scholarly journals Species dependent cardiac electrophysiological effects elicited by various potassium channel blocking drugs

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Tamás Árpádffy-Lovas ◽  
Muhammad Naveed ◽  
Aiman Saleh A. Mohammed ◽  
László Virág ◽  
István Baczkó ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Barium Chloride ◽  
Selective Inhibition ◽  
The Other ◽  
Cardiac Repolarization ◽  
Channel Blocking ◽  
Channel Expression ◽  
Large Animals ◽  
Electrophysiological Effects

Rodents are commonly used as models in electrophysiology. However, distinct differences exist between large animals and rodents in terms of their ion channel expression and action potential shapes, possibly limiting the translational value of findings obtained in rodents. We aimed for a direct comparison of the possible impact of selective inhibition of ion channels on the cardiac repolarization in preparations from human hearts and from model species. We applied the standard microelectrode technique at 37°C on cardiac ventricular preparations (papillary muscles and trabecules) from human (n = 63), dog (n = 47), guinea pig (n = 53), rat (n = 43), and rabbit (n = 16) hearts, paced at 1 Hz. To selectively block the IKur current, 1 µM XEN-D101; IK1 current, 10 µM barium chloride; IKr current, 50 nM dofetilide; IKs current, 500 nM HMR-1556; and Ito current, 100 µM chromanol-293B were applied directly to the tissue bath. The block of IKur and IK1 elicited significantly more prominent prolongation of APD in rats (35.6% and 67.9%, respectively) when compared with the other species, including that of human (1.0% and 2.6%, respectively). On the other hand, IKr block did not affect APD in rat preparations (1.6%), whereas it elicited marked prolongation in other species (9.0–47.7%), especially being pronounced in human preparations (60.3%). IKs inhibition elicited similar but minor APD prolongation (0.3–11.4%) in all species. Inhibition of Ito moderately lengthened APD in dog (22.3%) and rabbit (17.5%) preparations but elicited no change of APD in human preparations. In contrast, block of Ito caused marked APD prolongation in rat preparations (33.2%). Our findings suggest that the specific inhibition of various ion channels elicits fundamentally different effects in rodent ventricular action potential when compared with those of other species, including human. Therefore, from a translational standpoint, rodent models in cardiac electrophysiological and arrhythmia research should be used with great caution.

Molecular Physiology of Cardiac Repolarization

2005 ◽  
Vol 85 (4) ◽  
pp. 1205-1253 ◽  
Author(s):  
Jeanne M. Nerbonne ◽  
Robert S. Kass
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Future Research ◽  
Cardiac Repolarization ◽  
Molecular Physiology ◽  
Cardiac Ion Channels ◽  
Α Subunits

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na+ and Ca2+) and outward (K+) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na+, Ca2+, and K+ channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the Na+, Ca2+, and K+ currents that generate cardiac action potentials, and molecular cloning has revealed a large number of pore forming (α) and accessory (β, δ, and γ) subunits thought to contribute to the formation of these channels. Considerable progress has been made in defining the functional roles of the various channels and in identifying the α-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function as components of macromolecular complexes, comprising the α-subunits, one or more accessory subunit, and a variety of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as well as between cardiac structure and electrical functioning. Important areas of future research will be the identification of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

scholarly journals Ion channel expression and electrophysiology of singular human (primary and induced pluripotent stem cell derived) cardiomyocytes

2021 ◽  
Author(s):  
Christina Schmid ◽  
Najah Abi-Gerges ◽  
Dietmar Zellner ◽  
Georg Rast
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Single Cell ◽  
Action Potential Duration ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Inward Current ◽  
Beat Rate ◽  
Channel Expression

SUMMARYHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary human cardiomyocytes are used for in vitro cardiac safety testing. hiPSC-CMs have been associated with a vast heterogeneity regarding single-cell morphology, beating behavior and action potential duration, prompting a systematic analysis of single-cell characteristics. Previously published hiPSC-CM studies revealed action potentials with nodal-, atrial- or ventricular-like morphology, although ion channel expression of singular hiPSC-CMs is not fully understood. Other studies used single-cell RNA-sequencing, however, these studies did not extensively focus on expression patterns of cardiac ion channels or failed to detect ion channel transcripts. Thus, the current study used a single-cell patch-clamp-RT-qPCR approach to get insights into single-cell electrophysiology (capacitance, action potential duration at 90% of repolarization, upstroke velocity, spontaneous beat rate, and sodium-driven fast inward current) and ion channel expression (HCN4, CACNA1G, CACNA1D, KCNA5, KCNJ4, SCN5A, KCNJ2, CACNA1D, and KCNH2), the combination of both within individual cells, and their correlations in single cardiomyocytes. We used commercially available hiPSC-CMs (iCell cardiomyocytes, atrial and ventricular Pluricytes) and primary human adult atrial and ventricular cardiomyocytes. Recordings of electrophysiological parameters revealed differences between the cell groups and variation within the hiPSC-CMs groups as well as within primary ventricular cardiomyocytes. Expression analysis on mRNA level showed no-clear-cut discrimination between primary cardiac subtypes and revealed both similarities and differences between all cell groups. Higher expression of atrial-associated ion channels in primary atrial cardiomyocytes and atrial Pluricytes compared to their ventricular counterpart indicates a successful chamber-specific hiPSC differentiation. Interpretation of correlations between the single-cell parameters was challenging, as the total data set is complex, particularly for parameters depending on multiple processes, like the spontaneous beat rate. Yet, for example, expression of SCN5A correlated well with the fast inward current amplitude for all three hiPSC-CM groups. To further enhance our understanding of the physiology and composition of the investigated hiPSC-CMs, we compared beating and non-beating cells and assessed distributions of single-cell data. Investigating the single-cell phenotypes of hiPSC-CMs revealed a combination of attributes which may be interpreted as a mixture of traits of different adult cardiac cell types: (i) nodal-related pacemaking attributes are spontaneous generation of action potentials and high HCN4 expression; and (ii) non-nodal attributes: cells have a prominent INa-driven fast inward current, a fast upstroke velocity and a high expression of SCN5A. In conclusion, the combination of nodal- and non-nodal attributes in single hiPSC-CMs may hamper the interpretation of drug effects on complex electrophysiological parameters like beat rate and action potential duration. However, the proven expression of specific ion channels enables the evaluation of drug effects on ionic currents in a more realistic environment than in recombinant systems.

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.

Mechanisms and Physiological Implications of Cooperative Gating of Ion Channels Clusters

2021 ◽  
Author(s):  
Rose Ellen Dixon ◽  
Manuel F. Navedo ◽  
Marc D Binder ◽  
L. Fernando Santana
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Transient Receptor Potential ◽  
Imaging Techniques ◽  
Ryanodine Receptors ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Cardiac Cells ◽  
Fine Tuning ◽  
Voltage Gated

Ion channels play a central role in the regulation of nearly every cellular process. Dating back to the classic 1952 Hodgkin-Huxley model of the generation of the action potential, ion channels have always been thought of as independent agents. A myriad of recent experimental findings exploiting advances in electrophysiology, structural biology, and imaging techniques, however, have posed a serious challenge to this long-held axiom as several classes of ion channels appear to open and close in a coordinated, cooperative manner. Ion channel cooperativity ranges from variable-sized oligomeric cooperative gating in voltage-gated, dihydropyridine-sensitive Cav1.2 and Cav1.3 channels to obligatory dimeric assembly and gating of voltage-gated Nav1.5 channels. Potassium channels, transient receptor potential channels, hyperpolarization cyclic nucleotide-activated channels, ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3Rs) have also been shown to gate cooperatively. The implications of cooperative gating of these ion channels range from fine tuning excitation-contraction coupling in muscle cells to regulating cardiac function and vascular tone, to modulation of action potential and conduction velocity in neurons and cardiac cells, and to control of pace-making activity in the heart. In this review, we discuss the mechanisms leading to cooperative gating of ion channels, their physiological consequences and how alterations in cooperative gating of ion channels may induce a range of clinically significant pathologies.

Effects of estrogen on action potential and membrane currents in guinea pig ventricular myocytes

1999 ◽  
Vol 277 (2) ◽  
pp. H826-H833 ◽  
Author(s):  
Seiko Tanabe ◽  
Toshio Hata ◽  
Masayasu Hiraoka
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Action Potentials ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Membrane Currents ◽  
Patch Clamp Technique ◽  
17Β Estradiol ◽  
Electrophysiological Effects ◽  
Ionic Basis

To explore a possible ionic basis for the prolonged Q-T interval in women compared with that in men, we investigated the electrophysiological effects of estrogen in isolated guinea pig ventricular myocytes. Action potentials and membrane currents were recorded using the whole cell configuration of the patch-clamp technique. Application of 17β-estradiol (10–30 μM) significantly prolonged the action potential duration (APD) at 20% (APD20) and 90% repolarization (APD90) at stimulation rates of 0.1–2.0 Hz. In the presence of 30 μM 17β-estradiol, APD20 and APD90 at 0.1 Hz were prolonged by 46.2 ± 17.1 and 63.4 ± 11.7% of the control ( n = 5), respectively. In the presence of 30 μM 17β-estradiol the peak inward Ca2+ current ( I CaL) was decreased to 80.1 ± 2.5% of the control ( n = 4) without a shift in its voltage dependence. Application of 30 μM 17β-estradiol decreased the rapidly activating component of the delayed outward K+ current ( I Kr) to 63.4 ± 8% and the slowly activating component ( I Ks) to 65.8 ± 8.7% with respect to the control; the inward rectifier K+ current was barely affected. The results suggest that 17β-estradiol prolonged APD mainly by inhibiting the I Kcomponents I Krand I Ks.

Effects of some divalent cations on motoneurones in cats

1979 ◽  
Vol 57 (9) ◽  
pp. 944-956 ◽  
Author(s):  
K. Krnjević ◽  
Y. Lamour ◽  
J. F. MacDonald ◽  
A. Nistri
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Intracellular Recording ◽  
Dorsal Root ◽  
Divalent Cations ◽  
The Other ◽  
Depressant Effect ◽  
Na Inactivation ◽  
Conductance Increase ◽  
Root Stimulation

In cats under Dial, Co, Mn, La, and Sr were injected extracellularly near lumbosacral motoneurones. All tended to improve intracellular recording, but when the membrane potential was initially stable, Mn, and especially Co, had a moderate and reproducible depolarizing action. Both Mn and Co depressed excitatory postsynaptic potentials evoked by dorsal root stimulation. The prominent after-hyperpolarization (a.h.p.), which normally follows the motoneuronal action potential, was consistently and reversibly depressed by Mn and Co (as well as La), the underlying conductance increase being also diminished, but there was no significant reduction in the after-depolarization. By contrast, Sr tended to potentiate the a.h.p., especially when this was depressed by a previous injection of Co or Mn. Unlike the other cations, Co had a marked depressant effect on the action potential, particularly its rate of rise. Since the action potential could be immediately restored by hyperpolarization or by an injection of Sr (in the absence of depolarization), Co may enhance Na inactivation.

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