The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
Edward G Lakatta - One of the best experts on this subject based on the ideXlab platform.
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Abstract 15188: Basal Epac2 Activation Regulates Spontaneous Beating of Cardiac Pacemaker Cells
Circulation, 2017Co-Authors: Tatiana M Vinogradova, Kirill Tarasov, Edward G LakattaAbstract:Spontaneous firing of sinoatrial node cells (SANC) is regulated by submembrane local Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR). Spontaneous LCRs appear during Diastolic Depolarization (...
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Relative Contribution of Local Ca2+ Releases (LCRS) and AP-Induced Ca2+ Transient Decay to Diastolic Depolarization in Rabbit Sa Node Cells
Biophysical Journal, 2016Co-Authors: Oliver Monfredi, Edward G Lakatta, Alexander V. Maltsev, Sean P. Parsons, Bruce D. Ziman, Michael D. Stern, Victor A. MaltsevAbstract:Background: Intracellular Ca2+ dynamics contribute to cardiac pacemaker cell function via activation of electrogenic Na+/Ca2+ exchanger during Diastolic Depolarization. Two fundamental mechanisms have been implicated for the Diastolic Ca2+ signaling: LCRs and the decaying AP-induced Ca2+ transients. Their relative contributions, however, are unknown.Methods: We evaluated the relative contributions based on simultaneous high-speed camera recordings of Ca2+ signal, alongside membrane potential recordings by perforated patch clamp in single isolated rabbit SA node cells prior to and during beta-adrenergic receptor stimulation with isoproterenol (100 nM). We obtained further insights by employing simulations of our recent numerical model featuring local Ca2+ dynamics in 3D in these cells.Results: All cells tested (n=5) exhibited both LCRs and AP-induced-transient residuals during Diastolic Depolarization. Individual LCRs have been characterized in the 2D movies using our novel computer algorithm (see our poster on automated analysis of LCRs). The values of LCR signal mass and Ca2+ transient residuals were integrated within the entire cell perimeter in the focal plane of video-recording and compared. Both our analysis of the experimental data and model simulations demonstrated that LCRs provide a major part of the net Ca2+ Diastolic signal, both prior to and during isoproterenol exposure. The relative contribution of LCRs, however, substantially increased after isoproterenol application. Specifically, while the contribution of the transient residuals into the net Diastolic Ca2+ signal prior to isoproterenol is about 30%, the net signal following isoproterenol becomes almost completely driven by the LCRs, Ca2+ transient decays are accelerated and almost fully complete prior the maximum Diastolic Depolarization.Conclusions: Both LCRs and local Ca2+ transient residuals contribute to Diastolic Depolarization. As pacemaker rate increases LCR signal waxes, but the contribution of Ca2+ transient residuals wanes.
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Sarcoplasmic Reticulum Ca2+ Pumping Kinetics Regulates Timing of Local Ca2+ Releases and Spontaneous Beating Rate of Rabbit Sinoatrial Node Pacemaker Cells
Circulation research, 2010Co-Authors: Tatiana M Vinogradova, Harold A. Spurgeon, Didier X.p. Brochet, Syevda Sirenko, Edward G LakattaAbstract:Rationale:Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late Diastolic Depolarization. LCRs activate an inward Na+-Ca2+ exchange current (INCX), which accelerates Diastolic Depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca2+ transient and LCR appearance, defines the time of late Diastolic Depolarization INCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective:To determine dependence of the LCR period on SR Ca2+ refilling kinetics and establish links between regulation of SR Ca2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results:Spontaneous APs and SR luminal or cytosolic Ca2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca2+ following AP-induced Ca2+ transient was highly correlated with the time to 90% decay of cytosolic Ca2+ transient (T...
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Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels
Journal of molecular and cellular cardiology, 2009Co-Authors: Tatiana M Vinogradova, Edward G LakattaAbstract:Decades of intensive research of primary cardiac pacemaker, the sinoatrial node, have established potential roles of specific membrane channels in the generation of the Diastolic Depolarization, the major mechanism allowing sinoatrial node cells to generate spontaneous beating. During the last three decades, multiple studies made either in the isolated sinoatrial node or sinoatrial node cells have demonstrated a pivotal role of Ca(2+) and, specifically Ca(2+) release from sarcoplasmic reticulum, for spontaneous beating of cardiac pacemaker. Recently, spontaneous, rhythmic local subsarcolemmal Ca(2+) releases from ryanodine receptors during late half of the Diastolic Depolarization have been implicated as a vital factor in the generation of sinoatrial node cell spontaneous firing. Local Ca(2+) releases are driven by a unique combination of high basal cAMP production by adenylyl cyclases, high basal cAMP degradation by phosphodiesterases and a high level of cAMP-mediated PKA-dependent phosphorylation. These local Ca(2+) releases activate an inward Na(+)-Ca(2+) exchange current which accelerates the terminal Diastolic Depolarization rate and, thus, controls the spontaneous pacemaker firing. Both the basal primary pacemaker beating rate and its modulation via beta-adrenergic receptor stimulation appear to be critically dependent upon intact RyR function and local subsarcolemmal sarcoplasmic reticulum generated Ca(2+) releases. This review aspires to integrate the traditional viewpoint that has emphasized the supremacy of the ensemble of surface membrane ion channels in spontaneous firing of the primary cardiac pacemaker, and these novel perspectives of cAMP-mediated PKA-dependent Ca(2+) cycling in regulation of the heart pacemaker clock, both in the basal state and during beta-adrenergic receptor stimulation.
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Membrane Potential Fluctuations Resulting From Submembrane Ca2+ Releases in Rabbit Sinoatrial Nodal Cells Impart an Exponential Phase to the Late Diastolic Depolarization That Controls Their Chronotropic State
Circulation research, 2006Co-Authors: Konstantin Y Bogdanov, Tatiana M Vinogradova, Michael D. Stern, Victor A. Maltsev, Alexey E. Lyashkov, Harold A. Spurgeon, Edward G LakattaAbstract:Stochastic but roughly periodic LCRs (Local subsarcolemmal ryanodine receptor–mediated Ca 2+ Releases) during the late phase of Diastolic Depolarization (DD) in rabbit sinoatrial nodal pacemaker cells (SANCs) generate an inward current ( I NCX ) via the Na + /Ca 2+ exchanger. Although LCR characteristics have been correlated with spontaneous beating, the specific link between LCR characteristics and SANC spontaneous beating rate, ie, impact of LCRs on the fine structure of the DD, have not been explicitly defined. Here we determined how LCRs and resultant I NCX impact on the DD fine structure to control the spontaneous SANC firing rate. Membrane potential ( V m ) recordings combined with confocal Ca 2+ measurements showed that LCRs impart a nonlinear, exponentially rising phase to the DD later part, which exhibited beat-to-beat V m fluctuations with an amplitude of approximately 2 mV. Maneuvers that altered LCR timing or amplitude of the nonlinear DD (ryanodine, BAPTA, nifedipine or isoproterenol) produced corresponding changes in V m fluctuations during the nonlinear DD component, and the V m fluctuation response evoked by these maneuvers was tightly correlated with the concurrent changes in spontaneous beating rate induced by these perturbations. Numerical modeling, using measured LCR characteristics under these perturbations, predicted a family of local I NCX that reproduced V m fluctuations measured experimentally and determined the onset and amplitude of the nonlinear DD component and the beating rate. Thus, beat-to-beat V m fluctuations during late DD phase reflect the underlying LCR/ I NCX events, and the ensemble of these events forms the nonlinear DD component that ultimately controls the SANC chronotropic state in tight cooperation with surface membrane ion channels.
Tatiana M Vinogradova - One of the best experts on this subject based on the ideXlab platform.
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Abstract 15188: Basal Epac2 Activation Regulates Spontaneous Beating of Cardiac Pacemaker Cells
Circulation, 2017Co-Authors: Tatiana M Vinogradova, Kirill Tarasov, Edward G LakattaAbstract:Spontaneous firing of sinoatrial node cells (SANC) is regulated by submembrane local Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR). Spontaneous LCRs appear during Diastolic Depolarization (...
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Sarcoplasmic Reticulum Ca2+ Pumping Kinetics Regulates Timing of Local Ca2+ Releases and Spontaneous Beating Rate of Rabbit Sinoatrial Node Pacemaker Cells
Circulation research, 2010Co-Authors: Tatiana M Vinogradova, Harold A. Spurgeon, Didier X.p. Brochet, Syevda Sirenko, Edward G LakattaAbstract:Rationale:Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late Diastolic Depolarization. LCRs activate an inward Na+-Ca2+ exchange current (INCX), which accelerates Diastolic Depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca2+ transient and LCR appearance, defines the time of late Diastolic Depolarization INCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective:To determine dependence of the LCR period on SR Ca2+ refilling kinetics and establish links between regulation of SR Ca2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results:Spontaneous APs and SR luminal or cytosolic Ca2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca2+ following AP-induced Ca2+ transient was highly correlated with the time to 90% decay of cytosolic Ca2+ transient (T...
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Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels
Journal of molecular and cellular cardiology, 2009Co-Authors: Tatiana M Vinogradova, Edward G LakattaAbstract:Decades of intensive research of primary cardiac pacemaker, the sinoatrial node, have established potential roles of specific membrane channels in the generation of the Diastolic Depolarization, the major mechanism allowing sinoatrial node cells to generate spontaneous beating. During the last three decades, multiple studies made either in the isolated sinoatrial node or sinoatrial node cells have demonstrated a pivotal role of Ca(2+) and, specifically Ca(2+) release from sarcoplasmic reticulum, for spontaneous beating of cardiac pacemaker. Recently, spontaneous, rhythmic local subsarcolemmal Ca(2+) releases from ryanodine receptors during late half of the Diastolic Depolarization have been implicated as a vital factor in the generation of sinoatrial node cell spontaneous firing. Local Ca(2+) releases are driven by a unique combination of high basal cAMP production by adenylyl cyclases, high basal cAMP degradation by phosphodiesterases and a high level of cAMP-mediated PKA-dependent phosphorylation. These local Ca(2+) releases activate an inward Na(+)-Ca(2+) exchange current which accelerates the terminal Diastolic Depolarization rate and, thus, controls the spontaneous pacemaker firing. Both the basal primary pacemaker beating rate and its modulation via beta-adrenergic receptor stimulation appear to be critically dependent upon intact RyR function and local subsarcolemmal sarcoplasmic reticulum generated Ca(2+) releases. This review aspires to integrate the traditional viewpoint that has emphasized the supremacy of the ensemble of surface membrane ion channels in spontaneous firing of the primary cardiac pacemaker, and these novel perspectives of cAMP-mediated PKA-dependent Ca(2+) cycling in regulation of the heart pacemaker clock, both in the basal state and during beta-adrenergic receptor stimulation.
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Membrane Potential Fluctuations Resulting From Submembrane Ca2+ Releases in Rabbit Sinoatrial Nodal Cells Impart an Exponential Phase to the Late Diastolic Depolarization That Controls Their Chronotropic State
Circulation research, 2006Co-Authors: Konstantin Y Bogdanov, Tatiana M Vinogradova, Michael D. Stern, Victor A. Maltsev, Alexey E. Lyashkov, Harold A. Spurgeon, Edward G LakattaAbstract:Stochastic but roughly periodic LCRs (Local subsarcolemmal ryanodine receptor–mediated Ca 2+ Releases) during the late phase of Diastolic Depolarization (DD) in rabbit sinoatrial nodal pacemaker cells (SANCs) generate an inward current ( I NCX ) via the Na + /Ca 2+ exchanger. Although LCR characteristics have been correlated with spontaneous beating, the specific link between LCR characteristics and SANC spontaneous beating rate, ie, impact of LCRs on the fine structure of the DD, have not been explicitly defined. Here we determined how LCRs and resultant I NCX impact on the DD fine structure to control the spontaneous SANC firing rate. Membrane potential ( V m ) recordings combined with confocal Ca 2+ measurements showed that LCRs impart a nonlinear, exponentially rising phase to the DD later part, which exhibited beat-to-beat V m fluctuations with an amplitude of approximately 2 mV. Maneuvers that altered LCR timing or amplitude of the nonlinear DD (ryanodine, BAPTA, nifedipine or isoproterenol) produced corresponding changes in V m fluctuations during the nonlinear DD component, and the V m fluctuation response evoked by these maneuvers was tightly correlated with the concurrent changes in spontaneous beating rate induced by these perturbations. Numerical modeling, using measured LCR characteristics under these perturbations, predicted a family of local I NCX that reproduced V m fluctuations measured experimentally and determined the onset and amplitude of the nonlinear DD component and the beating rate. Thus, beat-to-beat V m fluctuations during late DD phase reflect the underlying LCR/ I NCX events, and the ensemble of these events forms the nonlinear DD component that ultimately controls the SANC chronotropic state in tight cooperation with surface membrane ion channels.
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Rhythmic ryanodine receptor Ca2+ releases during Diastolic Depolarization of sinoatrial pacemaker cells do not require membrane Depolarization
Circulation research, 2004Co-Authors: Tatiana M Vinogradova, Michael D. Stern, Victor A. Maltsev, Ying-ying Zhou, Alexey E. Lyashkov, Edward G LakattaAbstract:Localized, subsarcolemmal Ca 2+ release (LCR) via ryanodine receptors (RyRs) during Diastolic Depolarization of sinoatrial nodal cells augments the terminal Depolarization rate. We determined whether LCRs in rabbit sinoatrial nodal cells require the concurrent membrane Depolarization, or are intrinsically rhythmic, and whether rhythmicity is linked to the spontaneous cycle length. Confocal linescan images revealed persistent LCRs both in saponin-permeabilized cells and in spontaneously beating cells acutely voltage-clamped at the maximum Diastolic potential. During the initial stage of voltage clamp, the LCR spatiotemporal characteristics did not differ from those in spontaneously beating cells, or in permeabilized cells bathed in 150 nmol/L Ca 2+ . The period of persistent rhythmic LCRs during voltage clamp was slightly less than the spontaneous cycle length before voltage clamp. In spontaneously beating cells, in both transient and steady states, LCR period was highly correlated with the spontaneous cycle length; and regardless of the cycle length, LCRs occurred predominantly at a constant time, ie, 80% to 90% of the cycle length. Numerical model simulations incorporating LCRs reproduce the experimental results. We conclude that Diastolic LCRs reflect rhythmic intracellular Ca 2+ cycling that does not require the concomitant membrane Depolarization, and that LCR periodicity is closely linked to the spontaneous cycle length. Thus, the biological clock of sinoatrial nodal pacemaker cells, like that of many other rhythmic functions occurring throughout nature, involves an intracellular Ca 2+ rhythm.
Dario Difrancesco - One of the best experts on this subject based on the ideXlab platform.
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Modulation of rate by autonomic agonists in SAN cells involves changes in Diastolic Depolarization and the pacemaker current.
Journal of molecular and cellular cardiology, 2007Co-Authors: Annalisa Bucchi, Mirko Baruscotti, Richard B. Robinson, Dario DifrancescoAbstract:Two distinct intracellular mechanisms have been proposed to affect the firing rate of cardiac pacemaker cells: one involves modulation of the If current by the second messenger cAMP, and one relies upon disruption or alteration of SR Ca 2+ transients during activity. Although both mechanisms are necessary for proper automaticity and autonomic rate control, the specific contribution of each to pacemaking is still debated. We investigated if the two processes can be separated based on potentially different effects on action potential characteristics during rate modulation. To identify specific If-mediated effects, we used the selective If blocker ivabradine and found that ivabradine (3 μM) slows rate (�16.2%) by selectively reducing (�31.9%) the steepness of early Diastolic Depolarization (EDD). On the other hand ryanodine (3 μM), used to evaluate the effects of abolishment of SR Ca 2+ transients, slowed rate (�31.3%) by depolarizing the take-off potential (TOP, 18.1%) without affecting EDD. We therefore used these two parameters to identify If-based or SR Ca 2+ transients-based processes and analyzed the effects on action potential's characteristics of Rp-cAMPs (50 μM), a membrane permeable cAMP analogue directly activating f-channels; we found that Rp-cAMPs accelerates rate by increasing EDD (+42.3%) without modifying TOP. Finally, rate modulation was achieved by muscarinic (ACh 0.01 μM) or β-adrenergic (Iso 1 μM) stimulation; in both cases, rate changes were associated with modifications of EDD (ACh, �29.3% and Iso, +47.6%) and not of TOP. We conclude that rate-related changes in the EDD induced by autonomic agonists are mediated by If and not by processes involving SR Ca 2+ transients.
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Cardiac pacemaker I(f) current and its inhibition by heart rate-reducing agents.
Current medical research and opinion, 2005Co-Authors: Dario DifrancescoAbstract:ABSTRACTThe ‘funny’ (/f) current, first described by Brown et al. in 1979 in pacemaker myocytes, is an inward current that slowly activates on hyperpolarization to the Diastolic range of voltages. Extensive work has amply demonstrated its involvement in the generation of spontaneous activity. The extent of current activation determines the slope of Diastolic Depolarization and hence of pacemaker rate. Since /f is under cyclic adenosine monophosphate (cAMP)-mediated control by β-adrenergic and muscarinic stimulation, this mechanism underlies neurotransmitter modulation of cardiac rate and is therefore of fundamental physiological relevance. Their key role in pacemaking makes f‐channels a natural target for drugs aiming at regulation of pacemaker activity and cardiac rate. Both in the past and more recently, rate-reducing drugs that slow pacemaker activity by decreasing the rate of Diastolic Depolarization have been developed. These drugs act as specific f‐channel inhibitors. One of the latest such molecule...
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If inhibition: a novel mechanism of action
European Heart Journal Supplements, 2003Co-Authors: Dario DifrancescoAbstract:Aims It is well established that the cardiac pacemaker (‘funny’, or If) current plays an important role in the generation and autonomic modulation of cardiac rate by controlling the rate of Diastolic Depolarization. Here, the properties of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} and the criteria that permit identification of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} activation as the main mechanism responsible for Diastolic Depolarization are briefly summarized. The relationship between \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} inhibition by specific \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} channel blockers (rate-reducing agents) and reduction in pacemaker rate is also described. Methods and results The If data reported here were collected from rabbit sinoatrial node cells that were isolated and patch-clamped. Cs+ ions and, more efficiently, ‘rate-reduding’ agents block \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} and reduce the steepness of Diastolic Depolarization and frequency in spontaneously active sinoatrial node myocytes. Ivabradine (Procoralan®; Servier, Neuilly-sur-Seine, France), a recently developed molecule, blocks \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} channels when they are open and preferentially when the current is outward. Conclusions , If controls the slope of Diastolic Depolarization and cardiac frequency, and its inhibition causes heart rate reduction. The current-dependent blockade of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(I_{\mathrm{f}}\) \end{document} with ivabradine leads to a specific and use-dependent, heart rate reducing effect that may have therapeutic applications in clinical settings.
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Single-channel properties of the sinoatrial node Na+ current in the newborn rabbit
Pflugers Archiv : European journal of physiology, 2001Co-Authors: Mirko Baruscotti, Dario Difrancesco, Richard B. RobinsonAbstract:We have reported previously that the sinoatrial node (SAN) in the newborn rabbit expresses a Na+ current (INa) with properties similar to the neuronal type-I isoform and that this current contributes to the net inward current flowing during Diastolic Depolarization. To characterize this current further we conducted cell-attached single-channel experiments in isolated newborn SAN myocytes. The Na+ channel was sensitive to divalent cation block and had a single-channel conductance of 25.6 pS in the absence of divalent cations. Kinetic compatibility between single-channel and previous whole-cell data was confirmed by measuring the time constant of current decay. At pacemaker potentials, time constants were of the order of tens of milliseconds. Additional experiments indicated that this slow inactivation arises because the Na+ channels expressed in the neonatal SAN tend to re-open frequently at potentials in the pacemaker range. We suggest that this is the mechanism by which a small tetrodotoxin (TTX)-sensitive current contributes to the total inward current flowing during slow Diastolic Depolarization in neonatal (but not adult) pacemaker myocytes.
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Basal responses of the L-type Ca2+ and hyperpolarization-activated currents to autonomic agonists in the rabbit sino-atrial node.
The Journal of Physiology, 1996Co-Authors: Antonio Zaza, Richard B. Robinson, Dario DifrancescoAbstract:1. The dose dependence of the cholinergic agonist acetylcholine (ACh) and the beta-adrenergic agonist isoprenaline (Iso) were determined for the hyperpolarization-activated current (If) and the L-type Ca2+ current (ICa,L) in single cells isolated from the rabbit sino-atrial (SA) node. 2. ACh inhibited If by a negative shift of its activation curve with a maximal effect of -9.9 mV; half-maximal effect was produced by 0.019 microM ACh. High ACh concentrations were required to inhibit ICa,L only partially (31% inhibition at 300 microM). 3. In contrast, If and ICa,L responded to Iso over a similar dose range, with concentrations for half-maximal enhancement of 0.0136 and 0.0070 microM, respectively. 4. The effects on spontaneous activity of ACh (range 0.001-0.03 microM) and Iso (range 0.001-1 microM) were investigated. ACh decreased the slope of Diastolic Depolarization at concentrations similar to those inhibiting If (> 50% at 0.03 microM). Iso enhanced Diastolic Depolarization at concentrations similar to those affecting both If and ICa,L (half-maximal effect at 0.027 microM). 5. In a ramp-clamp protocol simulating Diastolic Depolarization, the threshold for activation of inward nifedipine-sensitive current was -41.22 +/- 0.68 mV. Although enhancing ICa,L, Iso did not affect this threshold. 6. Half-maximal ACh concentrations for inhibition of automaticity and If are similar and are lower than the threshold concentrations for modulation of ICa,L; this argues against a role of ICa,L in direct muscarinic modulation of pacemaking. In contrast, modulation of If, ICa,L and automaticity occur at similar Iso concentrations. The difference between maximum Diastolic potential (-61.95 +/- 0.93 mV) and the threshold for Iso-stimulated ICa,L (-39.54 +/- 1.03 mV) suggests that this current plays a role only at later stages of Diastolic Depolarization.
Hikaru Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of class I antiarrhythmic drugs on the guinea pig pulmonary vein myocardium: Inhibition of automatic activity correlates with blockade of a Diastolic sodium current component.
Journal of pharmacological sciences, 2020Co-Authors: Masahiko Irie, Haruhito Hiiro, Shogo Hamaguchi, Iyuki Namekata, Shu Kato, Mizuki Kuramochi, Hikaru TanakaAbstract:Abstract The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp methods. All of the drugs examined reduced the maximum rate of rise of automatic action potentials. The firing frequency and rate of Diastolic Depolarization were decreased by aprindine, flecainide and propafenone, but not by cibenzoline, disopyramide and pilsicainide, which correlated with blockade of the sodium current component induced by ramp Depolarization mimicking the Diastolic Depolarization. In conclusion, class I antiarrhythmic drugs which block the Diastolic sodium current component inhibit the automaticity of the pulmonary vein myocardium.
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Involvement of the persistent Na+ current in the Diastolic Depolarization and automaticity of the guinea pig pulmonary vein myocardium.
Journal of pharmacological sciences, 2019Co-Authors: Masahiko Irie, Haruhito Hiiro, Shogo Hamaguchi, Iyuki Namekata, Hikaru TanakaAbstract:Abstract The role of the Na+ current in the automaticity of the pulmonary vein myocardium was examined in isolated guinea pig pulmonary vein cardiomyocytes and tissue preparations. Tetrodotoxin inhibited the automaticity of pulmonary vein tissue preparations by suppressing the Diastolic Depolarization of the action potential. ATX-II, which increased the density of persistent component of the Na+ current (late INa), induced a Depolarization of the resting membrane potential followed by spontaneous firing of action potentials. GS-458967, which inhibited the late INa, suppressed the Diastolic Depolarization and the firing of action potentials. Pilsicainide, which inhibited only the transient component of Na+ current (peak INa), had no effect on the firing frequency. GS-458967 had no effect on the contractile force of the working myocardium. In conclusion, late INa is involved in the Diastolic Depolarization and automaticity of the pulmonary vein myocardium. Late INa inhibitors appear to be effective therapeutic agents for atrial fibrillation with minimum adverse effects on the working myocardium.
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involvement of the persistent na current in the Diastolic Depolarization and automaticity of the guinea pig pulmonary vein myocardium
Journal of Pharmacological Sciences, 2019Co-Authors: Masahiko Irie, Haruhito Hiiro, Shogo Hamaguchi, Iyuki Namekata, Hikaru TanakaAbstract:Abstract The role of the Na+ current in the automaticity of the pulmonary vein myocardium was examined in isolated guinea pig pulmonary vein cardiomyocytes and tissue preparations. Tetrodotoxin inhibited the automaticity of pulmonary vein tissue preparations by suppressing the Diastolic Depolarization of the action potential. ATX-II, which increased the density of persistent component of the Na+ current (late INa), induced a Depolarization of the resting membrane potential followed by spontaneous firing of action potentials. GS-458967, which inhibited the late INa, suppressed the Diastolic Depolarization and the firing of action potentials. Pilsicainide, which inhibited only the transient component of Na+ current (peak INa), had no effect on the firing frequency. GS-458967 had no effect on the contractile force of the working myocardium. In conclusion, late INa is involved in the Diastolic Depolarization and automaticity of the pulmonary vein myocardium. Late INa inhibitors appear to be effective therapeutic agents for atrial fibrillation with minimum adverse effects on the working myocardium.
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Angiotensin II Induces Automatic Activity of the Isolated Guinea Pig Pulmonary Vein Myocardium through Activation of the IP3 Receptor and the Na+-Ca2+ Exchanger
International journal of molecular sciences, 2019Co-Authors: Yusuke Tanaka, Shogo Hamaguchi, Iyuki Namekata, Kae Obata, Tamano Ohmori, Kohei Ishiwata, Manato Abe, Hikaru TanakaAbstract:The automaticity of the pulmonary vein myocardium is known to be the major cause of atrial fibrillation. We examined the involvement of angiotensin II in the automatic activity of isolated guinea pig pulmonary vein preparations. In tissue preparations, application of angiotensin II induced an automatic contractile activity; this effect was mimicked by angiotensin I and blocked by losartan, but not by PD123,319 or carvedilol. In cardiomyocytes, application of angiotensin II induced an increase in the frequency of spontaneous Ca2+ sparks and the generation of Ca2+ transients; these effects were inhibited by losartan or xestospongin C. In tissue preparations, angiotensin II caused membrane potential oscillations, which lead to repetitive generation of action potentials. Angiotensin II increased the Diastolic Depolarization slope of the spontaneous or evoked action potentials. These effects of angiotensin II were inhibited by SEA0400. In tissue preparations showing spontaneous firing of action potentials, losartan, xestospongin C or SEA0400 decreased the slope of the Diastolic Depolarization and inhibited the firing of action potentials. In conclusion, in the guinea pig pulmonary vein myocardium, angiotensin II induces the generation of automatic activity through activation of the IP3 receptor and the Na+-Ca2+ exchanger.
Marc Goethals - One of the best experts on this subject based on the ideXlab platform.
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use dependent block of the pacemaker current i f in rabbit sinoatrial node cells by zatebradine ul fs 49 on the mode of action of sinus node inhibitors
Circulation, 1993Co-Authors: Marc Goethals, Adam Raes, Pierre Paul Van BogaertAbstract:BACKGROUND Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of Diastolic Depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified. METHODS AND RESULTS We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying Diastolic Depolarization of isolated rabbit SA node cells. Low concentrations of zatebradine simultaneously reduced Diastolic Depolarization rate and the pacemaker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically relevant concentrations of the drug have little effect on the L-type calcium current or delayed rectifier potassium current. CONCLUSIONS This use-dependent block of the If channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent. Thus, the sinus node inhibitor zatebradine belongs to a new class of "I(f) blockers" with possible advantages over currently available drugs for the treatment of ischemic heart disease.
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Use-Dependent BlockofthePacemaker Current IfinRabbit Sinoatrial NodeCells byZatebradine (UL-FS49) OntheModeofAction ofSinusNodeInhibitors
1993Co-Authors: Marc Goethals, Pierre-paul VanbogaertAbstract:Background. Zatebradine (UL-FS49)isadrugwith aspecific bradycardiac electrophysiological profile. Itreduces heart ratebylengthening theduration ofDiastolic Depolarization inthesinoatrial (SA)node. Theionic basis ofthis action, however, isnotclarified. Methods andResults. Weusedthewhole-cell patch-clamp technique tostudy theeffects ofzatebradine on ionic currents underlying Diastolic Depolarization ofisolated rabbit SAnodecells. Lowconcentrations ofzatebradine simultaneously reduced Diastolic Depolarization rateandthepacemaker currentIf. The drugblocked thepacemaker current, If, ina use-dependent manner without causing a shift ofits activation curve.Athyperpolarized potentials, unblock ofIfoccurred. Clinically relevant concentrations ofthedrughavelittle effect on theL-type calcium current ordelayed rectifier potassium current. Conclsmions. Thisuse-dependent block oftheIfchannel can account formostofthepharmacological characteristics ofzatebradine andisprobably themechanism ofheart ratereduction caused bythis agent. Thus, thesinus nodeinhibitor zatebradine belongs toanewclass of"1I blockers" withpossible advantages over currently available drugs forthetreatment ofischemic heart disease. (Cruation. 1993;88[part 11:2389-2401.)
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Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors.
Circulation, 1993Co-Authors: Marc Goethals, Adam Raes, P P Van BogaertAbstract:Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of Diastolic Depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified. We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying Diastolic Depolarization of isolated rabbit SA node cells. Low concentrations of zatebradine simultaneously reduced Diastolic Depolarization rate and the pacemaker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically relevant concentrations of the drug have little effect on the L-type calcium current or delayed rectifier potassium current. This use-dependent block of the If channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent. Thus, the sinus node inhibitor zatebradine belongs to a new class of "I(f) blockers" with possible advantages over currently available drugs for the treatment of ischemic heart disease.