Dose-dependent alteration of rat cardiac sodium current by isoproterenol: Results from direct measurements on multicellular preparations

Kirstein, Michael; Eickhorn, Roland; Kochsiek, K; Langenfeld, Heiner

doi:10.1007/bf02207277

Cited by 17 publications

(9 citation statements)

References 28 publications

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“…This limitation was partially overcome by a modification of the cell-attached patch-clamp recording 42 , the loose patch clamp 21,22,43 . This technique has been used to measure ionic currents in multicellular cardiac preparations such as trabeculae and papillary muscle 44,45,46 . However, none of these reports was performed on an intact perfused heart during a physiological triggered AP.…”

Section: Discussionmentioning

confidence: 99%

Intact Heart Loose Patch Photolysis Reveals Ionic Current Kinetics During Ventricular Action Potentials

Ramos-Franco

Aguilar-Sánchez

Escobar

2016

Circulation Research

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Rationale Assessing the underlying ionic currents during a triggered action potential (AP) in intact perfused hearts offers the opportunity to link molecular mechanisms with pathophysiological problems in cardiovascular research. The developed Loose Patch Photolysis (LPP) technique can provide striking new insights into cardiac function at the whole heart level during health and disease. Objective To measure transmembrane ionic currents during an AP in order to determine how and when surface Ca2+ influx that triggers Ca2+ induced Ca2+ release (CICR) occurs and how Ca2+ activated conductances can contribute to the genesis of AP phase 2. Methods and Results LPP allows the measurement of transmembrane ionic currents in intact hearts. During a triggered AP, a voltage-dependent Ca2+ conductance was fractionally activated (dis-inhibited) by rapidly photo-degrading nifedipine, the Ca2+ channel blocker. The ionic currents during a mouse ventricular AP showed a fast early component and a slower late component. Pharmacological studies established that the molecular basis underlying the early component was driven by an influx of Ca2+ through the L-type channel, CaV 1.2. The late component was identified as a Na+-Ca2+ exchanger (NCX) current mediated by Ca2+ released from the sarcoplasmic reticulum (SR). Conclusions The novel LPP technique allowed the dissection of transmembrane ionic currents in the intact heart. We were able to determine that during an AP L-Type Ca2+ current contributes to phase 1 while NCX contributes to phase 2. In addition, LPP revealed that the influx of Ca2+ through L-type Ca2+ channels terminates due to voltage-dependent deactivation and not by Ca2+ dependent inactivation, as commonly believed.

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Section: Discussionmentioning

confidence: 99%

Intact Heart Loose Patch Photolysis Reveals Ionic Current Kinetics During Ventricular Action Potentials

Ramos-Franco

Aguilar-Sánchez

Escobar

2016

Circulation Research

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“…Activation of the β 1 -adrenergic signaling system with isoproterenol leads to an increase in the amplitude of I Na , however, without the effects on gating properties of the channel [84], [85]. Simultaneous activation of several components of the β 1 -adrenergic signaling system with cAMP-IBMX-forskolin cocktail or with excessive application of membrane permeant analogue of cAMP, CPTcAMP (5 mM), results in additional small shift in the G/G max and steady-state inactivation [86], [87], [88].…”

Section: Methodsmentioning

confidence: 99%

“…Panel C: An increase in peak I Na availability upon application of different concentrations of isoproterenol (in %). Experimental data by Kirstein et al [84] obtained from rat ventricular myocytes are shown by black bars with errors; corresponding simulation data are shown by gray bars. Peak current-voltage ( Panel D ) and steady-state inactivation ( Panel E ) relationships for the fast Na + current in ventricular myocytes upon stimulation with 0.1 µM isoproterenol.…”

Section: Methodsmentioning

confidence: 99%

A Compartmentalized Mathematical Model of the β1-Adrenergic Signaling System in Mouse Ventricular Myocytes

Bondarenko

2014

PLoS ONE

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The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca2+]i transients; changes in intracellular and transmembrane Ca2+ fluxes; and [Na+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca2+]i transients. In particular, the model includes two subpopulations of the L-type Ca2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions.

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“…However, the effects of isoprenaline on sodium-channel currents have not been resolved completely. Some studies have shown that sodium channels can be modulated via multiple mechanisms, including both direct and indirect pathways [1][2][3][4][5] . The direct mechanism of regulation, which is protein kinase A (PKA)-independent, increases sodium current without alternation of the single-channel characteristics and without shifting the activation of the voltage-dependent current.…”

Section: Introductionmentioning

confidence: 99%

Beta-receptor activation increases sodium current in guinea pig heart

et al. 2009

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Aim: To study the influence of β-receptor activation on sodium channel current and the physiological significance of increased sodium current with regard to the increased cardiac output caused by sympathetic excitation. Methods: Multiple experimental approaches, including ECG, action potential recording with conventional microelectrodes, whole-cell current measurements, single-channel recordings, and pumping-force measurements, were applied to guinea pig hearts and isolated ventricular myocytes. Results: Isoprenaline was found to dose-dependently shorten QRS waves, increase the amplitude and the V max of action potentials, augment the fast sodium current, and increase the occurrence frequencies and open time constants of the long-open and burst modes of the sodium channel. Increased levels of membrane-permeable cAMP have similar effects. In the presence of a calcium channel blocker, TTX reversed the increased pumping force produced by isoprenaline. Conclusion: Beta-adrenergic modulation increases the inward sodium current and accelerates the conduction velocity within the ventricles by changing the sodium channel modes, which might both be conducive to the synchronous contraction of the heart and enhance its pumping function.

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Dose-dependent alteration of rat cardiac sodium current by isoproterenol: Results from direct measurements on multicellular preparations

Cited by 17 publications

References 28 publications

Intact Heart Loose Patch Photolysis Reveals Ionic Current Kinetics During Ventricular Action Potentials

Intact Heart Loose Patch Photolysis Reveals Ionic Current Kinetics During Ventricular Action Potentials

A Compartmentalized Mathematical Model of the β1-Adrenergic Signaling System in Mouse Ventricular Myocytes

Beta-receptor activation increases sodium current in guinea pig heart

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