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Lothar A Blatter – One of the best experts on this subject based on the ideXlab platform.

  • Action potential shortening rescues atrial calcium alternans.
    The Journal of Physiology, 2018
    Co-Authors: Giedrius Kanaporis, Zane M. Kalik, Lothar A Blatter
    Abstract:

    KEY POINTS: Cardiac alternans refers to a beat-to-beat alternation in contraction, action potential (AP) morphology and Ca2+ transient (CaT) amplitude, and represents a risk factor for cardiac arrhythmia, including atrial fibrillation. We developed strategies to pharmacologically manipulate the AP waveform with the goal to reduce or eliminate the occurrence of CaT and contraction alternans in atrial tissue. With combined patch-clamp and intracellular Ca2+ measurements we investigated the effect of specific ion channel inhibitors and activators on alternans. In single rabbit atrial myocytes, suppression of Ca2+ -activated Cl- channels eliminated AP duration alternans, but prolonged the AP and failed to eliminate CaT alternans. In contrast, activation of K+ currents (IKs and IKr ) shortened the AP and eliminated both AP duration and CaT alternans. As demonstrated also at the whole heart level, activation of K+ conductances represents a promising strategy to suppress alternans, and thus reducing a risk factor for atrial fibrillation. ABSTRACT: 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). Alternans is a well-established risk factor for cardiac arrhythmia, including atrial fibrillation. This study investigates whether pharmacological manipulation of AP morphology is a viable strategy to reduce the risk of arrhythmogenic CaT alternans. Pacing-induced AP and CaT alternans were studied in rabbit atrial myocytes using combined Ca2+ imaging and electrophysiological measurements. Increased AP duration (APD) and beat-to-beat Alternations in AP morphology lowered the pacing frequency threshold and increased the degree of CaT alternans. Inhibition of Ca2+ -activated Cl- channels reduced beat-to-beat AP Alternations, but prolonged APD and failed to suppress CaT alternans. In contrast, AP shortening induced by activators of two K+ channels (ML277 for Kv7.1 and NS1643 for Kv11.1) abolished both APD and CaT alternans in field-stimulated and current-clamped myocytes. K+ channel activators had no effect on the degree of Ca2+ alternans in AP voltage-clamped cells, confirming that suppression of Ca2+ alternans was caused by the changes in AP morphology. Finally, activation of Kv11.1 channel significantly attenuated or even abolished atrial T-wave alternans in isolated Langendorff perfused hearts. In summary, AP shortening suppressed or completely eliminated both CaT and APD alternans in single atrial myocytes and atrial T-wave alternans at the whole heart level. Therefore, we suggest that AP shortening is a potential intervention to avert development of alternans with important ramifications for arrhythmia prevention and therapy.

  • the mechanisms of calcium cycling and action potential dynamics in cardiac alternans
    Circulation Research, 2015
    Co-Authors: Giedrius Kanaporis, Lothar A Blatter
    Abstract:

    Rationale: Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans manifests as beat-to-beat Alternations in contraction, action potential duration (APD), and magnitude of the Ca 2+ transient (CaT). Electromechanical and CaT alternans are highly correlated, however, it has remained controversial whether the primary cause of alternans is a disturbance of cellular Ca 2+ signaling or electrical membrane properties. Objective: To determine whether a primary failure of intracellular Ca 2+ regulation or disturbances in membrane potential and AP regulation are responsible for the occurrence of alternans in atrial myocytes. Methods and Results: Pacing-induced APD and CaT alternans were studied in single rabbit atrial and ventricular myocytes using combined [Ca 2+ ]i and electrophysiological measurements. In current-clamp experiments, APD and CaT alternans strongly correlated in time and magnitude. CaT alternans was observed without alternation in L-type Ca 2+ current, however, elimination of intracellular Ca 2+ release abolished APD alternans, indicating that [Ca 2+ ]i dynamics have a profound effect on the occurrence of CaT alternans. Trains of 2 distinctive voltage commands in form of APs recorded during large and small alternans CaTs were applied to voltage-clamped cells. CaT alternans was observed with and without alternation in the voltage command shape. During alternans AP-clamp large CaTs coincided with both long and short AP waveforms, indicating that CaT alternans develop irrespective of AP dynamics. Conclusions: The primary mechanism underlying alternans in atrial cells, similarly to ventricular cells, resides in a disturbance of Ca 2+ signaling, whereas APD alternans are a secondary consequence, mediated by Ca 2+ -dependent AP modulation.

  • cardiac alternans do not rely on diastolic sarcoplasmic reticulum calcium content fluctuations
    Circulation Research, 2006
    Co-Authors: Eckard Picht, Lothar A Blatter, Jaime Desantiago, Donald M. Bers
    Abstract:

    Cardiac alternans are thought to be a precursor to life-threatening arrhythmias. Previous studies suggested that alterations in sarcoplasmic retireticulum (SR) Ca 2+ content are either causative or not associated with myocyte Ca 2+ alternans. However, those studies used indirect measures of SR Ca 2+ . Here we used direct continuous measurement of intra-SR free [Ca 2+ ] ([Ca 2+ ] SR ) (using Fluo5N) during frequency-dependent Ca 2+ alternans in rabbit ventricular myocytes. We tested the hypothesis that alternating [Ca 2+ ] SR is required for Ca 2+ alternans. Amplitudes of [Ca 2+ ] SR depletions alternated in phase with cytosolic Ca 2+ transients and contractions. Some cells showed clear alternation in diastolic [Ca 2+ ] SR during alternans, with higher [Ca 2+ ] SR before the larger SR Ca 2+ releases. However, the extent of SR Ca 2+ release during the small beats was smaller than expected for the modest decrease in [Ca 2+ ] SR . In other cells, clear Ca 2+ alternans was observed without Alternations in diastolic [Ca 2+ ] SR . Additionally, alternating cells were observed, in which diastolic [Ca 2+ ] SR fluctuations occurred interspersed by depletions in which the amplitude was unrelated to the preceding diastolic [Ca 2+ ] SR . In all forms of alternans, the SR Ca 2+ release rate was higher during large depletions than during small depletions. Although [Ca 2+ ] SR exerts major influence on SR Ca 2+ release, Alternations in [Ca 2+ ] SR are not required for Ca 2+ alternans to occur. Rather, it seems likely that some other factor, such as ryanodine receptor availability after a prior beat (eg, recovery from inactivation), is of greater importance in initiating frequency-induced Ca 2+ alternans. However, once such a weak SR Ca 2+ release occurs, it can result in increased [Ca 2+ ] SR and further enhance SR Ca 2+ release at the next beat. In this way, diastolic [Ca 2+ ] SR alternans can enhance frequency-induced Ca 2+ alternans, even if they initiate by other means.

Giedrius Kanaporis – One of the best experts on this subject based on the ideXlab platform.

  • Action potential shortening rescues atrial calcium alternans.
    The Journal of Physiology, 2018
    Co-Authors: Giedrius Kanaporis, Zane M. Kalik, Lothar A Blatter
    Abstract:

    KEY POINTS: Cardiac alternans refers to a beat-to-beat alternation in contraction, action potential (AP) morphology and Ca2+ transient (CaT) amplitude, and represents a risk factor for cardiac arrhythmia, including atrial fibrillation. We developed strategies to pharmacologically manipulate the AP waveform with the goal to reduce or eliminate the occurrence of CaT and contraction alternans in atrial tissue. With combined patch-clamp and intracellular Ca2+ measurements we investigated the effect of specific ion channel inhibitors and activators on alternans. In single rabbit atrial myocytes, suppression of Ca2+ -activated Cl- channels eliminated AP duration alternans, but prolonged the AP and failed to eliminate CaT alternans. In contrast, activation of K+ currents (IKs and IKr ) shortened the AP and eliminated both AP duration and CaT alternans. As demonstrated also at the whole heart level, activation of K+ conductances represents a promising strategy to suppress alternans, and thus reducing a risk factor for atrial fibrillation. ABSTRACT: 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). Alternans is a well-established risk factor for cardiac arrhythmia, including atrial fibrillation. This study investigates whether pharmacological manipulation of AP morphology is a viable strategy to reduce the risk of arrhythmogenic CaT alternans. Pacing-induced AP and CaT alternans were studied in rabbit atrial myocytes using combined Ca2+ imaging and electrophysiological measurements. Increased AP duration (APD) and beat-to-beat Alternations in AP morphology lowered the pacing frequency threshold and increased the degree of CaT alternans. Inhibition of Ca2+ -activated Cl- channels reduced beat-to-beat AP Alternations, but prolonged APD and failed to suppress CaT alternans. In contrast, AP shortening induced by activators of two K+ channels (ML277 for Kv7.1 and NS1643 for Kv11.1) abolished both APD and CaT alternans in field-stimulated and current-clamped myocytes. K+ channel activators had no effect on the degree of Ca2+ alternans in AP voltage-clamped cells, confirming that suppression of Ca2+ alternans was caused by the changes in AP morphology. Finally, activation of Kv11.1 channel significantly attenuated or even abolished atrial T-wave alternans in isolated Langendorff perfused hearts. In summary, AP shortening suppressed or completely eliminated both CaT and APD alternans in single atrial myocytes and atrial T-wave alternans at the whole heart level. Therefore, we suggest that AP shortening is a potential intervention to avert development of alternans with important ramifications for arrhythmia prevention and therapy.

  • the mechanisms of calcium cycling and action potential dynamics in cardiac alternans
    Circulation Research, 2015
    Co-Authors: Giedrius Kanaporis, Lothar A Blatter
    Abstract:

    Rationale: Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans manifests as beat-to-beat Alternations in contraction, action potential duration (APD), and magnitude of the Ca 2+ transient (CaT). Electromechanical and CaT alternans are highly correlated, however, it has remained controversial whether the primary cause of alternans is a disturbance of cellular Ca 2+ signaling or electrical membrane properties. Objective: To determine whether a primary failure of intracellular Ca 2+ regulation or disturbances in membrane potential and AP regulation are responsible for the occurrence of alternans in atrial myocytes. Methods and Results: Pacing-induced APD and CaT alternans were studied in single rabbit atrial and ventricular myocytes using combined [Ca 2+ ]i and electrophysiological measurements. In current-clamp experiments, APD and CaT alternans strongly correlated in time and magnitude. CaT alternans was observed without alternation in L-type Ca 2+ current, however, elimination of intracellular Ca 2+ release abolished APD alternans, indicating that [Ca 2+ ]i dynamics have a profound effect on the occurrence of CaT alternans. Trains of 2 distinctive voltage commands in form of APs recorded during large and small alternans CaTs were applied to voltage-clamped cells. CaT alternans was observed with and without alternation in the voltage command shape. During alternans AP-clamp large CaTs coincided with both long and short AP waveforms, indicating that CaT alternans develop irrespective of AP dynamics. Conclusions: The primary mechanism underlying alternans in atrial cells, similarly to ventricular cells, resides in a disturbance of Ca 2+ signaling, whereas APD alternans are a secondary consequence, mediated by Ca 2+ -dependent AP modulation.

Randolph Blake – One of the best experts on this subject based on the ideXlab platform.

  • what causes Alternations in dominance during binocular rivalry
    Attention Perception & Psychophysics, 2010
    Co-Authors: Minsuk Kang, Randolph Blake
    Abstract:

    Several mechanisms have been proposed to account for perceptual alterations during binocular rivalry, including neural adaptation and neural noise. However, the importance of neural adaptation for producing perceptual alterations has been challenged in several articles (Y.-J. Kim, Grabowecky, & Suzuki, 2006; Moreno-Bote, Rinzel, & Rubin, 2007). We devised an “online” adaptation procedure to reexamine the role of adaptation in binocular rivalry. Periods of adaptation inserted into rivalry observation periods parametrically alter the dynamics of rivalry such that increased adaptation duration decreases dominance duration, which cannot be accounted for by neural noise. Analysis of the average dominance durations and their variance (coefficient of variation) provides evidence for an increasingly important role of noise in rivalry Alternations as a given dominance period continues in time, consistent with recent computational models.

  • intermittent ambiguous stimuli implicit memory causes periodic perceptual Alternations
    Journal of Vision, 2009
    Co-Authors: Jan W Brascamp, Joel Pearson, Randolph Blake, A V Van Den Berg
    Abstract:

    When viewing a stimulus that has multiple plausible real-world interpretations, perception alternates between these interpretations every few seconds. Alternations can be halted by intermittently removing the stimulus from view. The same interpretation dominates over many successive presentations, and perception stabilizes. Here we study perception during long sessions of such intermittent presentation. We demonstrate that, rather than causing truly stable perception, intermittent presentation gives rise to a perceptual alternation cycle with its own characteristics and dependencies, different from those during continuous presentation. Alternations during intermittent viewing typically occur once every few minutesVmuch less frequently than the seconds-scale Alternations during continuous viewing. Strikingly, Alternations during intermittent viewing occur at fairly regular intervals, making for a surprisingly periodic alternation cycle. The duration of this cycle becomes longer as the blank duration between presentations is increased, reaching dozens of minutes in some cases. We interpret our!ndings in terms of a mathematical model that describes a neural network with competition between alternative interpretations. Network sensitivities depend on prior dominance, thus providing a memory for past perception. Slow changes in sensitivity produce both perceptual stabilization and the regular but infrequent Alternations, meaning that the same memory traces are responsible for both. This model provides a good description of psychophysical!ndings, and offers several indications regarding their neural basis.

  • visual motion retards Alternations between conflicting perceptual interpretations
    Neuron, 2003
    Co-Authors: Randolph Blake, Kenith V Sobel, Lee A Gilroy
    Abstract:

    When the visual system is faced with conflicting or ambiguous stimulus information, visual percperception fluctuates over time. We found that perceptual Alternations are slowed when inducing stimuli move within the visual field, constantly engaging fresh, unadapted neural tissue. During binocular rivalry, dominance durations were longer when rival figures moved compared to when they were stationary, yielding lower alternation rates. Rate was not reduced, however, when observers tracked the moving targets, keeping the images on approximately the same retinal area. Alternations were reliably triggered when rival targets passed through a local region of the visual field preadapted to one of the rival targets. During viewing of a kinetic globe whose direction of rotation was ambiguous, observers experienced fewer Alternations in perceived direction when the globe moved around the visual field or when the globe’s axis of rotation changed continuously. Evidently, local neural adaptation is a key ingredient in the instability of perception.

Clayton T Dickson – One of the best experts on this subject based on the ideXlab platform.

  • spontaneous sleep like brain state Alternations and breathing characteristics in urethane anesthetized mice
    PLOS ONE, 2013
    Co-Authors: Silvia Pagliardini, Simon Gosgnach, Clayton T Dickson
    Abstract:

    Brain state Alternations resembling those of sleep spontaneously occur in rats under urethane anesthesia and they are closely linked with sleep-like respiratory changes. Although rats are a common model for both sleep and respiratory physiology, we sought to determine if similar brain state and respiratory changes occur in mice under urethane. We made local field potential recordings from the hippocampus and measured respiratory activity by means of EMG recordings in intercostal, genioglossus, and abdominal muscles. Similar to results in adult rats, urethane anesthetized mice displayed quasi-periodic spontaneous forebrain state Alternations between deactivated patterns resembling slow wave sleep (SWS) and activated patterns resembling rapid eye movement (REM) sleep. These Alternations were associated with an increase in breathing rate, respiratory variability, a depression of inspiratory related activity in genioglossus muscle and an increase in expiratory-related abdominal muscle activity when comparing deactivated (SWS-like) to activated (REM-like) states. These results demonstrate that urethane anesthesia consistently induces sleep-like brain state Alternations and correlated changes in respiratory activity across different rodent species. They open up the powerful possibility of utilizing transgenic mouse technology for the advancement and translation of knowledge regarding sleep cycle Alternations and their impact on respiration.

  • cyclic and sleep like spontaneous Alternations of brain state under urethane anaesthesia
    PLOS ONE, 2008
    Co-Authors: Elizabeth Clement, Alby Richard, Megan Thwaites, Jonathan Ailon, Steven R Peters, Clayton T Dickson
    Abstract:

    Background Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state. Methodology/principal findings Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state Alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state Alternations in sleep transiently disrupted state Alternations under urethane. Conclusions/significance Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their Alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state Alternations.

Anne Giersch – One of the best experts on this subject based on the ideXlab platform.

  • Novel method to measure temporal windows based on eye movements during viewing of the Necker cube
    PLoS ONE, 2020
    Co-Authors: Patrik Polgári, Jean-baptiste Causin, Luisa Weiner, Gilles Bertschy, Anne Giersch
    Abstract:

    Bistable stimuli can give rise to two different interpretations between which our perception will alternate. Recent results showed a strong coupling between eye movements and reports of perceptual Alternations with motion stimuli, which provides useful tools to objectively assess perceptual Alternations. However, motion might entrain eye movements, and here we check with a static picture, the Necker cube, whether eye movements and perceptual reports (manual responses) reveal similar or different alternation rates, and similar or different sensitivity to attention manipulations. Using a cluster analysis, ocular temporal windows were defined based on the dynamics of ocular fixations during viewing of the Necker cube and compared to temporal windows extracted from manual responses. Ocular temporal windows were measured also with a control condition, where the physical stimulus presented to viewers alternated between two non-ambiguous versions of the Necker cube. Attention was manipulated by asking subjects to either report spontaneous Alternations, focus on one percept, or switch as fast as possible between percepts. The validity of the ocular temporal windows was confirmed by the correspondence between ocular fixations when the physical stimulus changed and when the bistable Necker cube was presented. Ocular movements defined smaller time windows than time windows extracted from manual responses. The number of manual and ocular windows both increased between the spontaneous condition and the switch condition. However, only manual, and not ocular windows, increased in duration in the focus condition. Manual responses involve decisional mechanisms, and they may be decoupled from automatic oscillations between the two percepts, as suggested by the fact that both the number and duration of ocular windows remained stable between the spontaneous and focus conditions. In all, the recording of eye movements provides an objective measure of time windows, and reveals faster perceptual Alternations with the Necker cube and less sensitivity to attention manipulations than manual responses.