induced by rapid ventricular pacing. Comparison with control LVOT cardiomyocytes showed that control RVOT cardiomyocytes have a shorter action potential duration (APD), smaller late Na+ currents (INa-late), larger transient outward (Ito) and larger delayed rectifier K+ currents (IKr-tail), but had similar L-type Ca2+ currents (ICa-L) and Na+/Ca2+ exchanger (NCX) current. HF increased APD, INa-late and NCX, but decreased ICa-L and Ito in RVOT cardiomyocytes. In contrast with this, HF decreased APD and ICa-L, but increased Ito and IKr-tail in LVOT cardiomyocytes. In conclusion, RVOT and LVOT cardiomyocytes had distinctive electrophysiological characteristics. HF differentially modulates action potential morphology and ionic currents in RVOT and LVOT cardiomyocytes.

scholarly journals High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents

2011 ◽  
Vol 301 (5) ◽  
pp. H2006-H2017 ◽  
Author(s):  
Junyi Ma ◽  
Liang Guo ◽  
Steve J. Fiene ◽  
Blake D. Anson ◽  
James A. Thomson ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
High Purity ◽  
Action Potentials ◽  
Ionic Currents ◽  
Delayed Rectifier ◽  
Cardiovascular Research ◽  
Peak Voltage ◽  
Electrophysiological Properties ◽  
Induced Pluripotent ◽  
Multiple Drugs

Human-induced pluripotent stem cells (hiPSCs) can differentiate into functional cardiomyocytes; however, the electrophysiological properties of hiPSC-derived cardiomyocytes have yet to be fully characterized. We performed detailed electrophysiological characterization of highly pure hiPSC-derived cardiomyocytes. Action potentials (APs) were recorded from spontaneously beating cardiomyocytes using a perforated patch method and had atrial-, nodal-, and ventricular-like properties. Ventricular-like APs were more common and had maximum diastolic potentials close to those of human cardiac myocytes, AP durations were within the range of the normal human electrocardiographic QT interval, and APs showed expected sensitivity to multiple drugs (tetrodotoxin, nifedipine, and E4031). Early afterdepolarizations (EADs) were induced with E4031 and were bradycardia dependent, and EAD peak voltage varied inversely with the EAD take-off potential. Gating properties of seven ionic currents were studied including sodium ( INa), L-type calcium ( ICa), hyperpolarization-activated pacemaker ( If), transient outward potassium ( Ito), inward rectifier potassium ( IK1), and the rapidly and slowly activating components of delayed rectifier potassium ( IKr and IKs, respectively) current. The high purity and large cell numbers also enabled automated patch-clamp analysis. We conclude that these hiPSC-derived cardiomyocytes have ionic currents and channel gating properties underlying their APs and EADs that are quantitatively similar to those reported for human cardiac myocytes. These hiPSC-derived cardiomyocytes have the added advantage that they can be used in high-throughput assays, and they have the potential to impact multiple areas of cardiovascular research and therapeutic applications.

Modulatory effects of 5-hydroxytryptamine on voltage-activated currents in cultured antennal lobe neurones of the sphinx moth Manduca sexta.

1995 ◽  
Vol 198 (3) ◽  
pp. 613-627 ◽  
Author(s):  
A R Mercer ◽  
J H Hayashi ◽  
J G Hildebrand
Keyword(s):  
Manduca Sexta ◽  
Adult Development ◽  
Antennal Lobe ◽  
Ionic Currents ◽  
Delayed Rectifier ◽  
Patch Clamp Recording ◽  
Whole Cell Patch Clamp ◽  
K Current ◽  
Reversible Reduction

The modulatory effects of 5-hydroxytryptamine (5-HT or serotonin) on voltage-gated currents in central olfactory neurones of the moth Manduca sexta have been examined in vitro using whole-cell patch-clamp recording techniques. Central olfactory neurones were dissociated from the antennal lobes of animals at stage 5 of the 18 stages of metamorphic adult development. The modulatory actions of 5-HT on voltage-activated ionic currents were examined in a subset of morphologically identifiable antennal lobe neurones maintained for 2 weeks in primary cell culture. 5-HT caused reversible reduction of both a rapidly activating A-type K+ current and a relatively slowly activating K+ current resembling a delayed rectifier-type conductance. 5-HT also reduced the magnitude of voltage-activated Ca2+ influx in these cells. The functional significance of 5-HT-modulation of central neurones is discussed.

scholarly journals Heterologous expression of BI Ca2+ channels in dysgenic skeletal muscle.

1994 ◽  
Vol 104 (5) ◽  
pp. 985-996 ◽  
Author(s):  
B A Adams ◽  
Y Mori ◽  
M S Kim ◽  
T Tanabe ◽  
K G Beam
Keyword(s):  
Skeletal Muscle ◽  
Time Constant ◽  
Ionic Current ◽  
Ionic Currents ◽  
Rabbit Brain ◽  
Charge Movement ◽  
Patch Clamp Technique ◽  
Open Probability ◽  
Whole Cell Patch Clamp ◽  
Ca2 Channels

We have examined the ability of BI (class A) Ca2+ channels, cloned from rabbit brain, to mediate excitation-contraction (E-C) coupling in skeletal muscle. Expression plasmids carrying cDNA encoding BI channels were microinjected into the nuclei of dysgenic mouse myotubes grown in primary culture. Ionic currents and intramembrane charge movements produced by the BI channels were recorded using the whole-cell patch-clamp technique. Injected myotubes expressed high densities of ionic BI Ca2+ channel current (average 31 pA/pF) but did not display spontaneous contractions, and only very rarely displayed evoked contractions. The expressed ionic current was pharmacologically distinguished from the endogenous L-type current of dysgenic skeletal muscle (Idys) by its insensitivity to the dihydropyridine antagonist (+)-PN 200-110. Peak BI Ca2+ currents activated with a time constant (tau a) of approximately 2 ms and inactivated with a time constant (tau h) of approximately 260 ms (20-23 degrees C). The time constant of inactivation (tau h) was not increased by substituting Ba2+ for Ca2+ as charge carrier, demonstrating that BI channels expressed in dysgenic myotubes do not undergo Ca(2+)-dependent inactivation. The average maximal Ca2+ conductance (Gmax) produced by the BI channels was quite large (approximately 534 S/F). In contrast, the average maximal charge movement (Qmax) produced in the same myotubes (approximately 2.7 nC/microF) was quite small, being barely larger than Qmax in control dysgenic myotubes (approximately 2.3 nC/microF). Thus, the ratio Gmax/Qmax for the BI channels was considerably higher than previously found for cardiac or skeletal muscle L-type Ca2+ channels expressed in the same system, indicating that neuronal BI Ca2+ channels exhibit a much higher open probability than these L-type Ca2+ channels.

L-364,373 (R-L3) enantiomers have opposite modulating effects on IKs in mammalian ventricular myocytes

2013 ◽  
Vol 91 (8) ◽  
pp. 586-592 ◽  
Author(s):  
Claudia Corici ◽  
Zsófia Kohajda ◽  
Attila Kristóf ◽  
András Horváth ◽  
László Virág ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Guinea Pig ◽  
Action Potential ◽  
Right Ventricular ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Ventricular Arrhythmias ◽  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Whole Cell Patch Clamp

Activators of the slow delayed rectifier K+ current (IKs) have been suggested as promising tools for suppressing ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3) was nominated to activate IKs in myocytes from several species; however, in some studies, it failed to activate IKs. One later study suggested opposite modulating effects from the R-L3 enantiomers as a possible explanation for this discrepancy. Therefore, we analyzed the effect of the RL-3 enantiomers on IKs in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch-clamp techniques at 37 °C. We synthesized 2 substances, ZS_1270B (right) and ZS_1271B (left), the 2 enantiomers of R-L3. In rabbit myocytes, ZS_1270B enhanced the IKs tail current by approximately 30%, whereas ZS_1271B reduced IKs tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened APD90 (action potential duration measured at 90% repolarization) by 12%, whereas ZS_1271B lengthened it by approximately 15%. We concluded that R-L3 enantiomers in the same concentration range indeed have opposite modulating effects on IKs, which may explain why the racemic drug R-L3 previously failed to activate IKs. ZS_1270B is a potent IKs activator, therefore, this substance is appropriate to test whether IKs activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.

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