Ca<sup>2+</sup>-activated chloride channel activity during Ca<sup>2+</sup>alternans in ventricular myocytes

Kanaporis, Giedrius; Blatter, Lothar A.

doi:10.1080/19336950.2016.1207020

Cited by 6 publications

(5 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…APD alternans then results in CaT alternans due to V m -dependent regulation of Ca 2+ influx through L-type Ca 2+ channels and Ca 2+ extrusion via NCX. However, more recent findings that CaT alternans can be elicited in voltage-clamped myocytes in the absence of beat-to-beat alternans in V m [8, 15, 16, 30, 31] and therefore in the absence of AP alternans, support the alternative hypothesis that disturbances of intracellular Ca 2+ handling is the primary cause of alternans. CaT alternans results in AP alternans by the activity of Ca 2+ -regulated ion conductances such as NCX [32, 33], L-type Ca 2+ [32], Ca 2+ -activated chloride [30], small conductance Ca 2+ -activated K + channel currents [34].…”

Section: Discussionmentioning

confidence: 95%

Membrane potential determines calcium alternans through modulation of SR Ca 2+ load and L-type Ca 2+ current

Kanaporis

Blatter

2017

Journal of Molecular and Cellular Cardiology

Self Cite

View full text Add to dashboard Cite

Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans is observed as beat-to-beat alternations in contraction, action potential (AP) morphology and magnitude of the Ca2+ transient (CaT). It is widely accepted that the bidirectional interplay between membrane voltage and Ca2+ is crucial for the development of alternans, however recently the attention has shifted to instabilities in cellular Ca2+ handling, while the role of AP alternation remains poorly understood. This study provides new insights how beat- to-beat alternation in AP morphology affects occurrence of CaT alternans in atrial myocytes. Pacing-induced AP and CaT alternans were studied in rabbit atrial myocytes using combined Ca2+ imaging and electrophysiological measurements. To determine the role of AP morphology for the generation of CaT alternans, trains of two voltage commands in form of APs recorded during large and small alternans CaTs were applied to voltage-clamped cells. APs of longer duration (as observed during small amplitude alternans CaT) and especially beat-to-beat alternations in AP morphology (AP alternans) reduced the pacing frequency threshold and increased the degree of CaT alternans. AP morphology contributes to the development of CaT alternans by two mechanisms. First, the AP waveform observed during small alternans CaTs coincided with higher end-diastolic sarcoplasmic reticulum Ca2+ levels ([Ca2+]SR), and AP alternans resulted in beat-to-beat alternations in end-diastolic [Ca2+]SR. Second, L-type Ca2+ current was significantly affected by AP morphology, where the AP waveform observed during large CaT elicited L-type Ca2+ currents of higher magnitude and faster kinetics, resulting in more efficient triggering of SR Ca2+ release. In conclusion, alternation in AP morphology plays a significant role in the development and stabilization of atrial alternans. The demonstration that CaT alternans can be controlled or even prevented by modulating AP morphology has important ramifications for arrhythmia prevention and therapy strategies.

show abstract

Section: Discussionmentioning

confidence: 95%

Membrane potential determines calcium alternans through modulation of SR Ca 2+ load and L-type Ca 2+ current

Kanaporis

Blatter

2017

Journal of Molecular and Cellular Cardiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, experimental studies have und AP clamp suggested that blocking the K + using Cs under AP clamp, resulted in no change in the difference current between beats in alternans suggesting little role for the SK current alternans. The same study however found that the Ca 2+ -activated Cl − current did play a role [77]. For this reason, we did not include them in the current model and left them for future studies of arrhythmia and disease.…”

Section: Discussionmentioning

confidence: 97%

Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms

et al. 2021

View full text Add to dashboard Cite

Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release. We use a novel model of cardiac excitation-contraction (EC) coupling in the rat ventricular myocyte that includes 20,000 calcium release units (CRU) each with 49 ryanodine receptors (RyR2s) and 7 L-type calcium channels that are all stochastically gated. The model suggests that at the cellular level in the case of alternans produced by rapid pacing, the mechanism requires a synergy of voltage- and calcium-dependent mechanisms. The rapid pacing reduces AP duration and magnitude reducing the number of L-type calcium channels activating individual CRUs during each AP and thus increases the population of CRUs that can be recruited stochastically. Elevated myoplasmic and sarcoplasmic reticulum (SR) calcium, [Ca2+]myo and [Ca2+]SR respectively, increases ryanodine receptor open probability (Po) according to our model used in this simulation and this increased the probability of activating additional CRUs. A CRU that opens in one beat is less likely to open the subsequent beat due to refractoriness caused by incomplete refilling of the junctional sarcoplasmic reticulum (jSR). Furthermore, the model includes estimates of changes in Na+ fluxes and [Na+]i and thus provides insight into how changes in electrical activity, [Na+]i and sodium-calcium exchanger activity can modulate alternans. The model thus tracks critical elements that can account for rate-dependent changes in [Na+]i and [Ca2+]myo and how they contribute to the generation of Ca2+ signaling alternans in the heart.

show abstract

“…Recently we demonstrated that Ca 2+ -activated Cl − channels play a major role in sustaining APD alternans in rabbit atrial cells [86]. Our data indicated that while these channels might be also important in ventricular alternans [87], atrial myocytes exhibit a higher density of this current that could explain in part the significantly higher degree of beat-to-beat alternation in APD in atrial myocytes [17]. In addition, atrial tissue displays substantial regional heterogeneity in conduction velocity (CV) and AP morphology, ranging from a triangular shape with no sustained plateau to ventricular like APs [88].…”

Section: Differences Between Atrial and Ventricular Alternansmentioning

confidence: 71%

Alternans in atria: Mechanisms and clinical relevance

Kanaporis

Blatter

2017

Medicina

Self Cite

View full text Add to dashboard Cite

Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca2+ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria.

show abstract

Ca²⁺-activated chloride channel activity during Ca²⁺alternans in ventricular myocytes

Cited by 6 publications

References 62 publications

Membrane potential determines calcium alternans through modulation of SR Ca 2+ load and L-type Ca 2+ current

Membrane potential determines calcium alternans through modulation of SR Ca 2+ load and L-type Ca 2+ current

Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms

Alternans in atria: Mechanisms and clinical relevance

Contact Info

Product

Resources

About

Ca2+-activated chloride channel activity during Ca2+alternans in ventricular myocytes

Cited by 6 publications

References 62 publications

Membrane potential determines calcium alternans through modulation of SR Ca 2+ load and L-type Ca 2+ current

Membrane potential determines calcium alternans through modulation of SR Ca 2+ load and L-type Ca 2+ current

Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms

Alternans in atria: Mechanisms and clinical relevance

Contact Info

Product

Resources

About

Ca²⁺-activated chloride channel activity during Ca²⁺alternans in ventricular myocytes