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Sample records for action potential repolarization

  1. Components of action potential repolarization in cerebellar parallel fibres

    PubMed Central

    Pekala, Dobromila; Baginskas, Armantas; Szkudlarek, Hanna J; Raastad, Morten

    2014-01-01

    Repolarization of the presynaptic action potential is essential for transmitter release, excitability and energy expenditure. Little is known about repolarization in thin, unmyelinated axons forming en passant synapses, which represent the most common type of axons in the mammalian brain's grey matter. We used rat cerebellar parallel fibres, an example of typical grey matter axons, to investigate the effects of K+ channel blockers on repolarization. We show that repolarization is composed of a fast tetraethylammonium (TEA)-sensitive component, determining the width and amplitude of the spike, and a slow margatoxin (MgTX)-sensitive depolarized after-potential (DAP). These two components could be recorded at the granule cell soma as antidromic action potentials and from the axons with a newly developed miniaturized grease-gap method. A considerable proportion of fast repolarization remained in the presence of TEA, MgTX, or both. This residual was abolished by the addition of quinine. The importance of proper control of fast repolarization was demonstrated by somatic recordings of antidromic action potentials. In these experiments, the relatively broad K+ channel blocker 4-aminopyridine reduced the fast repolarization, resulting in bursts of action potentials forming on top of the DAP. We conclude that repolarization of the action potential in parallel fibres is supported by at least three groups of K+ channels. Differences in their temporal profiles allow relatively independent control of the spike and the DAP, whereas overlap of their temporal profiles provides robust control of axonal bursting properties. PMID:25239461

  2. Contributions of HERG K+ current to repolarization of the human ventricular action potential.

    PubMed

    Fink, Martin; Noble, Denis; Virag, Laszlo; Varro, Andras; Giles, Wayne R

    2008-01-01

    Action potential repolarization in the mammalian heart is governed by interactions of a number of time- and voltage-dependent channel-mediated currents, as well as contributions from the Na+/Ca2+ exchanger and the Na+/K+ pump. Recent work has shown that one of the K+ currents (HERG) which contributes to repolarization in mammalian ventricle is a locus at which a number of point mutations can have significant functional consequences. In addition, the remarkable sensitivity of this K+ channel isoform to inhibition by a variety of pharmacological agents and clinical drugs has resulted in HERG being a major focus for Safety Pharmacology requirements. For these reasons we and others have attempted to define the functional role for HERG-mediated K+ currents in repolarization of the action potential in the human ventricle. Here, we describe and evaluate changes in the formulations for two K+ currents, IK1 and HERG (or IK,r), within the framework of ten Tusscher model of the human ventricular action potential. In this computational study, new mathematical formulations for the two nonlinear K+ conductances, IK1 and HERG, have been developed based upon experimental data obtained from electrophysiological studies of excised human ventricular tissue and/or myocytes. The resulting mathematical model provides much improved simulations of the relative sizes and time courses of the K+ currents which modulate repolarization. Our new formulation represents an important first step in defining the mechanism(s) of repolarization of the membrane action potential in the human ventricle. Our overall goal is to understand the genesis of the T-wave of the human electrocardiogram.

  3. Action potential repolarization and a fast after-hyperpolarization in rat hippocampal pyramidal cells.

    PubMed

    Storm, J F

    1987-04-01

    1. The repolarization of the action potential, and a fast after-hyperpolarization (a.h.p.) were studied in CA1 pyramidal cells (n = 76) in rat hippocampal slices (28-37 degrees C). Single spikes were elicited by brief (1-3 ms) current pulses, at membrane potentials close to rest (-60 to -70 mV). 2. Each action potential was followed by four after-potentials: (a) the fast a.h.p., lasting 2-5 ms; (b) an after-depolarization; (c) a medium a.h.p., (50-100 ms); and (d) a slow a.h.p. (1-2 s). Both the fast a.h.p. and the slow a.h.p. (but not the medium a.h.p.) were inhibited by Ca2+-free medium or Ca2+-channel blockers (Co2+, Mn2+ or Cd2+); but tetraethylammonium (TEA; 0.5-2 nM) blocked only the fast a.h.p., and noradrenaline (2-5 microM) only the slow a.h.p. This suggests that two Ca2+-activated K+ currents were involved: a fast, TEA-sensitive one (IC) underlying the fast a.h.p., and a slow noradrenaline-sensitive one (IAHP) underlying the slow a.h.p. 3. Like the fast a.h.p., spike repolarization seems to depend on a Ca2+-dependent K+ current of the fast, TEA-sensitive kind (IC). The repolarization was slowed by Ca2+-free medium, Co2+, Mn2+, Cd2+, or TEA, but not by noradrenaline. Charybdotoxin (CTX; 30 nM), a scorpion toxin which blocks the large-conductance Ca2+-activated K+ channel in muscle, had a similar effect to TEA. The effects of TEA and Cd2+ (or Mn2+) showed mutual occlusion. Raising the external K+ concentration reduced the fast a.h.p. and slowed the spike repolarization, whereas Cl- loading of the cell was ineffective. 4. The transient K+ current, IA, seems also to contribute to spike repolarization, because: (a) 4-aminopyridine (4-AP; 0.1 mM), which blocks IA, slowed the spike repolarization; (b) depolarizing pre-pulses, which inactivate IA, had a similar effect; (c) hyperpolarizing pre-pulses speeded up the spike repolarization; (d) the effects of 4-AP and pre-pulses persisted during Ca2+ blockade (like IA); and (e) depolarizing pre-pulses reduced the

  4. Kv3.1 uses a timely resurgent K(+) current to secure action potential repolarization.

    PubMed

    Labro, Alain J; Priest, Michael F; Lacroix, Jérôme J; Snyders, Dirk J; Bezanilla, Francisco

    2015-12-17

    High-frequency action potential (AP) transmission is essential for rapid information processing in the central nervous system. Voltage-dependent Kv3 channels play an important role in this process thanks to their high activation threshold and fast closure kinetics, which reduce the neuron's refractory period. However, premature Kv3 channel closure leads to incomplete membrane repolarization, preventing sustainable AP propagation. Here, we demonstrate that Kv3.1b channels solve this problem by producing resurgent K(+) currents during repolarization, thus ensuring enough repolarizing power to terminate each AP. Unlike previously described resurgent Na(+) and K(+) currents, Kv3.1b's resurgent current does not originate from recovery of channel block or inactivation but results from a unique combination of steep voltage-dependent gating kinetics and ultra-fast voltage-sensor relaxation. These distinct properties are readily transferrable onto an orthologue Kv channel by transplanting the voltage-sensor's S3-S4 loop, providing molecular insights into the mechanism by which Kv3 channels contribute to high-frequency AP transmission.

  5. Kv3.1 uses a timely resurgent K+ current to secure action potential repolarization

    PubMed Central

    Labro, Alain J.; Priest, Michael F.; Lacroix, Jérôme J.; Snyders, Dirk J.; Bezanilla, Francisco

    2015-01-01

    High-frequency action potential (AP) transmission is essential for rapid information processing in the central nervous system. Voltage-dependent Kv3 channels play an important role in this process thanks to their high activation threshold and fast closure kinetics, which reduce the neuron's refractory period. However, premature Kv3 channel closure leads to incomplete membrane repolarization, preventing sustainable AP propagation. Here, we demonstrate that Kv3.1b channels solve this problem by producing resurgent K+ currents during repolarization, thus ensuring enough repolarizing power to terminate each AP. Unlike previously described resurgent Na+ and K+ currents, Kv3.1b's resurgent current does not originate from recovery of channel block or inactivation but results from a unique combination of steep voltage-dependent gating kinetics and ultra-fast voltage-sensor relaxation. These distinct properties are readily transferrable onto an orthologue Kv channel by transplanting the voltage-sensor's S3–S4 loop, providing molecular insights into the mechanism by which Kv3 channels contribute to high-frequency AP transmission. PMID:26673941

  6. Reconstruction of action potential of repolarization in patients with congenital long-QT syndrome

    NASA Astrophysics Data System (ADS)

    Kandori, Akihiko; Shimizu, Wataru; Yokokawa, Miki; Kamakura, Shiro; Miyatake, Kunio; Murakami, Masahiro; Miyashita, Tsuyoshi; Ogata, Kuniomi; Tsukada, Keiji

    2004-05-01

    A method for reconstructing an action potential during the repolarization period was developed. This method uses a current distribution—plotted as a current-arrow map (CAM)—calculated using magnetocardiogram (MCG) signals. The current arrows are summarized during the QRS complex period and subtracted during the ST-T wave period in order to reconstruct the action-potential waveform. To ensure the similarity between a real action potential and the reconstructed action potential using CAM, a monophasic action potential (MAP) and an MCG of the same patient with type-I long-QT syndrome were measured. Although the MAP had one notch that was associated with early afterdepolarization (EAD), the reconstructed action potential had two large and small notches. The small notch timing agreed with the occurrence of the EAD in the MAP. On the other hand, the initiation time of an abnormal current distribution coincides with the appearance timing of the first large notch, and its end time coincides with that of the second small notch. These results suggest that a simple reconstruction method using a CAM based on MCG data can provide a similar action-potential waveform to a MAP waveform without having to introduce a catheter.

  7. Uniform Action Potential Repolarization within the Sarcolemma of In Situ Ventricular Cardiomyocytes

    PubMed Central

    Bu, Guixue; Adams, Heather; Berbari, Edward J.; Rubart, Michael

    2009-01-01

    Previous studies have speculated, based on indirect evidence, that the action potential at the transverse (t)-tubules is longer than at the surface membrane in mammalian ventricular cardiomyocytes. To date, no technique has enabled recording of electrical activity selectively at the t-tubules to directly examine this hypothesis. We used confocal line-scan imaging in conjunction with the fast response voltage-sensitive dyes ANNINE-6 and ANNINE-6plus to resolve action potential-related changes in fractional dye fluorescence (ΔF/F) at the t-tubule and surface membranes of in situ mouse ventricular cardiomyocytes. Peak ΔF/F during action potential phase 0 depolarization averaged −21% for both dyes. The shape and time course of optical action potentials measured with the water-soluble ANNINE-6plus were indistinguishable from those of action potentials recorded with intracellular microelectrodes in the absence of the dye. In contrast, optical action potentials measured with the water-insoluble ANNINE-6 were significantly prolonged compared to the electrical recordings obtained from dye-free hearts, suggesting electrophysiological effects of ANNINE-6 and/or its solvents. With either dye, the kinetics of action potential-dependent changes in ΔF/F during repolarization were found to be similar at the t-tubular and surface membranes. This study provides what to our knowledge are the first direct measurements of t-tubule electrical activity in ventricular cardiomyocytes, which support the concept that action potential duration is uniform throughout the sarcolemma of individual cells. PMID:19289075

  8. Archaerhodopsin voltage imaging: synaptic calcium and BK channels stabilize action potential repolarization at the Drosophila neuromuscular junction.

    PubMed

    Ford, Kevin J; Davis, Graeme W

    2014-10-29

    The strength and dynamics of synaptic transmission are determined, in part, by the presynaptic action potential (AP) waveform at the nerve terminal. The ion channels that shape the synaptic AP waveform remain essentially unknown for all but a few large synapses amenable to electrophysiological interrogation. The Drosophila neuromuscular junction (NMJ) is a powerful system for studying synaptic biology, but it is not amenable to presynaptic electrophysiology. Here, we demonstrate that Archaerhodopsin can be used to quantitatively image AP waveforms at the Drosophila NMJ without disrupting baseline synaptic transmission or neuromuscular development. It is established that Shaker mutations cause a dramatic increase in neurotransmitter release, suggesting that Shaker is predominantly responsible for AP repolarization. Here we demonstrate that this effect is caused by a concomitant loss of both Shaker and slowpoke (slo) channel activity because of the low extracellular calcium concentrations (0.2-0.5 mM) used typically to assess synaptic transmission in Shaker. In contrast, at physiological extracellular calcium (1.5 mM), the role of Shaker during AP repolarization is limited. We then provide evidence that calcium influx through synaptic CaV2.1 channels and subsequent recruitment of Slo channel activity is important, in concert with Shaker, to ensure proper AP repolarization. Finally, we show that Slo assumes a dominant repolarizing role during repetitive nerve stimulation. During repetitive stimulation, Slo effectively compensates for Shaker channel inactivation, stabilizing AP repolarization and limiting neurotransmitter release. Thus, we have defined an essential role for Slo channels during synaptic AP repolarization and have revised our understanding of Shaker channels at this model synapse.

  9. Archaerhodopsin Voltage Imaging: Synaptic Calcium and BK Channels Stabilize Action Potential Repolarization at the Drosophila Neuromuscular Junction

    PubMed Central

    Ford, Kevin J.

    2014-01-01

    The strength and dynamics of synaptic transmission are determined, in part, by the presynaptic action potential (AP) waveform at the nerve terminal. The ion channels that shape the synaptic AP waveform remain essentially unknown for all but a few large synapses amenable to electrophysiological interrogation. The Drosophila neuromuscular junction (NMJ) is a powerful system for studying synaptic biology, but it is not amenable to presynaptic electrophysiology. Here, we demonstrate that Archaerhodopsin can be used to quantitatively image AP waveforms at the Drosophila NMJ without disrupting baseline synaptic transmission or neuromuscular development. It is established that Shaker mutations cause a dramatic increase in neurotransmitter release, suggesting that Shaker is predominantly responsible for AP repolarization. Here we demonstrate that this effect is caused by a concomitant loss of both Shaker and slowpoke (slo) channel activity because of the low extracellular calcium concentrations (0.2–0.5 mm) used typically to assess synaptic transmission in Shaker. In contrast, at physiological extracellular calcium (1.5 mm), the role of Shaker during AP repolarization is limited. We then provide evidence that calcium influx through synaptic CaV2.1 channels and subsequent recruitment of Slo channel activity is important, in concert with Shaker, to ensure proper AP repolarization. Finally, we show that Slo assumes a dominant repolarizing role during repetitive nerve stimulation. During repetitive stimulation, Slo effectively compensates for Shaker channel inactivation, stabilizing AP repolarization and limiting neurotransmitter release. Thus, we have defined an essential role for Slo channels during synaptic AP repolarization and have revised our understanding of Shaker channels at this model synapse. PMID:25355206

  10. A major role for calcium-dependent potassium current in action potential repolarization in adrenal chromaffin cells.

    PubMed

    Pancrazio, J J; Johnson, P A; Lynch, C

    1994-12-30

    To determine the extent which Ca dependent K current (IKCa) contributes during an action potential (AP), bovine chromaffin cells were voltage-clamped using a pre-recorded AP as the command voltage waveform. Based on (1) differential sensitivity of IKCa and Ca-independent K current (IK) to tetraethylammonium; (2) measurements of AP currents under conditions where Ca activation of IKCa had been abolished; and (3) blockade by charybdotoxin, IKCa comprised 70-90% of the outward K current during AP repolarization. In addition, observations are made concerning the form of AP-evoked Ca current.

  11. Resilient RTN fast spiking in Kv3.1 null mice suggests redundancy in the action potential repolarization mechanism.

    PubMed

    Porcello, Darrell M; Ho, Chi Shun; Joho, Rolf H; Huguenard, John R

    2002-03-01

    Fast spiking (FS), GABAergic neurons of the reticular thalamic nucleus (RTN) are capable of firing high-frequency trains of brief action potentials, with little adaptation. Studies in recombinant systems have shown that high-voltage-activated K(+) channels containing the Kv3.1 and/or Kv3.2 subunits display biophysical properties that may contribute to the FS phenotype. Given that RTN expresses high levels of Kv3.1, with little or no Kv3.2, we tested whether this subunit was required for the fast action potential repolarization mechanism essential to the FS phenotype. Single- and multiple-action potentials were recorded using whole-cell current clamp in RTN neurons from brain slices of wild-type and Kv3.1-deficient mice. At 23 degrees C, action potentials recorded from homozygous Kv3.1 deficient mice (Kv3.1(-/-)) compared with their wild-type (Kv3.1(+/+)) counterparts had reduced amplitudes (-6%) and fast after-hyperpolarizations (-16%). At 34 degrees C, action potentials in Kv3.1(-/-) mice had increased duration (21%) due to a reduced rate of repolarization (-30%) when compared with wild-type controls. Action potential trains in Kv3.1(-/-) were associated with a significantly greater spike decrement and broadening and a diminished firing frequency versus injected current relationship (F/I) at 34 degrees C. There was no change in either spike count or maximum instantaneous frequency during low-threshold Ca(2+) bursts in Kv3.1(-/-) RTN neurons at either temperature tested. Our findings show that Kv3.1 is not solely responsible for fast spikes or high-frequency firing in RTN neurons. This suggests genetic redundancy in the system, possibly in the form of other Kv3 members, which may suffice to maintain the FS phenotype in RTN neurons in the absence of Kv3.1.

  12. Role of gap junction channel in the development of beat-to-beat action potential repolarization variability and arrhythmias.

    PubMed

    Magyar, Janos; Banyasz, Tamas; Szentandrassy, Norbert; Kistamas, Kornel; Nanasi, Peter P; Satin, Jonathan

    2015-01-01

    The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling. Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR. Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

  13. Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of I(Ca,L).

    PubMed

    Christ, Torsten; Wettwer, Erich; Ravens, Ursula

    2005-05-01

    The neuroleptic risperidone is an effective blocker of the rapidly activating component of the delayed rectifier current (I(Kr)) and hence is expected to prolong cardiac action potential duration (APD). However, unlike with other typical I(Kr) blockers we failed to demonstrate a marked prolongation of late repolarization with risperidone. It is hypothesized that the APD-prolonging effect of risperidone is masked by the high repolarization reserve due to the prominent delayed rectifier currents I(Kr) and I(Ks) in guinea pig papillary muscle. Action potentials and force of contraction were recorded in isolated guinea pig papillary muscles. L-type calcium current I(Ca,L) and I(Kr) were measured using the standard patch clamp technique in single ventricular cardiomyocytes. Reduction of the repolarization reserve by the blocking of I(Ks) with chromanol 239B augmented the effect of the selective I(Kr) blocker E-4031, but not of risperidone, although both drugs completely blocked I(Kr). In contrast to E-4031 risperidone markedly reduced the force of contraction due to the partial blocking of I(Ca,L) in the same concentration range as required for block of I(Kr). Reduction of the repolarization reserve by the blocking of I(Ks) cannot exacerbate the APD-prolonging effect of risperidone. However, even incomplete concomitant blocking of I(Ca,L) attenuates the APD-prolonging effect of the complete blocking of I(Kr). This behaviour may explain the small APD-prolonging effect of risperidone despite the drug's robust blocking of I(Kr).

  14. Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons.

    PubMed

    Liu, Pin W; Bean, Bruce P

    2014-04-02

    Kv2 family "delayed-rectifier" potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60-80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from -70 mV, but not -80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at -70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation.

  15. Kv2 Channel Regulation of Action Potential Repolarization and Firing Patterns in Superior Cervical Ganglion Neurons and Hippocampal CA1 Pyramidal Neurons

    PubMed Central

    Liu, Pin W.

    2014-01-01

    Kv2 family “delayed-rectifier” potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60–80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from −70 mV, but not −80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at −70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation. PMID:24695716

  16. Calcium-activated potassium conductances contribute to action potential repolarization at the soma but not the dendrites of hippocampal CA1 pyramidal neurons.

    PubMed

    Poolos, N P; Johnston, D

    1999-07-01

    Evidence is accumulating that voltage-gated channels are distributed nonuniformly throughout neurons and that this nonuniformity underlies regional differences in excitability within the single neuron. Previous reports have shown that Ca2+, Na+, A-type K+, and hyperpolarization-activated, mixed cation conductances have varying distributions in hippocampal CA1 pyramidal neurons, with significantly different densities in the apical dendrites compared with the soma. Another important channel mediates the large-conductance Ca2+-activated K+ current (IC), which is responsible in part for repolarization of the action potential (AP) and generation of the afterhyperpolarization that follows the AP recorded at the soma. We have investigated whether this current is activated by APs retrogradely propagating in the dendrites of hippocampal pyramidal neurons using whole-cell dendritic patch-clamp recording techniques. We found no IC activation by back-propagating APs in distal dendritic recordings. Dendritic APs activated IC only in the proximal dendrites, and this activation decayed within the first 100-150 micrometer of distance from the soma. The decay of IC in the proximal dendrites occurred despite AP amplitude, plus presumably AP-induced Ca2+ influx, that was comparable with that at the soma. Thus we conclude that IC activation by action potentials is nonuniform in the hippocampal pyramidal neuron, which may represent a further example of regional differences in neuronal excitability that are determined by the nonuniform distribution of voltage-gated channels in dendrites.

  17. An analysis of the postnatal development of the action potential repolarization process in the working ventricular myocardium of albino rats (effect of tea, frequency, verapamil and adrenaline).

    PubMed

    Pucelík, P; Králícek, P; Barták, F; Jezek, K

    1983-01-01

    Using the glass microelectrodes techniques, we analysed the causes of the shortening of the ventricular myocardial action potentials (AP) of albino rats during postnatal development. Delayed outward currents were blocked with tetraethylammonium (TEA) in 20 mmol.l-1 concentration. TEA led to prolongation of action potentials and to accentuation of frequency sensitivity in all the given age groups, but a block of TEA-sensitive currents nevertheless does not permit the conclusion that the cause of postnatal AP shortening is due to an increase in the intensity of outward currents. Slow inward current (Isi) were blocked with verapamil (2.10(-5) mol.l-1), which markedly shortened the myocardial AP of newborn rats; with advancing age its effect diminished and shifted to the negative membrane voltage level. The Isi was stimulated by adrenaline (10(-5) mol.l-1), which markedly prolonged the AP of newborn animals; with advancing age its effect rapidly diminished and was virtually undetectable in 10-day-old animals. The results indicate that postnatal AP prolongation is caused by a drop in the Isi rate rather than by the growth of outward repolarizing currents.

  18. Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones.

    PubMed

    Kim, Jinhyun; Wei, Dong-Sheng; Hoffman, Dax A

    2005-11-15

    A-type potassium channels regulate neuronal firing frequency and the back-propagation of action potentials (APs) into dendrites of hippocampal CA1 pyramidal neurones. Recent molecular cloning studies have found several families of voltage-gated K(+) channel genes expressed in the mammalian brain. At present, information regarding the relationship between the protein products of these genes and the various neuronal functions performed by voltage-gated K(+) channels is lacking. Here we used a combination of molecular, electrophysiological and imaging techniques to show that one such gene, Kv4.2, controls AP half-width, frequency-dependent AP broadening and dendritic action potential propagation. Using a modified Sindbis virus, we expressed either the enhanced green fluorescence protein (EGFP)-tagged Kv4.2 or an EGFP-tagged dominant negative mutant of Kv4.2 (Kv4.2g(W362F)) in CA1 pyramidal neurones of organotypic slice cultures. Neurones expressing Kv4.2g(W362F) displayed broader action potentials with an increase in frequency-dependent AP broadening during a train compared with control neurones. In addition, Ca(2)(+) imaging of Kv4.2g(W362F) expressing dendrites revealed enhanced AP back-propagation compared to control neurones. Conversely, neurones expressing an increased A-type current through overexpression of Kv4.2 displayed narrower APs with less frequency dependent broadening and decreased dendritic propagation. These results point to Kv4.2 as the major contributor to the A-current in hippocampal CA1 neurones and suggest a prominent role for Kv4.2 in regulating AP shape and dendritic signalling. As Ca(2)(+) influx occurs primarily during AP repolarization, Kv4.2 activity can regulate cellular processes involving Ca(2)(+)-dependent second messenger cascades such as gene expression and synaptic plasticity.

  19. Somatic membrane potential and Kv1 channels control spike repolarization in cortical axon collaterals and presynaptic boutons.

    PubMed

    Foust, Amanda J; Yu, Yuguo; Popovic, Marko; Zecevic, Dejan; McCormick, David A

    2011-10-26

    The shape of action potentials invading presynaptic terminals, which can vary significantly from spike waveforms recorded at the soma, may critically influence the probability of synaptic neurotransmitter release. Revealing the conductances that determine spike shape in presynaptic boutons is important for understanding how changes in the electrochemical context in which a spike is generated, such as subthreshold depolarization spreading from the soma, can modulate synaptic strength. Utilizing recent improvements in the signal-to-noise ratio of voltage-sensitive dye imaging in mouse brain slices, we demonstrate that intracortical axon collaterals and en passant presynaptic terminals of layer 5 pyramidal cells exhibit a high density of Kv1 subunit-containing ion channels, which generate a slowly inactivating K(+) current critically important for spike repolarization in these compartments. Blockade of the current by low doses of 4-aminopyridine or α-dendrotoxin dramatically slows the falling phase of action potentials in axon collaterals and presynaptic boutons. Furthermore, subthreshold depolarization of the soma broadened action potentials in collaterals bearing presynaptic boutons, an effect abolished by blocking Kv1 channels with α-dendrotoxin. These results indicate that action potential-induced synaptic transmission may operate through a mix of analog-digital transmission owing to the properties of Kv1 channels in axon collaterals and presynaptic boutons.

  20. The contribution of ventricular apicobasal and transmural repolarization patterns to the development of the T wave body surface potentials in frogs (Rana temporaria) and pike (Esox lucius).

    PubMed

    Vaykshnorayte, Marina A; Azarov, Jan E; Tsvetkova, Alena S; Vityazev, Vladimir A; Ovechkin, Alexey O; Shmakov, Dmitry N

    2011-05-01

    The study aimed at the simultaneous determination of the transmural and apicobasal differences in the repolarization timing and the comparison of the contributions of these two repolarization gradients to the development of the body surface T wave potentials in animals with the single heart ventricle (fishes and amphibians). Unipolar potentials were measured on the body surface, epicardium and in the intramural (subepicardial, Epi; midmyocardial; and subendocardial, Endo) ventricular layers of 9 pike and 8 frogs. Activation times, repolarization times and activation-recovery intervals were determined. A transmural gradient in repolarization durations in frogs (Endo>Epi, P<0.024) corresponds to the gradient in repolarization times. No significant transmural difference in repolarization duration is observed in pike that produces a repolarization sequence from Endo to Epi (Endorepolarization sequence proceeds from apex to base (P<0.024) which is expressed in similar body surface potential distributions during the T wave in spite of the opposite transmural repolarization patterns. The present study suggests that the apicobasal repolarization gradient provides the major contribution to the development of the T wave potentials on the body surface in pike and frogs.

  1. Drug-induced spatial dispersion of repolarization

    PubMed Central

    Antzelevitch, Charles

    2008-01-01

    Spatial dispersion of repolarization in the form of transmural, trans-septal and apico-basal dispersion of repolarization creates voltage gradients that inscribe the J wave and T wave of the ECG. Amplification of this spatial dispersion of repolarization (SDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited or acquired ion channelopathies giving rise to the long QT, short QT and Brugada syndromes (BrS). This review focuses on the role of spatial dispersion of repolarization in drug-induced arrhythmogenesis associated with the long QT and BrS. In the long QT syndrome, drug-induced amplification of SDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the BrS, it is thought to be due to selective abbreviation of the APD of right ventricular epicardium. Among the challenges ahead is the identification of a means to quantitate SDR non-invasively. This review also discusses the value of the interval between the peak and end of the T wave (Tpeak–Tend, Tp–Te) as an index of SDR and transmural dispersion of repolarization, in particular. PMID:18651395

  2. Contribution of I Ks to ventricular repolarization in canine myocytes.

    PubMed

    Horváth, Balázs; Magyar, János; Szentandrássy, Norbert; Birinyi, Péter; Nánási, Péter P; Bányász, Tamás

    2006-09-01

    The role of the slow delayed rectifier K(+) current (I (Ks)) in cardiac repolarization seems to be largely influenced by the experimental conditions including the species and tissue studied. The aim of this study was to determine the contribution of I (Ks) to repolarization in canine ventricular myocytes by measuring the frequency dependent action potential lengthening effect of 10 microM chromanol 293B using sharp microelectrodes. Pretreatment with isoproterenol (2 nM), E-4031 (1 microM), and injection of inward current pulses were applied to modify action potential configuration. Chromanol alone caused moderate but statistically significant lengthening of action potentials at cycle lengths longer than 500 ms. The lengthening effect of chromanol, which was strongly enhanced in the presence of either isoproterenol or E-4031, was proportional to the amplitude of plateau, whereas poor correlation was found with action potential duration. Similar results were obtained when action potential configuration was modified by injection of depolarizing current pulses. Computer simulations revealed that activation of I (Ks) is a sharp function of the plateau amplitude within the physiological range, while elongation of repolarization may enhance I (Ks) only when it is excessive. It was concluded that the effect of I (Ks) on ventricular repolarization critically depends on the level of action potential plateau; however, other factors, like action potential duration, cycle length, or suppression of other K(+) currents can also influence its contribution.

  3. Mathematical Distinction in Action Potential between Primo-Vessels and Smooth Muscle

    PubMed Central

    Cho, Seong-Jin; Lee, Sang-Hun; Zhang, Wenji; Lee, Sae-Bhom; Choi, Kwang-Ho; Choi, Sun-Mi; Ryu, Yeon-Hee

    2012-01-01

    We studied the action potential of Primo-vessels in rats to determine the electrophysiological characteristics of these structures. We introduced a mathematical analysis method, a normalized Fourier transform that displays the sine and cosine components separately, to compare the action potentials of Primo-vessels with those for the smooth muscle. We found that Primo-vessels generated two types of action potential pulses that differed from those of smooth muscle: (1) Type I pulse had rapid depolarizing and repolarizing phases, and (2) Type II pulse had a rapid depolarizing phase and a gradually slowing repolarizing phase. PMID:22319544

  4. Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization.

    PubMed

    Gintant, G A

    2000-03-01

    Although inactivation of the rapidly activating delayed rectifier current (I(Kr)) limits outward current on depolarization, the role of I(Kr) (and recovery from inactivation) during repolarization is uncertain. To characterize I(Kr) during ventricular repolarization (and compare with the inward rectifier current, I(K1)), voltage-clamp waveforms simulating the action potential were applied to canine ventricular, atrial, and Purkinje myocytes. In ventricular myocytes, I(Kr) was minimal at plateau potentials but transiently increased during repolarizing ramps. The I(Kr) transient was unaffected by repolarization rate and maximal after 150-ms depolarizations (+25 mV). Action potential clamps revealed the I(Kr) transient terminating the plateau. Although peak I(Kr) transient density was relatively uniform among myocytes, potentials characterizing the peak transients were widely dispersed. In contrast, peak inward rectifier current (I(K1)) density during repolarization was dispersed, whereas potentials characterizing I(K1) defined a narrower (more negative) voltage range. In summary, rapidly activating I(Kr) provides a delayed voltage-dependent (and functionally time-independent) outward transient during ventricular repolarization, consistent with rapid recovery from inactivation. The heterogeneous voltage dependence of I(Kr) provides a novel means for modulating the contribution of this current during repolarization.

  5. Variations in onset of action potential broadening: effects on calcium current studied in chick ciliary ganglion neurones.

    PubMed

    Pattillo, J M; Artim, D E; Simples, J E; Meriney, S D

    1999-02-01

    1. The voltage dependence and kinetic properties of stage 40 ciliary ganglion calcium currents were determined using short (10 ms) voltage steps. These properties aided the interpretation of the action potential-evoked calcium current described below, and the comparison of our data with those observed in other preparations. 2. Three different natural action potential waveforms were modelled by a series of ramps to generate voltage clamp commands. Calcium currents evoked by these model action potentials were compared before and after alterations in the repolarization phase of each action potential. 3. Abrupt step repolarizations from various time points were used to estimate the time course of calcium current activation during each action potential. Calcium current evoked by fast action potentials (duration at half-amplitude, 0.5 or 1.0 ms) did not reach maximal activation until the action potential had repolarized by 40-50 %. In contrast, calcium current evoked by a slow action potential (duration at half-amplitude, 2.2 ms) was maximally activated near the peak of the action potential. 4. Slowing the rate of repolarization of the action potential (broadening) from different times was used to examine effects on peak and total calcium influx. With all three waveforms tested, broadening consistently increased total calcium influx (integral). However, peak calcium current was either increased or decreased depending on the duration of the control action potential tested and the specific timing of the initiation of broadening the repolarization phase. 5. The opposite effects on peak calcium current observed with action potential broadening beginning at different time points in repolarization may provide a mechanism for the variable effects of potassium channel blockers on transmitter release magnitude.

  6. Wheel-running exercise alters rat diaphragm action potentials and their regulation by K+ channels.

    PubMed

    Van Lunteren, Erik; Moyer, Michelle

    2003-08-01

    Endurance exercise modifies regulatory systems that control skeletal muscle Na+ and K+ fluxes, in particular Na+-K+-ATPase-mediated transport of these ions. Na+ and K+ ion channels also play important roles in the regulation of ionic movements, specifically mediating Na+ influx and K+ efflux that occur during contractions resulting from action potential depolarization and repolarization. Whether exercise alters skeletal muscle electrophysiological properties controlled by these ion channels is unclear. The present study tested the hypothesis that endurance exercise modifies diaphragm action potential properties. Exercised rats spent 8 wk with free access to running wheels, and they were compared with sedentary rats living in conventional rodent housing. Diaphragm muscle was subsequently removed under anesthesia and studied in vitro. Resting membrane potential was not affected by endurance exercise. Muscle from exercised rats had a slower rate of action potential repolarization than that of sedentary animals (P = 0.0098), whereas rate of depolarization was similar in the two groups. The K+ channel blocker 3,4-diaminopyridine slowed action potential repolarization and increased action potential area of both exercised and sedentary muscle. However, these effects were significantly smaller in diaphragm from exercised than sedentary rats. These data indicate that voluntary running slows diaphragm action potential repolarization, most likely by modulating K+ channel number or function.

  7. Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig.

    PubMed

    Osadchii, Oleg E

    2013-04-01

    Quinidine is a class Ia Na(+) channel blocker that prolongs cardiac repolarization owing to the inhibition of I(Kr), the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.

  8. Cardiac action potential imaging

    NASA Astrophysics Data System (ADS)

    Tian, Qinghai; Lipp, Peter; Kaestner, Lars

    2013-06-01

    Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

  9. Chronic Omega-3 Polyunsaturated Fatty Acid Treatment Variably Affects Cellular Repolarization in a Healed Post-MI Arrhythmia Model

    PubMed Central

    Bonilla, Ingrid M.; Nishijima, Yoshinori; Vargas-Pinto, Pedro; Baine, Stephen H.; Sridhar, Arun; Li, Chun; Billman, George E.; Carnes, Cynthia A.

    2016-01-01

    Introduction: Over the last 40 years omega-3 polyunsaturated fatty acids (PUFAs) have been shown to be anti-arrhythmic or pro-arrhythmic depending on the method and duration of administration and model studied. We previously reported that omega-3 PUFAs do not confer anti-arrhythmic properties and are pro-arrhythmic in canine model of sudden cardiac death (SCD). Here, we evaluated the effects of chronic omega-3 PUFA treatment in post-MI animals susceptible (VF+) or resistant (VF−) to ventricular tachyarrhythmias. Methods: Perforated patch clamp techniques were used to measure cardiomyocyte action potential durations (APD) at 50 and 90% repolarization and short term variability of repolarization. The early repolarizing transient outward potassium current Ito was also studied. Results: Omega-3 PUFAs prolonged the action potential in VF− myocytes at both 50 and 90% repolarization. Short term variability of repolarization was increased in both untreated and treated VF− myocytes vs. controls. Ito was unaffected by omega-3 PUFA treatment. Omega-3 PUFA treatment attenuated the action potential prolongation in VF+ myocytes, but did not return repolarization to control values. Conclusions: Omega-3 PUFAs do not confer anti-arrhythmic properties in the setting of healed myocardial infarction in a canine model of SCD. In canines previously resistant to ventricular fibrillation (VF−), omega-3 PUFA treatment prolonged the action potential in VF− myocytes, and may contribute to pro-arrhythmic responses. PMID:27378936

  10. Mechanism of alpha-2 adrenergic modulation of canine cardiac Purkinje action potential.

    PubMed

    Lee, H C; Cai, J J; Arnar, D O; Shibata, E F; Martins, J B

    1996-08-01

    We reported recently that stimulation of postjunctional alpha-2 adrenergic receptors prolongs the action potential durations (APD) of isolated canine Purkinje fibers. With standard microelectrode techniques, we examined the ionic mechanism through which alpha-2 adrenergic stimulation prolonged Purkinje APD, by measuring the effects of inhibitors of the various plateau currents on the alpha-2-mediated prolongation of APD. The alpha-2-specific agonist UK 14,304 (0.1 microM) prolonged the Purkinje APD at 50% repolarization and the APD at 90% repolarization, and these effects were inhibited by yohimbine (0.1 microM). The Purkinje APD at 50% repolarization and the APD at 90% repolarization were prolonged significantly with the transient outward potassium current inhibitor 4-aminopyridine (1 mM), the rapid component of delayed rectifier potassium current inhibitor d-sotalol (10 microM), the slow component of delayed rectifier potassium current inhibitor indapamide (0.1 microM) and the chloride current inhibitor mefenamic acid (10 nM) and were shortened significantly with the calcium current inhibitor nifedipine (0.3 microM). Prolongation of Purkinje APD at 50% repolarization and APD at 90% repolarization by UK 14,304 remained intact in the presence of d-sotalol, indapamide, mefenamic acid and nifedipine. All of these UK 14,304 effects were significantly reversed by yohimbine. Only in the presence of 4-aminopyridine did UK 14,304 fail to prolong Purkinje APD. The phase 1 magnitudes of Purkinje action potentials were also significantly inhibited by UK 14,304. This effect was completely abolished only in the presence of 4-aminopyridine. These results suggest that inhibition of the 4-aminopyridine-sensitive transient outward potassium current is the major ionic mechanism by which alpha-2 adrenergic stimulation prolongs Purkinje APD.

  11. Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes.

    PubMed

    Antzelevitch, Charles

    2005-11-01

    Torsades de pointes (TdP) is a potentially lethal arrhythmia that develops as a consequence of amplification of electrical heterogeneities intrinsic to the ventricular myocardium. These heterogeneities exist because of differences in the time course of repolarization of the three predominant cell types that make up the ventricular myocardium, giving rise to transmural voltage gradients and a dispersion of repolarization responsible for inscription of the ECG T wave. Antiarrhythmic agents with class III actions and/or the various mutations and cardiomyopathies associated with the long QT syndrome reduce net repolarizing current and amplify the intrinsic spatial dispersion of repolarization, thus creating the substrate for the development of reentry. The result is prolongation of the QT interval, abnormal T waves, and development of polymorphic reentrant ventricular tachycardia displaying characteristics of TdP. Prolongation of the QT interval apparently is not the sole determinant of a drug's potential to cause TdP. Agents that do not increase transmural dispersion of repolarization have little or no potential to induce TdP despite any ability to prolong the QT interval. In addition, drugs such as amiodarone and sodium pentobarbital can cause large QT prolongations but, by reducing transmural dispersion of repolarization, may reduce the likelihood of TdP. Arterially perfused wedge preparations of canine left ventricle can be used to explore the role of transmural dispersion of repolarization in the genesis of TdP. The purpose of this article is to review recent advances that have improved our understanding of these mechanisms, particularly the role of transmural dispersion of repolarization, in the genesis of drug-induced TdP and to examine how these advances can guide us toward the development of safer and more effective drugs.

  12. Local Left Ventricular Epicardial J Waves and Late Potentials in Brugada Syndrome Patients with Inferolateral Early Repolarization Pattern

    PubMed Central

    Nagase, Satoshi; Tanaka, Masamichi; Morita, Hiroshi; Nakagawa, Koji; Wada, Tadashi; Murakami, Masato; Nishii, Nobuhiro; Nakamura, Kazufumi; Ito, Hiroshi; Ohe, Tohru; Kusano, Kengo F.

    2017-01-01

    Background: Brugada syndrome (BrS) is characterized by J-point or ST-segment elevation on electrocardiograms (ECGs) and increased risk of ventricular fibrillation (VF). In BrS, epicardial depolarization abnormality with delayed potential on the right ventricular outflow tract is reportedly the predominant mechanism underlying VF. Yet VF occurrence is also associated with early repolarization (ER) pattern in the inferolateral ECG leads, which may represent the inferior and/or left lateral ventricular myocardium. The aim of this study was to examine epicardial electrograms recorded directly at the left ventricle (LV) in BrS patients after VF episodes. Methods: In 12 BrS patients who had experienced VF episodes and 17 control subjects, a multipolar catheter was introduced into the left lateral coronary vein for unipolar and bipolar electrogram recordings at the LV epicardium. Both inferior and lateral ER patterns on ECG were observed in three BrS patients and six control subjects. Results: In the epicardium, prominent J waves were detected using unipolar recording, and potentials after the QRS complex were detected using bipolar recording in three of the 12 BrS patients. These three patients also showed both inferior and lateral ER patterns on ECG. Neither prominent J waves nor potentials after the QRS complex were recorded at the endocardium of the LV in any of these three patients; nor were they seen at the epicardium in any of the control subjects. These features were accentuated on pilsicainide administration (n = 2) but diminished on constant atrial pacing (n = 3) and isoproterenol administration (n = 1). The J waves observed through unipolar recording coincided with the potentials after QRS complex observed through bipolar recording and with the inferolateral ER patterns on ECG. Conclusions: We recorded prominent J waves in unipolar electrogram and potentials after QRS complex in bipolar electrogram at the LV epicardium in BrS patients with global ER pattern

  13. Local Left Ventricular Epicardial J Waves and Late Potentials in Brugada Syndrome Patients with Inferolateral Early Repolarization Pattern.

    PubMed

    Nagase, Satoshi; Tanaka, Masamichi; Morita, Hiroshi; Nakagawa, Koji; Wada, Tadashi; Murakami, Masato; Nishii, Nobuhiro; Nakamura, Kazufumi; Ito, Hiroshi; Ohe, Tohru; Kusano, Kengo F

    2017-01-01

    Background: Brugada syndrome (BrS) is characterized by J-point or ST-segment elevation on electrocardiograms (ECGs) and increased risk of ventricular fibrillation (VF). In BrS, epicardial depolarization abnormality with delayed potential on the right ventricular outflow tract is reportedly the predominant mechanism underlying VF. Yet VF occurrence is also associated with early repolarization (ER) pattern in the inferolateral ECG leads, which may represent the inferior and/or left lateral ventricular myocardium. The aim of this study was to examine epicardial electrograms recorded directly at the left ventricle (LV) in BrS patients after VF episodes. Methods: In 12 BrS patients who had experienced VF episodes and 17 control subjects, a multipolar catheter was introduced into the left lateral coronary vein for unipolar and bipolar electrogram recordings at the LV epicardium. Both inferior and lateral ER patterns on ECG were observed in three BrS patients and six control subjects. Results: In the epicardium, prominent J waves were detected using unipolar recording, and potentials after the QRS complex were detected using bipolar recording in three of the 12 BrS patients. These three patients also showed both inferior and lateral ER patterns on ECG. Neither prominent J waves nor potentials after the QRS complex were recorded at the endocardium of the LV in any of these three patients; nor were they seen at the epicardium in any of the control subjects. These features were accentuated on pilsicainide administration (n = 2) but diminished on constant atrial pacing (n = 3) and isoproterenol administration (n = 1). The J waves observed through unipolar recording coincided with the potentials after QRS complex observed through bipolar recording and with the inferolateral ER patterns on ECG. Conclusions: We recorded prominent J waves in unipolar electrogram and potentials after QRS complex in bipolar electrogram at the LV epicardium in BrS patients with global ER pattern

  14. Ventricular repolarization measures for arrhythmic risk stratification

    PubMed Central

    Monitillo, Francesco; Leone, Marta; Rizzo, Caterina; Passantino, Andrea; Iacoviello, Massimo

    2016-01-01

    Ventricular repolarization is a complex electrical phenomenon which represents a crucial stage in electrical cardiac activity. It is expressed on the surface electrocardiogram by the interval between the start of the QRS complex and the end of the T wave or U wave (QT). Several physiological, pathological and iatrogenic factors can influence ventricular repolarization. It has been demonstrated that small perturbations in this process can be a potential trigger of malignant arrhythmias, therefore the analysis of ventricular repolarization represents an interesting tool to implement risk stratification of arrhythmic events in different clinical settings. The aim of this review is to critically revise the traditional methods of static analysis of ventricular repolarization as well as those for dynamic evaluation, their prognostic significance and the possible application in daily clinical practice. PMID:26839657

  15. Cardiac Repolarization Abnormalities and Potential Evidence for Loss of Cardiac Sodium Currents on ECGs of Patients with Chagas' Heart Disease

    NASA Technical Reports Server (NTRS)

    Schlegel, T. T.; Medina, R.; Jugo, D.; Nunez, T. J.; Borrego, A.; Arellano, E.; Arenare, B.; DePalma, J. L.; Greco, E. C.; Starc, V.

    2007-01-01

    were not significantly different between groups. Patients with Chagas heart disease have increased cardiac repolarization abnormalities, especially by advanced ECG. Moreover, as a group, they have decreased uncorrected JT and QT interval durations and increased filtered QRS interval durations (versus age/gender-matched controls), all suggesting a potential loss of cardiac sodium channel function that might be mediated, in part, by cardiac autonomic damage. Overall findings support Brugada et al's recent hypothesis that the pathway leading to sudden death may often be similar in Chagas' disease and Brugada syndrome i.e., damage to the sodium channel (infectious/immunologic/autonomic in Chagas' genetic in Brugada) with consequent loss of sodium currents may facilitate a phase II-reentry based arrhythmic substrate for ventricular fibrillation in both conditions. In general, JT interval-related results have been underreported in the Chagas literature.

  16. The Characteristics of Action Potentials in Primo Vessels and the Effects of Acetylcholine Injection to the Action Potentials

    PubMed Central

    Cho, Seong Jin; Lim, Jaekwan; Yeon, Sun Hee; Kwon, O. Sang; Choi, Kwang-Ho; Choi, Sun-Mi; Ryu, Yeon-Hee

    2013-01-01

    In a previous study, we found that Primo vessels generate different action potentials in smooth muscles, but this study compared the pulse shape to distinguish the two tissues. Thus, a more sophisticated extracellular experiment was performed in this study using an acetylcholine injection; we then observed changes in the amplitude, FWHM (full width at half maximum), and period to explore Primo vessel function. A third type of pulse was recorded for Primo vessels. We observed fast depolarizing and repolarizing phases for this pulse. Further, its FWHM was 30 ms between smooth muscles and neurons. Acetylcholine affected only the period. The amplitude and FWHM were consistent after injection. Primo-vessels generated action potentials at twice the frequency after injection. From the results, we speculate that Primo-vessels perform a role in transferring signals in a different manner, which may be relevant for acupuncture treatment. PMID:23861710

  17. The role of sodium channel current in modulating transmural dispersion of repolarization and arrhythmogenesis.

    PubMed

    Antzelevitch, Charles; Belardinelli, Luiz

    2006-05-01

    Ventricular myocardium in larger mammals is composed of three distinct cell types: epicardial, M, and endocardial cells. Epicardial and M cell, but not endocardial cell, action potentials have a prominent I(to)-mediated notch. M cells are distinguished from the other cell types in that they display a smaller I(Ks), but a larger late I(Na) and I(Na-Ca). These ionic differences may account for the longer action potential duration (APD) and steeper APD-rate relationship of the M cell. The difference in the time course of repolarization of phase 1 and phase 3 contributes to the inscription of the electrocardiographic J wave and T wave, respectively. These repolarization gradients are modulated by electrotonic interactions, [K(+)](o), and agents or mutations that alter net repolarizing current. An increase in late I(Na), as occurring under a variety of pathophysiological states or in response to certain toxins, leads to a preferential prolongation of the M cell action potential, thus prolonging the QT interval and increasing transmural dispersion of repolarization (TDR), which underlies the development of torsade de pointes (TdP) arrhythmias. Agents that reduce late I(Na) are effective in reducing TDR and suppressing TdP. A reduction in peak I(Na) or an increase in net repolarizing current in the early phases of the action potential can lead to a preferential abbreviation of the action potential of epicardium in the right ventricle, and thus the development of a large TDR, phase 2 reentry, and polymorphic ventricular tachycardia associated with the Brugada syndrome.

  18. Modulation by K+ channels of action potential-evoked intracellular Ca2+ concentration rises in rat cerebellar basket cell axons

    PubMed Central

    Tan, Y P; Llano, I

    1999-01-01

    Action potential-evoked [Ca2+]i rises in basket cell axons of rat cerebellar slices were studied using two-photon laser scanning microscopy and whole-cell recording, to identify the K+ channels controlling the shape of the axonal action potential. Whole-cell recordings of Purkinje cell IPSCs were used to screen K+ channel subtypes which could contribute to axonal repolarization. α-Dendrotoxin, 4-aminopyridine, charybdotoxin and tetraethylammonium chloride increased IPSC rate and/or amplitude, whereas iberiotoxin and apamin failed to affect the IPSCs. The effects of those K+ channel blockers that enhanced transmitter release on the [Ca2+]i rises elicited in basket cell axons by action potentials fell into three groups: 4-aminopyridine strongly increased action potential-evoked [Ca2+]i; tetraethylammonium and charybdotoxin were ineffective alone but augmented the effects of 4-aminopyridine; α-dendrotoxin had no effect. We conclude that cerebellar basket cells contain at least three pharmacologically distinct K+ channels, which regulate transmitter release through different mechanisms. 4-Aminopyridine-sensitive, α-dendrotoxin-insensitive K+ channels are mainly responsible for repolarization in basket cell presynaptic terminals. K+ channels blocked by charybdotoxin and tetraethylammonium have a minor role in repolarization. α-Dendrotoxin-sensitive channels are not involved in shaping the axonal action potential waveform. The two last types of channels must therefore exert control of synaptic activity through a pathway unrelated to axonal action potential broadening. PMID:10517801

  19. Modulation by K+ channels of action potential-evoked intracellular Ca2+ concentration rises in rat cerebellar basket cell axons.

    PubMed

    Tan, Y P; Llano, I

    1999-10-01

    1. Action potential-evoked [Ca2+]i rises in basket cell axons of rat cerebellar slices were studied using two-photon laser scanning microscopy and whole-cell recording, to identify the K+ channels controlling the shape of the axonal action potential. 2. Whole-cell recordings of Purkinje cell IPSCs were used to screen K+ channel subtypes which could contribute to axonal repolarization. alpha-Dendrotoxin, 4-aminopyridine, charybdotoxin and tetraethylammonium chloride increased IPSC rate and/or amplitude, whereas iberiotoxin and apamin failed to affect the IPSCs. 3. The effects of those K+ channel blockers that enhanced transmitter release on the [Ca2+]i rises elicited in basket cell axons by action potentials fell into three groups: 4-aminopyridine strongly increased action potential-evoked [Ca2+]i; tetraethylammonium and charybdotoxin were ineffective alone but augmented the effects of 4-aminopyridine; alpha-dendrotoxin had no effect. 4. We conclude that cerebellar basket cells contain at least three pharmacologically distinct K+ channels, which regulate transmitter release through different mechanisms. 4-Aminopyridine-sensitive, alpha-dendrotoxin-insensitive K+ channels are mainly responsible for repolarization in basket cell presynaptic terminals. K+ channels blocked by charybdotoxin and tetraethylammonium have a minor role in repolarization. alpha-Dendrotoxin-sensitive channels are not involved in shaping the axonal action potential waveform. The two last types of channels must therefore exert control of synaptic activity through a pathway unrelated to axonal action potential broadening.

  20. Transmural dispersion of repolarization and arrhythmogenicity: the Brugada syndrome versus the long QT syndrome.

    PubMed

    Antzelevitch, C; Yan, G X; Shimizu, W

    1999-01-01

    Recent studies have shown that ventricular myocardium is composed of at least 3 electrophysiologically distinct cell types: epicardial, endocardial, and M cells. Action potentials recorded from epicardial and M cells, unlike those recorded from endocardium, display a spike-and-dome morphology, the result of a prominent transient outward current-mediated phase 1. M cells are distinguished from endocardial and epicardial cells by the ability of their action potential to prolong disproportionately in response to a slowing of rate and/or to agents with class III actions. This intrinsic electrical heterogeneity contributes to the inscription of the electrocardiogram as well as to the development of a variety of cardiac arrhythmias. The transmural dispersion of repolarization is in large part responsible for the inscription of the J wave and T wave of the electrocardiogram. Because full repolarization of epicardium defines the peak of the T wave and that of the M cells, the end of the T wave, the interval between the peak and the end of the T wave provides a valuable index of transmural dispersion of repolarization. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often results in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of reentrant arrhythmias, including torsade de pointes (TdP) commonly associated with the long QT syndrome (LQTS) and the polymorphic ventricular tachycardia/fibrillation encountered in patients with the Brugada syndrome. Early repolarization of the epicardial action potential results in abnormal abbreviation of action potential duration due to an all-or-none repolarization at the end of phase 1 of the epicardial action potential. The loss of the action potential dome in epicardium but not endocardium gives rise to a large dispersion of repolarization across the ventricular wall, resulting in a transmural voltage

  1. Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells.

    PubMed

    Szabó, László; Szentandrássy, Norbert; Kistamás, Kornél; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Horváth, Balázs; Magyar, János; Bányász, Tamás; Pál, Balázs; Nánási, Péter P

    2013-03-01

    Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3-30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including I(Ca), I(to), I(K1), I(Kr), and I(Ks). Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.

  2. Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium.

    PubMed

    Heller, Simon; Darpö, Börje; Mitchell, Malcolm I; Linnebjerg, Helle; Leishman, Derek J; Mehrotra, Nitin; Zhu, Hao; Koerner, John; Fiszman, Mónica L; Balakrishnan, Suchitra; Xiao, Shen; Todaro, Thomas G; Hensley, Ingrid; Guth, Brian D; Michelson, Eric L; Sager, Philip

    2015-07-01

    Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy.

  3. Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve.

    PubMed

    Qu, Zhilin; Xie, Lai-Hua; Olcese, Riccardo; Karagueuzian, Hrayr S; Chen, Peng-Sheng; Garfinkel, Alan; Weiss, James N

    2013-07-01

    Early afterdepolarizations (EADs) are secondary voltage depolarizations during the repolarizing phase of the action potential, which can cause lethal cardiac arrhythmias. The occurrence of EADs requires a reduction in outward current and/or an increase in inward current, a condition called reduced repolarization reserve. However, this generalized condition is not sufficient for EAD genesis and does not explain the voltage oscillations manifesting as EADs. Here, we summarize recent progress that uses dynamical theory to build on and advance our understanding of EADs beyond the concept of repolarization reserve, towards the goal of developing a holistic and integrative view of EADs and their role in arrhythmogenesis. We first introduce concepts from nonlinear dynamics that are relevant to EADs, namely, Hopf bifurcation leading to oscillations and basin of attraction of an equilibrium or oscillatory state. We then present a theory of phase-2 EADs in nonlinear dynamics, which includes the formation of quasi-equilibrium states at the plateau voltage, their stabilities, and the bifurcations leading to and terminating the oscillations. This theory shows that the L-type calcium channel plays a unique role in causing the nonlinear dynamical behaviours necessary for EADs. We also summarize different mechanisms of phase-3 EADs. Based on the dynamical theory, we discuss the roles of each of the major ionic currents in the genesis of EADs, and potential therapeutic targets.

  4. Ionic currents underlying the action potential of Rana pipiens oocytes.

    PubMed

    Schlichter, L C

    1989-07-01

    Ionic currents in immature, ovulated Rana pipiens oocytes (metaphase I) were studied using the voltage-clamp technique. At this stage of maturity the oocyte can produce action potentials in response to depolarizing current or as an "off response" to hyperpolarizing current. Reducing external Na+ to 1/10 normal (choline substituted) eliminated the action potentials and both the negative-slope region and zero-crossing of the I-V relation. Reducing external Cl- to 1/10 or 1/100 normal (methanesulfonate substituted) lengthened the action potential. The outward current was reduced and a net inward current was revealed. By changing external Na+, Cl-, and K+ concentrations and using blocking agents (SITS, TEA), three voltage- and time-dependent currents were identified, INa, IK and ICl. The Na+ current activated at about 0 mV and reversed at very positive values which decreased during maturation. Inward Na+ current produced the upstroke of the action potential. During each voltage-clamp step the Na+ current activated slowly (seconds) and did not inactivate within many minutes. The Na+ current was not blocked by TTX at micromolar concentrations. The K+ current was present only in the youngest oocytes. Because IK was superimposed on a large leakage current, it appeared to reverse at the resting potential. When leakage currents were subtracted, the reversal potential for IK was more negative than -110 mV in Ringer's solution. IK was outwardly rectifying and strongly activated above -50 mV. The outward K+ current produced an after hyperpolarization at the end of each action potential. IK was blocked completely and reversibly by 20 mM external TEA. The Cl- current activated at about +10 mV and was outwardly rectifying. ICl was blocked completely and reversibly by 400 microM SITS added to the bathing medium. This current helped repolarize the membrane following an action potential in the youngest oocytes and was the only repolarizing current in more mature oocytes that had lost

  5. Prolonged modification of action potential shape by synaptic inputs in molluscan neurones.

    PubMed

    Winlow, W

    1985-01-01

    1. Somatic action potentials of Lymnaea neurons are modified by excitatory or inhibitory synaptic inputs and have been studied using phase-plane techniques and an action potential duration monitor. 2. Excitatory synaptic inputs increase the rate of neuronal discharge, cause action potential broadening, a decrease in the maximum rate of depolarization (Vd) and a decrease in the maximum rate of repolarization (Vr). 3. Inhibitory synaptic inputs decrease the discharge rate and cause narrowing of action potentials, an increase in Vd and an increase in Vr. 4. The effects reported above outlast the original synaptic inputs by many seconds and, if the somatic action potentials are similar to those in the axon terminals, they may have far-reaching effects on transmitter release.

  6. Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling.

    PubMed

    Lou, Qing; Janks, Deborah L; Holzem, Katherine M; Lang, Di; Onal, Birce; Ambrosi, Christina M; Fedorov, Vadim V; Wang, I-Wen; Efimov, Igor R

    2012-12-15

    Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ∼6.3 × 6.3 cm(2) field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF.

  7. Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling

    PubMed Central

    Lou, Qing; Janks, Deborah L.; Holzem, Katherine M.; Lang, Di; Onal, Birce; Ambrosi, Christina M.; Fedorov, Vadim V.; Wang, I-Wen

    2012-01-01

    Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ∼6.3 × 6.3 cm2 field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF. PMID:23042951

  8. Role of Mg(2+) block of the inward rectifier K(+) current in cardiac repolarization reserve: A quantitative simulation.

    PubMed

    Ishihara, Keiko; Sarai, Nobuaki; Asakura, Keiichi; Noma, Akinori; Matsuoka, Satoshi

    2009-07-01

    Different K(+) currents serve as "repolarization reserve" or a redundant repolarizing mechanism that protects against excessive prolongation of the cardiac action potential and therefore arrhythmia. Impairment of the inward rectifier K(+) current (I(K1)) has been implicated in the pathogenesis of cardiac arrhythmias. The characteristics of I(K1) reflect the kinetics of channel block by intracellular cations, primarily spermine (a polyamine) and Mg(2+), whose cellular levels may vary under various pathological conditions. However, the relevance of endogenous I(K1) blockers to the repolarization reserve is still not fully understood in detail. Here we used a mathematical model of a cardiac ventricular myocyte which quantitatively reproduces the dynamics of I(K1) block to examine the effects of the intracellular spermine and Mg(2+) concentrations, through modifying I(K1), on the action potential repolarization. Our simulation indicated that an I(K1) transient caused by relief of Mg(2+) block flows during early phase 3. Increases in the intracellular spermine/Mg(2+) concentration, or decreases in the intracellular Mg(2+) concentration, to levels outside their normal ranges prolonged action potential duration by decreasing the I(K1) transient. Moreover, reducing both the rapidly activating delayed rectifier current (I(Kr)) and the I(K1) transient caused a marked retardation of repolarization and early afterdepolarization because they overlap in the voltage range at which they flow. Our results indicate that the I(K1) transient caused by relief of Mg(2+) block is an important repolarizing current, especially when I(Kr) is reduced, and that abnormal intracellular free spermine/Mg(2+) concentrations may be a missing risk factor for malignant arrhythmias in I(Kr)-related acquired (drug-induced) and congenital long QT syndromes.

  9. Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia

    PubMed Central

    Ying, Shaozhen; Cao, Hong; Hu, He; Wang, Xin; Tang, Yanhong; Huang, Congxin

    2016-01-01

    We aimed to investigate the role of activin receptor-like kinase (ALK7) in regulating cardiac electrophysiology. Here, we showed that Alk7-/- mice exhibited prolonged QT intervals in telemetry ECG recordings. Furthermore, Langendorff-perfused Alk7-/- hearts had significantly longer action potential duration (APD) and greater incidence of ventricular arrhythmia (AV) induced by burst pacing. Using whole-cell patch clamp, we found that the densities of repolarizing K+ currents Ito and IK1 were profoundly reduced in Alk7-/- ventricular cardiomyocytes. Mechanistically, the expression of Kv4.2 (a major subunit of Ito carrying channel) and KCHIP2 (a key accessory subunit of Ito carrying channel), was markedly decreased in Alk7-/- hearts. These findings suggest that endogenous expression of ALK7 is necessary to maintain repolarizing K+ currents in ventricular cardiomyocytes, and finally prevent action potential prolongation and ventricular arrhythmia. PMID:26882027

  10. Profile of I(Ks) during the action potential questions the therapeutic value of I(Ks) blockade.

    PubMed

    Bányász, Tamás; Koncz, Roland; Fülöp, László; Szentandrássy, Norbert; Magyar, János; Nánási, Péter P

    2004-01-01

    The goal of this paper is two fold. First, we attempt to review the reports available on the role of I(Ks) in myocardial repolarization. Based on theoretical considerations and experimental results, it seems reasonable to assume that I(Ks)blockade will lengthen the action potential. However, results obtained with I(Ks) blockers, like chromanol 293B or L-735,821, are conflicting, since from slight lengthening to marked prolongation of action potentials were equally obtained. Although these contradictory results were explained by interspecies or regional differences, the role of I(Ks) in repolarization is a matter of growing dispute. In the second part of this study, we simulated the performance of I(Ks) during cardiac action potentials. We compared the profile of the predicted current in three mathematical models in order to determine the relative role of the current in repolarization. We studied the effect of the cycle length, action potential duration and height of the plateau on the profile of I(Ks) in epicardiac, endocardiac and midmyocardiac ventricular action potentials. The results indicate that the height of the plateau is the most important parameter to control activation of I(Ks)in cardiac tissues, and accordingly, the interspecies and regional differences observed in the efficacy of I(Ks) blockers are likely due to the known differences in action potential morphology. We conclude also that I(Ks)blockade may have unpredictable effects on the length of the action potential in a diseased heart, questioning the possible therapeutic value of drugs blocking I(Ks).

  11. Effects of Na+ channel blockers on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization.

    PubMed

    Osadchii, Oleg E

    2014-03-01

    Antiarrhythmic agents which belong to class Ia (quinidine) and Ic (flecainide) reportedly increase propensity to ventricular tachyarrhythmia, whereas class Ib agents (lidocaine and mexiletine) are recognized as safe antiarrhythmics. Clinically, tachyarrhythmia is often initiated by a premature ectopic beat, which increases spatial nonuniformities in ventricular conduction and repolarization thus facilitating reentry. This study examined if electrical derangements evoked by premature excitation may be accentuated by flecainide and quinidine, but unchanged by lidocaine and mexiletine, which would explain the difference in their safety profile. In perfused guinea pig hearts, a premature excitation evoked over late repolarization phase was associated with prolonged epicardial activation time, reduced monophasic action potential duration (APD), and increased transepicardial dispersion of the activation time and APD. Flecainide and quinidine increased conduction slowing evoked by extrasystolic stimulation, prolonged APD, and accentuated spatial heterogeneities in ventricular conduction and repolarization associated with premature excitation. Spontaneous episodes of nonsustained monomorphic ventricular tachycardia were observed in 50% of heart preparations exposed to drug infusion. In contrast, lidocaine and mexiletine had no effect on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization or arrhythmic susceptibility. These findings suggest that flecainide and quinidine may promote arrhythmia by exaggerating electrophysiological abnormalities evoked by ectopic beats.

  12. Interactions between Activation and Repolarization Restitution Properties in the Intact Human Heart: In-Vivo Whole-Heart Data and Mathematical Description

    PubMed Central

    Taggart, Peter; Srinivasan, Neil; Hayward, Martin; Lambiase, Pier D.

    2016-01-01

    Background The restitution of the action potential duration (APDR) and conduction velocity (CVR) are mechanisms whereby cardiac excitation and repolarization adapt to changes in heart rate. They modulate the vulnerability to dangerous arrhythmia, but the mechanistic link between restitution and arrhythmogenesis remains only partially understood. Methods This paper provides an experimental and theoretical study of repolarization and excitation restitution properties and their interactions in the intact human epicardium. The interdependence between excitation and repolarization dynamic is studied in 8 patients (14 restitution protocols, 1722 restitution curves) undergoing global epicardial mapping with multi-electrode socks before open heart surgery. A mathematical description of the contribution of both repolarization and conduction dynamics to the steepness of the APDR slope is proposed. Results This study demonstrates that the APDR slope is a function of both activation and repolarization dynamics. At short cycle length, conduction delay significantly increases the APDR slope by interacting with the diastolic interval. As predicted by the proposed mathematical formulation, the APDR slope was more sensitive to activation time prolongation than to the simultaneous shortening of repolarization time. A steep APDR slope was frequently identified, with 61% of all cardiac sites exhibiting an APDR slope > 1, suggesting that a slope > 1 may not necessarily promote electrical instability in the human epicardium. APDR slope did not change for different activation or repolarization times, and it was not a function of local baseline APD. However, it was affected by the spatial organization of electrical excitation, suggesting that in tissue APDR is not a unique function of local electrophysiological properties. Spatial heterogeneity in both activation and repolarization restitution contributed to the increase in the modulated dispersion of repolarization, which for short cycle

  13. Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly*

    PubMed Central

    Ednie, Andrew R.; Bennett, Eric S.

    2015-01-01

    Voltage-gated K+ channels (Kv) are responsible for repolarizing excitable cells and can be heavily glycosylated. Cardiac Kv activity is indispensable where even minimal reductions in function can extend action potential duration, prolong QT intervals, and ultimately contribute to life-threatening arrhythmias. Diseases such as congenital disorders of glycosylation often cause significant cardiac phenotypes that can include arrhythmias. Here we investigated the impact of reduced sialylation on ventricular repolarization through gene deletion of the sialyltransferase ST3Gal4. ST3Gal4-deficient mice (ST3Gal4−/−) had prolonged QT intervals with a concomitant increase in ventricular action potential duration. Ventricular apex myocytes isolated from ST3Gal4−/− mice demonstrated depolarizing shifts in activation gating of the transient outward (Ito) and delayed rectifier (IKslow) components of K+ current with no change in maximum current densities. Consistently, similar protein expression levels of the three Kv isoforms responsible for Ito and IKslow were measured for ST3Gal4−/− versus controls. However, novel non-enzymatic sialic acid labeling indicated a reduction in sialylation of ST3Gal4−/− ventricular Kv4.2 and Kv1.5, which contribute to Ito and IKslow, respectively. Thus, we describe here a novel form of regulating cardiac function through the activities of a specific glycogene product. Namely, reduced ST3Gal4 activity leads to a loss of isoform-specific Kv sialylation and function, thereby limiting Kv activity during the action potential and decreasing repolarization rate, which likely contributes to prolonged ventricular repolarization. These studies elucidate a novel role for individual glycogene products in contributing to a complex network of cardiac regulation under normal and pathologic conditions. PMID:25525262

  14. Effects of 4-aminopyridine on action potentials generation in mouse sinoauricular node strips

    PubMed Central

    Golovko, Vladimir; Gonotkov, Mikhail; Lebedeva, Elena

    2015-01-01

    The physiological role of Ito has yet to be clarified. The goal of this study is to investigate the possible contribution of the transient outward current (Ito) on the generation of transmembrane action potentials (APs) and the sensitivity of mouse sinoauricular node (SAN) cells to a 4-aminopyridine (4AP) as Ito blocker. The electrophysiological identification of cells was performed in the sinoauricular node artery area (nstrips = 38) of the subendocardial surface using microelectrode technique. In this study, for the first time, it was observed that dependence duration of action potential at the level of 20% repolarization (APD20) level under a 4AP concentration in the pacemaker SAN and auricular cells corresponds to a curve predicted by Hill’s equation. APD20 raised by 70% and spike duration of AP increased by 15–25%, when 4AP concentration was increased from 0.1 to 5.0 mmol/L. Auricular cells were found to be more sensitive to 4AP than true pacemaker cells. This was accompanied by a decrease in the upstroke velocity as compared to the control. Our data and previous findings in the literature lead us to hypothesize that the 4AP-sensitive current participates in the repolarization formation of pacemaker and auricular type cells. Thus, study concerning the inhibitory effects of lidocaine and TTX on APD20 can explain the phenomenon of the decrease in upstroke velocity, which, for the first time, was observed after exposure to 4AP. Duration of AP at the level of 20% repolarization (APD20) under a 4-AP concentration 0.5 mmol/L in the true pacemaker cells lengthen by 60–70% with a control. PMID:26156968

  15. Myocyte repolarization modulates myocardial function in aging dogs.

    PubMed

    Sorrentino, Andrea; Signore, Sergio; Qanud, Khaled; Borghetti, Giulia; Meo, Marianna; Cannata, Antonio; Zhou, Yu; Wybieralska, Ewa; Luciani, Marco; Kannappan, Ramaswamy; Zhang, Eric; Matsuda, Alex; Webster, Andrew; Cimini, Maria; Kertowidjojo, Elizabeth; D'Alessandro, David A; Wunimenghe, Oriyanhan; Michler, Robert E; Royer, Christopher; Goichberg, Polina; Leri, Annarosa; Barrett, Edward G; Anversa, Piero; Hintze, Thomas H; Rota, Marcello

    2016-04-01

    Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions.

  16. Phorbol esters broaden the action potential in CA1 hippocampal pyramidal cells.

    PubMed

    Storm, J F

    1987-03-20

    Intracellular recordings were made from CA1 pyramidal cells in rat hippocampal slices. Single action potentials were elicited by injection of brief current pulses. Bath application of phorbol esters (4 beta-phorbol-12,13-diacetate, 0.3-5 microM; or 4 beta-phorbol-12,13-dibutyrate, 5-10 microM) broadened the action potential in each of the cells tested (n = 9). The broadening reflected slowing of the repolarization, whereas the upstroke of the spike was unchanged. This effect may enhance transmitter release from synaptic terminals, and contribute to enhancement of synaptic transmission through activation of protein kinase C, a mechanism which has been associated with long term potentiation.

  17. Fractional diffusion models of cardiac electrical propagation: role of structural heterogeneity in dispersion of repolarization

    PubMed Central

    Bueno-Orovio, Alfonso; Kay, David; Grau, Vicente; Rodriguez, Blanca; Burrage, Kevin

    2014-01-01

    Impulse propagation in biological tissues is known to be modulated by structural heterogeneity. In cardiac muscle, improved understanding on how this heterogeneity influences electrical spread is key to advancing our interpretation of dispersion of repolarization. We propose fractional diffusion models as a novel mathematical description of structurally heterogeneous excitable media, as a means of representing the modulation of the total electric field by the secondary electrical sources associated with tissue inhomogeneities. Our results, analysed against in vivo human recordings and experimental data of different animal species, indicate that structural heterogeneity underlies relevant characteristics of cardiac electrical propagation at tissue level. These include conduction effects on action potential (AP) morphology, the shortening of AP duration along the activation pathway and the progressive modulation by premature beats of spatial patterns of dispersion of repolarization. The proposed approach may also have important implications in other research fields involving excitable complex media. PMID:24920109

  18. Restitution slope is principally determined by steady-state action potential duration.

    PubMed

    Shattock, Michael J; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela Wc; Niederer, Steve; MacLeod, Kenneth T; Winter, James

    2017-03-23

    AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and ResultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalising the restitution curve as a % of steady-state APD abolished the difference in restitution curves by all interventions. Altered restitution dynamics were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM, to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce

  19. Ultrafast action potentials mediate kilohertz signaling at a central synapse.

    PubMed

    Ritzau-Jost, Andreas; Delvendahl, Igor; Rings, Annika; Byczkowicz, Niklas; Harada, Harumi; Shigemoto, Ryuichi; Hirrlinger, Johannes; Eilers, Jens; Hallermann, Stefan

    2014-10-01

    Fast synaptic transmission is important for rapid information processing. To explore the maximal rate of neuronal signaling and to analyze the presynaptic mechanisms, we focused on the input layer of the cerebellar cortex, where exceptionally high action potential (AP) frequencies have been reported in vivo. With paired recordings between presynaptic cerebellar mossy fiber boutons and postsynaptic granule cells, we demonstrate reliable neurotransmission up to ∼1 kHz. Presynaptic APs are ultrafast, with ∼100 μs half-duration. Both Kv1 and Kv3 potassium channels mediate the fast repolarization, rapidly inactivating sodium channels ensure metabolic efficiency, and little AP broadening occurs during bursts of up to 1.5 kHz. Presynaptic Cav2.1 (P/Q-type) calcium channels open efficiently during ultrafast APs. Furthermore, a subset of synaptic vesicles is tightly coupled to Ca(2+) channels, and vesicles are rapidly recruited to the release site. These data reveal mechanisms of presynaptic AP generation and transmitter release underlying neuronal kHz signaling.

  20. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties

    PubMed Central

    Casale, Amanda E.; Foust, Amanda J.; Bal, Thierry

    2015-01-01

    The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca2+-activated K+ channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. SIGNIFICANCE STATEMENT Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons

  1. Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart

    NASA Technical Reports Server (NTRS)

    Sung, Derrick; Mills, Robert W.; Schettler, Jan; Narayan, Sanjiv M.; Omens, Jeffrey H.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    INTRODUCTION: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. METHODS AND RESULTS: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. CONCLUSION: Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.

  2. Effects of sparfloxacin, grepafloxacin, moxifloxacin, and ciprofloxacin on cardiac action potential duration.

    PubMed

    Patmore, L; Fraser, S; Mair, D; Templeton, A

    2000-10-20

    Fluoroquinolone antibiotics have been associated with QT prolongation following administration to humans. This study compares the effects of four fluoroquinolones, sparfloxacin, grepafloxacin, moxifloxacin and ciprofloxacin on action potential duration recorded from canine isolated cardiac Purkinje fibres. Left and right ventricular Purkinje fibres were isolated from canine hearts and continuously superfused with physiological salt solution. Action potential duration at 90% repolarization was recorded via intracellular microelectrodes. Sparfloxacin, grepafloxacin, moxifloxacin and ciprofloxacin prolonged action potential duration in a concentration dependent manner. Mean concentrations causing a 15% prolongation of action potential duration recorded at a stimulation frequency of 1 Hz were: sparfloxacin 4.2+/-0.7 microg/ml; grepafloxacin 9.3+/-0.9 microg/ml; moxifloxacin 9.9+/-1.6 microg/ml and ciprofloxacin 72.8+/-26.4 microg/ml. Prolongation was inverse frequency dependent with larger increases in action potential duration occurring when the stimulation frequency was reduced to 0.5 Hz. These results indicate that effects on action potential duration vary within this class of compound. Rank order of potency was sparfloxacin > grepafloxacin = moxifloxacin > ciprofloxacin.

  3. Effects of ropinirole on action potential characteristics and the underlying ion currents in canine ventricular myocytes.

    PubMed

    Simkó, József; Szentandrássy, Norbert; Harmati, Gábor; Bárándi, László; Horváth, Balázs; Magyar, János; Bányász, Tamás; Lorincz, István; Nánási, Péter P

    2010-09-01

    In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the dopamine receptor agonist ropinirole. In the present study, therefore, the concentration-dependent effects of ropinirole on action potential morphology and the underlying ion currents were studied in enzymatically dispersed canine ventricular cardiomyocytes using standard microelectrode, conventional whole-cell patch clamp, and action potential voltage clamp techniques. At concentrations > or = 1 microM, ropinirole increased action potential duration (APD(90)) and suppressed the rapid delayed rectifier K(+) current (I (Kr)) with an IC(50) value of 2.7 +/- 0.25 microM and Hill coefficient of 0.92 +/- 0.09. The block increased with increasing depolarizations to more positive voltages, but paradoxically, the activation of I (Kr) was accelerated by 3 muM ropinirole (time constant decreased from 34 +/- 4 to 14 +/- 1 ms). No significant changes in the fast and slow deactivation time constants were observed with ropinirole. At higher concentrations, ropinirole decreased the amplitude of early repolarization (at concentrations > or = 10 microM), reduced the maximum rate of depolarization and caused depression of the plateau (at concentrations > or = 30 microM), and shortened APD measured at 50% repolarization (at 300 microM) indicating a concentration-dependent inhibition of I (to), I (Na), and I (Ca). Suppression of I (Kr), I (to), and I (Ca) has been confirmed under conventional patch clamp and action potential voltage clamp conditions. I (Ks) and I (K1) were not influenced significantly by ropinirole at concentrations less than 300 microM. All these effects of ropinirole were fully reversible upon washout. The results indicate that ropinirole treatment may carry proarrhythmic risk for patients with inherited or acquired long QT syndrome due to inhibition of I (Kr)-especially in cases of accidental overdose or intoxication.

  4. Regional differences in action potential characteristics and membrane currents of guinea-pig left ventricular myocytes.

    PubMed

    Main, M C; Bryant, S M; Hart, G

    1998-11-01

    Regional differences in action potential characteristics and membrane currents were investigated in subendocardial, midmyocardial and subepicardial myocytes isolated from the left ventricular free wall of guinea-pig hearts. Action potential duration (APD) was dependent on the region of origin of the myocytes (P < 0.01, ANOVA). Mean action potential duration at 90 % repolarization (APD90) was 237 +/- 8 ms in subendocardial (n = 30 myocytes), 251 +/- 7 ms in midmyocardial (n = 30) and 204 +/- 7 ms in subepicardial myocytes (n = 36). L-type calcium current (ICa) density and background potassium current (IK1) density were similar in the three regions studied. Delayed rectifier current (IK) was measured as deactivating tail current, elicited on repolarization back to -45 mV after 2 s step depolarizations to test potentials ranging from -10 to +80 mV. Mean IK density (after a step to +80 mV) was larger in subepicardial myocytes (1.59 +/- 0.16 pA pF-1, n = 16) than in either subendocardial (1.16 +/- 0.12 pA pF-1, n = 17) or midmyocardial (1. 13 +/- 0.11 pA pF-1, n = 21) myocytes (P < 0.05, ANOVA). The La3+-insensitive current (IKs) elicited on repolarization back to -45 mV after a 250 ms step depolarization to +60 mV was similar in the three regions studied. The La3+-sensitive tail current, (IKr) was greater in subepicardial (0.50 +/- 0.04 pA pF-1, n = 11) than in subendocardial (0.25 +/- 0.05 pA pF-1, n = 9) or in midmyocardial myocytes (0.38 +/- 0.05 pA pF-1, n = 11, P < 0.05, ANOVA). The contribution of a Na+ background current to regional differences in APD was assessed by application of 0.1 microM tetrodotoxin (TTX). TTX-induced shortening of APD90 was greater in subendocardial myocytes (35.7 +/- 7.1 %, n = 11) than in midmyocardial (15.7 +/- 3. 8 %, n = 10) and subepicardial (20.2 +/- 4.3 %, n = 11) myocytes (P < 0.05, ANOVA). Regional differences in action potential characteristics between subendocardial, midmyocardial, and subepicardial myocytes isolated from

  5. Extracellular calcium transients and action potential configuration changes related to post-stimulatory potentiation in rabbit atrium.

    PubMed

    Hilgemann, D W

    1986-05-01

    Extracellular calcium transients were monitored with 2 mM tetramethylmurexide at low calcium (250 microM total, 130 microM free), and action potentials were monitored together with developed tension at normal calcium (1.3 mM) during the production and decay of post-stimulatory potentiation in rabbit left atrial strips. At normal calcium, the contractile potentiation produced by a brief burst of 4 Hz stimulation is lost in three to five post-stimulatory excitations, which correlate with a negative staircase of the late action potential. At low calcium, stimulation at 4 Hz for 3-8 s results in a net extracellular calcium depletion of 5-15 microM. At the subsequent potentiated contraction (1-45 s rest), total extracellular calcium increases by 4-8 microM. The contractile response at a second excitation is greatly suppressed and results in little or no further calcium shift; the sequence can be repeated immediately thereafter. Reducing external sodium to 60 mM (sucrose replacement) enhances post-rest contractions, suppresses the late action potential, nearly eliminates loss of contractility and net calcium efflux at post-rest excitations, and markedly reduces extracellular calcium depletion during rapid stimulation. 4-Aminopyridine (1 mM) markedly suppresses the rapid early repolarization of this preparation at post-rest excitations and the loss of contractility at post-rest stimulation from the rested state; during a post-stimulatory potentiation sequence at low calcium, replenishment of extracellular calcium takes several post-stimulatory excitations. Ryanodine (10 nM to 5 microM) abolishes the post-stimulatory contraction at rest periods of greater than 5 s. If the initial repolarization is rapid, ryanodine suppresses the late action potential, calcium efflux during quiescence is greatly accelerated, and subsequent excitations do not result in an accumulation of extracellular calcium. A positive staircase of the early action potential correlates with the magnitude

  6. Rate dependency of beta-adrenergic modulation of repolarizing currents in the guinea-pig ventricle.

    PubMed

    Rocchetti, M; Freli, V; Perego, V; Altomare, C; Mostacciuolo, G; Zaza, A

    2006-07-01

    Beta-adrenergic stimulation modulates ventricular currents and sinus cycle length (CL). We investigated how changes in CL affect the current induced by isoprenaline (Iso) during the action potential (AP) of guinea-pig ventricular myocytes. Action-potential clamp was applied at CLs of 250 and 1000 ms to measure: (1) the net current induced by 0.1 microm Iso (I(Iso)); (2) the L-type Ca2+ current I(CaL) and slow delayed rectifier current I(Ks) components of I(Iso) (I(IsoCa) and I(IsoK)), identified as the Iso-induced current sensitive to nifedipine and HMR1556, respectively; and (3) I(Iso) persisting after inhibition of both I(Ca) and I(Ks) (I(isoR)). The pause dependency of I(Ks) and its modulation were evaluated in voltage-clamp experiments. The rate dependency of the duration of the action potential at 90% repolarization (APD90) and its modulation by isoprenaline were tested in current-clamp experiments. At a CL of 250 ms I(Iso) was inward during initial repolarization and reversed at 59% of APD90. At a CL of 1000 ms I(Iso) became mostly inward in all cells. Switching to shorter CL did not change I(IsoCa) and I(IsoK) amplitudes, but moved their peak amplitudes to earlier repolarization; I(IsoR) was independent of CL. Acceleration of I(IsoK) at shorter CL was based on faster pause dependency of I(Ks) activation rate. The 'restitution' of activation rates was modulated by isoprenaline. The APD90-CL relation was rotated anticlockwise by isoprenaline and crossed the control curve at a CL of 150 ms (400 beats min(-1)). We conclude that: (1) isoprenaline induced markedly different current profiles according to pacing rate, involving CL-dependent I(Ca) and I(Ks) modulation; (2) the effect of isoprenaline on APD90 was CL dependent, and negligible during tachycardia; and (3) during sympathetic activation, repolarization stability may involve matched modulation of sinus rate and repolarizing currents.

  7. Beta-adrenergic stimulation reverses the IKr–IKs dominant pattern during cardiac action potential

    PubMed Central

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T.; Chen-Izu, Ye

    2014-01-01

    β-adrenergic stimulation differentially modulates different K+ channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of IKs, IKr, and IK1 current in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K+ current to the total repolarization reserve. In this study we used an innovative AP-clamp Sequential Dissection technique to directly record the dynamic –IKs, IKr, IK1– currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of IKs, IKr, IK1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca2+ homeostasis. We found that isoproterenol treatment significantly enhanced IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKrrepolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K+ currents in a dose-dependent manner. This Knowledge is important for designing anti-arrhythmic drug strategies to treat the hearts exposed to various sympathetic tones. PMID:24535581

  8. Paroxysmal beta-adrenergic receptor-mediated alterations in ventricular repolarization at rapid heart rates during inhibition of delayed rectifier currents.

    PubMed

    Overholser, Brian R; Zheng, Xiaomei; Tisdale, James E

    2009-09-01

    The contribution of the slow component of the delayed rectifier current (IKs) to ventricular repolarization is increased during rapid heart rates and prolonged repolarization. The objective was to characterize physiologically relevant paroxysmal beta-adrenergic receptor-mediated alterations on ventricular repolarization under these conditions. Paced guinea pig hearts were perfused with (1) control, (2) sparfloxacin (IKr inhibitor), or (3) sparfloxacin and HMR 1556 (IKs inhibitor). The mean +/- standard error of the mean epicardial action potential duration at 90% repolarization (APD90) increased from baseline with IKr inhibition (12.9% +/- 4.7%) and dual IKr/IKs inhibition (25.1% +/- 5.3). Paroxysmal isoproterenol (0.01 and 1.0 nM) significantly decreased APD90 in the presence of IKr inhibition but was attenuated with the addition of IKs inhibition. Spontaneous episodes of polymorphic ventricular tachycardia were observed with isoproterenol during dual IKr and IKs inhibition. The endocardial expression of KCNQ1 increased greater than 2-fold after exposure to IKr and dual IKr/IKs inhibition relative to control but was not altered in epicardial tissue. The beta-adrenergic receptor-mediated decrease in APD90 during IKr inhibition is reversed in the presence of IKs inhibition at rapid heart rates. IKs may serve as an important compensatory mechanism to protect against adrenergically induced arrhythmias when the repolarization reserve is depleted.

  9. Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells.

    PubMed

    Han, W; Wang, Z; Nattel, S

    2001-03-01

    Although cardiac Purkinje cells (PCs) are believed to be the source of early afterdepolarizations generating ventricular tachyarrhythmias in long Q-T syndromes (LQTS), the ionic determinants of PC repolarization are incompletely known. To evaluate the role of the slow delayed rectifier current (I(Ks)) in PC repolarization, we studied PCs from canine ventricular false tendons with whole cell patch clamp (37 degrees C). Typical I(Ks) voltage- and time-dependent properties were noted. Isoproterenol enhanced I(Ks) in a concentration-dependent fashion (EC(50) approximately 30 nM), negatively shifted I(Ks) activation voltage dependence, and accelerated I(Ks) activation. Block of I(Ks) with 293B did not alter PC action potential duration (APD) in the absence of isoproterenol; however, in the presence of isoproterenol, 293B significantly prolonged APD. We conclude that, without beta-adrenergic stimulation, I(Ks) contributes little to PC repolarization; however, beta-adrenergic stimulation increases the contribution of I(Ks) by increasing current amplitude, accelerating I(Ks) activation, and shifting activation voltage toward the PC plateau voltage range. I(Ks) may therefore provide an important "braking" function to limit PC APD prolongation in the presence of beta-adrenergic stimulation.

  10. Sodium-calcium exchange during the action potential in guinea-pig ventricular cells.

    PubMed Central

    Egan, T M; Noble, D; Noble, S J; Powell, T; Spindler, A J; Twist, V W

    1989-01-01

    1. Slow inward tail currents attributable to electrogenic sodium-calcium exchange can be recorded by imposing hyperpolarizing voltage clamp pulses during the normal action potential of isolated guinea-pig ventricular cells. The hyperpolarizations return the membrane to the resting potential (between -65 and -88 m V) allowing an inward current to be recorded. This current usually has peak amplitude when repolarization is imposed during the first 50 ms after the action potential upstroke, but becomes negligible once the final phase of repolarization is reached. The envelope of peak current tail amplitudes strongly resembles that of the intracellular calcium transient recorded in other studies. 2. Repetitive stimulation producing normal action potentials at a frequency of 2 Hz progressively augments the tail current recorded immediately after the stimulus train. Conversely, if each action potential is prematurely terminated at 0.1 Hz, repetitive stimulation produces a tail current much smaller than the control value. The control amplitude of inward current is only maintained if interrupted action potentials are separated by at least one full 'repriming' action potential. These effects mimic those on cell contraction (Arlock & Wohlfart, 1986) and suggest that progressive changes in tail current are controlled by variations in the amplitude and time course of the intracellular calcium transient. 3. When intracellular calcium is buffered sufficiently to abolish contraction, the tail current is abolished. Substitution of calcium with strontium greatly reduces the tail current. 4. The inward tail current can also be recorded at more positive membrane potentials using standard voltage clamp pulse protocols. In this way it was found that temperature has a large effect on the tail current, which can change from net inward at 22 degrees C to net outward at 37 degrees C. The largest inward currents are usually recorded at about 30 degrees C. It is shown that this effect is

  11. Estrogen Contributes to Gender Differences in Mouse Ventricular Repolarization

    PubMed Central

    Saito, Tomoaki; Ciobotaru, Andrea; Bopassa, Jean Chrisostome; Toro, Ligia; Stefani, Enrico; Eghbali, Mansoureh

    2010-01-01

    Rationale Fast-transient outward K+ (Ito,f) and ultra-rapid delayed rectifier K+ currents (IKur or IK,slow) contribute to mouse cardiac repolarization. Gender studies on these currents have reported conflicting results. Objective One key missing piece information in these studies is the animals’ estral stage. We decided to revisit gender-related differences in K+ currents, taking into consideration the females’ estral stage. Methods and Results We hypothesized that changes in estrogen levels during the estral cycle could play a role in determining the densities of K+ currents underlying ventricular repolarization. Peak total K+ current (IK,total) densities (pA/pF, at +40 mV) were much higher in males (48.6±3.0) than in females at estrus (27.2±2.3) but not at diestrus-2 (39.1±3.4). Underlying this change, Ito,f and IK,slow were lower in females at estrus vs males and diestrus-2 (IK,slow: male 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; Ito,f: male 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). The lower IK,slow in estrus was only due to IK,slow1 reduction without changes of IK,slow2. Estrogen treatment of ovariectomized mice decreased IK,total (46.4±3.0 to 28.4±1.6), Ito,f (26.6±1.6 to 12.8±1.0) and IK,slow (22.2±1.6 to 17.2±1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying Ito,f and IK,slow, respectively) were lower in estrus vs. diestrus-2 and male. In ovariectomized mice, estrogen treatment resulted in downregulation of Kv4.3 and Kv1.5, but not Kv4.2, KChIP2 and Kv2.1 transcripts. K+ current reduction in high estrogenic conditions were associated with prolongation of the action potential duration and corrected QT interval. Conclusion Downregulation of Kv4.3 and Kv1.5 transcripts by estrogen are one mechanism defining gender-related differences in mouse ventricular repolarization. PMID:19608983

  12. Simulation of action potential propagation in plants.

    PubMed

    Sukhov, Vladimir; Nerush, Vladimir; Orlova, Lyubov; Vodeneev, Vladimir

    2011-12-21

    Action potential is considered to be one of the primary responses of a plant to action of various environmental factors. Understanding plant action potential propagation mechanisms requires experimental investigation and simulation; however, a detailed mathematical model of plant electrical signal transmission is absent. Here, the mathematical model of action potential propagation in plants has been worked out. The model is a two-dimensional system of excitable cells; each of them is electrically coupled with four neighboring ones. Ion diffusion between excitable cell apoplast areas is also taken into account. The action potential generation in a single cell has been described on the basis of our previous model. The model simulates active and passive signal transmission well enough. It has been used to analyze theoretically the influence of cell to cell electrical conductivity and H(+)-ATPase activity on the signal transmission in plants. An increase in cell to cell electrical conductivity has been shown to stimulate an increase in the length constant, the action potential propagation velocity and the temperature threshold, while the membrane potential threshold being weakly changed. The growth of H(+)-ATPase activity has been found to induce the increase of temperature and membrane potential thresholds and the reduction of the length constant and the action potential propagation velocity.

  13. Imaging action potentials with calcium indicators.

    PubMed

    MacLean, Jason N; Yuste, Rafael

    2009-11-01

    The understanding of neuronal circuits has been, and will continue to be, greatly advanced by the simultaneous imaging of action potentials in neuronal ensembles. This protocol describes "bulk" loading of brain slices with acetoxymethyl (AM) ester calcium indicators in order to monitor action potential activity in large populations of neurons simultaneously. The imaging of calcium influx into neurons provides an indirect, but accurate, measure of action potential generation in individual neurons. Single-cell resolution, and thus the easy identification of every active cell, is the key advantage of the technique.

  14. Novel experimental results in human cardiac electrophysiology: measurement of the Purkinje fibre action potential from the undiseased human heart.

    PubMed

    Nagy, Norbert; Szél, Tamás; Jost, Norbert; Tóth, András; Gy Papp, Julius; Varró, András

    2015-09-01

    Data obtained from canine cardiac electrophysiology studies are often extrapolated to the human heart. However, it has been previously demonstrated that because of the lower density of its K(+) currents, the human ventricular action potential has a less extensive repolarization reserve. Since the relevance of canine data to the human heart has not yet been fully clarified, the aim of the present study was to determine for the first time the action potentials of undiseased human Purkinje fibres (PFs) and to compare them directly with those of dog PFs. All measurements were performed at 37 °C using the conventional microelectrode technique. At a stimulation rate of 1 Hz, the plateau potential of human PFs is more positive (8.0 ± 1.8 vs 8.6 ± 3.4 mV, n = 7), while the amplitude of the spike is less pronounced. The maximal rate of depolarization is significantly lower in human PKs than in canine PFs (406.7 ± 62 vs 643 ± 36 V/s, respectively, n = 7). We assume that the appreciable difference in the protein expression profiles of the 2 species may underlie these important disparities. Therefore, caution is advised when canine PF data are extrapolated to humans, and further experiments are required to investigate the characteristics of human PF repolarization and its possible role in arrhythmogenesis.

  15. How the knowledge of genetic "makeup" and cellular data can affect the analysis of repolarization in surface electrocardiogram.

    PubMed

    Shimizu, Wataru

    2010-01-01

    This review article sought to describe patterns of repolarization on the surface electrocardiogram in inherited cardiac arrhythmias and to discuss how the knowledge of genetic makeup and cellular data can affect the analysis based on the data derived from the experimental studies using arterially perfused canine ventricular wedge preparations. Molecular genetic studies have established a link between a number of inherited cardiac arrhythmia syndromes and mutations in genes encoding cardiac ion channels or membrane components during the past 2 decades. Twelve forms of congenital long QT syndrome have been so far identified, and genotype-phenotype correlations have been investigated especially in the 3 major genotypes-LQT1, LQT2, and LQT3. Abnormal T waves are reported in the LQT1, LQT2, and LQT3, and the differences in the time course of repolarization of the epicardial, midmyocardial, and endocardial cells give rise to voltage gradients responsible for the manifestation of phenotypic appearance of abnormal T waves. Brugada syndrome is characterized by ST-segment elevation in leads V1 to V3 and an episode of ventricular fibrillation, in which 7 genotypes have been reported. An intrinsically prominent transient outward current (I(to))-mediated action potential notch and a subsequent loss of action potential dome in the epicardium, but not in the endocardium of the right ventricular outflow tract, give rise to a transmural voltage gradient, resulting in ST-segment elevation, and a subsequent phase 2 reentry-induced ventricular fibrillation. In conclusion, transmural electrical heterogeneity of repolarization across the ventricular wall profoundly affects the phenotypic manifestation of repolarization patterns on the surface electrocardiogram in inherited cardiac arrhythmias.

  16. Beat-to-beat electrocardiographic analysis of ventricular repolarization variability in patients after myocardial infarction.

    PubMed

    Arini, Pedro D; Valverde, Esteban R

    2016-01-01

    Several studies have shown that the beat-to-beat variability of ventricular repolarization, which can be computed by T-wave spectral variance (TSV) index, constitutes a marker of cardiac risk. Moreover, the fact that properties of action potential duration are altered during the healing (days, weeks) and healed (months) infarct stages, have been reported. However, no data exist regarding the influence of the time elapsed after myocardial infarction (MI) on modulation of the beat-to-beat ventricular repolarization variability. In the present work we have evaluated TSV index during healing and healed stages of MI using 12 standard ECG leads. The ECG of control or healthy subjects (n = 49) and the ECGs in patients after MI (n = 38), one within the first seven days (MI7) and the other after 60 days (MI60) of cardiac infarction, have been analyzed. We have considered the preferential ECG leads as those leads in which TSV index have presented a relative change greater than 10 in MI7 respect to control. Results indicate that TSV index have shown a significant increase (p < 0.0005) in I, II, aVR, aVF, V3, V4, V5 and V6 leads in healing phase of MI (MI7) with respect to control. Further, in the healed phase of MI (MI60), the TSV index tends to decrease their values towards the control. Also, we have computed a multilead TSV index based on the preferential ECG leads. In that sense, the multilead criteria have shown better perfomance quantifying beat-to-beat repolarization variability than any single ECG lead considered. The sensitivity, specificity and AUC of TSV index were: 92%, 90% and 0.96 for MI7; and 76%, 84% and 0.81 for MI60, respectively. Moreover, the beat-to-beat ventricular repolarization variability has been quantified by the QT variability index (QTVI). Even though the results that we have obtained with TSV index have been comparable to those obtained with the QTVI, this latter has not reflected the modulation effect associated to time elapsed after MI. Also

  17. Properties and ionic basis of the action potentials in the periaqueductal grey neurones of the guinea-pig.

    PubMed Central

    Sánchez, D; Ribas, J

    1991-01-01

    1. Action potentials of neurones of the ventral part of the guinea-pig periaqueductal grey (PAG) were studied by intracellular recording in a mesencephalic slice preparation maintained in vitro. 2. Fast spikes spontaneously fired last 2.8 +/- 0.6 ms (mean +/- S.D.) and have an amplitude of 72.3 +/- 5.3 mV (n = 28). The neurones could be antidromically activated from the neighbouring white matter and these spikes show an initial segment component that triggers the soma-dendritic spike. These two components were dissociated by hyperpolarization. Action potentials are Na+ dependent and a Ca2+ conductance is responsible for the hump on the falling phase. Hyperpolarization makes the hump disappear and a faster rate of rise and fall are seen. Accommodation of the firing threshold is observed in response to depolarizing ramps, which is eliminated with hyperpolarization. 3. High-threshold Ca2+ spikes are evoked in either Na(+)-free solution or in the presence of tetrodotoxin (TTX). These presumed dendritic action potentials display a fast repolarization and a large after-hyperpolarization (AHP) that prevent repetitive firing. This AHP is mainly generated by Ca(2+)-dependent K+ conductances. 4. The repolarization of fast action potentials depends on the activation of K+ conductances as well as a Na+ inactivation process. A fast-activated tetraethyl-ammonium (TEA)-sensitive K+ conductance, that could be Ca2+ dependent, and a K+ conductance blocked by apamin seem to be involved in the repolarization. 5. Each fast action potential is followed by a pronounced AHP with two components, an initial fast and a slow decaying phase. Membrane hyperpolarization around -60 mV eliminated the first component and the AHP acquired a plateau-like shape. At -90 mV the AHP was nullified. The slow phase was Ca2+ dependent and an apamin-sensitive K+ conductance is involved in its generation. This conductance may be active during the early part of the AHP, but a fast-activated TEA-sensitive K

  18. Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

    PubMed

    Kistamás, Kornél; Szentandrássy, Norbert; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Bárándi, László; Horváth, Balázs; Szebeni, Andrea; Magyar, János; Bányász, Tamás; Kecskeméti, Valéria; Nánási, Péter P

    2013-06-15

    Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM. Action potentials were shortened by pioglitazone at concentrations ≥10 μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 μM, ICa, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations.

  19. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons.

    PubMed

    Raman, I M; Bean, B P

    1997-06-15

    Voltage-dependent sodium channels were studied in dissociated cerebellar Purkinje neurons from rats. In whole-cell recordings, a tetrodotoxin (TTX)-sensitive inward current was elicited when the membrane was repolarized to voltages between -60 and -20 mV after depolarizations to +30 mV long enough to produce maximal inactivation. At -40 mV, this "resurgent" current peaked in 8 msec and decayed with a time constant of 30 msec. With 50 mM sodium as a charge carrier, the resurgent current was on average approximately 120 pA. CA3 pyramidal neurons had no such current. The current may reflect recovery of inactivated channels through open states, because in Purkinje neurons (but not CA3 neurons) there was partial recovery from inactivation at -40 mV, coinciding with the rise of resurgent current. In single-channel recordings, individual channels gave openings corresponding to resurgent and conventional transient current. Action potentials were recorded from dissociated neurons under current clamp to investigate the role of the resurgent current in action potential formation. Purkinje neurons fired spontaneously at approximately 30 Hz. Hyperpolarization to -85 mV prevented spontaneous firing, and brief depolarization then induced all-or-none firing of conglomerate action potentials comprising three to four spikes. When conglomerate action potentials were used as command voltages in voltage-clamp experiments, TTX-sensitive sodium current was elicited between spikes. The falling phase of an action potential is similar to voltage patterns that activate resurgent sodium current, and thus, resurgent sodium current likely contributes to the formation of conglomerate action potentials in Purkinje neurons.

  20. Action Potentials and Ion Conductances in Wild-type and CALHM1-knockout Type II Taste Cells.

    PubMed

    Ma, Zhongming; Saung, Wint Thu; Foskett, J Kevin

    2017-02-15

    Taste bud type II cells fire action potentials in response to tastants, triggering non-vesicular ATP release to gustatory neurons via voltage-gated CALHM1-associated ion channels. Whereas CALHM1 regulates mouse cortical neuron excitability, its roles in regulating type II cell excitability are unknown. Here, we compared membrane conductances and action potentials in single identified TRPM5-GFP-expressing circumvallate papillae type II cells acutely isolated from wild-type (WT) and Calhm1-knockout (KO) mice. The activation kinetics of large voltage-gated outward currents were accelerated in cells from Calhm1-KO mice, and their associated non-selective tail currents, previously shown to be highly correlated with ATP release, were completely absent in Calhm1-KO cells, suggesting that CALHM1 contributes to all of these currents. Calhm1 deletion did not significantly alter resting membrane potential or input resistance, the amplitudes and kinetics of Na(+) currents either estimated from action potentials or recorded from steady-state voltage-pulses, or action potential threshold, overshoot peak, after-hyperpolarization and firing frequency. However, Calhm1-deletion reduced the half-widths of action potentials and accelerated the deactivation kinetics of transient outward currents, suggesting that the CALHM1-associated conductance becomes activated during the repolarization phase of action potentials.

  1. Effect of rapid delayed rectifier current on hysteresis in restitution of action potential duration in swine.

    PubMed

    Agarwal, Anuj; Jing, Linyuan; Patwardhan, Abhijit

    2012-01-01

    Electrical stability in the heart depends on two important factors; restitution of action potential duration (APD) and memory. Repolarization currents play an important role in determining APD and also affect memory. We determined the effects of blocking the rapid component of the delayed rectifier (I(Kr)) on a quantifiable measure of memory, i.e. hysteresis in restitution of APD, in swine. Transmembrane potentials were recorded from right ventricular endocardial tissues. Two pacing protocols with explicit control of diastolic interval (DI) were used to change DIs in a sequential and sinusoidal pattern to quantify hysteresis in restitution of APD. E-4031 (5 µM/L) was used to block I(Kr). Measures of memory and restitution were quantified by calculating hysteresis loop thickness, area, overall tilt, and maximum and minimum delays between DIs and APDs. Blocking I(Kr) with E-4031 increased the baseline APD, loop thickness, area, and tilt (p<0.05). However, loop thickness did not increase beyond what could be predicted by the increase in baseline APD after block of I(Kr). The substantial change in APD after blocking I(Kr) suggests that this current plays a major role in repolarization in the swine. Loop thickness is a measure of memory, an increase in which is predicted by theory to reduce instability in activation. In our study, the substantial increase in loop thickness could be accounted for by an equally substantial increase in APD and therefore does not necessarily indicate increased memory after blocking I(Kr). Our results also suggest that factors based on restitution and memory need to be considered in the context of operating point, i.e. baseline APD, when they are used to explore mechanisms that affect electrical stability in the heart.

  2. Modulation of Kv3.4 channel N-type inactivation by protein kinase C shapes the action potential in dorsal root ganglion neurons.

    PubMed

    Ritter, David M; Ho, Cojen; O'Leary, Michael E; Covarrubias, Manuel

    2012-01-01

    Fast inactivation of heterologously expressed Kv3.4 channels is dramatically slowed upon phosphorylation of the channel's N-terminal (N-type) inactivation gate by protein kinase C (PKC). However, the presence and physiological importance of this exquisite modulation in excitable tissues were unknown. Here, we employed minimally invasive cell-attached patch-clamping, single-cell qPCR and specific siRNAs to unambiguously demonstrate that fast-inactivating Kv3.4 channels underlie a robust high voltage-activated A-type K(+) current (I(AHV)) in nociceptive dorsal root ganglion neurons from 7-day-old rats. We also show that PKC activation with phorbol 12,13-dibutyrate (PDBu) causes a 4-fold slowing of Kv3.4 channel inactivation and, consequently, accelerates the repolarization of the action potential (AP) by 22%, which shortens the AP duration by 14%. G-protein coupled receptor (GPCR) agonists eliminate I(AHV) fast inactivation in a membrane-delimited manner, suggesting a Kv3.4 channel signalling complex. Preincubation of the neurons with the PKC inhibitor bisindolylmaleimide II inhibits the effect of GPCR agonists and PDBu. Furthermore, activation of PKC via GPCR agonists recapitulates the effects of PDBu on the AP. Finally, transfection of the neurons with Kv3.4 siRNA prolongs the AP by 25% and abolishes the GPCR agonist-induced acceleration of the AP repolarization. These results show that Kv3.4 channels help shape the repolarization of the nociceptor AP, and that modulation of Kv3.4 channel N-type inactivation by PKC regulates AP repolarization and duration. We propose that the dramatic modulation of I(AHV) fast inactivation by PKC represents a novel mechanism of neural plasticity with potentially significant implications in the transition from acute to chronic pain.

  3. Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration

    PubMed Central

    Medei, Emiliano Horacio; Nascimento, José H.M.; Pedrosa, Roberto C.; Barcellos, Luciane; Masuda, Masako O.; Sicouri, Serge; Elizari, Marcelo V.; Campos de Carvalho, Antonio C.

    2009-01-01

    Aims The aim of this study was to investigate whether the sera from chronic chagasic patients (CChPs) with beta-1 adrenergic activity (Ab-β) can modulate ventricular repolarization. Beta-adrenergic activity has been described in CChP. It increases the L-type calcium current and heart rate in isolated hearts, but its effects on ventricular repolarization has not been described. Methods and results In isolated rabbit hearts, under pacing condition, QT interval was measured under Ab-β perfusion. Beta-adrenergic activity was also tested in guinea pig ventricular M cells. Furthermore, the immunoglobulin fraction (IgG-β) of the Ab-β was tested on Ito, ICa, and Iks currents in rat, rabbit, and guinea pig myocytes, respectively. Beta-adrenergic activity shortened the QT interval. This effect was abolished in the presence of propranolol. In addition, sera from CChP without beta-adrenergic activity (Ab-β) did not modulate QT interval. The M cell action potential duration (APD) was reversibly shortened by Ab-β. Atenolol inhibited this effect of Ab-β, and Ab- did not modulate the AP of M cells. Ito was not modulated by isoproterenol nor by IgG-β. However, IgG-β increased ICa and IKs. Conclusion The shortening of the QT interval and APD in M cells and the increase of IKs and ICa induced by IgG-β contribute to repolarization changes that may trigger malignant ventricular arrhythmias observed in patients with chronic chagasic or idiopathic cardiomyopathy. PMID:18515284

  4. Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.

    PubMed

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T; Chen-Izu, Ye

    2014-11-01

    β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.

  5. Frequency-dependent action potential prolongation in Aplysia pleural sensory neurones.

    PubMed

    Edstrom, J P; Lukowiak, K D

    1985-10-01

    The effects of repetitive activity on action-potential shape in Aplysia californica pleural sensory cells are described. Action potentials were evoked by intracellular current injection at frequencies between 7.41 and 0.2 Hz. In contrast to other molluscan neurons having brief action potentials, it was found that at these firing rates the normally brief action potential develops a prominent shoulder or plateau during the repolarization phase. Higher stimulus rates broaden the action potential more rapidly and to a greater extent than lower stimulus rates. Inactivation is slow relative to activation; effects of 3-s 6-Hz trains are detectable after 1 min rest. The amplitude of the plateau voltage reaches a maximum of 50-70 mV at the highest stimulus rates tested. Frequency-dependent increases in action-potential duration measured at half-amplitude normally range between 6 and 15 ms. Cadmium, at concentrations between 0.05 and 0.5 mM, antagonizes frequency-dependent broadening. The increases in duration induced by repetitive activity are more sensitive to cadmium than are the increases in plateau amplitude. Tetraethylammonium, at concentrations between 0.5 and 10 mM, slightly increases the duration and amplitude of single action potentials. During repetitive activity at high stimulus rates the maximum duration and rate of broadening are both increased but the amplitude of the plateau potential is not affected by these tetraethylammonium concentrations. Above 10 mM, tetraethylammonium greatly increases the duration and amplitude of single action potentials as well as the rates of action-potential duration and amplitude increase during repetitive activity. These high tetraethylammonium concentrations also cause the normally smoothly increasing duration and amplitude to reach a maximum value early in a train and then decline slowly during the remainder of the train. The consequences of frequency-dependent spike broadening in these neurons have not yet been investigated

  6. Computer Simulation of the Neuronal Action Potential.

    ERIC Educational Resources Information Center

    Solomon, Paul R.; And Others

    1988-01-01

    A series of computer simulations of the neuronal resting and action potentials are described. Discusses the use of simulations to overcome the difficulties of traditional instruction, such as blackboard illustration, which can only illustrate these events at one point in time. Describes systems requirements necessary to run the simulations.…

  7. Introducing the Action Potential to Psychology Students

    ERIC Educational Resources Information Center

    Simon-Dack, Stephanie L.

    2014-01-01

    For this simple active learning technique for teaching, students are assigned "roles" and act out the process of the action potential (AP), including the firing threshold, ion-specific channels for ions to enter and leave the cell, diffusion, and the refractory period. Pre-post test results indicated that students demonstrated increased…

  8. Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia.

    PubMed

    Baker, L C; London, B; Choi, B R; Koren, G; Salama, G

    2000-03-03

    The heterogeneous distribution of ion channels in ventricular muscle gives rise to spatial variations in action potential (AP) duration (APD) and contributes to the repolarization sequence in healthy hearts. It has been proposed that enhanced dispersion of repolarization may underlie arrhythmias in diseases with markedly different causes. We engineered dominant negative transgenic mice that have prolonged QT intervals and arrhythmias due to the loss of a slowly inactivating K(+) current. Optical techniques are now applied to map APs and investigate the mechanisms underlying these arrhythmias. Hearts from transgenic and control mice were isolated, perfused, stained with di-4-ANEPPS, and paced at multiple sites to optically map APs, activation, and repolarization sequences at baseline and during arrhythmias. Transgenic hearts exhibited a 2-fold prolongation of APD, less shortening (8% versus 40%) of APDs with decreasing cycle length, altered restitution kinetics, and greater gradients of refractoriness from apex to base compared with control hearts. A premature impulse applied at the apex of transgenic hearts produced sustained reentrant ventricular tachycardia (n=14 of 15 hearts) that did not occur with stimulation at the base (n=8) or at any location in control hearts (n=12). In transgenic hearts, premature impulses initiated reentry by encountering functional lines of conduction block caused by enhanced dispersion of refractoriness. Reentrant VT had stable (>30 minutes) alternating long/short APDs associated with long/short cycle lengths and T wave alternans. Thus, optical mapping of genetically engineered mice may help elucidate some electrophysiological mechanisms that underlie arrhythmias and sudden death in human cardiac disorders.

  9. The action potential of Dionaea muscipula Ellis.

    PubMed

    Hodick, D; Sievers, A

    1988-04-01

    The intention of this investigation was to acquire more concise information about the nature of the action potential of Dionaea muscipula Ellis and the different types of cells generating and conducting it. It is shown by microelectrode measurements that, besides the sensory cells, all the major tissues of the trap lobes are excitable, firing action potentials with pronounced after-hyperpolarizations. The action potentials are strictly dependent on Ca(2+). Their peak depolarizations are shifted 25-27 mV in a positive direction after a tenfold increase in external Ca(2+) concentration. Perfusions with 1 mM ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or 1 mM LaCl3 completely inhibit excitability. Magnesium ions only slightly affect the peak depolarizations but considerably prolong action potentials. Sodium azide and 2,4-dinitrophenol also abolish excitation, probably by reducing the intracellular ATP concentration. Furthermore, it is tested whether the sensory cells can be distinguished from the other cells of the trap by their electrical behaviour. The resting potentials of sensory cells (-161±7 mV) and mesophyll cells (-155±8 mV) are of the same magnitude. Changes in external ion concentrations affect resting and action potentials in both cell types in a similar way. Additional freeze-fracture studies of both cell types reveal similar numbers and distributions of intramembrane particles on the fracture faces of the plasma membrane, which is most likely the mechanosensor. These findings stress the view that the high mechanosensitivity of the sensory hair results from its anatomy and not from a specialized perception mechanism. It is proposed that trap closure is triggered by a rise in the cytoplasmic concentration of Ca(2+) or a Ca(2+)-activated regulatory complex, which must exceed a threshold concentration. Since the Ca(2+) influx during a single action potential does not suffice to reach this threshold, at least two stimulations

  10. Cyclical modulation of human ventricular repolarization by respiration

    PubMed Central

    Hanson, Ben; Gill, Jaswinder; Western, David; Gilbey, Michael P.; Bostock, Julian; Boyett, Mark R.; Zhang, Henggui; Coronel, Ruben; Taggart, Peter

    2012-01-01

    Background: Respiratory modulation of autonomic input to the sinus node results in cyclical modulation of heart rate, known as respiratory sinus arrhythmia (RSA). We hypothesized that the respiratory cycle may also exert cyclical modulation on ventricular repolarization, which may be separately measurable using local endocardial recordings. Methods and Results: The study included 16 subjects with normal ventricles undergoing routine clinical electrophysiological procedures for supraventricular arrhythmias. Unipolar electrograms were recorded from 10 right and 10 left ventricular endocardial sites. Breathing was voluntarily regulated at 5 fixed frequencies (6, 9, 12, 15, and 30 breaths per min) and heart rate was clamped by RV pacing. Activation-recovery intervals (ARI: a surrogate for APD) exhibited significant (p < 0.025) cyclical variation at the respiratory frequency in all subjects; ARI shortened with inspiration and lengthened with expiration. Peak-to-peak ARI variation ranged from 0–26 ms; the spatial pattern varied with subject. Arterial blood pressure also oscillated at the respiratory frequency (p < 0.025) and lagged behind respiration by between 1.5 s and 0.65 s from slowest to fastest breathing rates respectively. Systolic oscillation amplitude was significantly greater than diastolic (14 ± 5 vs. 8 ± 4 mm Hg ± SD, p < 0.001). Conclusions: Observations in humans with healthy ventricles using multiple left and right ventricular endocardial recordings showed that ARI action potential duration (APD) varied cyclically with respiration. PMID:23055983

  11. An in vitro model for assessment of drug-induced torsade de pointes arrhythmia : effects of haloperidol and dofetilide on potential duration, repolarization inhomogeneities, and torsade de pointes arrhythmia.

    PubMed

    Dhein, Stefan; Perlitz, Franziska; Mohr, Friedrich-Wilhelm

    2008-12-01

    Torsade de pointes (TdP) is a serious side effect of many drugs. We aimed to establish an in vitro TdP model for drug testing, which includes typical risk factors, such as female gender, hypokalemia, low magnesium levels, and bradycardia. Isolated, spontaneously beating rabbit hearts (female White New Zealand rabbits) were perfused according to the Langendorff technique and submitted to conditions known as risk factors for TdP, i.e., [K(+)](e) = 2.5 mM and [Mg(++)](e) = 0.5 mM, with 10(-8) M noradrenaline and 10(-7) M carbachol. Thereafter, cumulative concentration-response curves for haloperidol (10, 100, 200, 1,000, and 2,000 nM) and dofetilide (1, 10, 20, 100, and 200 nM) were performed, while cardiac activation and repolarization was measured at 256 ventricular sites (unipolar extracellular potentials). We found in three of six hearts under haloperidol TdP arrhythmias in supratherapeutic concentrations > or =100 nM. Dofetilide also induced TdP (three of seven) in concentrations > or =20 nM. The TdP showed a complex pattern being initiated in one region by an early R-on-T ventricular extrasystole, when in the other regions high activation-recovery interval (ARI) dispersion occurred, then spreading in complex beat-to-beat changing patterns until self-termination. Dofetilide and haloperidol significantly prolonged ARI and QTc. Haloperidol significantly increased dispersion predominantly at the right wall and prolonged basic cycle length. Dofetilide also increased dispersion and slowed basic cycle length. Haloperidol (> or =100 nM) and dofetilide (> or =20 nM) can induce TdP by prolongation of ARI, slowing of heart rate, and increasing repolarization inhomogeneities. The linear combination of the independent variables QTc, BCL and dispersion could highly significantly predict TaP (adjusted R(2): 0.896, p < 0.001) The model seems suitable to identify a pharmacological risk for TdP in vitro within a limited number of animals.

  12. Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation.

    PubMed

    Terrenoire, Cecile; Clancy, Colleen E; Cormier, Joseph W; Sampson, Kevin J; Kass, Robert S

    2005-03-18

    I(Ks), the slowly activating component of the delayed rectifier current, plays a major role in repolarization of the cardiac action potential (AP). Genetic mutations in the alpha- (KCNQ1) and beta- (KCNE1) subunits of I(Ks) underlie Long QT Syndrome type 1 and 5 (LQT-1 and LQT-5), respectively, and predispose carriers to the development of polymorphic ventricular arrhythmias and sudden cardiac death. beta-adrenergic stimulation increases I(Ks) and results in rate dependent AP shortening, a control system that can be disrupted by some mutations linked to LQT-1 and LQT-5. The mechanisms by which I(Ks) regulates action potential duration (APD) during beta-adrenergic stimulation at different heart rates are not known, nor are the consequences of mutation induced disruption of this regulation. Here we develop a complementary experimental and theoretical approach to address these questions. We reconstituted I(Ks) in CHO cells (ie, KCNQ1 coexpressed with KCNE1 and the adaptator protein Yotiao) and quantitatively examined the effects of beta-adrenergic stimulation on channel kinetics. We then developed theoretical models of I(Ks) in the absence and presence of beta-adrenergic stimulation. We simulated the effects of sympathetic stimulation on channel activation (speeding) and deactivation (slowing) kinetics on the whole cell action potential under different pacing conditions. The model suggests these kinetic effects are critically important in rate-dependent control of action potential duration. We also investigate the effects of two LQT-5 mutations that alter kinetics and impair sympathetic stimulation of I(Ks) and show the likely mechanism by which they lead to tachyarrhythmias and indicate a distinct role of I(KS) kinetics in this electrical dysfunction. The full text of this article is available online at http://circres.ahajournals.org.

  13. Off-site control of repolarization alternans in cardiac fibers

    PubMed Central

    Karma, Alain; Riccio, Mark L.; Jordan, Peter N.; Christini, David J.; Gilmour, Robert F.

    2010-01-01

    Repolarization alternans, a beat-to-beat alternation in action potential duration, has been putatively linked to the onset of cardiac reentry. Anti-alternans control strategies can eliminate alternans in individual cells by exploiting the rate dependence of action potential duration. The same approach, when applied to a common measuring/stimulating site at one end of a cardiac fiber, has been shown to have limited spatial efficacy. As a first step toward spatially distributed electrode control systems, we investigated “off-site” control in canine Purkinje fibers, in which the recording and control sites are different. We found experimentally that alternans can be eliminated at, or very near, the recording site, and that varying the location of the recording site along the fiber causes the node (the location with no alternans) to move along the fiber in close proximity to the recording site. Theoretical predictions based on an amplitude equation [B. Echebarria and A. Karma, Chaos 12, 923 (2002)] show that those findings follow directly from the wave nature of alternans: the most unstable mode of alternans along the fiber is a wave solution of a one-dimensional Helmholtz equation with a node position that only deviates slightly from the recording site by an amount dependent on electrotonic coupling. Computer simulations using a Purkinje fiber model confirm these theoretical and experimental results. Although off-site alternans control does not suppress alternans along the entire fiber, our results indicate that placing the node away from the stimulus site reduces alternans amplitude along the fiber, and may therefore have implications for antiarrhythmic strategies based on alternans termination. PMID:20365407

  14. Conscious awareness of action potentiates sensorimotor learning.

    PubMed

    Boutin, Arnaud; Blandin, Yannick; Massen, Cristina; Heuer, Herbert; Badets, Arnaud

    2014-10-01

    Many everyday skills are unconsciously learned through repetitions of the same behaviour by binding independent motor acts into unified sets of actions. However, our ability to be consciously aware of producing newly and highly trained motor skills raises the question of the role played by conscious awareness of action upon skill acquisition. In this study we strengthened conscious awareness of self-produced sequential finger movements by way of asking participants to judge their performance in terms of maximal fluency after each trial. Control conditions in which participants did not make any judgment or performance-unrelated judgments were also included. Findings indicate that conscious awareness of action, enhanced via subjective appraisal of motor efficiency, potentiates sensorimotor learning and skilful motor production in optimising the processing and sequencing of action units, as compared to the control groups. The current work lends support to the claim that the learning and skilful expression of sensorimotor behaviours might be grounded upon our ability to be consciously aware of our own motor capability and efficiency.

  15. The Role of Spatial Dispersion of Repolarization in Inherited and Acquired Sudden Cardiac Death Syndromes

    PubMed Central

    Antzelevitch, Charles

    2007-01-01

    This review examines the role of spatial electrical heterogeneity within ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia (CPVT) are critically examined. In the long QT Syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada Syndrome, it is thought to be due to selective abbreviation of the APD of right ventricular (RV) epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but which share a common final pathway in causing sudden cardiac death. PMID:17586620

  16. Clarithromycin reduces Isus and Ito currents in human atrial myocytes with minor repercussions on action potential duration.

    PubMed

    Gluais, Pascale; Bastide, Michèle; Grandmougin, Daniel; Fayad, Georges; Adamantidis, Monique

    2003-12-01

    The macrolide antibacterial agent clarithromycin has been shown to cause QT interval prolongation on the electrocardiogram. In rabbit heart preparations clarithromycin (concentration dependently) lengthened the action potential duration and blocked the delayed rectifier current. The aim of the present study was to investigate the clarithromycin effects: (i) on the Ca2+ L-type and the main K+ repolarizing currents on human atrial myocytes, using whole-cell patch clamp recordings and (ii) on action potentials recorded from human atrial and ventricular myocardium using conventional microelectrodes. It has been found that (i) 10-30 microM clarithromycin reduced the sustained current Isus significantly and that a 100 microM concentration was needed to cause a significant reduction in the transient outward current Ito, whereas clarithomycin did not affect the calcium current and (ii) clarithromycin (10-100 microM) prolonged the action potential duration in atrial preparations but did not alter the different parameters of the ventricular action potential. It is concluded that clarithromycin exerts direct cardiac electrophysiological effects that may contribute to pro-arrythmic potential.

  17. miR-19b Regulates Ventricular Action Potential Duration in Zebrafish

    PubMed Central

    Benz, Alexander; Kossack, Mandy; Auth, Dominik; Seyler, Claudia; Zitron, Edgar; Juergensen, Lonny; Katus, Hugo A.; Hassel, David

    2016-01-01

    Sudden cardiac death due to ventricular arrhythmias often caused by action potential duration (APD) prolongation is a common mode of death in heart failure (HF). microRNAs, noncoding RNAs that fine tune gene expression, are frequently dysregulated during HF, suggesting a potential involvement in the electrical remodeling process accompanying HF progression. Here, we identified miR-19b as an important regulator of heart function. Zebrafish lacking miR-19b developed severe bradycardia and reduced cardiac contractility. miR-19b deficient fish displayed increased sensitivity to AV-block, a characteristic feature of long QT syndrome in zebrafish. Patch clamp experiments from whole hearts showed that miR-19b deficient zebrafish exhibit significantly prolonged ventricular APD caused by impaired repolarization. We found that miR-19b directly and indirectly regulates the expression of crucial modulatory subunits of cardiac ion channels, and thereby modulates AP duration and shape. Interestingly, miR-19b knockdown mediated APD prolongation can rescue a genetically induced short QT phenotype. Thus, miR-19b might represent a crucial modifier of the cardiac electrical activity, and our work establishes miR-19b as a potential candidate for human long QT syndrome. PMID:27805004

  18. Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells

    PubMed Central

    Szentandrássy, N; Harmati, G; Bárándi, L; Simkó, J; Horváth, B; Magyar, J; Bányász, T; Lőrincz, I; Szebeni, A; Kecskeméti, V; Nánási, PP

    2011-01-01

    BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration-dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts. EXPERIMENTAL APPROACH Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts. KEY RESULTS At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase-1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration-dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC50 value for this inhibition was 25.2 ± 2.7 µM for the transient outward K+ current (Ito), 72.3 ± 9.3 µM for the rapid delayed rectifier K+ current (IKr) and 82.5 ± 9.4 µM for the L-type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of Ito, IKr, and ICa was confirmed also under action potential voltage clamp conditions. CONCLUSIONS AND IMPLICATIONS Alterations in the densities and kinetic properties of ion currents may carry serious pro-arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients. LINKED ARTICLE This article is commented on by Hancox, pp. 496–498 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01281.x PMID:21232044

  19. Action potential broadening induced by lithium may cause a presynaptic enhancement of excitatory synaptic transmission in neonatal rat hippocampus.

    PubMed

    Colino, A; García-Seoane, J J; Valentín, A

    1998-07-01

    Lithium enhances excitatory synaptic transmission in CA1 pyramidal cells, but the mechanisms remain unclear. The present study demonstrates that lithium enhances the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptor-mediated components of the excitatory postsynaptic current (EPSC). Lithium decreased the magnitude of paired-pulse facilitation and presented an inverse correlation between the lithium-induced enhancement of synaptic transmission and initial paired-pulse facilitation, which is consistent with a presynaptic mode of action. The enhancement of synaptic strength is likely to act, at least in part, by increasing the amplitude of the presynaptic Ca2+ transient. One mechanism which could account for this change of the presynaptic Ca2+ transient is an increase in the duration of the action potential. We investigated action potential in hippocampal pyramidal neurons and found that lithium (0.5-6 mM) increased the half-amplitude duration and reduced the rate of repolarization, whereas the rate of depolarization remained similar. To find out whether the lithium synaptic effects might be explained by spike broadening, we investigated the field recording of the excitatory postsynaptic potential (EPSP) in hippocampal slices and found three lines of evidence. First, the prolongation of the presynaptic action potential with 4-aminopyridine and tetraethylammonium blocked or reduced the synaptic effects of lithium. Second, the lithium-induced synaptic enhancement was modulated when presynaptic Ca2+ influx was varied by changing the external Ca2+ concentration. Finally, both effects, the synaptic transmission increment and the action potential broadening, were independent of inositol depletion. These results suggest that lithium enhances synaptic transmission in the hippocampus via a presynaptic site of action: the mechanism underlying the potentiating effect may be attributable to an increased Ca2+ influx consequent

  20. Weber potential from finite velocity of action?

    NASA Astrophysics Data System (ADS)

    Wesley, J. P.

    1992-12-01

    The Weber potential energy U for charges q and q' separated by the distance R is U = (qq'/R)[1 - (dR/dt)2/2c2]. If this potential arises from a finite velocity c of energy transfer Q', where the retarded rate of transfer from q' to q is dQ(t-R/c)/dt = Q'[1 - (dR/dt)/c] and where the advanced rate from q to q' is dQ(t+R/c)/dt = Q'[1 + (dR/dt)/c], then the resultant time-average root-mean-square action is given by{{Q'}}sqrt {1 - {{({{{{{dR}}} {{{dt}}}}} )^2} {{{c}}^{{2}} }}} ≈ {{Q'}}[ {{{1 - }}{{( {{{{{dR}}} {{{dt}}}}} )^2 {{{{dR}}} {{{dt}}}}})^2 {2{{c}}^{{2}} }}}]. Identifying Q' with the Coulomb potential energy qq'/R, the Weber potential is obtained. Using the same argument, Newtonian gravitation yields a corresponding Weber potential energy, qq'/R being replaced by ( - Gmm'/R).

  1. Analogue modulation of back-propagating action potentials enables dendritic hybrid signalling.

    PubMed

    Brunner, János; Szabadics, János

    2016-10-05

    We report that back-propagating action potentials (bAPs) are not simply digital feedback signals in dendrites but also carry analogue information about the overall state of neurons. Analogue information about the somatic membrane potential within a physiological range (from -78 to -64 mV) is retained by bAPs of dentate gyrus granule cells as different repolarization speeds in proximal dendrites and as different peak amplitudes in distal regions. These location-dependent waveform changes are reflected by local calcium influx, leading to proximal enhancement and distal attenuation during somatic hyperpolarization. The functional link between these retention and readout mechanisms of the analogue content of bAPs critically depends on high-voltage-activated, inactivating calcium channels. The hybrid bAP and calcium mechanisms report the phase of physiological somatic voltage fluctuations and modulate long-term synaptic plasticity in distal dendrites. Thus, bAPs are hybrid signals that relay somatic analogue information, which is detected by the dendrites in a location-dependent manner.

  2. Analogue modulation of back-propagating action potentials enables dendritic hybrid signalling

    PubMed Central

    Brunner, János; Szabadics, János

    2016-01-01

    We report that back-propagating action potentials (bAPs) are not simply digital feedback signals in dendrites but also carry analogue information about the overall state of neurons. Analogue information about the somatic membrane potential within a physiological range (from −78 to −64 mV) is retained by bAPs of dentate gyrus granule cells as different repolarization speeds in proximal dendrites and as different peak amplitudes in distal regions. These location-dependent waveform changes are reflected by local calcium influx, leading to proximal enhancement and distal attenuation during somatic hyperpolarization. The functional link between these retention and readout mechanisms of the analogue content of bAPs critically depends on high-voltage-activated, inactivating calcium channels. The hybrid bAP and calcium mechanisms report the phase of physiological somatic voltage fluctuations and modulate long-term synaptic plasticity in distal dendrites. Thus, bAPs are hybrid signals that relay somatic analogue information, which is detected by the dendrites in a location-dependent manner. PMID:27703164

  3. Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release.

    PubMed

    Hu, H; Shao, L R; Chavoshy, S; Gu, N; Trieb, M; Behrens, R; Laake, P; Pongs, O; Knaus, H G; Ottersen, O P; Storm, J F

    2001-12-15

    Large-conductance Ca(2+)-activated K(+) channels (BK, also called Maxi-K or Slo channels) are widespread in the vertebrate nervous system, but their functional roles in synaptic transmission in the mammalian brain are largely unknown. By combining electrophysiology and immunogold cytochemistry, we demonstrate the existence of functional BK channels in presynaptic terminals in the hippocampus and compare their functional roles in somata and terminals of CA3 pyramidal cells. Double-labeling immunogold analysis with BK channel and glutamate receptor antibodies indicated that BK channels are targeted to the presynaptic membrane facing the synaptic cleft in terminals of Schaffer collaterals in stratum radiatum. Whole-cell, intracellular, and field-potential recordings from CA1 pyramidal cells showed that the presynaptic BK channels are activated by calcium influx and can contribute to repolarization of the presynaptic action potential (AP) and negative feedback control of Ca(2+) influx and transmitter release. This was observed in the presence of 4-aminopyridine (4-AP, 40-100 microm), which broadened the presynaptic compound action potential. In contrast, the presynaptic BK channels did not contribute significantly to regulation of action potentials or transmitter release under basal experimental conditions, i.e., without 4-AP, even at high stimulation frequencies. This is unlike the situation in the parent cell bodies (CA3 pyramidal cells), where BK channels contribute strongly to action potential repolarization. These results indicate that the functional role of BK channels depends on their subcellular localization.

  4. Epac activator critically regulates action potential duration by decreasing potassium current in rat adult ventricle.

    PubMed

    Brette, Fabien; Blandin, Erick; Simard, Christophe; Guinamard, Romain; Sallé, Laurent

    2013-04-01

    Sympathetic stimulation is an important modulator of cardiac function via the classic cAMP-dependent signaling pathway, PKA. Recently, this paradigm has been challenged by the discovery of a family of guanine nucleotide exchange proteins directly activated by cAMP (Epac), acting in parallel to the classic signaling pathway. In cardiac myocytes, Epac activation is known to modulate Ca(2+) cycling yet their actions on cardiac ionic currents remain poorly characterized. This study attempts to address this paucity of information using the patch clamp technique to record action potential (AP) and ionic currents on rat ventricular myocytes. Epac was selectively activated by 8-CPT-AM (acetoxymethyl ester form of 8-CPT). AP amplitude, maximum depolarization rate and resting membrane amplitude were unaltered by 8-CPT-AM, strongly suggesting that Na(+) current and inward rectifier K(+) current are not regulated by Epac. In contrast, AP duration was significantly increased by 8-CPT-AM (prolongation of duration at 50% and 90% of repolarization by 41±10% and 43±8% respectively, n=11). L-type Ca(2+) current density was unaltered by 8-CPT-AM (n=16) so this cannot explain the action potential lengthening. However, the steady state component of K(+) current was significantly inhibited by 8-CPT-AM (-38±6%, n=15), while the transient outward K(+) current was unaffected by 8-CPT-AM. These effects were PKA-independent since they were observed in the presence of PKA inhibitor KT5720. Isoprenaline (100nM) induced a significant prolongation of AP duration, even in the presence of KT5720. This study provides the first evidence that the cAMP-binding protein Epac critically modulates cardiac AP duration by decreasing steady state K(+) current. These observations may be relevant to diseases in which Epac is upregulated, like cardiac hypertrophy.

  5. A Drug-Sensitized Zebrafish Screen Identifies Multiple Genes, Including GINS3, as Regulators of Myocardial Repolarization

    PubMed Central

    Milan, David J.; Kim, Albert M.; Winterfield, Jeffrey R.; Jones, Ian L.; Pfeufer, Arne; Sanna, Serena; Arking, Dan E.; Amsterdam, Adam H.; Sabeh, Khaled M.; Mably, John D.; Rosenbaum, David S.; Peterson, Randall T.; Chakravarti, Aravinda; Kääb, Stefan; Roden, Dan M.; MacRae, Calum A.

    2009-01-01

    Background Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. While genetic studies of familial long QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals. Methods and Results We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3, that affect cardiac repolarization. Testing these genes for human relevance in two concurrently completed genome wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus which is strongly associated with QT interval. Conclusions This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3, the human ortholog of which is a major locus in two concurrent human genome wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization. PMID:19652097

  6. Action-potential modulation during axonal conduction.

    PubMed

    Sasaki, Takuya; Matsuki, Norio; Ikegaya, Yuji

    2011-02-04

    Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A(1) receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring.

  7. The effects of ventricular end-diastolic and systolic pressures on action potential and duration in anaesthetized dogs.

    PubMed Central

    Coulshed, D S; Cowan, J C; Drinkhill, M J; Hainsworth, R

    1992-01-01

    1. Although it is known that mechanical events in the heart influence the duration of the cardiac action potential, there is no quantitative information on the effects of independent changes in ventricular end-diastolic and systolic pressures. 2. Experiments were carried out on open-chest anaesthetized dogs in which the autonomic nervous influences on the heart were prevented and monophasic action potentials were recorded form the epicardial surface of the left ventricle. The duration of these action potentials was taken as the interval from the upstroke to the point of 90% repolarization. 3. Elevation of left ventricular peak systolic pressure, at constant end-diastolic pressure, significantly shortened the monophasic action potential. 4. Elevation of end-diastolic pressure at constant peak systolic pressure significantly lengthened the monophasic action potential. 5. Responses were not dependent on release of noradrenaline from sympathetic nerve terminals because they persisted after administration of bretylium tosylate. They were also not due to myocardial ischaemia because they persisted when coronary perfusion pressure was maintained at a constant high level. 6. Simultaneous recordings of changes in myocardial segment length showed the expected responses to changes in ventricular pressures: increases in shortening in response to increases in diastolic pressure and no consistent effect from changes in systolic pressure. 7. These investigations demonstrate the independent effects of changes in systolic and end-diastolic pressures on cardiac action potential duration. This effect is likely to be an effect of the mechanical events, i.e. contraction-excitation feedback. This response may be mediated through changes in myocardial fibre tension, the consequent changes in fibre shortening, or both. PMID:1297849

  8. Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

    PubMed Central

    Kimm, Tilia; Khaliq, Zayd M.

    2015-01-01

    Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency–current (f–I) relationship, whereas BK channel inhibition had little effect on the f–I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f–I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. SIGNIFICANCE STATEMENT This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra

  9. Mechanical Surface Waves Accompany Action Potential Propagation

    NASA Astrophysics Data System (ADS)

    Machta, Benjamin; El Hady, Ahmed

    2015-03-01

    The action potential (AP) is the basic mechanism by which information is transmitted along neuronal axons. Although the excitable nature of axons is understood to be primarily electrical, many experimental studies have shown that a mechanical displacement of the axonal membrane co-propagates with the electrical signal. While the experimental evidence for co-propagating mechanical waves is diverse and compelling, there is no consensus for their physical underpinnings. We present a model in which these mechanical displacements arise from the driving of mechanical surface waves, in which potential energy is stored in elastic deformations of the neuronal membrane and cytoskeleton while kinetic energy is stored in the movement of the axoplasmic fluid. In our model these surface waves are driven by the traveling wave of electrical depolarization that characterizes the AP, altering the electrostatic forces across the membrane as it passes. Our model allows us to predict the shape of the displacement that should accompany any traveling wave of voltage, including the well-characterized AP. We expect our model to serve as a framework for understanding the physical origins and possible functional roles of these AWs in neurobiology. See Arxiv/1407.7600

  10. Stability and bifurcation in an integral-delay model of cardiac reentry including spatial coupling in repolarization.

    PubMed

    Comtois, Philippe; Vinet, Alain

    2003-11-01

    We present the bifurcation analysis of a revised version of the integral-delay model [Courtemanche et al., Siam J. Appl. Math. 56, 119 (1996)] of reentry in a one-dimensional ring that includes a spatial coupling in the calculation of the action potential duration. This coupling is meant to reproduce the modulation of repolarization by the diffusive current flowing through the intercellular resistance. We show that coupling modifies the criterion for the stability of the period-1 solution, which is no longer uniquely related to the action potential restitution curve, but depends also on the degree of coupling between cells and on the dispersion relation of the velocity. Coupling also changes the scenario from an infinite-dimension Hopf bifurcation to a finite sequence of Hopf bifurcations that take place at different ring lengths.

  11. Stability and bifurcation in an integral-delay model of cardiac reentry including spatial coupling in repolarization

    NASA Astrophysics Data System (ADS)

    Comtois, Philippe; Vinet, Alain

    2003-11-01

    We present the bifurcation analysis of a revised version of the integral-delay model [Courtemanche et al., Siam J. Appl. Math. 56, 119 (1996)] of reentry in a one-dimensional ring that includes a spatial coupling in the calculation of the action potential duration. This coupling is meant to reproduce the modulation of repolarization by the diffusive current flowing through the intercellular resistance. We show that coupling modifies the criterion for the stability of the period-1 solution, which is no longer uniquely related to the action potential restitution curve, but depends also on the degree of coupling between cells and on the dispersion relation of the velocity. Coupling also changes the scenario from an infinite-dimension Hopf bifurcation to a finite sequence of Hopf bifurcations that take place at different ring lengths.

  12. Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice.

    PubMed

    Farkas, Attila S; Nattel, Stanley

    2010-03-26

    Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na+-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhythmogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural dispersion of repolarization. In vitro screening, increasingly involving high-throughput assays, is used to assess potential candidate molecules and eliminate potentially problematic structures at an early stage of development. The most commonly used screening assays assess drug block of the K+ current carried by human ether-à-go-go (hERG) subunits, corresponding to the rapid delayed-rectifier K+ channel, the overwhelmingly most common target of TdP-inducing drugs. In addition, the effects of drugs on AP duration or the in vivo equivalent, QT interval, are often assessed in animal models. Methods available for repolarization-related proarrhythmic risk assessment include in vitro (Langendorff-perfused rabbit or guinea pig hearts) and in vivo models (such as alpha-adrenoceptor-stimulated rabbits, rabbits with reduced repolarization reserve due to block of slow delayed-rectifier current, animals with chronic atrioventricular block or animals with cardiac remodelling caused by congestive heart failure). In silico modelling may be helpful for molecular design of non-hERG blocking candidates and for optimization of compound selection (at the molecular and pharmacological profile levels). Finally, clinical evaluation of effects on

  13. Idiopathic ventricular fibrillation, early repolarization and other J wave-related ventricular fibrillation syndromes: from an electrocardiographic enigma to an electrophysiologic dogma.

    PubMed

    Nam, Gi-Byoung

    2012-01-01

    Current clinical and experimental data demonstrate that the electrocardiographic J wave plays a critical role in the pathogenesis of ventricular fibrillation (VF) in patients with Brugada syndrome (BS) and early repolarization (ER) syndrome (ERS). This has generated renewed interest in the presence of J waves and ERS in the general population, yet the identification of high-risk ECG markers and the risk stratification of subjects with ERS remain to be established. More recently, this concept has been expanded to VF mechanisms in patients with structural heart diseases. Some of the fatal arrhythmias in the setting of acute myocardial ischemia or infarction may share a similar, J wave-related electrophysiologic process. In canine arterially perfused wedge preparations, the occurrence of J wave-related arrhythmias is mediated by phase 2 reentry. The stability of the action potential (AP) dome in the ventricular epicardium is dependent on the prominence of the AP phase 1 notch. The ability to maintain the AP dome depends on a delicate balance between inward and outward ionic currents during depolarization and the early phase of repolarization. Outward shifts of the balance and inability to maintain the AP dome result in marked dispersion of repolarization and vulnerability to VF. This review describes the electrocardiographic and clinical features of the J waves in idiopathic VF and other structural heart diseases.

  14. Excitable Membranes and Action Potentials in Paramecia: An Analysis of the Electrophysiology of Ciliates

    PubMed Central

    Schlaepfer, Charles H.; Wessel, Ralf

    2015-01-01

    The ciliate Paramecium caudatum possesses an excitable cell membrane whose action potentials (APs) modulate the trajectory of the cell swimming through its freshwater environment. While many stimuli affect the membrane potential and trajectory, students can use current injection and extracellular ionic concentration changes to explore how APs cause reversal of the cell’s motion. Students examine these stimuli through intracellular recordings, also gaining insight into the practices of electrophysiology. Paramecium’s large size of around 150 µm, simple care, and relative ease to penetrate make them ideal model organisms for undergraduate students’ laboratory study. The direct link between behavior and excitable membranes has thought provoking evolutionary implications for the study of paramecia. Recording from the cell, students note a small resting potential around −30 mV, differing from animal resting potentials. By manipulating ion concentrations, APs of the relatively long length of 20–30 ms up to several minutes with depolarizations maxing over 0 mV are observed. Through comparative analysis of membrane potentials and the APs induced by either calcium or barium, students can deduce the causative ions for the APs as well as the mechanisms of paramecium APs. Current injection allows students to calculate quantitative electric characteristics of the membrane. Analysis will follow the literature’s conclusion in a V-Gated Ca++ influx and depolarization resulting in feedback from intracellular Ca++ that inactivates V-Gated Ca++ channels and activates Ca-Dependent K+ channels through a secondary messenger cascade that results in the K+ efflux and repolarization. PMID:26557800

  15. Action potential broadening in a presynaptic channelopathy

    PubMed Central

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

    2016-01-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction. PMID:27381274

  16. Action potential broadening in a presynaptic channelopathy

    NASA Astrophysics Data System (ADS)

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

    2016-07-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

  17. Action Potential Initiation in Neocortical Inhibitory Interneurons

    PubMed Central

    Li, Tun; Tian, Cuiping; Scalmani, Paolo; Frassoni, Carolina; Mantegazza, Massimo; Wang, Yonghong; Yang, Mingpo; Wu, Si; Shu, Yousheng

    2014-01-01

    Action potential (AP) generation in inhibitory interneurons is critical for cortical excitation-inhibition balance and information processing. However, it remains unclear what determines AP initiation in different interneurons. We focused on two predominant interneuron types in neocortex: parvalbumin (PV)- and somatostatin (SST)-expressing neurons. Patch-clamp recording from mouse prefrontal cortical slices showed that axonal but not somatic Na+ channels exhibit different voltage-dependent properties. The minimal activation voltage of axonal channels in SST was substantially higher (∼7 mV) than in PV cells, consistent with differences in AP thresholds. A more mixed distribution of high- and low-threshold channel subtypes at the axon initial segment (AIS) of SST cells may lead to these differences. Surprisingly, NaV1.2 was found accumulated at AIS of SST but not PV cells; reducing NaV1.2-mediated currents in interneurons promoted recurrent network activity. Together, our results reveal the molecular identity of axonal Na+ channels in interneurons and their contribution to AP generation and regulation of network activity. PMID:25203314

  18. Action potential broadening in a presynaptic channelopathy.

    PubMed

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E; Kullmann, Dimitri M

    2016-07-06

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca(2+) influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

  19. Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations.

    PubMed

    Bárándi, László; Virág, László; Jost, Norbert; Horváth, Zoltán; Koncz, István; Papp, Rita; Harmati, Gábor; Horváth, Balázs; Szentandrássy, Norbert; Bányász, Tamás; Magyar, János; Zaza, Antonio; Varró, András; Nánási, Péter P

    2010-05-01

    Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate-dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for RRD in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit and guinea pig ventricular myocardium in a rate-dependent manner varying the cycle length (CL) between 0.3 and 5 s. Rate-dependent drug effects were studied using agents known to lengthen or shorten action potentials, and these drug-induced changes in APD were correlated with baseline APD values. Both drug-induced lengthening (by dofetilide, sotalol, E-4031, BaCl(2), veratrine, BAY K 8644) and shortening (by mexiletine, tetrodotoxin, lemakalim) of action potentials displayed RRD, i.e., changes in APD were greater at longer than at shorter CLs. In rabbit, where APD is a biphasic function of CL, the drug-induced APD changes were proportional to baseline APD values but not to CL. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In each case the change in APD was proportional to baseline APD (i.e., that measured before the superfusion of drug or injection of current). Also, the net membrane current (I (net)), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD and consequently with to CL. The results indicate that RRD is a common characteristic of all the drugs tested regardless of the modified ion current species. Thus, drug-induced RRD can be considered as an intrinsic property of cardiac membranes based on the inverse relationship between I (net) and APD.

  20. Evaluation of the acute electrophysiologic effects of intravenous dronedarone, an amiodarone-like agent, with special emphasis on ventricular repolarization and acquired torsade de pointes arrhythmias.

    PubMed

    Verduyn, S C; Vos, M A; Leunissen, H D; van Opstal, J M; Wellens, H J

    1999-02-01

    In the anesthetized dog with complete chronic AV block (CAVB), we evaluated and compared the acute electrophysiologic effects of dronedarone i.v. (Dron, 2 times 2.5 mg/kg/10 min) and amiodarone i.v. (Amio, 2 times 5 mg/kg/10 min). This canine model with a high sensitivity for acquired torsade de pointes (TdP) provides an ideal substrate to evaluate ventricular repolarization abnormalities. Six ECG leads and two endocardial monophasic action potential (MAP) recordings in the left and right ventricle (LV and RV) were simultaneously recorded to measure QT time, action-potential duration (APD), interventricular dispersion (deltaAPD = LV(APD) - RV(APD)), early afterdepolarizations (EADs), ectopic beats (EBs), and TdP. Measurements were made at the spontaneous idioventricular rhythm (IVR) and 1,000-ms steady-state pacing. To investigate its short-term, antiarrhythmic properties, Dron was given after almokalant (0.12 mg/kg)-induced TdP. Furthermore, in another set of experiments, oral Dron (20 mg/kg, b.i.d) was given for 3 weeks to conscious CAVB dogs. Dron, i.v., shortened ventricular repolarization (QT, 435 +/- 60 to 360 +/- 55; LV(APD) 395 +/- 75 to 335 +/- 60 ms; p < 0.05), whereas IVR and ventricular effective refractory period (VERP, 225 +/- 30 to 230 +/- 30 ms) remained similar. Therefore the VERP/QT ratio increased (0.55 +/- 0.04 to 0.61 +/- 0.03; p < 0.05). Similar results were obtained with Amio, i.v.. Almokalant-induced TdP was characterized by an increased repolarization duration, deltaAPD, and EADs. Dron, i.v., suppressed the EADs, EBs, and TdP by a reduction and homogenization of repolarization (LV(APD), 505 +/- 110 to 455 +/- 80 ms, and deltaAPD, 110 +/- 55 to 65 +/- 40 ms). Long-term oral Dron increased the PP interval, CL-IVR, and QT(c) time. In contrast to oral treatment, Dron i.v. shortens ventricular repolarization parameters, resulting in suppression of EAD-dependent acquired TdP. The increased VERP/QT ratio after Dron i.v. may indicate an important

  1. Optogenetics-enabled dynamic modulation of action potential duration in atrial tissue: feasibility of a novel therapeutic approach

    PubMed Central

    Karathanos, Thomas V.; Boyle, Patrick M.; Trayanova, Natalia A.

    2014-01-01

    Aims Diseases that abbreviate the cardiac action potential (AP) by increasing the strength of repolarizing transmembrane currents are highly arrhythmogenic. It has been proposed that optogenetic tools could be used to restore normal AP duration (APD) in the heart under such disease conditions. This study aims to evaluate the efficacy of an optogenetic treatment modality for prolonging pathologically shortened APs in a detailed computational model of short QT syndrome (SQTS) in the human atria, and compare it to drug treatment. Methods and results We used a human atrial myocyte model with faster repolarization caused by SQTS; light sensitivity was inscribed via the presence of channelrhodopsin-2 (ChR2). We conducted simulations in single cells and in a magnetic resonance imaging-based model of the human left atrium (LA). Application of an appropriate optical stimulus to a diseased cell dynamically increased APD, producing an excellent match to control AP (<1.5 mV deviation); treatment of a diseased cell with an AP-prolonging drug (chloroquine) also increased APD, but the match to control AP was worse (>5 mV deviation). Under idealized conditions in the LA (uniform ChR2-expressing cell distribution, no light attenuation), optogenetics-based therapy outperformed chloroquine treatment (APD increased to 87% and 81% of control). However, when non-uniform ChR2-expressing cell distribution and light attenuation were incorporated, optogenetics-based treatment was less effective (APD only increased to 55%). Conclusion This study demonstrates proof of concept for optogenetics-based treatment of diseases that alter atrial AP shape. We identified key practical obstacles intrinsic to the optogenetic approach that must be overcome before such treatments can be realized. PMID:25362173

  2. Chronic left atrial volume overload abbreviates the action potential duration of the canine pulmonary vein myocardium via activation of IK channel.

    PubMed

    Nouchi, Hideaki; Takahara, Akira; Nakamura, Hideki; Namekata, Iyuki; Sugimoto, Takahiko; Tsuneoka, Yayoi; Takeda, Kiyoshi; Tanaka, Toshikazu; Shigenobu, Koki; Sugiyama, Atsushi; Tanaka, Hikaru

    2008-11-12

    Electrophysiological properties of the pulmonary vein myocardium were assessed in a canine chronic atrioventricular block model resulting in left atrial volume overload. Five chronic atrioventricular block dogs and five sham-operated dogs were used. The heart was removed two months after a surgical procedure causing atrioventricular block, when atrial structural remodeling was established. Standard microelectrode penetrations were made with glass microelectrodes to obtain action potential signals of left atrium and pulmonary vein myocardia. The resting membrane potential in the pulmonary vein was more positive than that in the left atrium (-69 mV vs -74 mV) in both animal groups. The action potential duration at 50% repolarization of the pulmonary vein was shorter in the chronic atrioventricular block dogs than in the sham-operated dogs (38 ms vs 63 ms), whereas no significant difference was detected in the action potential duration of the left atrium between the two animal groups (67 ms vs 61 ms). The action potential duration of the pulmonary vein in the chronic atrioventricular block dogs was prolonged by charybdotoxin but not by iberiotoxin. Such prolongation was not observed in the normal pulmonary vein. These results suggest that long-term left atrial dilatation shortened the action potential duration of pulmonary vein myocardium, which may be associated with activation of the intermediate conductance Ca2+-activated K+ channel (IK channel).

  3. Calcium‐activated chloride current determines action potential morphology during calcium alternans in atrial myocytes

    PubMed Central

    Kanaporis, Giedrius

    2016-01-01

    Key points Cardiac alternans – periodic beat‐to‐beat alternations in contraction, action potential (AP) morphology or cytosolic calcium transient (CaT) amplitude – is a high risk indicator for cardiac arrhythmias and sudden cardiac death. However, it remains an unresolved issue whether beat‐to‐beat alternations in intracellular Ca2+ ([Ca2+]i) or AP morphology are the primary cause of pro‐arrhythmic alternans.Here we show that in atria AP alternans occurs secondary to CaT alternans.CaT alternans leads to complex beat‐to‐beat changes in Ca2+‐regulated ion currents that determine alternans of AP morphology.We report the novel finding that alternans of AP morphology is largely sustained by the activity of Ca2+‐activated Cl− channels (CaCCs). Suppression of the CaCCs significantly reduces AP alternans, while CaT alternans remains unaffected.The demonstration of a major role of CaCCs in the development of AP alternans opens new possibilities for atrial alternans and arrhythmia prevention. Abstract Cardiac alternans, described as periodic beat‐to‐beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias and sudden cardiac death. We investigated mechanisms of cardiac alternans in single rabbit atrial myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. Beat‐to‐beat alternations of AP morphology and CaT amplitude revealed a strong quantitative correlation. Application of voltage clamp protocols in the form of pre‐recorded APs (AP‐clamp) during pacing‐induced CaT alternans revealed a Ca2+‐dependent current consisting of a large outward component (4.78 ± 0.58 pA pF–1 in amplitude) coinciding with AP phases 1 and 2 that was followed by an inward current (−0.42 ± 0.03 pA pF–1; n = 21) during AP repolarization. Approximately 90% of the initial outward current

  4. Effects of Na+ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization

    PubMed Central

    Zhang, Jingtao; Lin, Jialun; Han, Guilai

    2016-01-01

    Fibrotic remodeling, characterized by fibroblast phenotype switching, is often associated with atrial fibrillation and heart failure. This study aimed to investigate the effects on electrotonic myofibroblast-myocyte (Mfb-M) coupling on cardiac myocytes excitability and repolarization of the voltage-gated sodium channels (VGSCs) and single mechanogated channels (MGCs) in human atrial Mfbs. Mathematical modeling was developed from a combination of (1) models of the human atrial myocyte (including the stretch activated ion channel current, ISAC) and Mfb and (2) our formulation of currents through VGSCs (INa_Mfb) and MGCs (IMGC_Mfb) based upon experimental findings. The effects of changes in the intercellular coupling conductance, the number of coupled Mfbs, and the basic cycle length on the myocyte action potential were simulated. The results demonstrated that the integration of ISAC, INa_Mfb, and IMGC_Mfb reduced the amplitude of the myocyte membrane potential (Vmax) and the action potential duration (APD), increased the depolarization of the resting myocyte membrane potential (Vrest), and made it easy to trigger spontaneous excitement in myocytes. For Mfbs, significant electrotonic depolarizations were exhibited with the addition of INa_Mfb and IMGC_Mfb. Our results indicated that ISAC, INa_Mfb, and IMGC_Mfb significantly influenced myocytes and Mfbs properties and should be considered in future cardiac pathological mathematical modeling. PMID:27980607

  5. A rapidly activating sustained K+ current modulates repolarization and excitation-contraction coupling in adult mouse ventricle.

    PubMed Central

    Fiset, C; Clark, R B; Larsen, T S; Giles, W R

    1997-01-01

    1. The K+ currents which control repolarization in adult mouse ventricle, and the effects of changes in action potential duration on excitation-contraction coupling in this tissue, have been studied with electrophysiological methods using single cell preparations and by recording mechanical parameters from an in vitro working heart preparation. 2. Under conditions where Ca(2+)-dependent currents were eliminated by buffering intracellular Ca2+ with EGTA, depolarizing voltage steps elicited two rapidly activating outward K+ currents: (i) a transient outward current, and (ii) a slowly inactivating or 'sustained' delayed rectifier. 3. These two currents were separated pharmacologically by the K+ channel blocker 4-amino-pyridine (4-AP). 4-AP at concentrations between 3 and 200 microM resulted in (i) a marked increase in action potential duration and a large decrease in the sustained K+ current at plateau potentials, as well as (ii) a significant increase in left ventricular systolic pressure in the working heart preparation. 4. The current-voltage (I-V) relation, kinetics, and block by low concentrations of 4-AP strongly suggest that the rapid delayed rectifier in adult mouse ventricles is the same K+ current (Kv1.5) that has been characterized in detail in human and canine atria. 5. These results show that the 4-AP-sensitive rapid delayed rectifier is a very important repolarizing current in mouse ventricle. The enhanced contractility produced by 4-AP (50 microM) in the working heart preparation demonstrates that modulation of the action potential duration, by blocking a K+ current, is a very significant inotropic variable. PMID:9401964

  6. Effect of NIP-142 on potassium channel alpha-subunits Kv1.5, Kv4.2 and Kv4.3, and mouse atrial repolarization.

    PubMed

    Tanaka, Hikaru; Namekata, Iyuki; Hamaguchi, Shogo; Kawamura, Taro; Masuda, Hiroyuki; Tanaka, Yoshio; Iida-Tanaka, Naoko; Takahara, Akira

    2010-01-01

    Effects of NIP-142, a benzopyran compound which terminates experimental atrial arrhythmia, on potassium channel alpha-subunits and mouse atrial repolarization were examined. NIP-142 concentration-dependently blocked the outward current through potassium channel alpha subunits Kv1.5, Kv4.2 and Kv4.3 expressed in Xenopus oocytes. In isolated mouse atrial myocardia, NIP-142 prolonged the action potential duration and effective refractory period, and increased the contractile force. These results suggest that NIP-142 blocks the potassium channels underlying the transient and sustained outward currents, which may contribute to its antiarrhythmic activity.

  7. Inhibition of a cAMP-dependent Ca-activated K conductance by forskolin prolongs Ca action potential duration in lamprey sensory neurons.

    PubMed

    Womble, M D; Wickelgren, W O

    1990-06-04

    Intracellular recordings from primary mechanosensory neurons (dorsal cells) of the lamprey spinal cord were made to test the membrane effects of forskolin, an activator of adenylate cyclase in these cells. At a concentration of 50 microM, forskolin was found to have a pronounced broadening effect on calcium action potentials (Ca APs) produced in the presence of voltage-activated K channel blockers (TEA, 3,4-DAP). Forskolin had no effect on passive membrane properties of the cells, such as resting potential or input resistance. Nor did it affect delayed rectification or Na APs and thus appeared not to block voltage-activated K channels. Forskolin's effect was evident only when a significant Ca component to the AP was present. It appeared not to increase the conductance of the Ca channel since its action was accompanied by a decrease in membrane conductance during the Ca AP, indicating instead an inhibition of a repolarizing Ca-activated conductance, other than a Ca-activated Cl conductance. The prolongation of Ca APs by forskolin, barium or the neurotransmitter GABA were all correlated in voltage-clamp with a decrease in outward current. Under the conductions used here, the major outward conductance in dorsal cells is a Ca-activated K conductance (gK(Ca]28, and it is concluded that the most probable mode of action for forskolin is via a cyclic AMP-mediated inhibition of this conductance. GABA has also been shown to prolong Ca APs in lamprey dorsal cells by inhibiting a repolarizing gK(Ca)28. Thus, the action of this transmitter may be mediated by an increase in intracellular cyclic AMP.

  8. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    PubMed Central

    Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W.H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; zu Schwabedissen, Henriette Meyer; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; consortium, HRGEN; den Hoed, Marcel; Loos, Ruth J.F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A.M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; Fabiola Del, Greco M.; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C.M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Leach, Irene Mateo; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C.M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R.P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I.W.; Newton-Cheh, Christopher

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD. PMID:24952745

  9. Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart

    PubMed Central

    Orini, Michele; Simon, Ron B.; Providência, Rui; Khan, Fakhar Z.; Segal, Oliver R.; Babu, Girish G.; Bradley, Richard; Rowland, Edward; Ahsan, Syed; Chow, Anthony W.; Lowe, Martin D.; Taggart, Peter

    2016-01-01

    The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1–S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope −1.36 ± 1.9 and −0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic. PMID:27371682

  10. Action potential initiation and propagation in rat neocortical pyramidal neurons.

    PubMed

    Stuart, G; Schiller, J; Sakmann, B

    1997-12-15

    1. Initiation and propagation of action potentials evoked by extracellular synaptic stimulation was studied using simultaneous dual and triple patch pipette recordings from different locations on neocortical layer 5 pyramidal neurons in brain slices from 4-week-old rats (P26-30) at physiological temperatures. 2. Simultaneous cell-attached and whole-cell voltage recordings from the apical trunk (up to 700 microns distal to the soma) and the soma indicated that proximal synaptic stimulation (layer 4) initiated action potentials first at the soma, whereas distal stimulation (upper layer 2/3) could initiate dendritic regenerative potentials prior to somatic action potentials following stimulation at higher intensity. 3. Somatic action potentials, once initiated, propagated back into the apical dendrites in a decremented manner which was frequency dependent. The half-width of back propagating action potentials increased and their maximum rate of rise decreased with distance from the soma, with the peak of these action potentials propagating with a conduction velocity of approximately 0.5 m s-1. 4. Back-propagation of action potentials into the dendritic tree was associated with dendritic calcium electrogenesis, which was particularly prominent during bursts of somatic action potentials. 5. When dendritic regenerative potentials were evoked prior to somatic action potentials, the more distal the dendritic recording was made from the soma the longer the time between the onset of the dendritic regenerative potential relative to somatic action potential. This suggested that dendritic regenerative potentials were initiated in the distal apical dendrites, possibly in the apical tuft. 6. At any one stimulus intensity, the initiation of dendritic regenerative potentials prior to somatic action potentials could fluctuate, and was modulated by depolarizing somatic or hyperpolarizing dendritic current injection. 7. Dendritic regenerative potentials could be initiated prior to

  11. Conduction velocity of antigravity muscle action potentials.

    PubMed

    Christova, L; Kosarov, D; Christova, P

    1992-01-01

    The conduction velocity of the impulses along the muscle fibers is one of the parameters of the extraterritorial potentials of the motor units allowing for the evaluation of the functional state of the muscles. There are no data about the conduction velocities of antigravity muscleaction potentials. In this paper we offer a method for measuring conduction velocity of potentials of single MUs and the averaged potentials of the interference electromiogram (IEMG) lead-off by surface electrodes from mm. sternocleidomastoideus, trapezius, deltoideus (caput laterale) and vastus medialis. The measured mean values of the conduction velocity of antigravity muscles potentials can be used for testing the functional state of the muscles.

  12. Conopressin affects excitability, firing, and action potential shape through stimulation of transient and persistent inward currents in mulluscan neurons.

    PubMed

    van Soest, P F; Kits, K S

    1998-04-01

    shown that both currents contribute to the action potential. The calcium current, which is activated mainly during the repolarizing phase of the action potential, is augmented by conopressin. Thus conopressin may directly modulate the shape of the action potential. In summary, conopressin may act simultaneously on multiple inward currents in anterior lobe neurons of Lymnaea to affect firing activity, excitability, and action potential shape.

  13. Action potential duration determines sarcoplasmic reticulum Ca2+ reloading in mammalian ventricular myocytes

    PubMed Central

    Bassani, Rosana A; Altamirano, Julio; Puglisi, José L; Bers, Donald M

    2004-01-01

    After sarcoplasmic reticulum (SR) Ca2+ depletion in intact ventricular myocytes, electrical activity promotes SR Ca2+ reloading and recovery of twitch amplitude. In ferret, recovery of twitch and caffeine-induced contracture required fewer twitches than in rabbit or rat. In rat, there was no difference in action potential duration at 90% repolarization (APD90) at steady state (SS) versus at the first post-depletion (PD) twitch. The SS APD90 was similar in ferret and rabbit (but longer than in rat). However, compared to SS, the PD APD90 was lengthened in ferret, but shortened in rabbit. When rabbit myocytes were subjected to AP-clamp patterns during SR Ca2+ reloading (ferret- or rabbit-type APs), reloading was much faster using the ferret AP templates. We conclude that the faster SR Ca2+ refilling in ferret is due to the increased Ca2+ influx during the longer PD AP. The PD versus SS APD90 difference was suppressed by thapsigargin in ferret (indicating Ca2+ dependence). In rabbit, the PD AP shortening depended on the preceding diastolic interval (rather than Ca2+), because rest produced the same AP shortening, and SS APD90 increased as a function of frequency (in contrast to ferret). Transient outward current (Ito) was larger and recovered from inactivation much faster in ferret than in rabbit. Moreover, slow Ito recovery (τ ∼ 3 s) in rabbit was a much larger fraction of Ito. Our data and a computational model (including two Ito components) suggest that in rabbit the slowly recovering Ito is responsible for short post-rest and PD APs, for the unusual frequency dependence of APD90, and ultimately for the slower post-depletion SR Ca2+ reloading. PMID:15243136

  14. [Cardiac electric field at the period of depolarization and repolarization of the frog heart ventricle].

    PubMed

    Vaĭkshnoraĭte, M A; Belogolova, A S; Vitiazev, V A; Azarov, Ia E; Shmakov, D N

    2008-01-01

    Multichannel mapping of electrical field on heart ventricle epicardium and the body surface in frogs Rana esculenta and Rana temporaria was performed at periods of the ventricular myocardium depolarization and repolarization. The zone of the epicardium early depolarization is located on epicardium of the ventricle base posterior wall, while the late depolarization zone--on its apex and on the base anterior wall. The total vector of sequence of the ventricle epicardium depolarization is directed from the base to the apex. The zone of the early repolarization is located in the apical area, while that of the late one--in the area of the base. On the frog body surface the cardioelectric field with the cranial zone of negative and the caudal zone of positive potentials is formed before the appearance of the QRS complex on ECG. At the period of the heart ventricle repolarization the zone of the cardioelectric field negative potentials is located in the cranial, while that of the positive ones--in the body surface caudal parts. The cardioelectric field on the frog body surface at the periods of depolarization and repolarization of the ventricle myocardium reflects adequately the projection of sequence of involvement with excitation and of distribution of potentials on epicardium.

  15. A study of the verapamil-induced changes in conductivity and refractoriness and monophasic action potentials of the dog heart in situ.

    PubMed

    Landmark, K; Amlie, J P

    1976-12-01

    In the dog heart in situ, verapamil 0.30 mg/kg injected intravenously did not impair intraatrial, His--Purkinje and intraventricular conduction. The monophasic action potential (MAP) derived from the right atrium and ventricle was not altered by the drug. The functional refractory period (FRP) and the effective refractory period (ERP) of the atrium was not changed by verapamil. However, the drug caused a small but statistically significant decrease in the ratio between 50 and 90% repolarization, respectively, and the ERP of the right atrium, i.e. the ERP of the atrium increased in relation to the MAP duration. Verapamil used a marked reduction of the conduction velocity within and a pronounced increase of the AV nodal FRP and ERP. These changes were reversed by a rapid injection of calcium gluconate 40 mg/kg. The sinus node automaticity was not influenced by verapamil.

  16. Experimentally-Based Computational Investigation into Beat-To-Beat Variability in Ventricular Repolarization and Its Response to Ionic Current Inhibition

    PubMed Central

    Britton, O. J.; Virág, L.; Kistamás, K.; Szentandrássy, N.; Jost, N.; Varró, A.; Nánási, P. P.; Burrage, K.; Rodríguez, B.

    2016-01-01

    Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. The mechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potential measurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, Ito1, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, IKs. In contrast, IKs and the L-type calcium current, ICaL, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassium current, IKr. This highlights both IKs and Ito1 as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of Ito1 channel numbers as an important independent determinant of the magnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of IKs and ICaL channels only become independent determinants of the magnitude of BVR upon complete inhibition of IKr. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition. PMID:27019293

  17. Theophylline-induced potentiation of the antinociceptive action of baclofen.

    PubMed

    Sawynok, J

    1983-02-01

    1--Theophylline (35, 50 mg/kg) potentiated the antinociceptive action of intraperitoneally administered baclofen in the tail flick and hot plate tests. Potentiation was most marked when the pretreatment time was 1 h, but some potentiation was still apparent following a 2 h pretreatment. 2--Theophylline alone (50 mg/kg) produced only slight alterations in reaction latency in the two tests. 3--When baclofen was applied directly into the spinal subarachnoid space, a 1 h pretreatment with theophylline produced minimal effects, but a 2 h pretreatment produced an increase in the antinociceptive action of baclofen. 4--These results suggest that theophylline can potentiate the antinociceptive action of baclofen by actions at both supraspinal and spinal sites.

  18. Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

    PubMed Central

    Dutta, Sara; Mincholé, Ana; Zacur, Ernesto; Quinn, T. Alexander; Taggart, Peter; Rodriguez, Blanca

    2016-01-01

    Aims Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia. Methods and results A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase. Conclusions Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve. PMID:26850675

  19. Layer I neurons of rat neocortex. I. Action potential and repetitive firing properties.

    PubMed

    Zhou, F M; Hablitz, J J

    1996-08-01

    1. Whole cell patch-clamp techniques, combined with direct visualization of neurons, were used to study action potential (AP) and repetitive firing properties of layer I neurons in slices of rat neocortex. 2. Layer I neurons had resting membrane potentials (RMP) of -59.8 +/- 4.7 mV (mean +/- SD) and input resistances (RN) of 592 +/- 284 M Omega. Layer II/III pyramidal neurons had RMPs and RNs of -61.5 +/- 5.6 mV and 320 +/- 113 M omega, respectively. A double exponential function was needed to describe the charging curves of both neuron types. In layer I neurons, tau(0) was 45 +/- 22 ms and tau(1) was 5 +/- 3.3 ms whereas in layer II/III pyramidal neurons, tau(0) was 41 +/- 11 ms and tau(1) was 3 +/- 2.6 ms. Estimates of specific membrane resistance (Rm) for layer I and layer II/III cells were 45 +/- 22 and 41 +/- 11 k omega cm2, respectively (Cm was assumed to be 1 microF/cm2). 3. AP threshold was -41 +/- 2 mV in layer I neurons. Spike amplitudes, measured from threshold to peak, were 90.6 +/- 7.7 mV. AP durations, measured both at the base and half maximal amplitude, were 2.5 +/- 0.4 and 1.1 +/- 0.2 ms, respectively. AP 10-90% rise and repolarization times were 0.6 +/- 0.1 and 1.1 +/- 0.2 ms, respectively. In layer II/III pyramidal neurons, AP threshold was -41 +/- 2.5 mV and spike amplitude was 97 +/- 9.7 mV. AP duration at base and half maximal amplitude was 5.4 +/- 1.1 ms and 1.8 +/- 0.2 ms, respectively. AP 10-90% rise and decay times were 0.6 +/- 0.1 ms and 2.8 +/- 0.6 ms, respectively. 4. Layer I neurons were fast spiking cells that showed little frequency adaptation, a large fast afterhyperpolarization (fAHP), and no slow afterhyperpolarization (sAHP). Some cells had a medium afterhyperpolarization (mAHP) and a slow afterdepolarization (sADP). All pyramidal cells in layer II/III and "atypical" pyramidal neurons in upper layer II showed regular spiking behavior, prominent frequency adaptation, and marked sAHPs. 5. In both layer I neurons and layer II

  20. Dopamine gates action potential backpropagation in midbrain dopaminergic neurons.

    PubMed

    Gentet, Luc J; Williams, Stephen R

    2007-02-21

    Dopamine is released from both axonal and somatodendritic sites of midbrain dopaminergic neurons in an action potential-dependent manner. In contrast to the majority of central neurons, the axon of dopaminergic neurons typically originates from a dendritic site, suggesting a specialized computational function. Here, we examine the initiation and spread of action potentials in dopaminergic neurons of the substantia nigra pars reticulata and reveal that the displacement of the axon to a dendritic site allows highly compartmentalized electrical signaling. In response to a train of synaptic input, action potentials initiated at axon-bearing dendritic sites formed a variable trigger for invasion to the soma and contralateral dendritic tree, with action potentials often confined to the axon-bearing dendrite. The application of dopamine increased this form of electrical compartmentalization, an effect mediated by a tonic membrane potential hyperpolarization leading to an increased availability of a class of voltage-dependent potassium channel. These data suggest that the release of dopamine from axonal and somatodendritic sites are dissociable, and that dopamine levels within the midbrain are dynamically controlled by the somatodendritic spread of action potentials.

  1. A physical action potential generator: design, implementation and evaluation

    PubMed Central

    Latorre, Malcolm A.; Chan, Adrian D. C.; Wårdell, Karin

    2015-01-01

    The objective was to develop a physical action potential generator (Paxon) with the ability to generate a stable, repeatable, programmable, and physiological-like action potential. The Paxon has an equivalent of 40 nodes of Ranvier that were mimicked using resin embedded gold wires (Ø = 20 μm). These nodes were software controlled and the action potentials were initiated by a start trigger. Clinically used Ag-AgCl electrodes were coupled to the Paxon for functional testing. The Paxon's action potential parameters were tunable using a second order mathematical equation to generate physiologically relevant output, which was accomplished by varying the number of nodes involved (1–40 in incremental steps of 1) and the node drive potential (0–2.8 V in 0.7 mV steps), while keeping a fixed inter-nodal timing and test electrode configuration. A system noise floor of 0.07 ± 0.01 μV was calculated over 50 runs. A differential test electrode recorded a peak positive amplitude of 1.5 ± 0.05 mV (gain of 40x) at time 196.4 ± 0.06 ms, including a post trigger delay. The Paxon's programmable action potential like signal has the possibility to be used as a validation test platform for medical surface electrodes and their attached systems. PMID:26539072

  2. Simulations of the cardiac action potential based on the Hodgkin-Huxley kinetics with the use of Microsoft Excel spreadsheets.

    PubMed

    Wu, Sheng-Nan

    2004-03-31

    The purpose of this study was to develop a method to simulate the cardiac action potential using a Microsoft Excel spreadsheet. The mathematical model contained voltage-gated ionic currents that were modeled using either Beeler-Reuter (B-R) or Luo-Rudy (L-R) phase 1 kinetics. The simulation protocol involves the use of in-cell formulas directly typed into a spreadsheet. The capability of spreadsheet iteration was used in these simulations. It does not require any prior knowledge of computer programming, although the use of the macro language can speed up the calculation. The normal configuration of the cardiac ventricular action potential can be well simulated in the B-R model that is defined by four individual ionic currents, each representing the diffusion of ions through channels in the membrane. The contribution of Na+ inward current to the rate of depolarization is reproduced in this model. After removal of Na+ current from the model, a constant current stimulus elicits an oscillatory change in membrane potential. In the L-R phase 1 model where six types of ionic currents were defined, the effect of extracellular K+ concentration on changes both in the time course of repolarization and in the time-independent K+ current can be demonstrated, when the solutions are implemented in Excel. Using the simulation protocols described here, the users can readily study and graphically display the underlying properties of ionic currents to see how changes in these properties determine the behavior of the heart cell. The method employed in these simulation protocols may also be extended or modified to other biological simulation programs.

  3. Early Afterdepolarizations with Growing Amplitudes via Delayed Subcritical Hopf Bifurcations and Unstable Manifolds of Saddle Foci in Cardiac Action Potential Dynamics

    PubMed Central

    Kügler, Philipp

    2016-01-01

    Early afterdepolarizations (EADs) are pathological oscillations in cardiac action potentials during the repolarization phase and may be caused by drug side effects, ion channel disease or oxidative stress. The most widely observed EAD pattern is characterized by oscillations with growing amplitudes. So far, its occurence has been explained in terms of a supercritical Hopf bifurcation in the fast subsystem of the action potential dynamics from which stable limit cycles with growing amplitudes emerge. The novel contribution of this article is the introduction of two alternative explanations of EAD genesis with growing amplitudes that do not involve stable limit cycles in fast subsystems. In particular, we demonstrate that EAD patterns with growing amplitudes may alternatively arise due to a delayed subcritical Hopf bifurcation or an unstable manifold of a saddle focus fixed point in the full fast-slow system modelling the action potential. Our work extends the list of possible dynamical EAD mechanisms and may contribute to a classification of drug effects in preclinical cardiotoxicity testing. PMID:26977805

  4. A fast algorithm for estimating actions in triaxial potentials

    NASA Astrophysics Data System (ADS)

    Sanders, Jason L.; Binney, James

    2015-03-01

    We present an approach to approximating rapidly the actions in a general triaxial potential. The method is an extension of the axisymmetric approach presented by Binney, and operates by assuming that the true potential is locally sufficiently close to some Stäckel potential. The choice of Stäckel potential and associated ellipsoidal coordinates is tailored to each individual input phase-space point. We investigate the accuracy of the method when computing actions in a triaxial Navarro-Frenk-White potential. The speed of the algorithm comes at the expense of large errors in the actions, particularly for the box orbits. However, we show that the method can be used to recover the observables of triaxial systems from given distribution functions to sufficient accuracy for the Jeans equations to be satisfied. Consequently, such models could be used to build models of external galaxies as well as triaxial components of our own Galaxy. When more accurate actions are required, this procedure can be combined with torus mapping to produce a fast convergent scheme for action estimation.

  5. Membrane, action, and oscillatory potentials in simulated protocells

    NASA Technical Reports Server (NTRS)

    Syren, R. M.; Fox, S. W.; Przybylski, A. T.; Stratten, W. P.

    1982-01-01

    Electrical membrane potentials, oscillations, and action potentials are observed in proteinoid microspheres impaled with (3 M KCl) microelectrodes. Although effects are of greater magnitude when the vesicles contain glycerol and natural or synthetic lecithin, the results in the purely synthetic thermal protein structures are substantial, attaining 20 mV amplitude in some cases. The results add the property of electrical potential to the other known properties of proteinoid microspheres, in their role as models for protocells.

  6. Regional segmentation of ventricular models to achieve repolarization dispersion in cardiac electrophysiology modeling.

    PubMed

    Perotti, L E; Krishnamoorthi, S; Borgstrom, N P; Ennis, D B; Klug, W S

    2015-08-01

    The electrocardiogram (ECG) is one of the most significant outputs of a computational model of cardiac electrophysiology because it relates the numerical results to clinical data and is a universal tool for diagnosing heart diseases. One key features of the ECG is the T-wave, which is caused by longitudinal and transmural heterogeneity of the action potential duration (APD). Thus, in order to model a correct wave of repolarization, different cell properties resulting in different APDs must be assigned across the ventricular wall and longitudinally from apex to base. To achieve this requirement, a regional parametrization of the heart is necessary. We propose a robust approach to obtain the transmural and longitudinal segmentation in a general heart geometry without relying on ad hoc procedures. Our approach is based on auxiliary harmonic lifting analyses, already used in the literature to generate myocardial fiber orientations. Specifically, the solution of a sequence of Laplace boundary value problems allows parametrically controlled segmentation of both heart ventricles. The flexibility and simplicity of the proposed method is demonstrated through several representative examples, varying the locations and extents of the epicardial, midwall, and endocardial layers. Effects of the control parameters on the T-wave morphology are illustrated via computed ECGs.

  7. Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents.

    PubMed

    Livshitz, Leonid M; Rudy, Yoram

    2007-06-01

    Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca(2+) transient (CaT). Because of experimental difficulty in independently controlling the Ca(2+) and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca(2+) release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (I(Kr)) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while I(Kr) enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and I(Kr) enhancement as a possible antiarrhythmic intervention.

  8. Transmural dispersion of repolarization as a preclinical marker of drug-induced proarrhythmia.

    PubMed

    Said, Tamer H; Wilson, Lance D; Jeyaraj, Darwin; Fossa, Anthony A; Rosenbaum, David S

    2012-08-01

    Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.

  9. Drug-induced changes in action potential duration are proportional to action potential duration in rat ventricular myocardium.

    PubMed

    Bárándi, László; Harmati, Gábor; Horváth, Balázs; Szentandrássy, Norbert; Magyar, János; Varró, András; Nánási, Péter P; Bányász, Tamás

    2010-09-01

    Several cardioactive agents exhibit direct or reverse rate-dependent effects on action potential duration (APD) depending on the experimental conditions. Recently, a new theory has been proposed, suggesting that the reverse rate-dependent mode of drug-action may be a common property of canine, rabbit, guinea pig and human cardiac tissues, and this phenomenon is based on the dependence of drug-action on baseline APD. The aim of the present work was to examine the limitations of this hypothesis by studying the APD lengthening effect of K(+) channel blockers and the APD shortening effect of Ca(2+) channel blockers during the electrical restitution process of rat ventricular action potentials. Rat ventricular muscle was chosen because it has a set of ion currents markedly different from those of other species, its APD is shorter by one order of magnitude than that of the "plateau-forming" larger mammals, and most importantly, its APD increases at higher heart rates - opposite to many other species. The restitution of APD was studied as a function of the diastolic interval, a parameter indicating the proximity of action potentials. It was found that drug-induced APD changes in rat myocardium are proportional with the pre-drug value of APD but not with the diastolic interval, indicating that not the proximity of consecutive action potentials, but the baseline APD itself may determine the magnitude of drug-induced APD changes.

  10. Responses of action potential and K+ currents to temperature acclimation in fish hearts: phylogeny or thermal preferences?

    PubMed

    Haverinen, Jaakko; Vornanen, Matti

    2009-01-01

    Electrical activity of the heart is assumed to be one of the key factors that set thermal tolerance limits for ectothermic vertebrates. Therefore, we hypothesized that in thermal acclimation--the duration of cardiac action potential and the repolarizing K+ currents that regulate action potential duration (APD)--the rapid component of the delayed rectifier K+ current (I(Kr)) and the inward rectifier K+ current (I(K1)) are more plastic in eurythermal than in stenothermal fish species. The hypothesis was tested in six freshwater teleosts representing four different fish orders (Cadiformes, Cypriniformes, Perciformes, Salmoniformes) acclimated at +4 degrees C (cold acclimation) or +18 degrees C (warm acclimation). In cold acclimation, a compensatory shortening of APD occurred in all species regardless of thermal tolerances, life styles, or phylogenies of the fish, suggesting that this response is a common characteristic of the teleost heart. The strength of the response did not, however, obey simple eurythermy-stenothermy gradation but differed among the phylogenetic groups. Salmoniformes fish showed the greatest acclimation capacity of cardiac electrical activity, whereas the weakest response appeared in the perch (Perciformes) heart. The underlying ionic mechanisms were also partly phylogeny dependent. Modification of the I(Kr) current was al- most ubiquitously involved in acclimation response of fish cardiac myocytes to temperature, while the ability to change the I(K1) current under chronic thermal stress was absent or showed inverse compensation in Salmoniformes species. Thus, in Salmoniformes fish, the thermal plasticity of APD is strongly based on I(Kr), while other fish groups rely on both I(Kr) and I(K1).

  11. High prevalence of altered cardiac repolarization in patients with COPD

    PubMed Central

    2014-01-01

    Background Altered cardiac repolarization and increased dispersion of repolarization have been identified as risk factors for sudden cardiac death (SCD). The prevalence of and the mechanisms contributing to altered cardiac repolarization are currently unknown in COPD. Methods In 91 COPD patients, 32 controls matched for age, cardiovascular risk and medication, and 41 healthy subjects, measures of cardiac repolarization and dispersion of repolarization (QTc interval, QT dispersion) were derived from 12-lead electrocardiography (ECG). Prevalence rates of heart rate corrected QT (QTc) >450ms and QT dispersion >60ms were determined to assess the number of subjects at risk for SCD. Univariate and multivariate analyses were used to identify possible factors contributing to altered cardiac repolarization. Results QTc was found to be prolonged in 31.9% and QT dispersion in 24.2% of the COPD patients compared to 12.5% in matched controls and 0% in healthy subjects. The QTc interval was longer in COPD patients compared to matched and healthy controls respectively (437.9 ± 29.5 vs. 420.1 ± 25.3 ms, p = 0.001 and vs. 413.4 ± 18.2 ms, p < 0.001). QT dispersion was significantly increased in COPD patients compared to healthy subjects (45.4 (34.8 , 59.5) vs. 39.7 (29.3 , 54.8) ms, p = 0.049). Only oxygen saturation was independently associated with QTc duration in multivariate analysis (β = -0.29, p = 0.015). Conclusion One third of a typical COPD population has altered cardiac repolarization and increased dispersion of repolarization, which may be related to hypoxia. Altered cardiac repolarization may expose these patients to an increased risk for malignant ventricular arrhythmias and SCD. PMID:24690123

  12. Model-based source localization of extracellular action potentials.

    PubMed

    Somogyvári, Zoltán; Zalányi, László; Ulbert, István; Erdi, Péter

    2005-09-30

    A new model-based analysis method was set up for revealing information encrypted in extracellular spatial potential patterns of neocortical action potentials. Spikes were measured by extracellular linear multiple microelectrode in vivo cat's primary auditory cortex and were analyzed based on current source density (CSD) distribution models. Validity of the monopole and other point source approximations were tested on the measured potential patterns by numerical fitting. We have found, that point source models could not provide accurate description of the measured patterns. We introduced a new model of the CSD distribution on a spiking cell, called counter-current model (CCM). This new model was shown to provide better description of the spatial current distribution of the cell during the initial negative deflection of the extracellular action potential, from the onset of the spike to the negative peak. The new model was tested on simulated extracellular potentials. We proved numerically, that all the parameters of the model could be determined accurately based on measurements. Thus, fitting of the CCM allowed extraction of these parameters from the measurements. Due to model fitting, CSD could be calculated with much higher accuracy as done with the traditional method because distance dependence of the spatial potential patterns was explicitly taken into consideration in our method. Average CSD distribution of the neocortical action potentials was calculated and spatial decay constant of the dendritic trees was determined by applying our new method.

  13. Action prediction based on anticipatory brain potentials during simulated driving

    NASA Astrophysics Data System (ADS)

    Khaliliardali, Zahra; Chavarriaga, Ricardo; Gheorghe, Lucian Andrei; Millán, José del R.

    2015-12-01

    Objective. The ability of an automobile to infer the driver’s upcoming actions directly from neural signals could enrich the interaction of the car with its driver. Intelligent vehicles fitted with an on-board brain-computer interface able to decode the driver’s intentions can use this information to improve the driving experience. In this study we investigate the neural signatures of anticipation of specific actions, namely braking and accelerating. Approach. We investigated anticipatory slow cortical potentials in electroencephalogram recorded from 18 healthy participants in a driving simulator using a variant of the contingent negative variation (CNV) paradigm with Go and No-go conditions: count-down numbers followed by ‘Start’/‘Stop’ cue. We report decoding performance before the action onset using a quadratic discriminant analysis classifier based on temporal features. Main results. (i) Despite the visual and driving related cognitive distractions, we show the presence of anticipatory event related potentials locked to the stimuli onset similar to the widely reported CNV signal (with an average peak value of -8 μV at electrode Cz). (ii) We demonstrate the discrimination between cases requiring to perform an action upon imperative subsequent stimulus (Go condition, e.g. a ‘Red’ traffic light) versus events that do not require such action (No-go condition; e.g. a ‘Yellow’ light); with an average single trial classification performance of 0.83 ± 0.13 for braking and 0.79 ± 0.12 for accelerating (area under the curve). (iii) We show that the centro-medial anticipatory potentials are observed as early as 320 ± 200 ms before the action with a detection rate of 0.77 ± 0.12 in offline analysis. Significance. We show for the first time the feasibility of predicting the driver’s intention through decoding anticipatory related potentials during simulated car driving with high recognition rates.

  14. Overexpression of the Large-Conductance, Ca2+-Activated K+ (BK) Channel Shortens Action Potential Duration in HL-1 Cardiomyocytes.

    PubMed

    Stimers, Joseph R; Song, Li; Rusch, Nancy J; Rhee, Sung W

    2015-01-01

    Long QT syndrome is characterized by a prolongation of the interval between the Q wave and the T wave on the electrocardiogram. This abnormality reflects a prolongation of the ventricular action potential caused by a number of genetic mutations or a variety of drugs. Since effective treatments are unavailable, we explored the possibility of using cardiac expression of the large-conductance, Ca2+-activated K+ (BK) channel to shorten action potential duration (APD). We hypothesized that expression of the pore-forming α subunit of human BK channels (hBKα) in HL-1 cells would shorten action potential duration in this mouse atrial cell line. Expression of hBKα had minimal effects on expression levels of other ion channels with the exception of a small but significant reduction in Kv11.1. Patch-clamped hBKα expressing HL-1 cells exhibited an outward voltage- and Ca2+-sensitive K+ current, which was inhibited by the BK channel blocker iberiotoxin (100 nM). This BK current phenotype was not detected in untransfected HL-1 cells or in HL-1 null cells sham-transfected with an empty vector. Importantly, APD in hBKα-expressing HL-1 cells averaged 14.3 ± 2.8 ms (n = 10), which represented a 53% reduction in APD compared to HL-1 null cells lacking BKα expression. APD in the latter cells averaged 31.0 ± 5.1 ms (n = 13). The shortened APD in hBKα-expressing cells was restored to normal duration by 100 nM iberiotoxin, suggesting that a repolarizing K+ current attributed to BK channels accounted for action potential shortening. These findings provide initial proof-of-concept that the introduction of hBKα channels into a cardiac cell line can shorten APD, and raise the possibility that gene-based interventions to increase hBKα channels in cardiac cells may hold promise as a therapeutic strategy for long QT syndrome.

  15. Propagation of Action Potentials: An Active Participation Exercise.

    ERIC Educational Resources Information Center

    Felsten, Gary

    1998-01-01

    Describes an active participation exercise that demonstrates the propagation of action potentials (the ability to transmit information through the neural network, dependent upon chemical interactions in the brain). Students assume the structure and function of the network by lining up around the room and communicating through hand signals and…

  16. Action potential and contraction of Dionaea muscipula (Venus flytrap).

    PubMed

    DI PALMA, J R; MOHL, R; BEST, W

    1961-03-24

    Observation of the action potential and contraction of the leaf of Dionaea muscipula Ellis revealed several interesting phenomena. Two successive stimuli are generally necessary to cause contraction. The first and ineffective stimulus is associated with slow depolarization. The second stimulus has much more rapid depolarization and initiates contraction.

  17. Passive Responses Resembling Action Potentials: A Device for the Classroom

    ERIC Educational Resources Information Center

    Newman, Ian A.; Pickard, Barbara G.

    1975-01-01

    Describes the construction and operation of a network of entirely passive electrical components that gives a response to an electrical shock similar to an action potential. The network of resistors, capacitors, and diodes was developed to produce responses that would mimic those observed, for example, when a dark-grown pea epicotyl is shocked…

  18. Sodium and potassium conductance changes during a membrane action potential

    PubMed Central

    Bezanilla, Francisco; Rojas, Eduardo; Taylor, Robert E.

    1970-01-01

    1. A method for turning a membrane potential control system on and off in less than 10 μsec is described. This method was used to record membrane currents in perfused giant axons from Dosidicus gigas and Loligo forbesi after turning on the voltage clamp system at various times during the course of a membrane action potential. 2. The membrane current measured just after the capacity charging transient was found to have an almost linear relation to the controlled membrane potential. 3. The total membrane conductance taken from these current—voltage curves was found to have a time course during the action potential similar to that found by Cole & Curtis (1939). 4. The instantaneous current voltage curves were linear enough to make it possible to obtain a good estimate of the individual sodium and potassium channel conductances, either algebraically or by clamping to the sodium, or potassium, reversal potentials. Good general agreement was obtained with the predictions of the Hodgkin—Huxley equations. 5. We consider these results to constitute the first direct experimental demonstration of the conductance changes to sodium and potassium during the course of an action potential. PMID:5505231

  19. Sodium and potassium conductance changes during a membrane action potential.

    PubMed

    Bezanilla, F; Rojas, E; Taylor, R E

    1970-12-01

    1. A method for turning a membrane potential control system on and off in less than 10 musec is described. This method was used to record membrane currents in perfused giant axons from Dosidicus gigas and Loligo forbesi after turning on the voltage clamp system at various times during the course of a membrane action potential.2. The membrane current measured just after the capacity charging transient was found to have an almost linear relation to the controlled membrane potential.3. The total membrane conductance taken from these current-voltage curves was found to have a time course during the action potential similar to that found by Cole & Curtis (1939).4. The instantaneous current voltage curves were linear enough to make it possible to obtain a good estimate of the individual sodium and potassium channel conductances, either algebraically or by clamping to the sodium, or potassium, reversal potentials. Good general agreement was obtained with the predictions of the Hodgkin-Huxley equations.5. We consider these results to constitute the first direct experimental demonstration of the conductance changes to sodium and potassium during the course of an action potential.

  20. The Pathophysiological Mechanism Underlying Brugada Syndrome. Depolarization versus Repolarization

    PubMed Central

    Wilde, Arthur A.M.; Postema, Pieter G.; Di Diego, José M.; Viskin, Sami; Morita, Hiroshi; Fish, Jeffrey M.; Antzelevitch, Charles

    2010-01-01

    This Point/Counterpoint presents a scholarly debate of the mechanisms underlying the electrocardiographic and arrhythmic manifestations of Brugada syndrome (BrS), exploring in detail the available evidence in support of the repolarization vs. depolarization hypothesis. PMID:20659475

  1. Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels.

    PubMed

    Telinius, Niklas; Majgaard, Jens; Kim, Sukhan; Katballe, Niels; Pahle, Einar; Nielsen, Jørn; Hjortdal, Vibeke; Aalkjaer, Christian; Boedtkjer, Donna Briggs

    2015-07-15

    Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In the present study, we report the electrical activity and APs of small human lymphatic collecting vessels, as well as mRNA expression and function of VGSC in small and large human lymphatic vessels. The VGSC blocker TTX inhibited spontaneous contractions in six of 10 spontaneously active vessels, whereas ranolazine, which has a narrower VGSC blocking profile, had no influence on spontaneous activity. TTX did not affect noradrenaline-induced contractions. The VGSC opener veratridine induced contractions in a concentration-dependent manner (0.1-30 μm) eliciting a stable tonic contraction and membrane depolarization to -18 ± 0.6 mV. Veratridine-induced depolarizations and contractions were reversed ∼80% by TTX, and were dependent on Ca(2+) influx via L-type calcium channels and the sodium-calcium exchanger in reverse mode. Molecular analysis determined NaV 1.3 to be the predominantly expressed VGSC isoform. Electrophysiology of mesenteric lymphatics determined the resting membrane potential to be -45 ± 1.7 mV. Spontaneous APs were preceded by a slow depolarization of 5.3 ± 0.6 mV after which a spike was elicited that almost completely repolarized before immediately depolarizing again to plateau. Vessels transiently hyperpolarized prior to returning to the resting membrane potential. TTX application blocked APs. We have shown that VGSC are necessary for initiating and maintaining APs and spontaneous contractions in human lymphatic vessels and our data suggest the main contribution from comes NaV 1.3. We have also shown that activation of these channels augments the contractile activity of the vessels.

  2. K+-induced twitch potentiation is not due to longer action potential.

    PubMed

    Yensen, Craig; Matar, Wadih; Renaud, Jean-Marc

    2002-07-01

    The objective of this study was to determine whether an increased duration of the action potential contributes to the K+-induced twitch potentiation at 37 degrees C. Twitch contractions were elicited by field stimulation, and action potentials were measured with conventional microelectrodes. For mouse extensor digitorum longus (EDL) muscle, twitch force was greater at 7-13 mM K+ than at 4.7 mM (control). For soleus muscle, twitch force potentiation was observed between 7 and 11 mM K+. Time to peak and half-relaxation time were not affected by the increase in extracellular K+ concentration in EDL muscle, whereas both parameters became significantly longer in soleus muscle. Decrease in overshoot and prolongation of the action potential duration observed at 9 and 11 mM K+ were mimicked when muscles were respectively exposed to 25 and 50 nM tetrodotoxin (TTX; used to partially block Na+ channels). Despite similar action potentials, twitch force was not potentiated by TTX. It is therefore suggested that the K+-induced potentiation of the twitch in EDL muscle is not due to a prolongation of the action potential and contraction time, whereas a longer contraction, especially the relaxation phase, may contribute to the potentiation in soleus muscle.

  3. Focused ultrasound effects on nerve action potential in vitro

    PubMed Central

    Colucci, Vincent; Strichartz, Gary; Jolesz, Ferenc; Vykhodtseva, Natalia; Hynynen, Kullervo

    2009-01-01

    Minimally invasive applications of thermal and mechanical energy to selective areas of the human anatomy have led to significant advances in treatment of and recovery from typical surgical interventions. Image-guided focused ultrasound allows energy to be deposited deep into the tissue, completely noninvasively. There has long been interest in using this focal energy delivery to block nerve conduction for pain control and local anesthesia. In this study, we have performed an in vitro study to further extend our knowledge of this potential clinical application. The sciatic nerves from the bullfrog (Rana catesbeiana) were subjected to focused ultrasound (at frequencies of 0.661MHz and 1.986MHz) and to heated Ringer’s solution. The nerve action potential was shown to decrease in the experiments and correlated with temperature elevation measured in the nerve. The action potential recovered either completely, partially, or not at all, depending on the parameters of the ultrasound exposure. The reduction of the baseline nerve temperature by circulating cooling fluid through the sonication chamber did not prevent the collapse of the nerve action potential; but higher power was required to induce the same endpoint as without cooling. These results indicate that a thermal mechanism of focused ultrasound can be used to block nerve conduction, either temporarily or permanently. PMID:19647923

  4. Bifurcation diagrams of frequency dependence of repolarization during long QT syndrome using the Luo-Rudy model of cardiac repolarization

    NASA Astrophysics Data System (ADS)

    Bondarenko, V. E.; Doedel, E. J.; Rasmusson, R. L.

    2000-02-01

    We applied bifurcation analysis to the Luo-Rudy model of the guinea pig cardiac ventricular cell to investigate the behavior of repolarization in response to a simulated form of inherited arrhythmia, long QT syndrome. In this paper, we simulate pathological changes in cardiac repolarization through reductions in IKr. Decreased expression of this current has been linked to an inherited form of long QT syndrome which results in a high mortality, presumably due to sudden cardiac death from ventricular fibrillation.

  5. Leptin decreases heart rate associated with increased ventricular repolarization via its receptor.

    PubMed

    Lin, Yen-Chang; Huang, Jianying; Hileman, Stan; Martin, Karen H; Hull, Robert; Davis, Mary; Yu, Han-Gang

    2015-11-15

    Leptin has been proposed to modulate cardiac electrical properties via β-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1-30 μg/kg) decreased resting heart rate; at high doses (150-300 μg/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03-0.3 μg/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of β-adrenergic receptor stimulation. During inhibition of β-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias.

  6. Using extracellular action potential recordings to constrain compartmental models.

    PubMed

    Gold, Carl; Henze, Darrell A; Koch, Christof

    2007-08-01

    We investigate the use of extracellular action potential (EAP) recordings for biophysically faithful compartmental models. We ask whether constraining a model to fit the EAP is superior to matching the intracellular action potential (IAP). In agreement with previous studies, we find that the IAP method under-constrains the parameters. As a result, significantly different sets of parameters can have virtually identical IAP's. In contrast, the EAP method results in a much tighter constraint. We find that the distinguishing characteristics of the waveform--but not its amplitude-resulting from the distribution of active conductances are fairly invariant to changes of electrode position and detailed cellular morphology. Based on these results, we conclude that EAP recordings are an excellent source of data for the purpose of constraining compartmental models.

  7. Sodium action potentials in the dendrites of cerebellar Purkinje cells.

    PubMed

    Regehr, W G; Konnerth, A; Armstrong, C M

    1992-06-15

    We report here that in cerebellar Purkinje cells from which the axon has been removed, positive voltage steps applied to the voltage-clamped soma produce spikes of active current. The spikes are inward, are all-or-none, have a duration of approximately 1 ms, and are reversibly eliminated by tetrodotoxin, a Na channel poison. From cell to cell, the amplitude of the spikes ranges from 4 to 20 nA. Spike latency decreases as the depolarizing step is made larger. These spikes clearly arise at a site where the voltage is not controlled, remote from the soma. From these facts we conclude that Purkinje cell dendrites contain a sufficient density of Na channels to generate action potentials. Activation by either parallel fiber or climbing fiber synapses produces similar spikes, suggesting that normal input elicits Na action potentials in the dendrites. These findings greatly alter current views of how dendrites in these cells respond to synaptic input.

  8. Stability of Cardiac Action Potential Duration under Periodic Pacing.

    PubMed

    Xiaodong, Han; Hailang, Song; Xiaomei, Wu; Cuiwei, Yang; Zuxiang, Fang

    2005-01-01

    Action potential duration (APD) alternans is believed to be a loss of stability and contributes much to the reentry arrhythmias. The purpose of this study is to analyze the stability conditions for one-dimension model and higher dimension model. These criterions are concluded by linear stability analysis in nonlinear dynamics. They should be useful for finding of cardiac control algorithms in low energy defibrillation and the designing of antiarrhythmic drug.

  9. Warm body temperature facilitates energy efficient cortical action potentials.

    PubMed

    Yu, Yuguo; Hill, Adam P; McCormick, David A

    2012-01-01

    The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na(+) channel inactivation, resulting in a marked reduction in overlap of the inward Na(+), and outward K(+), currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na(+) entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37-42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code.

  10. Reflex autonomic modulation of automatically measured repolarization parameters.

    PubMed

    Ghuran, A; Batchvarov, V; Dilaveris, P; Färbom, P; Camm, A J; Malik, M

    2000-11-01

    Automatic recognition of repolarization abnormalities from the standard electrocardiogram (ECG) is of considerable clinical importance. This study examined the autonomic variations in automatically measured repolarization parameters, including maximum QT interval (QTmax), global QT dispersion (QTd), T area dispersion (T area D) and principal component analysis ratio 2 (PCA-2). Twelve-lead ECGs were recorded continuously in 40 healthy subjects during supine, sitting and standing positions, and during the Valsalva maneuver. With the exception of PCA-2, the other repolarization parameters correlated either moderately or strongly during the steady-state supine position. QTmax, PCA-2, and T area D decreased significantly between supine and sitting position (P < 0.001, P < 0.001 and P < 0.01, respectively). QTmax, QTD, and T area D decreased significantly between sitting and standing (P < 0.001, P < 0.05 and P < 0.01, respectively). All parameters significantly decreased between supine and standing position: QTmax (P < 0.001), QTD (P < 0.05), PCA-2 (P < 0.05) and T area D (P < 0.001). During Valsalva, only PCA-2 increased significantly (P < 0.001) between supine and standing position. There were no significant changes in QT dispersion and dispersion of T wave area during Valsalva, compared to baseline, in both supine and standing positions. Automatic conventional measures of repolarization heterogeneity have limited practical value in detecting the effects of autonomic changes on ventricular repolarization. Newer concepts evaluating spatial and temporal irregularity of ventricular repolarization are still needed to reliably detect the effects of autonomic activity on ventricular repolarization.

  11. Decision making and action implementation: evidence for an early visually triggered motor activation specific to potential actions.

    PubMed

    Tandonnet, Christophe; Garry, Michael I; Summers, Jeffery J

    2013-07-01

    To make a decision may rely on accumulating evidence in favor of one alternative until a threshold is reached. Sequential-sampling models differ by the way of accumulating evidence and the link with action implementation. Here, we tested a model's prediction of an early action implementation specific to potential actions. We assessed the dynamics of action implementation in go/no-go and between-hand choice tasks by transcranial magnetic stimulation of the motor cortex (single- or paired-pulse TMS; 3-ms interstimulus interval). Prior to implementation of the selected action, the amplitude of the motor evoked potential first increased whatever the visual stimulus but only for the hand potentially involved in the to-be-produced action. These findings suggest that visual stimuli can trigger an early motor activation specific to potential actions, consistent with race-like models with continuous transmission between decision making and action implementation.

  12. Delayed rectifier K(+) currents and cardiac repolarization.

    PubMed

    Charpentier, Flavien; Mérot, Jean; Loussouarn, Gildas; Baró, Isabelle

    2010-01-01

    The two components of the cardiac delayed rectifier current have been the subject of numerous studies since firstly described. This current controls the action potential duration and is highly regulated. After identification of the channel subunits underlying IKs, KCNQ1 associated with KCNE1, and IKr, HERG, their involvement in human cardiac channelopathies have provided various models allowing the description of the molecular mechanisms of the KCNQ1 and HERG channels trafficking, activity and regulation. More recently, studies have been focusing on the unveiling of different partners of the pore-forming proteins that contribute to their maturation, trafficking, activity and/or degradation, on one side, and on their respective expression in the heterogeneous cardiac tissue, on the other side. The aim of this review is to report and discuss the major works on IKs and IKr and the most recent ones that help to understand the precise function of these currents in the heart.

  13. A Parsimonious Model of the Rabbit Action Potential Elucidates the Minimal Physiological Requirements for Alternans and Spiral Wave Breakup

    PubMed Central

    2016-01-01

    Elucidating the underlying mechanisms of fatal cardiac arrhythmias requires a tight integration of electrophysiological experiments, models, and theory. Existing models of transmembrane action potential (AP) are complex (resulting in over parameterization) and varied (leading to dissimilar predictions). Thus, simpler models are needed to elucidate the “minimal physiological requirements” to reproduce significant observable phenomena using as few parameters as possible. Moreover, models have been derived from experimental studies from a variety of species under a range of environmental conditions (for example, all existing rabbit AP models incorporate a formulation of the rapid sodium current, INa, based on 30 year old data from chick embryo cell aggregates). Here we develop a simple “parsimonious” rabbit AP model that is mathematically identifiable (i.e., not over parameterized) by combining a novel Hodgkin-Huxley formulation of INa with a phenomenological model of repolarization similar to the voltage dependent, time-independent rectifying outward potassium current (IK). The model was calibrated using the following experimental data sets measured from the same species (rabbit) under physiological conditions: dynamic current-voltage (I-V) relationships during the AP upstroke; rapid recovery of AP excitability during the relative refractory period; and steady-state INa inactivation via voltage clamp. Simulations reproduced several important “emergent” phenomena including cellular alternans at rates > 250 bpm as observed in rabbit myocytes, reentrant spiral waves as observed on the surface of the rabbit heart, and spiral wave breakup. Model variants were studied which elucidated the minimal requirements for alternans and spiral wave break up, namely the kinetics of INa inactivation and the non-linear rectification of IK.The simplicity of the model, and the fact that its parameters have physiological meaning, make it ideal for engendering generalizable

  14. Effects of Sleep Deprivation on Action Potential and Transient Outward Potassium Current in Ventricular Myocytes in Rats

    PubMed Central

    Fang, Zhou; Ren, Yi-Peng; Lu, Cai-Yi; Li, Yang; Xu, Qiang; Peng, Li; Fan, Yong-Yan

    2015-01-01

    Background Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. Material/Methods Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. Results Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I–V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. Conclusions APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito. PMID:25694200

  15. Information Encoding and Reconstruction from the Phase of Action Potentials

    PubMed Central

    Nadasdy, Zoltan

    2009-01-01

    Fundamental questions in neural coding are how neurons encode, transfer, and reconstruct information from the pattern of action potentials (APs) exchanged between different brain structures. We propose a general model of neural coding where neurons encode information by the phase of their APs relative to their subthreshold membrane oscillations. We demonstrate by means of simulations that AP phase retains the spatial and temporal content of the input under the assumption that the membrane potential oscillations are coherent across neurons and between structures and have a constant spatial phase gradient. The model explains many unresolved physiological observations and makes a number of concrete, testable predictions about the relationship between APs, local field potentials, and subthreshold membrane oscillations, and provides an estimate of the spatio-temporal precision of neuronal information processing. PMID:19668700

  16. Intracochlear and extracochlear ECAPs suggest antidromic action potentials.

    PubMed

    Miller, Charles A; Abbas, Paul J; Hay-McCutcheon, Marcia J; Robinson, Barbara K; Nourski, Kirill V; Jeng, Fuh-Cherng

    2004-12-01

    With experimental animals, the electrically evoked compound action potential (ECAP) can be recorded from multiple sites (e.g., round window, intracranial and intracochlear sites). However, human ECAPs are typically recorded from intracochlear electrodes of the implanted array. To bridge this difference, we obtained ECAPs from cats using both intracochlear and nerve-trunk recording sites. We also sought to determine how recording the site influences the acquired evoked potential and how those differences may provide insight into basic excitation properties. In the main experiment, ECAPs were recorded from four acutely deafened cats after implanting a Nucleus-style banded electrode array. Potentials were recorded from an electrode positioned on the nerve trunk and an intracochlear electrode. We manipulated stimulus level, electrode configuration (monopolar vs bipolar) and stimulus polarity, variables that influence the site of excitation. Intracochlear ECAPs were found to be an order of magnitude greater than those obtained with the nerve-trunk electrode. Also, compared with the nerve-trunk potentials, the intracochlear ECAPs more closely resembled those obtained from humans in that latencies were shorter and the waveform morphology was typically biphasic (a negative peak followed by a positive peak). With anodic monophasic stimuli, the ECAP had a unique positive-to-negative morphology which we attributed to antidromic action potentials resulting from a relatively central site of excitation. We also collected intracochlear ECAPs from twenty Nucleus 24 implant users. Compared with the feline ECAPs, the human potentials had smaller amplitudes and longer latencies. It is not clear what underlies these differences, although several factors are considered.

  17. Action currents, internodal potentials, and extracellular records of myelinated mammalian nerve fibers derived from node potentials.

    PubMed Central

    Marks, W B; Loeb, G E

    1976-01-01

    The potential distribution within the internodal axon of mammalian nerve fibers is derived by applying known node potential waveforms to the ends of an equivalent circuit model of the internode. The complete spatial/temporal profile of action potentials synthesized from the internodal profiles is used to compute the node current waveforn, and the extracellular action potential around fibers captured within a tubular electrode. For amphibia, the results agreed with empirical values. For mammals, the amplitude of the node currents plotted against conduction velocity was fitted by a straight line. The extracellular potential waveform depended on the location of the nodes within the tube. For tubes of length from 2 to 8 internodes, extracellular wave amplitude (mammals) was about one-third of the product of peak node current and tube resistance (center to ends). The extracellular potentials developed by longitudinal and radial currents in an anisotropic medium (fiber bundle) are compared. PMID:1276389

  18. Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents.

    PubMed

    Clarke, Stephen G; Scarnati, Matthew S; Paradiso, Kenneth G

    2016-11-09

    At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes.

  19. Electrotonic and action potentials in the Venus flytrap.

    PubMed

    Volkov, Alexander G; Vilfranc, Chrystelle L; Murphy, Veronica A; Mitchell, Colee M; Volkova, Maia I; O'Neal, Lawrence; Markin, Vladislav S

    2013-06-15

    The electrical phenomena and morphing structures in the Venus flytrap have attracted researchers since the nineteenth century. We have observed that mechanical stimulation of trigger hairs on the lobes of the Venus flytrap induces electrotonic potentials in the lower leaf. Electrostimulation of electrical circuits in the Venus flytrap can induce electrotonic potentials propagating along the upper and lower leaves. The instantaneous increase or decrease in voltage of stimulating potential generates a nonlinear electrical response in plant tissues. Any electrostimulation that is not instantaneous, such as sinusoidal or triangular functions, results in linear responses in the form of small electrotonic potentials. The amplitude and sign of electrotonic potentials depend on the polarity and the amplitude of the applied voltage. Electrical stimulation of the lower leaf induces electrical signals, which resemble action potentials, in the trap between the lobes and the midrib. The trap closes if the stimulating voltage is above the threshold level of 4.4V. Electrical responses in the Venus flytrap were analyzed and reproduced in the discrete electrical circuit. The information gained from this study can be used to elucidate the coupling of intracellular and intercellular communications in the form of electrical signals within plants.

  20. Early Repolarization Syndrome; Mechanistic Theories and Clinical Correlates

    PubMed Central

    Mercer, Ben N.; Begg, Gordon A.; Page, Stephen P.; Bennett, Christopher P.; Tayebjee, Muzahir H.; Mahida, Saagar

    2016-01-01

    The early repolarization (ER) pattern on the 12-lead electrocardiogram is characterized by J point elevation in the inferior and/or lateral leads. The ER pattern is associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Based on studies in animal models and genetic studies, it has been proposed that J point elevation in ER is a manifestation of augmented dispersion of repolarization which creates a substrate for ventricular arrhythmia. A competing theory regarding early repolarization syndrome (ERS) proposes that the syndrome arises as a consequence of abnormal depolarization. In recent years, multiple clinical studies have described the characteristics of ER patients with VF in more detail. The majority of these studies have provided evidence to support basic science observations. However, not all clinical observations correlate with basic science findings. This review will provide an overview of basic science and genetic research in ER and correlate basic science evidence with the clinical phenotype. PMID:27445855

  1. Small Conductance Calcium-Activated Potassium Current is Important in Transmural Repolarization of Failing Human Ventricles

    PubMed Central

    Yu, Chih-Chieh; Corr, Christopher; Shen, Changyu; Shelton, Richard; Yadava, Mrinal; Rhea, Isaac; Straka, Susan; Fishbein, Michael C.; Chen, Zhenhui; Lin, Shien-Fong; Lopshire, John C.; Chen, Peng-Sheng

    2015-01-01

    Background The transmural distribution of apamin-sensitive small conductance Ca2+-activated K+ (SK) current (IKAS) in failing human ventricles remains unclear. Methods and Results We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nM apamin administration in all wedges and after sequential administration of apamin, chromanol and E4031 in 4 wedges. Apamin prolonged APD from 363 ms [95% confidence interval (CI), 341 to 385] to 409 [CI, 385 to 434] (p<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s [CI, 30 to 42] to 32 cm/s [CI, 27 to 37] (p=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only one wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol and E4031 were 9.1% [CI, 3.9 to 14.2], 17.3% [CI, 3.1 to 31.5] and 35.9% [CI, 15.7 to 56.1], respectively. Immunohistochemical staining of subtype 2 of SK (SK2) protein showed increased expression in intercalated discs of myocytes. Conclusions SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant SK2 protein in the intercalated discs of myocytes. PMID:25908692

  2. MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

    PubMed Central

    Wystub, Katharina; Bachmann, Angela; Wietelmann, Astrid; Sasse, Philipp; Fleischmann, Bernd K.; Braun, Thomas; Boettger, Thomas

    2014-01-01

    The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart. PMID:25415383

  3. Uncertainty Propagation in Nerve Impulses Through the Action Potential Mechanism.

    PubMed

    Torres Valderrama, Aldemar; Witteveen, Jeroen; Navarro, Maria; Blom, Joke

    2015-12-01

    We investigate the propagation of probabilistic uncertainty through the action potential mechanism in nerve cells. Using the Hodgkin-Huxley (H-H) model and Stochastic Collocation on Sparse Grids, we obtain an accurate probabilistic interpretation of the deterministic dynamics of the transmembrane potential and gating variables. Using Sobol indices, out of the 11 uncertain parameters in the H-H model, we unravel two main uncertainty sources, which account for more than 90 % of the fluctuations in neuronal responses, and have a direct biophysical interpretation. We discuss how this interesting feature of the H-H model allows one to reduce greatly the probabilistic degrees of freedom in uncertainty quantification analyses, saving CPU time in numerical simulations and opening possibilities for probabilistic generalisation of other deterministic models of great importance in physiology and mathematical neuroscience.

  4. A web portal for in-silico action potential predictions

    PubMed Central

    Williams, Geoff; Mirams, Gary R.

    2015-01-01

    Introduction Multiple cardiac ion channels are prone to block by pharmaceutical compounds, and this can have large implications for cardiac safety. The effect of a compound on individual ion currents can now be measured in automated patch clamp screening assays. In-silico action potential models are proposed as one way of predicting the integrated compound effects on whole-cell electrophysiology, to provide an improved indication of pro-arrhythmic risk. Methods We have developed open source software to run cardiac electrophysiology simulations to predict the overall effect of compounds that block IKr, ICaL, INa, IKs, IK1 and Ito to varying degrees, using a choice of mathematical electrophysiology models. To enable safety pharmacology teams to run and evaluate these simulations easily, we have also developed an open source web portal interface to this simulator. Results The web portal can be found at https://chaste.cs.ox.ac.uk/ActionPotential. Users can enter details of compound affinities for ion channels in the form of IC50 or pIC50 values, run simulations, store the results for later retrieval, view summary graphs of the results, and export data to a spreadsheet format. Discussion This web portal provides a simple interface to reference versions of mathematical models, and well-tested state-of-the-art equation solvers. It provides safety teams easy access to the emerging technology of cardiac electrophysiology simulations for use in the drug-discovery process. PMID:25963830

  5. Flexible graphene transistors for recording cell action potentials

    NASA Astrophysics Data System (ADS)

    Blaschke, Benno M.; Lottner, Martin; Drieschner, Simon; Bonaccini Calia, Andrea; Stoiber, Karolina; Rousseau, Lionel; Lissourges, Gaëlle; Garrido, Jose A.

    2016-06-01

    Graphene solution-gated field-effect transistors (SGFETs) are a promising platform for the recording of cell action potentials due to the intrinsic high signal amplification of graphene transistors. In addition, graphene technology fulfills important key requirements for in-vivo applications, such as biocompability, mechanical flexibility, as well as ease of high density integration. In this paper we demonstrate the fabrication of flexible arrays of graphene SGFETs on polyimide, a biocompatible polymeric substrate. We investigate the transistor’s transconductance and intrinsic electronic noise which are key parameters for the device sensitivity, confirming that the obtained values are comparable to those of rigid graphene SGFETs. Furthermore, we show that the devices do not degrade during repeated bending and the transconductance, governed by the electronic properties of graphene, is unaffected by bending. After cell culture, we demonstrate the recording of cell action potentials from cardiomyocyte-like cells with a high signal-to-noise ratio that is higher or comparable to competing state of the art technologies. Our results highlight the great capabilities of flexible graphene SGFETs in bioelectronics, providing a solid foundation for in-vivo experiments and, eventually, for graphene-based neuroprosthetics.

  6. Click- and chirp-evoked human compound action potentials.

    PubMed

    Chertoff, Mark; Lichtenhan, Jeffery; Willis, Marie

    2010-05-01

    In the experiments reported here, the amplitude and the latency of human compound action potentials (CAPs) evoked from a chirp stimulus are compared to those evoked from a traditional click stimulus. The chirp stimulus was created with a frequency sweep to compensate for basilar membrane traveling wave delay using the O-Chirp equations from Fobel and Dau [(2004). J. Acoust. Soc. Am. 116, 2213-2222] derived from otoacoustic emission data. Human cochlear traveling wave delay estimates were obtained from derived compound band action potentials provided by Eggermont [(1979). J. Acoust. Soc. Am. 65, 463-470]. CAPs were recorded from an electrode placed on the tympanic membrane (TM), and the acoustic signals were monitored with a probe tube microphone attached to the TM electrode. Results showed that the amplitude and latency of chirp-evoked N1 of the CAP differed from click-evoked CAPs in several regards. For the chirp-evoked CAP, the N1 amplitude was significantly larger than the click-evoked N1s. The latency-intensity function was significantly shallower for chirp-evoked CAPs as compared to click-evoked CAPs. This suggests that auditory nerve fibers respond with more unison to a chirp stimulus than to a click stimulus.

  7. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell.

    PubMed

    Liu, D W; Antzelevitch, C

    1995-03-01

    Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch-clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358 +/- 16 (mean +/- SEM), 262 +/- 12, and 287 +/- 11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode's solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was conducted in a Na(+)-, K(+)-, and Ca(2+)-free bath solution to isolate the slowly activating component of the delayed rectifier (IKs) from the rapidly activating component (IKr). IKs was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -20 mV, IKs tail current density was 1.99 +/- 0.30 pA/pF (mean +/- SEM) in epicardial cells, 1.83 +/- 0.18 pA/pF in endocardial cells, and 0.92 +/- 0.14 pA/pF in M cells. Voltage dependence and time course of activation and deactivation of IKs were similar in the three cell types. The relative contribution of IKr and IKs among the three cell types was examined by using 6 mmol/L [K+]o Tyrode's solution with and without E-4031, a highly selective blocker of IKr. An E-4031-sensitive current was observed in the presence but not in the absence of extracellular K+. This rapidly activating component showed characteristics similar to those of IKr as described in rabbit and cat

  8. The Potential of Deweyan-Inspired Action Research

    ERIC Educational Resources Information Center

    Stark, Jody L.

    2014-01-01

    In its broadest sense, pragmatism could be said to be the philosophical orientation of all action research. Action research is characterized by research, action, and participation grounded in democratic principles and guided by the aim of social improvement. Furthermore, action research is an active process of inquiry that does not admit…

  9. Narrow and wide field amacrine cells fire action potentials in response to depolarization and light stimulation.

    PubMed

    Heflin, Stephanie J; Cook, Paul B

    2007-01-01

    Action potentials in amacrine cells are important for lateral propagation of signals across the inner retina, but it is unclear how many subclasses of amacrine cells contain voltage-gated sodium channels or can fire action potentials. This study investigated the ability of amacrine cells with narrow ( <200 microm) and wide (>200 microm) dendritic fields to fire action potentials in response to depolarizing current injections and light stimulation. The pattern of action potentials evoked by current injections revealed two distinct classes of amacrine cells; those that responded with a single action potential (single-spiking cells) and those that responded with repetitive action potentials (repetitive-spiking cells). Repetitive-spiking cells differed from single-spiking cells in several regards: Repetitive-spiking cells were more often wide field cells, while single-spiking cells were more often narrow field cells. Repetitive-spiking cells had larger action potential amplitudes, larger peak voltage-gated NaV currents lower action potential thresholds, and needed less current to induce action potentials. However, there was no difference in the input resistance, holding current or time constant of these two classes of cells. The intrinsic capacity to fire action potentials was mirrored in responses to light stimulation; single-spiking amacrine cells infrequently fired action potentials to light steps, while repetitive-spiking amacrine cells frequently fired numerous action potentials. These results indicate that there are two physiologically distinct classes of amacrine cells based on the intrinsic capacity to fire action potentials.

  10. BK and Kv3.1 potassium channels control different aspects of deep cerebellar nuclear neurons action potentials and spiking activity.

    PubMed

    Pedroarena, Christine M

    2011-12-01

    Deep cerebellar nuclear neurons (DCNs) display characteristic electrical properties, including spontaneous spiking and the ability to discharge narrow spikes at high frequency. These properties are thought to be relevant to processing inhibitory Purkinje cell input and transferring well-timed signals to cerebellar targets. Yet, the underlying ionic mechanisms are not completely understood. BK and Kv3.1 potassium channels subserve similar functions in spike repolarization and fast firing in many neurons and are both highly expressed in DCNs. Here, their role in the abovementioned spiking characteristics was addressed using whole-cell recordings of large and small putative-glutamatergic DCNs. Selective BK channel block depolarized DCNs of both groups and increased spontaneous firing rate but scarcely affected evoked activity. After adjusting the membrane potential to control levels, the spike waveforms under BK channel block were indistinguishable from control ones, indicating no significant BK channel involvement in spike repolarization. The increased firing rate suggests that lack of DCN-BK channels may have contributed to the ataxic phenotype previously found in BK channel-deficient mice. On the other hand, block of Kv3.1 channels with low doses of 4-aminopyridine (20 μM) hindered spike repolarization and severely depressed evoked fast firing. Therefore, I propose that despite similar characteristics of BK and Kv3.1 channels, they play different roles in DCNs: BK channels control almost exclusively spontaneous firing rate, whereas DCN-Kv3.1 channels dominate the spike repolarization and enable fast firing. Interestingly, after Kv3.1 channel block, BK channels gained a role in spike repolarization, demonstrating how the different function of each of the two channels is determined in part by their co-expression and interplay.

  11. Atrial cell action potential parameter fitting using genetic algorithms.

    PubMed

    Syed, Z; Vigmond, E; Nattel, S; Leon, L J

    2005-09-01

    Understanding of the considerable variation in action potential (AP) shape throughout the heart is necessary to explain normal and pathological cardiac function. Existing mathematical models reproduce typical APs, but not all measured APs, as fitting the sets of non-linear equations is a tedious process. The study describes the integration of a pre-existing mathematical model of an atrial cell AP with a genetic algorithm to provide an automated tool to generate APs for arbitrary cells by fitting ionic channel conductances. Using the Nygren model as the base, the technique was first verified by starting with random values and fitting the Nygren model to itself with an error of only 0.03%. The Courtemanche model, which has a different morphology from that of the Nygren model, was successfully fitted. The AP duration restitution curve generated by the fit matched that of the target model very well. Finally, experimentally recorded APs were reproduced. To match AP duration restitution behaviour properly, it was necessary simultaneously to fit over several stimulation frequencies. Also, fitting of the upstroke was better if the stimulating current pulse replicated that found in situ as opposed to a rectangular pulse. In conclusion, the modelled parameters were successfully able to reproduce any given atrial AP. This tool can be useful for determining parameters in new AP models, reproducing specific APs, as well as determining the locus of drug action by examining changes in conductance values.

  12. Temperature dependence of action potential parameters in Aplysia neurons.

    PubMed

    Hyun, Nam Gyu; Hyun, Kwang-Ho; Lee, Kyungmin; Kaang, Bong-Kiun

    2012-01-01

    Although the effects of temperature changes on the activity of neurons have been studied in Aplysia, the reproducibility of the temperature dependence of the action potential (AP) parameters has not been verified. To this end, we performed experiments using Aplysia neurons. Fourteen AP parameters were analyzed using the long-term data series recorded during the experiments. Our analysis showed that nine of the AP parameters decreased as the temperature increased: the AP amplitude (A(AP)), membrane potential at the positive peak (V(pp)), interspike interval, first half (Δt(r1)) and last half (Δt(r2)) of the temperature rising phase, first half (Δt(f1)) and last half (Δt(f2)) of the temperature falling phase, AP (Δt(AP, 1/2)), and differentiated signal (Δt(DS, 1/2)) half-width durations. Five of the AP parameters increased with temperature: the differentiated signal amplitude (A(DS)), absolute value of the membrane potential at negative peak (|V(np)|), absolute value of the maximum slope of the AP during the temperature rising (|-MSR|) and falling (|MSF|) phases, and spiking frequency (Frequency). This work could provide the basis for a better understanding of the elementary processes underlying the temperature-dependent neuronal activity in Aplysia.

  13. Mice with cardiac overexpression of PPARγ have impaired repolarization and spontaneous fatal ventricular arrhythmias (Morrow, PPARγ overexpression induces fatal arrhythmias)

    PubMed Central

    Morrow, John P.; Katchman, Alexander; Son, Ni-Huiping; Trent, Chad M.; Khan, Raffay; Shiomi, Takayuki; Huang, Haiyan; Amin, Vaibhav; Lader, Joshua M.; Vasquez, Carolina; Morley, Gregory E.; D'Armiento, Jeanine; Homma, Shunichi; Goldberg, Ira J.; Marx, Steven O.

    2011-01-01

    Background Diabetes and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electrical properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation versus the contribution of global metabolic defects to the increased incidence of sudden death and electrical abnormalities. Methods and Results In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes and obesity, we studied cardiac-specific transgenic mice expressing PPARγ1 via the cardiac α-myosin heavy-chain promoter. The PPARγ-transgenic mice develop abnormal accumulation of intracellular lipids and die as young adults, prior to a significant reduction in systolic function. Using implantable ECG telemeters, we found that these mice have prolongation of the QRS and QT intervals, and spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillation. Isolated cardiomyocytes demonstrated prolonged action potential duration caused by reduced expression and function of the potassium channels responsible for repolarization. Short-term exposure to pioglitazone, a PPARγ agonist, had no effect on mortality or rhythm in WT mice, but further exacerbated the arrhythmic phenotype and increased the mortality in the PPARγ TG mice. Conclusions Our findings support an important link between PPARγ activation, cardiomyocyte lipid accumulation, ion channel remodeling and increased cardiac mortality. PMID:22124376

  14. Regulation of Ca2+ and electrical alternans in cardiac myocytes: Role of CaMKII and repolarizing currents

    PubMed Central

    Livshitz, Leonid M.; Rudy, Yoram

    2007-01-01

    Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca2+ transient (CaT). Because of experimental difficulty in independently controlling the Ca2+ and electrical subsystems, mathematical modelling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1. (I) CaT alternans results from refractoriness of the SR Ca2+ release system; alternation of the L-type calcium current (ICa(L)) has a negligible effect; (II) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger (INaCa) and underlies APD alternans; (III) Increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; (IV). Increase of the rapid delayed rectifier current (IKr) also suppresses APD alternans, but without suppressing CaT alternans. Thus, CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans), while IKr enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and IKr enhancement as a possible antiar-rhythmic intervention. PMID:17277017

  15. Potential anti-inflammatory actions of the elmiric (lipoamino) acids

    PubMed Central

    Burstein, Sumner H.; Adams, Jeffrey K.; Bradshaw, Heather B.; Fraioli, Cristian; Rossetti, Ronald G.; Salmonsen, Rebecca A.; Shaw, John W.; Walker, J. Michael; Zipkin, Robert E.; Zurier, Robert B.

    2007-01-01

    A library of amino acid-fatty acid conjugates (elmiric acids) was synthesized and evaluated for activity as potential anti-inflammatory agents. The compounds were tested in vitro for their effects on cell proliferation and prostaglandin production and compared with their effects on in vivo models of inflammation. LPS stimulated RAW 267.4 mouse macrophage cells was the in vitro model and phorbol ester-induced mouse ear edema served as the principal in vivo model. The prostaglandin responses were found to be strongly dependent on the nature of the fatty acid part of the molecule. Polyunsaturated acid conjugates produced a marked increase in media levels of i15-deoxy-PGJ2 with minimal effects on PGE production. It is reported in the literature that prostaglandin ratios in which the J series predominates over the E series promote the resolution of inflammatory conditions. Several of the elmiric acids tested here produced such favorable ratios suggesting that their potential anti-inflammatory activity occurs via a novel mechanism of action. The ear edema assay results were generally in agreement with the prostaglandin assay findings indicating a connection between them. PMID:17383881

  16. Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers.

    PubMed

    Pedersen, Thomas Holm; de Paoli, Frank Vincenzo; de Paoli, Frank Vinzenco; Flatman, John A; Nielsen, Ole Baekgaard

    2009-10-01

    Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers covers membrane conductances for K(+) (G(K)) and Cl(-) (G(Cl)). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of G(K) and G(Cl) to inversely interfere with muscle excitability. However, whether regulation of G(K) and G(Cl) occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of G(Cl) and G(K) with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of G(m) in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in G(Cl) of approximately 70% caused G(m) to decline by approximately 55% in a manner that is well described by a single exponential function characterized by a time constant of approximately 200 APs (phase 1). When stimulation was continued beyond approximately 1,800 APs, synchronized elevations in G(K) ( approximately 14-fold) and G(Cl) ( approximately 3-fold) caused G(m) to rise sigmoidally to approximately 400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, G(m) recovered to its level before AP firing in approximately 1 min. Experiments with glibenclamide (K(ATP) channel inhibitor) and 9-anthracene carboxylic acid (ClC-1 Cl(-) channel inhibitor) revealed that the decreased G(m) during phase 1 reflected ClC-1 channel inhibition, whereas the massively elevated G(m) during phase 2 reflected synchronized openings of ClC-1 and K(ATP) channels. In conclusion, G(Cl) and G(K) are acutely regulated in AP

  17. Metabolic Energy of Action Potentials Modulated by Spike Frequency Adaptation

    PubMed Central

    Yi, Guo-Sheng; Wang, Jiang; Li, Hui-Yan; Wei, Xi-Le; Deng, Bin

    2016-01-01

    Spike frequency adaptation (SFA) exists in many types of neurons, which has been demonstrated to improve their abilities to process incoming information by synapses. The major carrier used by a neuron to convey synaptic signals is the sequences of action potentials (APs), which have to consume substantial metabolic energies to initiate and propagate. Here we use conductance-based models to investigate how SFA modulates the AP-related energy of neurons. The SFA is attributed to either calcium-activated K+ (IAHP) or voltage-activated K+ (IM) current. We observe that the activation of IAHP or IM increases the Na+ load used for depolarizing membrane, while produces few effects on the falling phase of AP. Then, the metabolic energy involved in Na+ current significantly increases from one AP to the next, while for K+ current it is less affected. As a consequence, the total energy cost by each AP gets larger as firing rate decays down. It is also shown that the minimum Na+ charge needed for the depolarization of each AP is unaffected during the course of SFA. This indicates that the activation of either adaptation current makes APs become less efficient to use Na+ influx for their depolarization. Further, our simulations demonstrate that the different biophysical properties of IM and IAHP result in distinct modulations of metabolic energy usage for APs. These investigations provide a fundamental link between adaptation currents and neuronal energetics, which could facilitate to interpret how SFA participates in neuronal information processing. PMID:27909394

  18. Steroid inhibitors of androgen-potentiated actions on skin.

    PubMed

    Ebling, F J; Randall, V A

    1983-07-01

    Antiandrogens, such as cyproterone acetate, and oestrogens both inhibit sebaceous secretion in rats and have a potentiality for the treatment of hirsutism and acne in the human female. However, they act at different points. In castrated rats treated with testosterone, 3 micrograms/day oestradiol produced a greater decrease in sebum secretion than a dose of cyproterone acetate over 1000 times larger; moreover the antiandrogen reduced the incidence of sebaceous mitoses whereas the oestradiol did not. In hirsute women, oral administration of 100 mg of cyproterone acetate daily caused a 40% reduction in sebum secretion within 10 days; a further 20% was subsequently produced by combined therapy with cyproterone acetate and ethinyloestradiol. Significant decreases in the diameter and rate of growth of thigh hairs were not established until around the fourth monthly cycle of treatment. The actions were believed to be mainly peripheral, though contributory factors could also have been the small but significant reductions in plasma androgens produced by the antiandrogen, and the marked rise in sex hormone binding globulin produced by the oestrogen. That it is theoretically possible for cyproterone acetate or oestradiol to act locally follows from an unequivocal demonstration that either compound produced a local depression of sebum secretion when applied topically to rats.

  19. Short latency compound action potentials from mammalian gravity receptor organs

    NASA Technical Reports Server (NTRS)

    Jones, T. A.; Jones, S. M.

    1999-01-01

    Gravity receptor function was characterized in four mammalian species using far-field vestibular evoked potentials (VsEPs). VsEPs are compound action potentials of the vestibular nerve and central relays that are elicited by linear acceleration ramps applied to the cranium. Rats, mice, guinea pigs, and gerbils were studied. In all species, response onset occurred within 1.5 ms of the stimulus onset. Responses persisted during intense (116 dBSPL) wide-band (50 to 50 inverted question mark omitted inverted question mark000 Hz) forward masking, whereas auditory responses to intense clicks (112 dBpeSPL) were eliminated under the same conditions. VsEPs remained after cochlear extirpation but were eliminated following bilateral labyrinthectomy. Responses included a series of positive and negative peaks that occurred within 8 ms of stimulus onset (range of means at +6 dBre: 1.0 g/ms: P1=908 to 1062 micros, N1=1342 to 1475 micros, P2=1632 to 1952 micros, N2=2038 to 2387 micros). Mean response amplitudes at +6 dBre: 1.0 g/ms ranged from 0.14 to 0.99 microV. VsEP input/output functions revealed latency slopes that varied across peaks and species ranging from -19 to -51 micros/dB. Amplitude-intensity slopes also varied ranging from 0.04 to 0.08 microV/dB for rats and mice. Latency values were comparable to those of birds although amplitudes were substantially smaller in mammals. VsEP threshold values were considerably higher in mammals compared to birds and ranged from -8.1 to -10.5 dBre 1.0 g/ms across species. These results support the hypothesis that mammalian gravity receptors are less sensitive to dynamic stimuli than are those of birds.

  20. Effects of troglitazone and pioglitazone on the action potentials and membrane currents of rabbit ventricular myocytes.

    PubMed

    Ikeda, S; Watanabe, T

    1998-09-18

    The effects of the antidiabetic thiazolidinediones troglitazone and pioglitazone on action potentials and membrane currents were studied in rabbit ventricular myocytes. Troglitazone (10 microM) reversibly reduced excitability of the myocytes and modified their action potential configuration. It significantly increased the stimulation threshold required to elicit action potentials and decreased action potential amplitude and the maximum upstroke velocity of the action potentials. The Inhibition of the maximum upstroke velocity by troglitazone was also significant at 1 microM. Voltage-clamp experiments revealed that troglitazone (10 microM) reversibly inhibited both the slow inward Ca2+ current and the steady-state K+ current. In contrast to troglitazone, pioglitazone (1-10 microM) had no significant effect on the excitability, action potential configuration, or membrane currents of myocytes. These results suggest that troglitazone, but not pioglitazone, modulates Na+, Ca2+ and K+ currents, leading to the changes in excitability and action potential configuration of ventricular myocytes.

  1. The multiple electrocardiographic manifestations of ventricular repolarization memory.

    PubMed

    Chiale, Pablo A; Etcheverry, Daniel; Pastori, Julio D; Fernandez, Pablo A; Garro, Hugo A; González, Mario D; Elizari, Marcelo V

    2014-08-01

    T wave "memory" is a peculiar variety of cardiac remodeling caused by a transient change in the course of ventricular depolarization (due to ventricular pacing, rate-dependent intraventricular block, ventricular preexcitation or tachyarrhythmias with wide QRS complexes). It is usually manifested by inverted T waves that appears when normal ventricular activation is restored. This phenomenon is cumulative and occurs earlier if the ventricular myocardium has previously been exposed to the same conditioning stimuli. In this article the different conditions giving rise to "classical" T wave memory development are reviewed and also "another" type of T wave memory is described. It is also shown that cardiac memory may induce not only negative (pseudo-primary) T waves but also a reversal of primary and pseudoprimary T waves leading to "normalization" of ventricular repolarization. The knowledge of these dissimilar consequences of T wave memory is essential to assess the characteristics of ventricular repolarization.

  2. Development of action potentials and apamin-sensitive after-potentials in mouse vestibular nucleus neurones.

    PubMed

    Dutia, M B; Johnston, A R

    1998-01-01

    The postnatal maturation of medial vestibular nucleus (MVN) neurones was examined in slices of the dorsal brainstem prepared from balb/c mice at specific stages during the first postnatal month. Using spike-shape averaging to analyse the intracellularly recorded action potentials and after-hyperpolarizations (AHPs) in each cell, all the MVN neurones recorded in the young adult (postnatal day 30; P30) mouse were shown to have either a single deep AHP (type A cells), or an early fast and a delayed slow AHP (type B cells). The relative proportions of the two subtypes were similar to those in the young adult rat. At P5, all the MVN cells recorded showed immature forms of either the type A or the type B action potential shape. Immature type A cells had broad spontaneous spikes, and the characteristic single AHP was small in amplitude. Immature type B cells had somewhat narrower spontaneous spikes that were followed by a delayed, apamin-sensitive AHP. The delayed AHP was separated from the repolarisation phase of the spike by a period of isopotentiality. Over the period P10-P15, the mean resting potentials of the MVN cells became more negative, their action potential fall-times became shorter, the single AHP in type A cells became deeper, and the early fast AHP appeared in type B cells. Until P15 cells of varying degrees of electrophysiological maturity were found in the MVN but by P30 all MVN cells recorded were typical adult type A or type B cells. Exposure to the selective blocker of SK-type Ca-activated K channels, apamin (0.3 microM), induced depolarising plateaux and burst firing in immature type B cells at rest. The duration of the apamin-induced bursts and the spike frequency during the bursts were reduced but not abolished after blockade of Ca channels in Ca-free artificial cerebrospinal fluid containing Cd2+. By contrast, in mature type B cells at rest apamin selectively abolished the delayed slow AHP but did not induce bursting activity. Apamin had no effect

  3. Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation.

    PubMed

    Grill, Warren M; Cantrell, Meredith B; Robertson, Matthew S

    2008-02-01

    Electrical stimulation of the central nervous system creates both orthodromically propagating action potentials, by stimulation of local cells and passing axons, and antidromically propagating action potentials, by stimulation of presynaptic axons and terminals. Our aim was to understand how antidromic action potentials navigate through complex arborizations, such as those of thalamic and basal ganglia afferents-sites of electrical activation during deep brain stimulation. We developed computational models to study the propagation of antidromic action potentials past the bifurcation in branched axons. In both unmyelinated and myelinated branched axons, when the diameters of each axon branch remained under a specific threshold (set by the antidromic geometric ratio), antidromic propagation occurred robustly; action potentials traveled both antidromically into the primary segment as well as "re-orthodromically" into the terminal secondary segment. Propagation occurred across a broad range of stimulation frequencies, axon segment geometries, and concentrations of extracellular potassium, but was strongly dependent on the geometry of the node of Ranvier at the axonal bifurcation. Thus, antidromic activation of axon terminals can, through axon collaterals, lead to widespread activation or inhibition of targets remote from the site of stimulation. These effects should be included when interpreting the results of functional imaging or evoked potential studies on the mechanisms of action of DBS.

  4. The impact of synaptic conductance on action potential waveform: evoking realistic action potentials with a simulated synaptic conductance.

    PubMed

    Johnston, Jamie; Postlethwaite, Michael; Forsythe, Ian D

    2009-10-15

    Most current clamp studies trigger action potentials (APs) by step current injection through the recording electrode and assume that the resulting APs are essentially identical to those triggered by orthodromic synaptic inputs. However this assumption is not always valid, particularly when the synaptic conductance is of large magnitude and of close proximity to the axon initial segment. We addressed this question of similarity using the Calyx of Held/MNTB synapse; we compared APs evoked by long duration step current injections, short step current injections and orthodromic synaptic stimuli. Neither injected current protocol evoked APs that matched the evoked orthodromic AP waveform, showing differences in AP height, half-width and after-hyperpolarization. We postulated that this 'error' could arise from changes in the instantaneous conductance during the combined synaptic and AP waveforms, since the driving forces for the respective ionic currents are integrating and continually evolving over this time-course. We demonstrate that a simple Ohm's law manipulation of the EPSC waveform, which accounts for the evolving driving force on the synaptic conductance during the AP, produces waveforms that closely mimic those generated by physiological synaptic stimulation. This stimulation paradigm allows supra-threshold physiological stimulation (single stimuli or trains) without the variability caused by quantal fluctuation in transmitter release, and can be implemented without a specialised dynamic clamp system. Combined with pharmacological tools this method provides a reliable means to assess the physiological roles of postsynaptic ion channels without confounding affects from the presynaptic input.

  5. Differential effects of K(+) channel blockers on frequency-dependent action potential broadening in supraoptic neurons.

    PubMed

    Hlubek, M D; Cobbett, P

    2000-09-15

    Recordings were made from magnocellular neuroendocrine cells dissociated from the supraoptic nucleus of the adult guinea pig to determine the role of voltage gated K(+) channels in controlling the duration of action potentials and in mediating frequency-dependent action potential broadening exhibited by these neurons. The K(+) channel blockers charybdotoxin (ChTx), tetraethylammonium (TEA), and 4-aminopyridine (4-AP) increased the duration of individual action potentials indicating that multiple types of K(+) channel are important in controlling action potential duration. The effect of these K(+) channel blockers was almost completely reversed by simultaneous blockade of voltage gated Ca(2+) channels with Cd(2+). Frequency-dependent action potential broadening was exhibited by these neurons during trains of action potentials elicited by membrane depolarizing current pulses presented at 10 Hz but not at 1 Hz. 4-AP but not ChTx or TEA inhibited frequency-dependent action potential broadening indicating that frequency-dependent action potential broadening is dependent on increasing steady-state inactivation of A-type K(+) channels (which are blocked by 4-AP). A model of differential contributions of voltage gated K(+) channels and voltage gated Ca(2+) channels to frequency-dependent action potential broadening, in which an increase of Ca(2+) current during each successive action potential is permitted as a result of the increasing steady-state inactivation of A-type K(+) channels, is presented.

  6. Evaluation of inhomogeneities of repolarization in patients with psoriasis vulgaris

    PubMed Central

    İnci, Sinan; Aksan, Gökhan; Nar, Gökay; Yüksel, Esra Pancar; Ocal, Hande Serra; Çapraz, Mustafa; Yüksel, Serkan; Şahin, Mahmut

    2016-01-01

    Introduction The arrhythmia potential has not been investigated adequately in psoriatic patients. In this study, we assessed the ventricular repolarization dispersion, using the Tp-e interval and the Tp-e/QT ratio, and investigated the association with inflammation. Material and methods Seventy-one psoriasis vulgaris patients and 70 age- and gender-matched healthy individuals were enrolled in the study. The severity of the disease was calculated using Psoriasis Area and Severity Index scoring. The QTd was defined as the difference between the maximum and minimum QT intervals. The Tp-e interval was defined as the interval from the peak of the T wave to the end of the T wave. The Tp-e interval was corrected for heart rate. The Tp-e/QT ratio was calculated using these measurements. Results There were no significant differences between the groups with respect to basal clinical and laboratory characteristics (p > 0.05). The Tp-e interval, the corrected Tp-e interval (cTp-e) and the Tp-e/QT ratio were also significantly higher in psoriasis patients compared to the control group (78.5 ±8.0 ms vs. 71.4 ±7.6 ms, p < 0.001, 86.3 ±13.2 ms vs. 77.6 ±9.0 ms, p < 0.001 and 0.21 ±0.02 vs. 0.19 ±0.02, p < 0.001 respectively). A significant correlation was detected between the cTp-e time and the Tp-e/QT ratio and the PASI score in the group of psoriatic patients (r = 0.51, p < 0.001; r = 0.59, p < 0.001, respectively). Conclusions In our study, we detected a significant increase in the Tp-e interval and the Tp-e/QT ratio in patients with psoriasis vulgaris. The Tp-e interval and the Tp-e/QT ratio may be predictors for ventricular arrhythmias in patients with psoriasis vulgaris. PMID:27904512

  7. Coronary Artery Disease Alters Ventricular Repolarization Dynamics in Type 2 Diabetes

    NASA Technical Reports Server (NTRS)

    Vrtovec, Bojan; Sinkovec, Matjaz; Starc, Vito; Radovancevic, Branislav; Schlegel, Todd T.

    2005-01-01

    Ventricular repolarization dynamics (VRD) is an important predictor of outcome in diabetes. We examined the potential impact of coronary artery disease (CAD) on VRD in type 2 diabetic patients. We recorded 5-min high-resolution resting electrocardiograms (ECG) in 38 diabetic patients undergoing elective coronary angiography, and in 38 age- and gender- matched apparently healthy subjects (Controls). Using leads I and II, time-domain indices of VRD were calculated. Coronary angiography was regarded as positive if a 350% stenosis was found. Angiography was positive in 21 diabetic patients (55%). Patients with CAD had a significantly higher degree of VRD than Controls (SDNN(QT): 15.81+/-7.22 ms vs. 8.94+/-6.04 ms; P <0.001, rMSSD(QT): 21.02k7.07 ms vs. 11.18k7.45 ms; P <0.001). VRD in diabetic patients with negative angiograms did not differ from VRD in Controls (SDNN(QT): 8.94+/-6.04 ms vs. 7.44+/-5.72 ms; P=0.67, rMSSD(QT): 11.18+/-7.45 ms vs. 10.22+/-5.35 ms; P=O. 82). CAD increases VRD in patients with type 2 diabetes. Therefore, changes in ventricular repolarization in diabetic patients may be due to silent CAD rather than to diabetes per se.

  8. Characteristics of single large-conductance Ca2+-activated K+ channels and their regulation of action potentials and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus.

    PubMed

    Lin, Min; Hatcher, Jeff T; Wurster, Robert D; Chen, Qin-Hui; Cheng, Zixi Jack

    2014-01-15

    Large-conductance Ca2(+)-activated K+ channels (BK) regulate action potential (AP) properties and excitability in many central neurons. However, the properties and functional roles of BK channels in parasympathetic cardiac motoneurons (PCMNs) in the nucleus ambiguus (NA) have not yet been well characterized. In this study, the tracer X-rhodamine-5 (and 6)-isothiocyanate (XRITC) was injected into the pericardial sac to retrogradely label PCMNs in FVB mice at postnatal 7-9 days. Two days later, XRITC-labeled PCMNs in brain stem slices were identified. Using excised patch single-channel recordings, we identified voltage-gated and Ca(2+)-dependent BK channels in PCMNs. The majority of BK channels exhibited persistent channel opening during voltage holding. These BK channels had a conductance of 237 pS and a 50% opening probability at +27.9 mV, the channel open time constant was 3.37 ms at +20 mV, and dwell time increased exponentially as the membrane potential depolarized. At the +20-mV holding potential, the [Ca2+]50 was 15.2 μM with a P0.5 of 0.4. Occasionally, some BK channels showed a transient channel opening and fast inactivation. Using whole cell voltage clamp, we found that BK channel mediated outward currents and afterhyperpolarization currents (IAHP). Using whole cell current clamp, we found that application of BK channel blocker iberiotoxin (IBTX) increased spike half-width and suppressed fast afterhyperpolarization (fAHP) amplitude following single APs. In addition, IBTX application increased spike half-width and reduced the spike frequency-dependent AP broadening in trains and spike frequency adaption (SFA). Furthermore, BK channel blockade decreased spike frequency. Collectively, these results demonstrate that PCMNs have BK channels that significantly regulate AP repolarization, fAHP, SFA, and spike frequency. We conclude that activation of BK channels underlies one of the mechanisms for facilitation of PCMN excitability.

  9. Characteristics of single large-conductance Ca2+-activated K+ channels and their regulation of action potentials and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus

    PubMed Central

    Lin, Min; Hatcher, Jeff T.; Wurster, Robert D.; Chen, Qin-Hui

    2013-01-01

    Large-conductance Ca2+-activated K+ channels (BK) regulate action potential (AP) properties and excitability in many central neurons. However, the properties and functional roles of BK channels in parasympathetic cardiac motoneurons (PCMNs) in the nucleus ambiguus (NA) have not yet been well characterized. In this study, the tracer X-rhodamine-5 (and 6)-isothiocyanate (XRITC) was injected into the pericardial sac to retrogradely label PCMNs in FVB mice at postnatal 7–9 days. Two days later, XRITC-labeled PCMNs in brain stem slices were identified. Using excised patch single-channel recordings, we identified voltage-gated and Ca2+-dependent BK channels in PCMNs. The majority of BK channels exhibited persistent channel opening during voltage holding. These BK channels had a conductance of 237 pS and a 50% opening probability at +27.9 mV, the channel open time constant was 3.37 ms at +20 mV, and dwell time increased exponentially as the membrane potential depolarized. At the +20-mV holding potential, the [Ca2+]50 was 15.2 μM with a P0.5 of 0.4. Occasionally, some BK channels showed a transient channel opening and fast inactivation. Using whole cell voltage clamp, we found that BK channel mediated outward currents and afterhyperpolarization currents (IAHP). Using whole cell current clamp, we found that application of BK channel blocker iberiotoxin (IBTX) increased spike half-width and suppressed fast afterhyperpolarization (fAHP) amplitude following single APs. In addition, IBTX application increased spike half-width and reduced the spike frequency-dependent AP broadening in trains and spike frequency adaption (SFA). Furthermore, BK channel blockade decreased spike frequency. Collectively, these results demonstrate that PCMNs have BK channels that significantly regulate AP repolarization, fAHP, SFA, and spike frequency. We conclude that activation of BK channels underlies one of the mechanisms for facilitation of PCMN excitability. PMID:24196530

  10. Differential regulation of action potential firing in adult murine thalamocortical neurons by Kv3.2, Kv1, and SK potassium and N-type calcium channels

    PubMed Central

    Kasten, Michael R; Rudy, Bernardo; Anderson, Matthew P

    2007-01-01

    Sensory signals of widely differing dynamic range and intensity are transformed into a common firing rate code by thalamocortical neurons. While a great deal is known about the ionic currents, far less is known about the specific channel subtypes regulating thalamic firing rates. We hypothesized that different K+ and Ca2+ channel subtypes control different stimulus–response curve properties. To define the channels, we measured firing rate while pharmacologically or genetically modulating specific channel subtypes. Inhibiting Kv3.2 K+ channels strongly suppressed maximum firing rate by impairing membrane potential repolarization, while playing no role in the firing response to threshold stimuli. By contrast, inhibiting Kv1 channels with α-dendrotoxin or maurotoxin strongly increased firing rates to threshold stimuli by reducing the membrane potential where action potentials fire (Vth). Inhibiting SK Ca2+-activated K+ channels with apamin robustly increased gain (slope of the stimulus–response curve) and maximum firing rate, with minimum effects on threshold responses. Inhibiting N-type Ca2+ channels with ω-conotoxin GVIA or ω-conotoxin MVIIC partially mimicked apamin, while inhibiting L-type and P/Q-type Ca2+ channels had small or no effects. EPSC-like current injections closely mimicked the results from tonic currents. Our results show that Kv3.2, Kv1, SK potassium and N-type calcium channels strongly regulate thalamic relay neuron sensory transmission and that each channel subtype controls a different stimulus–response curve property. Differential regulation of threshold, gain and maximum firing rate may help vary the stimulus–response properties across and within thalamic nuclei, normalize responses to diverse sensory inputs, and underlie sensory perception disorders. PMID:17761775

  11. Ontogeny of Vestibular Compound Action Potentials in the Domestic Chicken

    PubMed Central

    M. Jones, Sherri

    2000-01-01

    Compound action potentials of the vestibular nerve were measured from the surface of the scalp in 148 chickens (Gallus domesticus). Ages ranged from incubation day 18 (E18) to 22 days posthatch (P22). Responses were elicited using linear acceleration cranial pulses. Response thresholds decreased at an average rate of –0.45 dB/day. The decrease was best fit by an exponential model with half-maturity time constant of 5.1 days and asymptote of approximately –25.9 dB re:1.0 g/ms. Mean threshold approached within 3 dB of the asymptote by ages P6–P9. Similarly, response latencies decreased exponentially to within 3% of mature values at ages beyond P9. The half-maturity time constant for peripheral response peak latencies P1, N1, and P2 was comparable to thresholds and ranged from approximately 4.6 to 6.2 days, whereas central peaks (N2, P3, and N3) ranged from 2.9 to 3.4 days. Latency-intensity slopes for P1, N1, and P2 tended to decrease with age, reaching mature values within approximately 100 hours of hatching. Amplitudes increased as a function of age with average growth rates for response peaks ranging from 0.04 to 0.09 μV/day. There was no obvious asymptote to the growth of amplitudes over the ages studied. Amplitude-intensity slopes also increased modestly with age. The results show that gravity receptors are responsive to transient cranial stimuli as early as E19 in the chicken embryo. The functional response of gravity receptors continues to develop for many days after all major morphological structures are in place. Distinct maturational processes can be identified in central and peripheral neural relays. Functional improvements during maturation may result from refinements in the receptor epithelia, improvements in central and peripheral synaptic transmission, increased neural myelination, as well as changes in the mechanical coupling between the cranium and receptor organ. PMID:11545229

  12. Ontogeny of vestibular compound action potentials in the domestic chicken

    NASA Technical Reports Server (NTRS)

    Jones, S. M.; Jones, T. A.

    2000-01-01

    Compound action potentials of the vestibular nerve were measured from the surface of the scalp in 148 chickens (Gallus domesticus). Ages ranged from incubation day 18 (E18) to 22 days posthatch (P22). Responses were elicited using linear acceleration cranial pulses. Response thresholds decreased at an average rate of -0.45 dB/day. The decrease was best fit by an exponential model with half-maturity time constant of 5.1 days and asymptote of approximately -25.9 dB re:1.0 g/ms. Mean threshold approached within 3 dB of the asymptote by ages P6-P9. Similarly, response latencies decreased exponentially to within 3% of mature values at ages beyond P9. The half-maturity time constant for peripheral response peak latencies P1, N1, and P2 was comparable to thresholds and ranged from approximately 4.6 to 6.2 days, whereas central peaks (N2, P3, and N3) ranged from 2.9 to 3.4 days. Latency-intensity slopes for P1, N1, and P2 tended to decrease with age, reaching mature values within approximately 100 hours of hatching. Amplitudes increased as a function of age with average growth rates for response peaks ranging from 0.04 to 0.09 microV/day. There was no obvious asymptote to the growth of amplitudes over the ages studied. Amplitude-intensity slopes also increased modestly with age. The results show that gravity receptors are responsive to transient cranial stimuli as early as E19 in the chicken embryo. The functional response of gravity receptors continues to develop for many days after all major morphological structures are in place. Distinct maturational processes can be identified in central and peripheral neural relays. Functional improvements during maturation may result from refinements in the receptor epithelia, improvements in central and peripheral synaptic transmission, increased neural myelination, as well as changes in the mechanical coupling between the cranium and receptor organ.

  13. Understanding the Electrical Behavior of the Action Potential in Terms of Elementary Electrical Sources

    ERIC Educational Resources Information Center

    Rodriguez-Falces, Javier

    2015-01-01

    A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However,…

  14. Hydrogen peroxide decelerates recovery of action potential after high-frequency fatigue in skeletal muscle.

    PubMed

    Oba, T; Ishikawa, T; Takaishi, T; Aoki, T; Yamaguchi, M

    2000-10-01

    Effects of reactive oxygen species (ROS), especially hydrogen peroxide (H(2)O(2)), on recovery of action potential by resting for 30 min after high-frequency fatigue were studied using frog skeletal muscle fibers. After stimulation at a frequency of 50 HZ for 2 min, the action potential amplitude was decreased by 14.5 mV from controls, and resting membrane was depolarized by 15.4 mV. Action potential duration was also prolonged by high-frequency stimulation (1.5 ms in controls to 2.6 ms). The high-frequency stimulation used here caused no muscle damage. The action potential was partially improved after a 30-min rest. Addition of catalase at 500 units/ml or H(2)O(2) at 0.5 mM to sartorius muscle did not alter any of the parameters of the action potential after high-frequency stimulation. Treatment with catalase accelerated post-fatigue recovery of the action potential. Application of H(2)O(2) delayed post-fatigue recovery of resting and action potentials. When added to detubulated toe muscle fibers, catalase no longer improved the attenuation of action potential induced by high-frequency stimulation, even after a 30-min rest. These findings suggest that removal of H(2)O(2) from transverse tubules is effective for post-fatigue recovery of action potential in skeletal muscle.

  15. The conventional antihistamine drug cyproheptadine lacks QT-interval-prolonging action in halothane-anesthetized guinea pigs: comparison with hydroxyzine.

    PubMed

    Kobayashi, Kazuko; Omuro, Naoki; Takahara, Akira

    2014-01-01

    Antihistamines are known to belong to the chemical class that may induce long QT syndrome. Among them, cyproheptadine has been shown to exert multifaceted actions on the ventricular repolarization phase; namely, shortening of the action potential duration at supra-therapeutic concentrations of 2 - 8 μM and prolongation of the QT interval at ≥ 10 μM. Since information is limited regarding the in vivo electrophysiological effects of cyproheptadine, we assessed it using the halothane-anesthetized guinea-pig model, which was compared with effects of another antihistamine drug, hydroxyzine. Sub-therapeutic to therapeutic doses of hydroxyzine at 1 and 10 mg/kg, i.v. prolonged the QT interval and duration of monophasic action potential, whereas therapeutic to supra-therapeutic doses of cyproheptadine at 0.1 and 1 mg/kg, i.v. hardly affected the indices of ventricular repolarization. These results suggest that cyproheptadine may be categorized into antihistamines with little effect on the ventricular repolarization.

  16. On the excitation of action potentials by protons and its potential implications for cholinergic transmission.

    PubMed

    Fillafer, Christian; Schneider, Matthias F

    2016-03-01

    One of the most conserved mechanisms for transmission of a nerve pulse across a synapse relies on acetylcholine (ACh). Ever since the Nobel Prize-winning works of Dale and Loewi, it has been assumed that ACh-subsequent to its action on a postsynaptic cell-is split into inactive by-products by acetylcholinesterase (AChE). Herein, the widespread assumption of inactivity of ACh's hydrolysis products is falsified. Excitable cells (Chara braunii internodes), which had previously been unresponsive to ACh, became ACh-sensitive in the presence of AChE. The latter was evidenced by a striking difference in cell membrane depolarization upon exposure to 10 mM intact ACh (∆V = -2 ± 5 mV) and its hydrolysate (∆V = 81 ± 19 mV), respectively, for 60 s. This pronounced depolarization, which also triggered action potentials, was clearly attributed to one of the hydrolysis products: acetic acid (∆V = 87 ± 9 mV at pH 4.0; choline ineffective in the range 1-10 mM). In agreement with our findings, numerous studies in the literature have reported that acids excite gels, lipid membranes, plant cells, erythrocytes, as well as neurons. Whether excitation of the postsynaptic cell in a cholinergic synapse is due to protons or due to intact ACh is a most fundamental question that has not been addressed so far.

  17. Ionic differences between somatic and axonal action potentials in snail giant neurones

    PubMed Central

    Wald, Flora

    1972-01-01

    1. The ionic requirements of the somatic and axonal action potentials of `H' neurones of the snail Cryptomphallus aspersa were studied using intracellular micro-electrodes. 2. The overshoot of the somatic action potential increased by 10 mV for a tenfold increase in [Ca2+]o. In calcium-free media the action potential decreased gradually to values of 50 to 90% of the control and they could be completely eliminated with 2 mM-EGTA. The maximum rate of rise also varied with [Ca2+]o. 3. After 2 hr in sodium-free solution the somatic action potential decreased 6% in overshoot and 24% in rate of rise. 4. The somatic action potential was not affected by TTX, 5 × 10-6 g/ml. Procaine, 18 mM, reduced its rate of rise but did not eliminate it whereas 30 mM-CoCl2 did. 5. The size of the axonal action potential increased with increased [Na+]o, but decreased with an increase in [Ca2+]o. 6. Procaine, 18 mM, abolished the axonal action potential whereas it was not affected by TTX, 5 × 10-6 g/ml., nor, usually, by 30 mM-CoCl2. 7. The results obtained by studying the compound action potential of the nerves were similar to those from axonal action potentials. 8. The possibility that the somatic action potential is mainly calcium dependent while the axonal action potential is mainly produced by sodium is discussed. PMID:5014099

  18. Oxidative shift in tissue redox potential increases beat-to-beat variability of action potential duration.

    PubMed

    Kistamás, Kornél; Hegyi, Bence; Váczi, Krisztina; Horváth, Balázs; Bányász, Tamás; Magyar, János; Szentandrássy, Norbert; Nánási, Péter P

    2015-07-01

    Profound changes in tissue redox potential occur in the heart under conditions of oxidative stress frequently associated with cardiac arrhythmias. Since beat-to-beat variability (short term variability, SV) of action potential duration (APD) is a good indicator of arrhythmia incidence, the aim of this work was to study the influence of redox changes on SV in isolated canine ventricular cardiomyocytes using a conventional microelectrode technique. The redox potential was shifted toward a reduced state using a reductive cocktail (containing dithiothreitol, glutathione, and ascorbic acid) while oxidative changes were initiated by superfusion with H2O2. Redox effects were evaluated as changes in "relative SV" determined by comparing SV changes with the concomitant APD changes. Exposure of myocytes to the reductive cocktail decreased SV significantly without any detectable effect on APD. Application of H2O2 increased both SV and APD, but the enhancement of SV was the greater, so relative SV increased. Longer exposure to H2O2 resulted in the development of early afterdepolarizations accompanied by tremendously increased SV. Pretreatment with the reductive cocktail prevented both elevation in relative SV and the development of afterdepolarizations. The results suggest that the increased beat-to-beat variability during an oxidative stress contributes to the generation of cardiac arrhythmias.

  19. Potential effects of intrinsic heart pacemaker cell mechanisms on dysrhythmic cardiac action potential firing

    PubMed Central

    Yaniv, Yael; Tsutsui, Kenta; Lakatta, Edward G.

    2015-01-01

    The heart's regular electrical activity is initiated by specialized cardiac pacemaker cells residing in the sinoatrial node. The rate and rhythm of spontaneous action potential firing of sinoatrial node cells are regulated by stochastic mechanisms that determine the level of coupling of chemical to electrical clocks within cardiac pacemaker cells. This coupled-clock system is modulated by autonomic signaling from the brain via neurotransmitter release from the vagus and sympathetic nerves. Abnormalities in brain-heart clock connections or in any molecular clock activity within pacemaker cells lead to abnormalities in the beating rate and rhythm of the pacemaker tissue that initiates the cardiac impulse. Dysfunction of pacemaker tissue can lead to tachy-brady heart rate alternation or exit block that leads to long atrial pauses and increases susceptibility to other cardiac arrhythmia. Here we review evidence for the idea that disturbances in the intrinsic components of pacemaker cells may be implemented in arrhythmia induction in the heart. PMID:25755643

  20. [Phenibut potentiation of the therapeutic action of antiparkinson agents].

    PubMed

    Gol'dblat, Iu V; Lapin, I P

    1986-01-01

    It was observed in experiments on mice that the central action of phenibut (beta-phenyl-gamma-aminobutyric acid) diminished after destruction of brain dopaminergic neurons by 6-hydroxydopamine and after pretreatment with the dopamine receptor blocker haloperidol which suggests the dopaminergic component in the action of phenibut. In 13 of 16 patients receiving long-term treatment with antiparkinsonic drugs, addition of phenibut (0.25 g thrice daily for 10 days) resulted in marked clinical improvement with a significant increase of motor activity, as well as diminution of both rigidity and tremor. Follow-up showed a significant lowering of muscle tone of rigid muscles, augmentation of their strength and amplitude of movements. In 8 patients receiving phenibut without antiparkinsonic drugs the results were negligible.

  1. Antimalarial action of hydroxamate-based iron chelators and potentiation of desferrioxamine action by reversed siderophores.

    PubMed Central

    Golenser, J; Tsafack, A; Amichai, Y; Libman, J; Shanzer, A; Cabantchik, Z I

    1995-01-01

    Hydroxamate-based chelators of iron are potent inhibitors of in vitro growth of Plasmodium falciparum. Two types of such chelators, the natural desferrioxamine and the synthetic reversed siderophore RSFileum2, are prototypes of antimalarial agents whose action spectra differ in the speed of action, stage dependence, and degree of reversibility of effects. This work explores the possibility of improving the antimalarial efficacy of these agents by using them in various combinations on in vitro cultures of P. falciparum. Growth assessment was based both on total nucleic acid synthesis and on parasitemia. The results indicate that the synthetic reversed siderophore more than complements the antimalarial action of desferrioxamine when applied during either ring, trophozoite, or mixed stages. The combined drug effects were significantly higher than the additive effect of the individual drugs. Qualitatively similar results were obtained for both reversible effects and irreversible (i.e., sustained) effects. Following an 8-h window of exposure the combined drug treatment caused parasite growth arrest and prevented its recovery, even 3 days after the treatment. The fact that such a combination of iron chelators displays a wider action spectrum than either drug alone has implications for the design of chemotherapy regimens. PMID:7695330

  2. Action potentials and twitch forces of rabbit masseter motor units at optimum jaw angle.

    PubMed

    van Eijden, T M G J; Turkawski, S J J

    2002-08-01

    This study examines mutual correlations between electrical and contractile motor-unit properties. Action potentials and twitch force responses of 42 masseter motor units were recorded in 14 rabbits. Motor units were excited by stimulating motoneurones in the trigeminal motor nucleus. Action potentials and twitches were measured at different jaw gapes between 0 and 21 degrees, in steps of 3 degrees. For each motor unit, the jaw angle-active force interrelation was determined and variables for action potential and force were compared at the jaw angle at which the motor unit produced the largest force. The results showed a large variation in variables for action potential and force, possibly related to the variation in motor-unit morphology. A weak correlation was found between the variables for action-potential amplitude and the magnitude of optimum force, indicating that motor units producing larger forces tended to have action potentials with larger amplitudes. Twitch-contraction time and the moment arm of the motor unit correlated positively with both the median frequency and the duration of the action potential. This indicates that slower contracting motor units had longer action potentials and is in accord with the earlier observation that slower motor units are preferentially located in the anterior regions of the masseter.

  3. Action potentials of isolated single muscle fibers recorded by potential-sensitive dyes

    PubMed Central

    Nakajima, S.; Gilai, A.

    1980-01-01

    Light transmission changes upon massive stimulation of single muscle fibers of Xenopus were studied with the potential-sensitive nonpermeant dyes, merocyanine rhodanine (WW375) and merocyanine oxazolone (NK2367). Upon stimulation an absorption change (wave a) occurred, which probably represents the sum of action potentials in the transverse tubules and surface membrane. In WW375-stained fibers wave a is a decrease in transmission over the range of 630 to 730 nm (with NK2367, over the range of 590 to 700 nm) but becomes an increase outside this range, thus showing a triphasic spectral pattern. This spectrum differs from that of the squid axon, in which depolarization produces only an increase in transmission over the whole range of wavelengths (Ross et al. 1977. J. Membr. Biol. 33:141-183). When wave a was measured at the edge of the fiber to obtain more signal from the surface membrane, the spectrum did not seem to differ markedly from that obtained from the entire width of the fiber. Thus, the difference in the spectrum between the squid axon and the vertebrate muscle cannot be attributed to the presence of the tubular system. PMID:10822501

  4. Activation and repolarization patterns in the ventricular epicardium under sinus rhythm in frog and rabbit hearts.

    PubMed

    Azarov, Jan E; Shmakov, Dmitry N; Vityazev, Vladimir A; Roshchevskaya, Irina M; Roshchevsky, Mikhail P

    2007-03-01

    Our study compared the contributions of activation sequence and local repolarization durations distribution in the organization of epicardial repolarization in animals with fast (rabbit) and slow (frog) myocardial activation under sinus rhythm. Activation times, repolarization times and activation-recovery intervals (ARI) were obtained from ventricular epicardial unipolar electrograms recorded in 13 Chinchilla rabbits (Oryctolagus cuniculus) and 10 frogs (Rana temporaria). In frogs, depolarization travels from the atrioventricular ring radially. ARIs increased progressively from the apex to the middle portion and finally to the base (502+/-75, 557+/-73, 606+/-79 ms, respectively; P<0.01). In rabbits, depolarization spread from two epicardial breakthroughs with the duration of epicardial activation being lower than that in frogs (17+/-3 vs. 44+/-18 ms; P<0.001). ARI durations were 120+/-37, 143+/-45, and 163+/-40 ms in the left ventricular apex, left, and right ventricular bases, respectively (P<0.05). In both species, repolarization sequence was directed from apex to base according to the ARI distribution with dispersion of repolarization being higher than that of activation (P<0.001). Thus, excitation spread sequence and velocity per se do not play a crucial role in the formation of ventricular epicardial repolarization pattern, but the chief factor governing repolarization sequences is the distribution of local repolarization durations.

  5. Dispersion in ventricular repolarization in the human, canine and porcine heart.

    PubMed

    Opthof, Tobias; Janse, Michiel J; Meijborg, Veronique M F; Cinca, Juan; Rosen, Michael R; Coronel, Ruben

    2016-01-01

    Dispersion in repolarization is important for the genesis of the T wave, and for the induction of reentrant arrhtyhmias. Because the T wave differs across species our intent here is to review the epicardial, endocardial and transmural repolarization patterns contributing to repolarization in whole hearts from man, dog and pig. The major points we emphasize are: transmural repolarization time gradients are small and are directed from endocardium (early) to epicardium (late) in dog and human and from epicardium to endocardium in pig; the right ventricle tends to repolarize before the left ventricle and this difference is larger in dog than in pig; a negative relation between the activation times and the repolarization times is rare in man, and absent in dog and pig. Given the above, a large dispersion in repolarization between two myocardial areas does not lead to arrhythmias without a premature beat. Moreover, an arrhythmic substrate can be identified by a metric composed of activation times and repolarization times, the reentry vulnerability index, RVI.

  6. Epidermal laser stimulation of action potentials in the frog sciatic nerve

    NASA Astrophysics Data System (ADS)

    Jindra, Nichole M.; Goddard, Douglas; Imholte, Michelle; Thomas, Robert J.

    2010-01-01

    Measurements of laser-stimulated action potentials in the sciatic nerve of leopard frogs (Rana pipiens) are made using two infrared lasers. The dorsal sides of the frog's hind limbs are exposed to short-pulsed 1540- and 1064-nm wavelengths at three separate spot sizes: 2, 3, and 4 mm. Energy density thresholds are determined for eliciting an action potential at each experimental condition. Results from these exposures show similar evoked potential thresholds for both wavelengths. The 2-mm-diam spot sizes yield action potentials at radiant exposure levels almost double that seen with larger beam sizes.

  7. Genotoxic potential of glyphosate formulations: mode-of-action investigations.

    PubMed

    Heydens, William F; Healy, Charles E; Hotz, Kathy J; Kier, Larry D; Martens, Mark A; Wilson, Alan G E; Farmer, Donna R

    2008-02-27

    A broad array of in vitro and in vivo assays has consistently demonstrated that glyphosate and glyphosate-containing herbicide formulations (GCHF) are not genotoxic. Occasionally, however, related and contradictory data are reported, including findings of mouse liver and kidney DNA adducts and damage following intraperitoneal (ip) injection. Mode-of-action investigations were therefore undertaken to determine the significance of these contradictory data while concurrently comparing results from ip and oral exposures. Exposure by ip injection indeed produced marked hepatic and renal toxicity, but oral administration did not. The results suggest that ip injection of GCHF may induce secondary effects mediated by local toxicity rather than genotoxicity. Furthermore, these results continue to support the conclusion that glyphosate and GCHF are not genotoxic under exposure conditions that are relevant to animals and humans.

  8. Neuroactive steroids have multiple actions to potentiate GABAA receptors.

    PubMed

    Akk, Gustav; Bracamontes, John R; Covey, Douglas F; Evers, Alex; Dao, Tim; Steinbach, Joe Henry

    2004-07-01

    The effects of neuroactive steroids on the function of GABAA receptors were studied using cell-attached records of single channel activity recorded from HEK293 cells transfected with alpha1 beta2 gamma2L subunits. Activity was elicited with a half-maximal (50 microM) concentration of GABA. Two steroids were studied in detail: ACN ((3alpha,5alpha,17beta)-3-hydroxyandrostane-17-carbonitrile) and B285 ((3alpha,5beta,17beta)-3-hydroxy-18-norandrostane-17-carbonitrile). Four effects on channel activity were seen, two on open time distributions and two on closed times. When clusters of openings were elicited in the absence of steroid, the open time distribution contained three components. ACN produced concentration-dependent alterations in the open time distribution. The prevalence of the longest duration class of open times was increased from about 15% to about 40% (EC50 about 180 nM ACN), while the duration of the longest class increased from 7.4 ms to 27 ms (EC50 about 35 nM ACN). B285 also increased the prevalence of the longest duration open times (EC50 about 18 nM B285) but increased the duration only at concentrations close to 10 microM. The differences in the actions of these two steroids suggest that the effects on proportion and duration of the long duration open time component are produced by independent mechanisms and that there are separate recognition sites for the steroids which are associated with the two functional actions. The closed time distributions also showed three components in the absence of steroid. The rate of occurrence of the two brief duration closed time components decreased with increasing ACN, with an EC50 of about 50 nM ACN. In contrast, B285 did not reduce the rate of occurrence of the brief closings until high concentrations were applied. However, both B285 and ACN reduced the rate of occurrence of the activation-related closed state selectively, with comparable IC50 concentrations (about 40 nM ACN, 20 nM B285). As in the case for

  9. The Multiple Electrocardiographic Manifestations of Ventricular Repolarization Memory

    PubMed Central

    Chiale, Pablo A; Etcheverry, Daniel; Pastori, Julio D; Fernández, Pablo A; Garro, Hugo A; González, Mario D; Elizari, Marcelo V

    2014-01-01

    T wave “memory” is a peculiar variety of cardiac remodeling caused by a transient change in the course of ventricular depolarization (due to ventricular pacing, rate-dependent intraventricular block, ventricular preexcitation or tachyarrhythmias with wide QRS complexes). It is usually manifested by inverted T waves that appears when normal ventricular activation is restored. This phenomenon is cumulative and occurs earlier if the ventricular myocardium has previously been exposed to the same conditioning stimuli. In this article the different conditions giving rise to “classical” T wave memory development are reviewed and also “another” type of T wave memory is described. It is also shown that cardiac memory may induce not only negative (pseudo-primary) T waves but also a reversal of primary and pseudo-primary T waves leading to “normalization” of ventricular repolarization. The knowledge of these dissimilar consequences of T wave memory is essential to assess the characteristics of ventricular repolarization. PMID:24827802

  10. Effects of milnacipran on cardiac repolarization in healthy participants.

    PubMed

    Periclou, Antonia; Palmer, Robert H; Zheng, Hongjie; Lindamood, Charles

    2010-04-01

    Milnacipran is approved for management of fibromyalgia in the United States. In this double-blind, placebo- and active drug-controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time-matched baseline-adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest difference in baseline-adjusted QTcNi between milnacipran 300 mg bid and placebo was -4.7 ms (90% confidence interval [CI]: -9.4 to -0.1), indicating no QT prolongation. Analysis using the Fridericia formula (QTcF) showed a maximum adjusted mean change of +7.7 ms, but QTcF versus RR interval plots indicated overcorrection with this method. The piecewise QTcNi correction method demonstrated a more accurate correction for drug-induced heart rate increase; mean baseline-adjusted between-group difference was +0.9 ms (90% CI: -6.6 to 8.3). The results suggest that milnacipran would not significantly affect cardiac repolarization at clinically relevant therapeutic and supratherapeutic concentrations.

  11. Ventricular repolarization markers for predicting malignant arrhythmias in clinical practice

    PubMed Central

    Castro-Torres, Yaniel; Carmona-Puerta, Raimundo; Katholi, Richard E

    2015-01-01

    Malignant cardiac arrhythmias which result in sudden cardiac death may be present in individuals apparently healthy or be associated with other medical conditions. The way to predict their appearance represents a challenge for the medical community due to the tragic outcomes in most cases. In the last two decades some ventricular repolarization (VR) markers have been found to be useful to predict malignant cardiac arrhythmias in several clinical conditions. The corrected QT, QT dispersion, Tpeak-Tend, Tpeak-Tend dispersion and Tp-e/QT have been studied and implemented in clinical practice for this purpose. These markers are obtained from 12 lead surface electrocardiogram. In this review we discuss how these markers have demonstrated to be effective to predict malignant arrhythmias in medical conditions such as long and short QT syndromes, Brugada syndrome, early repolarization syndrome, acute myocardial ischemia, heart failure, hypertension, diabetes mellitus, obesity and highly trained athletes. Also the main pathophysiological mechanisms that explain the arrhythmogenic predisposition in these diseases and the basis for the VR markers are discussed. However, the same results have not been found in all conditions. Further studies are needed to reach a global consensus in order to incorporate these VR parameters in risk stratification of these patients. PMID:26301231

  12. Excess centrosomes perturb dynamic endothelial cell repolarization during blood vessel formation

    PubMed Central

    Kushner, Erich J.; Ferro, Luke S.; Yu, Zhixian; Bautch, Victoria L.

    2016-01-01

    Blood vessel formation requires dynamic movements of endothelial cells (ECs) within sprouts. The cytoskeleton regulates migratory polarity, and centrosomes organize the microtubule cytoskeleton. However, it is not well understood how excess centrosomes, commonly found in tumor stromal cells, affect microtubule dynamics and interphase cell polarity. Here we find that ECs dynamically repolarize during sprouting angiogenesis, and excess centrosomes block repolarization and reduce migration and sprouting. ECs with excess centrosomes initially had more centrosome-derived microtubules but, paradoxically, fewer steady-state microtubules. ECs with excess centrosomes had elevated Rac1 activity, and repolarization was rescued by blockade of Rac1 or actomyosin blockers, consistent with Rac1 activity promoting cortical retrograde actin flow and actomyosin contractility, which precludes cortical microtubule engagement necessary for dynamic repolarization. Thus normal centrosome numbers are required for dynamic repolarization and migration of sprouting ECs that contribute to blood vessel formation. PMID:27099371

  13. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

    PubMed

    Jaffer, Fatima; Avbersek, Andreja; Vavassori, Rosaria; Fons, Carmen; Campistol, Jaume; Stagnaro, Michela; De Grandis, Elisa; Veneselli, Edvige; Rosewich, Hendrik; Gianotta, Melania; Zucca, Claudio; Ragona, Francesca; Granata, Tiziana; Nardocci, Nardo; Mikati, Mohamed; Helseth, Ashley R; Boelman, Cyrus; Minassian, Berge A; Johns, Sophia; Garry, Sarah I; Scheffer, Ingrid E; Gourfinkel-An, Isabelle; Carrilho, Ines; Aylett, Sarah E; Parton, Matthew; Hanna, Michael G; Houlden, Henry; Neville, Brian; Kurian, Manju A; Novy, Jan; Sander, Josemir W; Lambiase, Pier D; Behr, Elijah R; Schyns, Tsveta; Arzimanoglou, Alexis; Cross, J Helen; Kaski, Juan P; Sisodiya, Sanjay M

    2015-10-01

    with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

  14. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

    PubMed Central

    Jaffer, Fatima; Avbersek, Andreja; Vavassori, Rosaria; Fons, Carmen; Campistol, Jaume; Stagnaro, Michela; De Grandis, Elisa; Veneselli, Edvige; Rosewich, Hendrik; Gianotta, Melania; Zucca, Claudio; Ragona, Francesca; Granata, Tiziana; Nardocci, Nardo; Mikati, Mohamed; Helseth, Ashley R.; Boelman, Cyrus; Minassian, Berge A.; Johns, Sophia; Garry, Sarah I.; Scheffer, Ingrid E.; Gourfinkel-An, Isabelle; Carrilho, Ines; Aylett, Sarah E.; Parton, Matthew; Hanna, Michael G.; Houlden, Henry; Neville, Brian; Kurian, Manju A.; Novy, Jan; Sander, Josemir W.; Lambiase, Pier D.; Behr, Elijah R.; Schyns, Tsveta; Arzimanoglou, Alexis; Cross, J. Helen; Kaski, Juan P.

    2015-01-01

    , compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable. PMID:26297560

  15. Alteration of neural action potential patterns by axonal stimulation: the importance of stimulus location

    PubMed Central

    Crago, Patrick E; Makowski, Nathan S

    2014-01-01

    Objective Stimulation of peripheral nerves is often superimposed on ongoing motor and sensory activity in the same axons, without a quantitative model of the net action potential train at the axon endpoint. Approach We develop a model of action potential patterns elicited by superimposing constant frequency axonal stimulation on the action potentials arriving from a physiologically activated neural source. The model includes interactions due to collision block, resetting of the neural impulse generator, and the refractory period of the axon at the point of stimulation. Main Results Both the mean endpoint firing rate and the probability distribution of the action potential firing periods depend strongly on the relative firing rates of the two sources and the intersite conduction time between them. When the stimulus rate exceeds the neural rate, neural action potentials do not reach the endpoint and the rate of endpoint action potentials is the same as the stimulus rate, regardless of the intersite conduction time. However, when the stimulus rate is less than the neural rate, and the intersite conduction time is short, the two rates partially sum. Increases in stimulus rate produce non-monotonic increases in endpoint rate and continuously increasing block of neurally generated action potentials. Rate summation is reduced and more neural action potentials are blocked as the intersite conduction time increases.. At long intersite conduction times, the endpoint rate simplifies to being the maximum of either the neural or the stimulus rate. Significance This study highlights the potential of increasing the endpoint action potential rate and preserving neural information transmission by low rate stimulation with short intersite conduction times. Intersite conduction times can be decreased with proximal stimulation sites for muscles and distal stimulation sites for sensory endings. The model provides a basis for optimizing experiments and designing neuroprosthetic

  16. Alteration of neural action potential patterns by axonal stimulation: the importance of stimulus location

    NASA Astrophysics Data System (ADS)

    Crago, Patrick E.; Makowski, Nathaniel S.

    2014-10-01

    Objective. Stimulation of peripheral nerves is often superimposed on ongoing motor and sensory activity in the same axons, without a quantitative model of the net action potential train at the axon endpoint. Approach. We develop a model of action potential patterns elicited by superimposing constant frequency axonal stimulation on the action potentials arriving from a physiologically activated neural source. The model includes interactions due to collision block, resetting of the neural impulse generator, and the refractory period of the axon at the point of stimulation. Main results. Both the mean endpoint firing rate and the probability distribution of the action potential firing periods depend strongly on the relative firing rates of the two sources and the intersite conduction time between them. When the stimulus rate exceeds the neural rate, neural action potentials do not reach the endpoint and the rate of endpoint action potentials is the same as the stimulus rate, regardless of the intersite conduction time. However, when the stimulus rate is less than the neural rate, and the intersite conduction time is short, the two rates partially sum. Increases in stimulus rate produce non-monotonic increases in endpoint rate and continuously increasing block of neurally generated action potentials. Rate summation is reduced and more neural action potentials are blocked as the intersite conduction time increases. At long intersite conduction times, the endpoint rate simplifies to being the maximum of either the neural or the stimulus rate. Significance. This study highlights the potential of increasing the endpoint action potential rate and preserving neural information transmission by low rate stimulation with short intersite conduction times. Intersite conduction times can be decreased with proximal stimulation sites for muscles and distal stimulation sites for sensory endings. The model provides a basis for optimizing experiments and designing neuroprosthetic

  17. Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons

    PubMed Central

    Lee, Philip R.; Cohen, Jonathan E.; Iacobas, Dumitru A.; Iacobas, Sanda; Fields, R. Douglas

    2017-01-01

    Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life. PMID:28256583

  18. Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons.

    PubMed

    Lee, Philip R; Cohen, Jonathan E; Iacobas, Dumitru A; Iacobas, Sanda; Fields, R Douglas

    2017-03-03

    Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life.

  19. Action potentials in retinal ganglion cells are initiated at the site of maximal curvature of the extracellular potential

    NASA Astrophysics Data System (ADS)

    Eickenscheidt, Max; Zeck, Günther

    2014-06-01

    Objective. The initiation of an action potential by extracellular stimulation occurs after local depolarization of the neuronal membrane above threshold. Although the technique shows remarkable clinical success, the site of action and the relevant stimulation parameters are not completely understood. Approach. Here we identify the site of action potential initiation in rabbit retinal ganglion cells (RGCs) interfaced to an array of extracellular capacitive stimulation electrodes. We determine which feature of the extracellular potential governs action potential initiation by simultaneous stimulation and recording RGCs interfaced in epiretinal configuration. Stimulation electrodes were combined to areas of different size and were presented at different positions with respect to the RGC. Main results. Based on stimulation by electrodes beneath the RGC soma and simultaneous sub-millisecond latency measurement we infer axonal initiation at the site of maximal curvature of the extracellular potential. Stimulation by electrodes at different positions along the axon reveals a nearly constant threshold current density except for a narrow region close to the cell soma. These findings are explained by the concept of the activating function modified to consider a region of lower excitability close to the cell soma. Significance. We present a framework how to estimate the site of action potential initiation and the stimulus required to cross threshold in neurons tightly interfaced to capacitive stimulation electrodes. Our results underscore the necessity of rigorous electrical characterization of the stimulation electrodes and of the interfaced neural tissue.

  20. Antioxidant properties of melatonin and its potential action in diseases.

    PubMed

    Karaaslan, Cigdem; Suzen, Sibel

    2015-01-01

    In recent years, relationship between free radicals and oxidative stress with aging, cancer, atherosclerosis, neurodegenerative disorders, diabetes, and inflammatory diseases became increasingly clear. Confirming the role of oxidants in numerous pathological conditions such as cancer, the antioxidants developed as therapeutics have been proven ineffective. It is well established that melatonin (MLT) and its metabolites are able to function as endogenous free-radical scavengers and broadspectrum antioxidants. Numerous studies also proved the role of MLT and its derivatives in many physiological processes and therapeutic functions, such as the regulation of circadian rhythm and immune functions. The aim of this review is to arouse attention to MLT as a potentially valuable agent in the prevention and/or treatment of some diseases.

  1. Acute alteration of cardiac ECG, action potential, I{sub Kr} and the human ether-a-go-go-related gene (hERG) K{sup +} channel by PCB 126 and PCB 77

    SciTech Connect

    Park, Mi-Hyeong; Park, Won Sun; Jo, Su-Hyun

    2012-07-01

    Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K{sup +} current (I{sub Kr}) of guinea pigs' hearts, and hERG K{sup +} current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD{sub 90}), and 50% of repolarization (APD{sub 50}) (P < 0.05) without changing the action potential duration at 20% (APD{sub 20}). PCB 77 decreased APD{sub 20} (P < 0.05) without affecting QTc, APD{sub 90}, and APD{sub 50}. The PCB 126 increased the I{sub Kr} in guinea-pig ventricular myocytes held at 36 °C and hERG K{sup +} current amplitude at the end of the voltage steps in voltage-dependent mode (P < 0.05); however, PCB 77 did not change the hERG K{sup +} current amplitude. The PCB 77 increased the diastolic Ca{sup 2+} and decreased Ca{sup 2+} transient amplitude (P < 0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD{sub 90} possibly by increasing I{sub Kr}, while PCB 77 decreased the APD{sub 20} possibly by other modulation related with intracellular Ca{sup 2+}. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca{sup 2+}, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body. -- Highlights: ► PCBs are known as serious environmental pollutants and developmental disruptors. ► PCB 126 shortened QT interval of ECG and action potential duration. ► PCB 126 increased human ether-a-go-go-related K{sup +} current and I{sub Kr}. ► PCB

  2. Changes of endothelin-1 and big endothelin-1 levels and action potential duration during myocardial ischemia-reperfusion in dogs with and without ventricular fibrillation.

    PubMed

    Vágó, Hajnalka; Soós, Pál; Zima, Endre; Gellér, László; Keltai, Katalin; Róka, Attila; Kékesi, Violetta; Juhász-Nagy, Alexander; Merkely, Béla

    2004-11-01

    Myocardial ischemia-reperfusion is associated with increased production of endothelin-1 (ET-1). Moreover, exogenous ET-1 has arrhythmogenic properties. Our aim was to investigate the correlation between endogenous ET-1, big ET-1 levels and epicardial monophasic action potential duration during myocardial ischemia-reperfusion in anesthetized dogs. Thirty-minute myocardial ischemia was followed by a 90-minute reperfusion period in 18 mongrel dogs. The total incidence of ventricular fibrillation (VF) during ischemia and reperfusion was 11.1% and 33.3%, respectively. During ischemia, the monophasic action potential duration at 90% repolarization (MAPD90) decreased significantly (control versus ischemia, 30 minutes, 224.7 +/- 7.1 ms versus 173.8 +/- 7.6 ms; P < 0.05), while during reperfusion a significant prolongation of MAPD90 was observed (ischemia, 30 minutes versus reperfusion, 30 minutes, 173.8 +/- 7.6 ms versus 249.7 +/- 9.9 ms, P < 0.05). During reperfusion ET-1 and big ET-1 levels increased significantly in the coronary sinus and femoral artery (control versus reperfusion, 90 minutes: coronary sinus ET-1, 15.1 +/- 1.4 fmol/mL versus 22.3 +/- 1.1 fmol/mL; big ET-1, 14.7 +/- 1.9 fmol/mL versus 27.4 +/- 2.3 fmol/mL; P < 0.05). The ET-1 concentration increased to a higher level during ischemia in dogs with VF compared with dogs surviving ischemia-reperfusion (non-VF versus VF: control, 15.1 +/- 1.3 versus 15.2 +/- 1.3; ischemia, 30 minutes, 17.6 +/- 1.2 fmol/mL versus 22 +/- 1.6 fmol/mL; P < 0.05), demonstrating a trend of correlation between endothelin levels and development of VF (P = 0.07). ET-1 and big ET-1 levels increased during reperfusion and in the VF group during ischemia; however, there was no correlation between endothelin levels and MAPD90.

  3. Primary cortical representation of sounds by the coordination of action-potential timing.

    PubMed

    deCharms, R C; Merzenich, M M

    1996-06-13

    Cortical population coding could in principle rely on either the mean rate of neuronal action potentials, or the relative timing of action potentials, or both. When a single sensory stimulus drives many neurons to fire at elevated rates, the spikes of these neurons become tightly synchronized, which could be involved in 'binding' together individual firing-rate feature representations into a unified object percept. Here we demonstrate that the relative timing of cortical action potentials can signal stimulus features themselves, a function even more basic than feature grouping. Populations of neurons in the primary auditory cortex can coordinate the relative timing of their action potentials such that spikes occur closer together in time during continuous stimuli. In this way cortical neurons can signal stimuli even when their firing rates do not change. Population coding based on relative spike timing can systemically signal stimulus features, it is topographically mapped, and it follows the stimulus time course even where mean firing rate does not.

  4. Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy.

    PubMed

    Kole, Maarten H P; Letzkus, Johannes J; Stuart, Greg J

    2007-08-16

    Action potentials are binary signals that transmit information via their rate and temporal pattern. In this context, the axon is thought of as a transmission line, devoid of a role in neuronal computation. Here, we show a highly localized role of axonal Kv1 potassium channels in shaping the action potential waveform in the axon initial segment (AIS) of layer 5 pyramidal neurons independent of the soma. Cell-attached recordings revealed a 10-fold increase in Kv1 channel density over the first 50 microm of the AIS. Inactivation of AIS and proximal axonal Kv1 channels, as occurs during slow subthreshold somatodendritic depolarizations, led to a distance-dependent broadening of axonal action potentials, as well as an increase in synaptic strength at proximal axonal terminals. Thus, Kv1 channels are strategically positioned to integrate slow subthreshold signals, providing control of the presynaptic action potential waveform and synaptic coupling in local cortical circuits.

  5. Pharmacological actions and potential uses of Momordica charantia: a review.

    PubMed

    Grover, J K; Yadav, S P

    2004-07-01

    Since ancient times, plants and herbal preparations have been used as medicine. Research carried out in last few decades has certified several such claims of use of several plants of traditional medicine. Popularity of Momordica charantia (MC) in various systems of traditional medicine for several ailments (antidiabetic, abortifacient, anthelmintic, contraceptive, dysmenorrhea, eczema, emmenagogue, antimalarial, galactagogue, gout, jaundice, abdominal pain, kidney (stone), laxative, leprosy, leucorrhea, piles, pneumonia, psoriasis, purgative, rheumatism, fever and scabies) focused the investigator's attention on this plant. Over 100 studies using modern techniques have authenticated its use in diabetes and its complications (nephropathy, cataract, insulin resistance), as antibacterial as well as antiviral agent (including HIV infection), as anthelmintic and abortifacient. Traditionally it has also been used in treating peptic ulcers, interestingly in a recent experimental studies have exhibited its potential against Helicobacter pylori. Most importantly, the studies have shown its efficacy in various cancers (lymphoid leukemia, lymphoma, choriocarcinoma, melanoma, breast cancer, skin tumor, prostatic cancer, squamous carcinoma of tongue and larynx, human bladder carcinomas and Hodgkin's disease). There are few reports available on clinical use of MC in diabetes and cancer patients that have shown promising results.

  6. J Wave syndromes: Brugada and Early Repolarization Syndromes

    PubMed Central

    Antzelevitch, Charles; Yan, Gan-Xin

    2015-01-01

    A prominent J wave is encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada (BrS) and early repolarization (ERS) syndromes. BrS and ERS differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. Despite two decades of intensive research, risk stratification and the approach to therapy of these two inherited cardiac arrhythmia syndromes are still undergoing rapid evolution. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, as well as the molecular, ionic, cellular and genetic mechanisms underlying these two fascinating syndromes that have captured the interest and attention of the cardiology community in recent years. PMID:25869754

  7. Early repolarization, acute emotional stress and sudden death.

    PubMed

    Palmiere, Cristian; Lesta, Maria del Mar; Vanhaebost, Jessica; Mangin, Patrice; Augsburger, Marc; Vogt, Pierre

    2014-05-01

    We herein report the case of a 36-year-old man who died suddenly after a fight with another man. Forensic investigations included unenhanced computed tomography, postmortem angiography, autopsy, histology, neuropathology, toxicology, and biochemistry and allowed a traumatic cause of death to be excluded. An electrocardiogram recorded some years prior to death revealed the presence of an early repolarization pattern. Based on the results of all investigations, the cause of death was determined to be cardiac arrhythmia and cardiac arrest during an emotionally stressful event associated with physical assault. Direct third party involvement, however, was excluded, and the manner of death was listed as natural. The case was not pursued any further by the public prosecutor.

  8. Epidermal Laser Stimulation of Action Potentials in the Frog Sciatic Nerve

    DTIC Science & Technology

    2008-10-01

    Laser Stimulation of Action Potentials in the Frog Sciatic Nerve Nichole M. Jindra Robert J. Thomas Human Effectiveness Directorate Directed...in the Frog Sciatic Nerve 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 62202F 6. AUTHOR(S) .Nichole M. Jindra, Robert J. Thomas, Douglas N...Alan Rice 14. ABSTRACT Measurements of laser stimulated action potentials in the sciatic nerve of leopard frogs (Rana pipiens) were made using

  9. Action potential broadening and frequency-dependent facilitation of calcium signals in pituitary nerve terminals.

    PubMed

    Jackson, M B; Konnerth, A; Augustine, G J

    1991-01-15

    Hormone release from nerve terminals in the neurohypophysis is a sensitive function of action potential frequency. We have investigated the cellular mechanisms responsible for this frequency-dependent facilitation by combining patch clamp and fluorimetric Ca2+ measurements in single neurosecretory terminals in thin slices of the rat posterior pituitary. In these terminals both action potential-induced changes in the intracellular Ca2+ concentration ([Ca2+]i) and action potential duration were enhanced by high-frequency stimuli, all with a frequency dependence similar to that of hormone release. Furthermore, brief voltage clamp pulses inactivated a K+ current with a very similar frequency dependence. These results support a model for frequency-dependent facilitation in which the inactivation of a K+ current broadens action potentials, leading to an enhancement of [Ca2+]i signals. Further experiments tested for a causal relationship between action potential broadening and facilitation of [Ca2+]i changes. First, increasing the duration of depolarization, either by broadening action potentials with the K(+)-channel blocker tetraethylammonium or by applying longer depolarizing voltage clamp steps, increased [Ca2+]i changes. Second, eliminating frequency-dependent changes in duration, by voltage clamping the terminal with constant duration pulses, substantially reduced the frequency-dependent enhancement of [Ca2+]i changes. These results indicate that action potential broadening contributes to frequency-dependent facilitation of [Ca2+]i changes. However, the small residual frequency dependence of [Ca2+]i changes seen with constant duration stimulation suggests that a second process, distinct from action potential broadening, also contributes to facilitation. These two frequency-dependent mechanisms may also contribute to activity-dependent plasticity in synaptic terminals.

  10. A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates.

    PubMed

    Mahajan, Aman; Shiferaw, Yohannes; Sato, Daisuke; Baher, Ali; Olcese, Riccardo; Xie, Lai-Hua; Yang, Ming-Jim; Chen, Peng-Sheng; Restrepo, Juan G; Karma, Alain; Garfinkel, Alan; Qu, Zhilin; Weiss, James N

    2008-01-15

    Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Ca(i)) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (I(Ca,L)) and Ca(i) cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35-37 degrees C. Incorporating a minimal seven-state Markovian model of I(Ca,L) that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Ca(i) cycling model, the new model replicates experimentally observed action potential duration and Ca(i) transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing.

  11. Modeling of action potential generation in NG108-15 cells.

    PubMed

    Molnar, Peter; Hickman, James J

    2014-01-01

    In order to explore the possibility of identifying toxins based on their effect on the shape of action potentials, we created a computer model of the action potential generation in NG108-15 cells (a neuroblastoma/glioma hybrid cell line). To generate the experimental data for model validation, voltage-dependent sodium, potassium and high-threshold calcium currents, as well as action potentials, were recorded from NG108-15 cells with conventional whole-cell patch-clamp methods. Based on the classic Hodgkin-Huxley formalism and the linear thermodynamic description of the rate constants, ion-channel parameters were estimated using an automatic fitting method. Utilizing the established parameters, action potentials were generated using the Hodgkin-Huxley formalism and were fitted to the recorded action potentials. To demonstrate the applicability of the method for toxin detection and discrimination, the effect of tetrodotoxin (a sodium channel blocker) and tefluthrin (a pyrethroid that is a sodium channel opener) were studied. The two toxins affected the shape of the action potentials differently, and their respective effects were identified based on the predicted changes in the fitted parameters.

  12. A Rabbit Ventricular Action Potential Model Replicating Cardiac Dynamics at Rapid Heart Rates

    PubMed Central

    Mahajan, Aman; Shiferaw, Yohannes; Sato, Daisuke; Baher, Ali; Olcese, Riccardo; Xie, Lai-Hua; Yang, Ming-Jim; Chen, Peng-Sheng; Restrepo, Juan G.; Karma, Alain; Garfinkel, Alan; Qu, Zhilin; Weiss, James N.

    2008-01-01

    Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Cai) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (ICa,L) and Cai cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35–37°C. Incorporating a minimal seven-state Markovian model of ICa,L that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Cai cycling model, the new model replicates experimentally observed action potential duration and Cai transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing. PMID:18160660

  13. All optical experimental design for neuron excitation, inhibition, and action potential detection

    NASA Astrophysics Data System (ADS)

    Walsh, Alex J.; Tolstykh, Gleb; Martens, Stacey; Sedelnikova, Anna; Ibey, Bennett L.; Beier, Hope T.

    2016-03-01

    Recently, infrared light has been shown to both stimulate and inhibit excitatory cells. However, studies of infrared light for excitatory cell inhibition have been constrained by the use of invasive and cumbersome electrodes for cell excitation and action potential recording. Here, we present an all optical experimental design for neuronal excitation, inhibition, and action potential detection. Primary rat neurons were transfected with plasmids containing the light sensitive ion channel CheRiff. CheRiff has a peak excitation around 450 nm, allowing excitation of transfected neurons with pulsed blue light. Additionally, primary neurons were transfected with QuasAr2, a fast and sensitive fluorescent voltage indicator. QuasAr2 is excited with yellow or red light and therefore does not spectrally overlap CheRiff, enabling imaging and action potential activation, simultaneously. Using an optic fiber, neurons were exposed to blue light sequentially to generate controlled action potentials. A second optic fiber delivered a single pulse of 1869nm light to the neuron causing inhibition of the evoked action potentials (by the blue light). When used in concert, these optical techniques enable electrode free neuron excitation, inhibition, and action potential recording, allowing research into neuronal behaviors with high spatial fidelity.

  14. Pulsed magnetic stimulation modifies amplitude of action potentials in vitro via ionic channels-dependent mechanism.

    PubMed

    Ahmed, Zaghloul; Wieraszko, Andrzej

    2015-07-01

    This paper investigates the influence of pulsed magnetic fields (PMFs) on amplitude of evoked, compound action potential (CAP) recorded from the segments of sciatic nerve in vitro. PMFs were applied for 30 min at frequency of 0.16 Hz and intensity of 15 mT. In confirmation of our previous reports, PMF exposure enhanced amplitude of CAPs. The effect persisted beyond PMF activation period. As expected, CAP amplitude was attenuated by antagonists of sodium channel, lidocaine, and tetrodotoxin. Depression of the potential by sodium channels antagonists was reversed by subsequent exposure to PMFs. The effect of elevated potassium concentration and veratridine on the action potential was modified by exposure to PMFs as well. Neither inhibitors of protein kinase C and protein kinase A, nor known free radicals scavengers had any effects on PMF action. Possible mechanisms of PMF action are discussed.

  15. Direct depolarization and antidromic action potentials transiently suppress dendritic IPSPs in hippocampal CA1 pyramidal cells.

    PubMed

    Morishita, W; Alger, B E

    2001-01-01

    Whole-cell current-clamp recordings were made from distal dendrites of rat hippocampal CA1 pyramidal cells. Following depolarization of the dendritic membrane by direct injection of current pulses or by back-propagating action potentials elicited by antidromic stimulation, evoked gamma-aminobutyric acid-A (GABA(A)) receptor-mediated inhibitory postsynaptic potentials (IPSPs) were transiently suppressed. This suppression had properties similar to depolarization-induced suppression of inhibition (DSI): it was enhanced by carbachol, blocked by dendritic hyperpolarization sufficient to prevent action potential invasion, and reduced by 4-aminopyridine (4-AP) application. Thus DSI or a DSI-like process can be recorded in CA1 distal dendrites. Moreover, localized application of TTX to stratum pyramidale blocked somatic action potentials and somatic IPSPs, but not dendritic IPSPs or DSI induced by direct dendritic depolarization, suggesting DSI is expressed in part in the dendrites. These data extend the potential physiological roles of DSI.

  16. The Flash-Triggering Action Potential of the Luminescent Dinoflagellate Noctiluca

    PubMed Central

    Eckert, Roger; Sibaoka, Takao

    1968-01-01

    The action potential which elicits luminescence in Noctiluca is recorded from the flotation vacuole as a transient all-or-none hyperpolarization in response to either local or general application of inward (bath to vacuole) current. Experiments were performed to determine whether the unorthodox polarities of both the stimulus current and the potential response resulted from uncommon bioelectric mechanisms or from special morphological features of this species. The findings all indicate that the action potential belongs to the familiar class of responses which have their origin in voltage- and time-dependent selective increases in membrane permeability, and that morphological factors account for the observed deviations from normal behavior. Both the stimulus and the response have orthodox polarities provided the vacuole is designated as an "external" extracytoplasmic compartment. Differential recording between vacuole and cytoplasm showed that the action potential occurs across the vacuolar membrane, with the cytoplasmic potential, which at rest is negative with respect to the vacuole, overshooting zero and reversing sign to become transiently electropositive. The rising phase of the action potential therefore depends on active current flow through the vacuolar membrane from the vacuole into the cytoplasm. Propagation of the action potential over the subspherical cell from the locus of stimulation is thought to depend largely on the core conductor properties of the thin perivacuolar shell of cytoplasm which is bounded on its inner surface by the excitable membrane and on its outer surface by inexcitable membranes. PMID:5672004

  17. Minocycline inhibits D-amphetamine-elicited action potential bursts in a central snail neuron.

    PubMed

    Chen, Y-H; Lin, P-L; Wong, R-W; Wu, Y-T; Hsu, H-Y; Tsai, M-C; Lin, M-J; Hsu, Y-C; Lin, C-H

    2012-10-25

    Minocycline is a second-generation tetracycline that has been reported to have powerful neuroprotective properties. In our previous studies, we found that d-amphetamine (AMPH) elicited action potential bursts in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. This study sought to determine the effects of minocycline on the AMPH-elicited action potential pattern changes in the central snail neuron, using the two-electrode voltage clamping method. Extracellular application of AMPH at 300 μM elicited action potential bursts in the RP4 neuron. Minocycline dose-dependently (300-900 μM) inhibited the action potential bursts elicited by AMPH. The inhibitory effects of minocycline on AMPH-elicited action potential bursts were restored by forskolin (50 μM), an adenylate cyclase activator, and by dibutyryl cAMP (N(6),2'-O-Dibutyryladenosine 3',5'-cyclic monophosphate; 1mM), a membrane-permeable cAMP analog. Co-administration of forskolin (50 μM) plus tetraethylammonium chloride (TEA; 5mM) or co-administration of TEA (5mM) plus dibutyryl cAMP (1mM) also elicited action potential bursts, which were prevented and inhibited by minocycline. In addition, minocycline prevented and inhibited forskolin (100 μM)-elicited action potential bursts. Notably, TEA (50mM)-elicited action potential bursts in the RP4 neuron were not affected by minocycline. Minocycline did not affect steady-state outward currents of the RP4 neuron. However, minocycline did decrease the AMPH-elicited steady-state current changes. Similarly, minocycline decreased the effects of forskolin-elicited steady-state current changes. Pretreatment with H89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; 10 μM), a protein kinase A inhibitor, inhibited AMPH-elicited action potential bursts and decreased AMPH-elicited steady-state current changes. These results suggest that the cAMP-protein kinase A signaling pathway and the steady-state current are involved in

  18. Anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-Ala-Gly-OH reduces dispersion of action potential duration during ischemia/reperfusion in rabbit hearts.

    PubMed

    Kjølbye, Anne Louise; Holstein-Rathlou, Niels-Henrik; Petersen, Jørgen Søberg

    2002-11-01

    During ischemia, cardiac gap junctions close and neighboring cells uncouple. This leads to slow conduction, increased dispersion of APD90 (duration from action potential beginning to 90% of repolarization), nonuniform anisotropy, and unidirectional conduction block, all of which favor the induction of reentry arrhythmias. It has been suggested that anti-arrhythmic peptides increase gap junction conductance during states of reduced coupling. The aim of this study was to test the effect of the anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-Ala-Gly-OH (HP-5) (10(-10) ) on dispersion of epicardial APD90 during both normokalemic and hypokalemic ischemia/reperfusion in isolated perfused rabbit hearts. HP-5 did not affect average APD90, heart rate, left ventricular contractility (LVP dP/dtmax), or mean coronary flow. HP-5 significantly reduced the epicardial APD dispersion during hypokalemic ischemia (HP-5 treated: 24.1 +/- 3.4 ms, untreated: 33.9 +/- 3.1 ms, p < 0.05 versus untreated) and during normokalemic reperfusion but not during normokalemic ischemia or control conditions. In addition, among untreated hearts subjected to hypokalemic ischemia/reperfusion, seven of 10 developed ventricular fibrillation, whereas only three of nine hearts perfused with HP-5 developed ventricular fibrillation. These results show that HP-5 is able to reduce APD90 dispersion during hypokalemic ischemia in rabbit hearts.

  19. Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study.

    PubMed

    Lesh, M D; Pring, M; Spear, J F

    1989-11-01

    Although slow conduction is a requirement for the preparation of sustained reentry, it alone is not sufficient for the initiation of reentry. Additionally, unidirectional block and recovery of excitability distal to the site of block must occur. Thus, a comprehensive description of the electrophysiological determinants of reentry must explain both slow conduction and unidirectional block. Although there is a growing body of research exploring the influence of axial resistivity and anisotropy on slow conduction, somewhat less is known about the relation of axial resistivity to spatial dispersion of action potential duration, a condition favorable to the development of unidirectional block. We hypothesized that when cells are well coupled, local differences in intrinsic action potential duration are not evident and that, as axial resistivity increases, local variation in action potential duration becomes manifest. We tested this hypothesis in a numerical model of electrical propagation in a grid of resistively coupled ionic current sources simulating a sheet of ventricular myocardium. Spatial dispersion of intrinsic action potential duration was simulated by varying the magnitude of the fully activated slow inward conductance in Beeler-Reuter membrane ionic kinetics. By then altering coupling resistance, we showed that dispersion of manifest action potential duration is masked in the setting of normal low-resistance cellular coupling and unmasked by increased axial resistance. When nonuniform anisotropy was simulated, dramatic pacing-site-dependent changes in both the pattern of activation and dispersion of action potential duration were noted. These findings may be important in understanding the mechanism of reentrant tachycardia initiation in the border zone of chronic, healed myocardial infarctions where evidence suggests that abnormal cellular coupling is the predominant electrophysiological derangement. In this study, we have shown, using a detailed ionic

  20. Active action potential propagation but not initiation in thalamic interneuron dendrites

    PubMed Central

    Casale, Amanda E.; McCormick, David A.

    2012-01-01

    Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

  1. Effect of an educational game on university students' learning about action potentials.

    PubMed

    Luchi, Kelly Cristina Gaviao; Montrezor, Luís Henrique; Marcondes, Fernanda K

    2017-06-01

    The aim of this study was to evaluate the effect of an educational game that is used for teaching the mechanisms of the action potentials in cell membranes. The game was composed of pieces representing the intracellular and extracellular environments, ions, ion channels, and the Na(+)-K(+)-ATPase pump. During the game activity, the students arranged the pieces to demonstrate how the ions move through the membrane in a resting state and during an action potential, linking the ion movement with a graph of the action potential. To test the effect of the game activity on student understanding, first-year dental students were given the game to play at different times in a series of classes teaching resting membrane potential and action potentials. In all experiments, students who played the game performed better in assessments. According to 98% of the students, the game supported the learning process. The data confirm the students' perception, indicating that the educational game improved their understanding about action potentials.

  2. Unmyelinated visceral afferents exhibit frequency dependent action potential broadening while myelinated visceral afferents do not.

    PubMed

    Li, Bai-Yan; Feng, Bin; Tsu, Hwa Y; Schild, John H

    2007-06-21

    Sensory information arising from visceral organ systems is encoded into action potential trains that propagate along afferent fibers to target nuclei in the central nervous system. These information streams range from tight patterns of action potentials that are well synchronized with the sensory transduction event to irregular, patternless discharge with no clear correlation to the sensory input. In general terms these afferent pathways can be divided into unmyelinated and myelinated fiber types. Our laboratory has a long standing interest in the functional differences between these two types of afferents in terms of the preprocessing of sensory information into action potential trains (synchrony, frequency, duration, etc.), the reflexogenic consequences of this sensory input to the central nervous system and the ionic channels that give rise to the electrophysiological properties of these unique cell types. The aim of this study was to determine whether there were any functional differences in the somatic action potential characteristics of unmyelinated and myelinated vagal afferents in response to different rates of sensory nerve stimulation. Our results showed that activity and frequency-dependent widening of the somatic action potential was quite prominent in unmyelinated but not myelinated vagal afferents. Spike broadening often leads to increased influx of Ca(2+) ions that has been associated with a diverse range of modulatory mechanisms both at the cell body and central synaptic terminations (e.g. increased neurotransmitter release.) We conclude that our observations are indicative of fundamentally different mechanisms for neural integration of sensory information arising from unmyelinated and myelinated vagal afferents.

  3. Photodynamic action of chlorin e6 on thymocyte plasmatic and mitochondrial membrane potentials

    NASA Astrophysics Data System (ADS)

    Gyulkhandanyan, Grigor V.

    2005-08-01

    Transmembrane potentials appear to be cell state sensitive characteristics and can give information about cell damage initial stage. Photodynamic action of the photosensitizer chlorin e6 on plasmatic and mitochondrial membrane potentials of the rat thymus lymphocytes was studied using voltage-sensitive dye rhodamine 6G. It has been revealed that mitochondrial membrane potential is more sensitive characteristic of membrane disfunction than plasmatic one at the cell photodamage.

  4. Optical magnetic detection of single-neuron action potentials using NV-diamond

    NASA Astrophysics Data System (ADS)

    Turner, Matthew; Barry, John; Schloss, Jennifer; Glenn, David; Walsworth, Ron

    2016-05-01

    A key challenge for neuroscience is noninvasive, label-free sensing of action potential dynamics in whole organisms with single-neuron resolution. Here, we report a new approach to this problem: using nitrogen-vacancy (NV) color centers in diamond to measure the time-dependent magnetic fields produced by single-neuron action potentials. We demonstrate our method using excised single neurons from two invertebrate species, marine worm and squid; and then by single-neuron action potential magnetic sensing exterior to whole, live, opaque marine worms for extended periods with no adverse effect. The results lay the groundwork for real-time, noninvasive 3D magnetic mapping of functional mammalian neuronal networks.

  5. Initiation and blocking of the action potential in an axon in weak ultrasonic or microwave fields.

    PubMed

    Shneider, M N; Pekker, M

    2014-05-01

    In this paper, we analyze the effect of the redistribution of the transmembrane ion channels in an axon caused by longitudinal acoustic vibrations of the membrane. These oscillations can be excited by an external source of ultrasound and weak microwave radiation interacting with the charges sitting on the surface of the lipid membrane. It is shown, using the Hodgkin-Huxley model of the axon, that the density redistribution of transmembrane sodium channels may reduce the threshold of the action potential, up to its spontaneous initiation. At the significant redistribution of sodium channels in the membrane, the rarefaction zones of the transmembrane channel density are formed, blocking the propagation of the action potential. Blocking the action potential propagation along the axon is shown to cause anesthesia in the example case of a squid axon. Various approaches to experimental observation of the effects considered in this paper are discussed.

  6. DBI potential, DBI inflation action and general Lagrangian relative to phantom, K-essence and quintessence

    SciTech Connect

    Zhang, Qing; Huang, Yong-Chang

    2011-11-01

    We derive a Dirac-Born-Infeld (DBI) potential and DBI inflation action by rescaling the metric. The determinant of the induced metric naturally includes the kinetic energy and the potential energy. In particular, the potential energy and kinetic energy can convert into each other in any order, which is in agreement with the limit of classical physics. This is quite different from the usual DBI action. We show that the Taylor expansion of the DBI action can be reduced into the form in the non-linear classical physics. These investigations are the support for the statement that the results of string theory are consistent with quantum mechanics and classical physics. We deduce the Phantom, K-essence, Quintessence and Generalized Klein-Gordon Equation from the DBI model.

  7. Optical coherence tomography for detection of compound action potential in Xenopus Laevis sciatic nerve

    NASA Astrophysics Data System (ADS)

    Troiani, Francesca; Nikolic, Konstantin; Constandinou, Timothy G.

    2016-03-01

    Due to optical coherence tomography (OCT) high spatial and temporal resolution, this technique could be used to observe the quick changes in the refractive index that accompany action potential. In this study we explore the use of time domain Optical Coherence Tomography (TD-OCT) for real time action potential detection in ex vivo Xenopus Laevis sciatic nerve. TD-OCT is the easiest and less expensive OCT technique and, if successful in detecting real time action potential, it could be used for low cost monitoring devices. A theoretical investigation into the order of magnitude of the signals detected by a TD-OCT setup is provided by this work. A linear dependence between the refractive index and the intensity changes is observed and the minimum SNR for which the setup could work is found to be SNR = 2 x 104.

  8. Initiation and blocking of the action potential in an axon in weak ultrasonic or microwave fields

    NASA Astrophysics Data System (ADS)

    Shneider, M. N.; Pekker, M.

    2014-05-01

    In this paper, we analyze the effect of the redistribution of the transmembrane ion channels in an axon caused by longitudinal acoustic vibrations of the membrane. These oscillations can be excited by an external source of ultrasound and weak microwave radiation interacting with the charges sitting on the surface of the lipid membrane. It is shown, using the Hodgkin-Huxley model of the axon, that the density redistribution of transmembrane sodium channels may reduce the threshold of the action potential, up to its spontaneous initiation. At the significant redistribution of sodium channels in the membrane, the rarefaction zones of the transmembrane channel density are formed, blocking the propagation of the action potential. Blocking the action potential propagation along the axon is shown to cause anesthesia in the example case of a squid axon. Various approaches to experimental observation of the effects considered in this paper are discussed.

  9. A phantom axon setup for validating models of action potential recordings.

    PubMed

    Rossel, Olivier; Soulier, Fabien; Bernard, Serge; Guiraud, David; Cathébras, Guy

    2016-08-01

    Electrode designs and strategies for electroneurogram recordings are often tested first by computer simulations and then by animal models, but they are rarely implanted for long-term evaluation in humans. The models show that the amplitude of the potential at the surface of an axon is higher in front of the nodes of Ranvier than at the internodes; however, this has not been investigated through in vivo measurements. An original experimental method is presented to emulate a single fiber action potential in an infinite conductive volume, allowing the potential of an axon to be recorded at both the nodes of Ranvier and the internodes, for a wide range of electrode-to-fiber radial distances. The paper particularly investigates the differences in the action potential amplitude along the longitudinal axis of an axon. At a short radial distance, the action potential amplitude measured in front of a node of Ranvier is two times larger than in the middle of two nodes. Moreover, farther from the phantom axon, the measured action potential amplitude is almost constant along the longitudinal axis. The results of this new method confirm the computer simulations, with a correlation of 97.6 %.

  10. Incorporated Fish Oil Fatty Acids Prevent Action Potential Shortening Induced by Circulating Fish Oil Fatty Acids

    PubMed Central

    Ruijter, Hester M. Den; Verkerk, Arie O.; Coronel, Ruben

    2010-01-01

    Increased consumption of fatty fish, rich in omega-3-polyunsaturated fatty acids (ω3-PUFAs) reduces the severity and number of arrhythmias. Long-term ω3-PUFA-intake modulates the activity of several cardiac ion channels leading to cardiac action potential shortening. Circulating ω3-PUFAs in the bloodstream and incorporated ω3-PUFAs in the cardiac membrane have a different mechanism to shorten the action potential. It is, however, unknown whether circulating ω3-PUFAs in the bloodstream enhance or diminish the effects of incorporated ω3-PUFAs. In the present study, we address this issue. Rabbits were fed a diet rich in fish oil (ω3) or sunflower oil (ω9, as control) for 3 weeks. Ventricular myocytes were isolated by enzymatic dissociation and action potentials were measured using the perforated patch-clamp technique in the absence and presence of acutely administered ω3-PUFAs. Plasma of ω3 fed rabbits contained more free eicosapentaenoic acid (EPA) and isolated myocytes of ω3 fed rabbits contained higher amounts of both EPA and docosahexaenoic acid (DHA) in their sarcolemma compared to control. In the absence of acutely administered fatty acids, ω3 myocytes had a shorter action potential with a more negative plateau than ω9 myocytes. In the ω9 myocytes, but not in the ω3 myocytes, acute administration of a mixture of EPA + DHA shortened the action potential significantly. From these data we conclude that incorporated ω3-PUFAs into the sarcolemma and acutely administered ω3 fatty acids do not have a cumulative effect on action potential duration and morphology. As a consequence, patients with a high cardiac ω3-PUFA status will probably not benefit from short term ω3 supplementation as an antiarrhythmic therapy. PMID:21423389

  11. Selective effects of potassium elevations on glutamate signaling and action potential conduction in hippocampus.

    PubMed

    Meeks, Julian P; Mennerick, Steven

    2004-01-07

    High-frequency synaptic transmission is depressed by moderate rises in the extracellular potassium concentration ([K+]o). Previous reports have indicated that depression of action potential signaling may underlie the synaptic depression. Here, we investigated the specific contribution of K+-induced action potential changes to synaptic depression. We found that glutamatergic transmission in the hippocampal area CA1 was significantly depressed by 8-10 mM [K+]o, but that GABAergic transmission remained intact. Riluzole, a drug that slows recovery from inactivation of voltage-gated sodium channels (NaChs), interacts with subthreshold [K+]o to depress afferent volleys and EPSCs strongly. Thus, elevated [K+]o likely depresses synapses by slowing NaCh recovery from inactivation. It is unclear from previous studies whether [K+]o-induced action potential depression is caused by changes in initiation, reliability, or waveform. We investigated these possibilities explicitly. [K+]o-induced afferent volley depression was independent of stimulus strength, suggesting that changes in action potential initiation do not explain [K+]o-induced depression. Measurements of action potentials from single axons revealed that 8 mM [K+]o increased conduction failures in a subpopulation of fibers and depressed action potential amplitude in all fibers. Together, these changes quantitatively account for the afferent volley depression. We estimate that conduction failure explains more than half of the synaptic depression observed at 8 mM [K+]o, with the remaining depression likely explained by waveform changes. These mechanisms of selective sensitivity of glutamate release to [K+]o accumulation represent a unique neuromodulatory mechanism and a brake on runaway excitation.

  12. The neuroendocrine action potential. Winner of the 2008 Frank Beach Award in Behavioral Neuroendocrinology.

    PubMed

    Hofmann, Hans A

    2010-09-01

    Animals are remarkably well equipped to respond to changes in their environment across different time scales and levels of biological organization. Here, I introduce a novel perspective that incorporates the three main processes the nervous system uses to integrate and process information: electrophysiological, genomic, and neuroendocrine action potentials. After discussing several examples of neuroendocrine action potentials, I lay out the commonalities of these temporally organized responses and how they might be interrelated with electrophysiological activity and genomic responses. This framework provides a novel outlook on longstanding questions in behavioral neuroendocrinology and suggests exciting new avenues for further research that will integrate across disciplines and levels of biological organization.

  13. Effects of some heavy metals on the action potentials of an identified Helix pomatia photosensitive neuron.

    PubMed

    Kartelija, Gordana; Radenović, Lidija; Todorović, Natasa; Nedeljković, Miodrag

    2005-06-01

    In the photosensitive MB neuron in the left parietal ganglion of Helix pomatia, the onset of light prolongs significantly (by about 40%) the duration of the action potential. The broadening of the action potential after the onset of light was found to be due to its calcium component and could not be induced after blocking Ca(2+) channels by Cd(2+) and Pb(2+) and in absence of Ca(2+) in medium. The blocking effect of both compounds was reversible. It was found that CdCl(2) exhibited a more intense blocking effect than PbCl(2).

  14. Naturalistic stimulation changes the dynamic response of action potential encoding in a mechanoreceptor

    PubMed Central

    Pfeiffer, Keram; French, Andrew S.

    2015-01-01

    Naturalistic signals were created from vibrations made by locusts walking on a Sansevieria plant. Both naturalistic and Gaussian noise signals were used to mechanically stimulate VS-3 slit-sense mechanoreceptor neurons of the spider, Cupiennius salei, with stimulus amplitudes adjusted to give similar firing rates for either stimulus. Intracellular microelectrodes recorded action potentials, receptor potential, and receptor current, using current clamp and voltage clamp. Frequency response analysis showed that naturalistic stimulation contained relatively more power at low frequencies, and caused increased neuronal sensitivity to higher frequencies. In contrast, varying the amplitude of Gaussian stimulation did not change neuronal dynamics. Naturalistic stimulation contained less entropy than Gaussian, but signal entropy was higher than stimulus in the resultant receptor current, indicating addition of uncorrelated noise during transduction. The presence of added noise was supported by measuring linear information capacity in the receptor current. Total entropy and information capacity in action potentials produced by either stimulus were much lower than in earlier stages, and limited to the maximum entropy of binary signals. We conclude that the dynamics of action potential encoding in VS-3 neurons are sensitive to the form of stimulation, but entropy and information capacity of action potentials are limited by firing rate. PMID:26578975

  15. Event-related potentials to intact and disrupted actions in children and adults

    PubMed Central

    Pace, Amy; Carver, Leslie J.; Friend, Margaret

    2013-01-01

    The current research used event-related potentials (ERPs) to investigate neurophysiological responses to intact and disrupted actions embedded within an event in children and adults. Responses were recorded as children (24-month-olds) and adults observed a relatively novel event composed of three actions. In one condition pauses were inserted at intact boundaries (i.e., at the endpoint of each action), whereas in the other condition they were inserted at breakpoints that disrupted the action (i.e., in the middle of each action). Evoked responses revealed differences across conditions in both groups; disrupted actions elicited a prolonged negative slow wave from 100 to 700 ms in children, whereas adults demonstrated two distinct negative peaks between 50–150 and 250–350 ms. These findings contribute the first electrophysiological evidence that children readily detect disruptions to ongoing events by the end of the second year, even with limited exposure to the event itself. Furthermore, they suggest that adults rely on two distinct mechanisms when processing novel events. Results are discussed in relation to the role of perceptual and conceptual levels of analysis in the development of action processing. PMID:23374603

  16. Investigating a Potential Auxin-Related Mode of Hormetic/Inhibitory Action of the Phytotoxin Parthenin.

    PubMed

    Belz, Regina G

    2016-01-01

    Parthenin is a metabolite of Parthenium hysterophorus and is believed to contribute to the weed's invasiveness via allelopathy. Despite the potential of parthenin to suppress competitors, low doses stimulate plant growth. This biphasic action was hypothesized to be auxin-like and, therefore, an auxin-related mode of parthenin action was investigated using two approaches: joint action experiments with Lactuca sativa, and dose-response experiments with auxin/antiauxin-resistant Arabidopsis thaliana genotypes. The joint action approach comprised binary mixtures of subinhibitory doses of the auxin 3-indoleacetic acid (IAA) mixed with parthenin or one of three reference compounds [indole-3-butyric acid (IBA), 2,3,5-triiodobenzoic acid (TIBA), 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB)]. The reference compounds significantly interacted with IAA at all doses, but parthenin interacted only at low doses indicating that parthenin hormesis may be auxin-related, in contrast to its inhibitory action. The genetic approach investigated the response of four auxin/antiauxin-resistant mutants and a wildtype to parthenin or two reference compounds (IAA, PCIB). The responses of mutant plants to the reference compounds confirmed previous reports, but differed from the responses observed for parthenin. Parthenin stimulated and inhibited all mutants independent of resistance. This provided no indication for an auxin-related action of parthenin. Therefore, the hypothesis of an auxin-related inhibitory action of parthenin was rejected in two independent experimental approaches, while the hypothesis of an auxin-related stimulatory effect could not be rejected.

  17. Action potential propagation and propagation block by GABA in rat posterior pituitary nerve terminals.

    PubMed Central

    Jackson, M B; Zhang, S J

    1995-01-01

    1. A theoretical model was developed to investigate action potential propagation in posterior pituitary nerve terminals. This model was then used to evaluate the efficacy of depolarizing and shunting GABA responses on action potential propagation. 2. Experimental data obtained from the posterior pituitary with patch clamp techniques were used to derive empirical expressions for the voltage and time dependence of the nerve terminal Na+ and K+ channels. The essential structure employed here was based on anatomical and cable data from the posterior pituitary, and consisted of a long cylindrical axon (diameter, 0.5 mm) with a large spherical swelling (diameter, 4-21 mm) in the middle. 3. In the absence of an inhibitory conductance, simulated action potentials propagated with high fidelity through the nerve terminal. Swellings could block propagation, but only when sizes exceeded those observed in the posterior pituitary. Adding axonal branches reduced the critical size only slightly. These results suggested that action potentials invade the entire posterior pituitary nerve terminal in the absence of inhibition or depression. 4. The addition of inhibitory conductance to a swelling caused simulated action potentials to fail at the swelling. Depolarizing inhibitory conductances were 1.6 times more effective than shunting inhibitory conductances in blocking propagation. 5. Inhibitory conductances within the range of experimentally observed magnitudes and localized to swellings in the observed range of sizes were too weak to block simulated action potentials. However, twofold enhancement of GABA responses by neurosteroid resulted in currents strong enough to block propagation in realistic swelling sizes. 6. GABA could block simulated propagation without neurosteroid enhancement provided that GABA was present throughout a region in the order of a few hundred micrometres. For this widespread inhibition depolarizing conductance was 2.2 times more effective than shunting

  18. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    SciTech Connect

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  19. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 alpha subunit.

    PubMed

    Xu, H; Barry, D M; Li, H; Brunet, S; Guo, W; Nerbonne, J M

    1999-10-01

    An in vivo experimental strategy, involving cardiac-specific expression of a mutant Kv 2.1 subunit that functions as a dominant negative, was exploited in studies focused on exploring the role of members of the Kv2 subfamily of pore-forming (alpha) subunits in the generation of functional voltage-gated K(+) channels in the mammalian heart. A mutant Kv2.1 alpha subunit (Kv2.1N216) was designed to produce a truncated protein containing the intracellular N terminus, the S1 membrane-spanning domain, and a portion of the S1/S2 loop. The truncated Kv2.1N216 was epitope tagged at the C terminus with the 8-amino acid FLAG peptide to generate Kv2. 1N216FLAG. No ionic currents are detected on expression of Kv2. 1N216FLAG in HEK-293 cells, although coexpression of this construct with wild-type Kv2.1 markedly reduced the amplitudes of Kv2. 1-induced currents. Using the alpha-myosin heavy chain promoter to direct cardiac specific expression of the transgene, 2 lines of Kv2. 1N216FLAG-expressing transgenic mice were generated. Electrophysiological recordings from ventricular myocytes isolated from these animals revealed that I(K, slow) is selectively reduced. The attenuation of I(K, slow) is accompanied by marked action potential prolongation, and, occasionally, spontaneous triggered activity (apparently induced by early afterdepolarizations) is observed. The time constant of inactivation of I(K, slow) in Kv2. 1N216FLAG-expressing cells (mean+/-SEM=830+/-103 ms; n=17) is accelerated compared with the time constant of I(K, slow) inactivation (mean+/-SEM=1147+/-57 ms; n=25) in nontransgenic cells. In addition, unlike I(K, slow) in wild-type cells, the component of I(K, slow) remaining in the Kv2.1N216FLAG-expressing cells is insensitive to 25 mmol/L tetraethylammonium. Taken together, these observations suggest that there are 2 distinct components of I(K, slow) in mouse ventricular myocytes and that Kv2 alpha subunits underlie the more slowly inactivating, tetraethylammonium

  20. Zinc-dependent action potentials in giant neurons of the snail, Euhadra quaestia.

    PubMed

    Kawa, K

    1979-09-14

    In giant neurons of subesophageal ganglion of the Japanese land snail, Euhadra quaestia Deshayes, permeation of Zn ions through Ca channels were investigated with a conventional current clamp method. All-or-none action potentials of long duration (90 to 120 sec) were evoked in 24 mM Zn containing salines. The overshoots were about +10 mV and the maximum rate of rises (MRRs) was about 2.9 V/sec. The amplitudes and the MRRs of the action potentials depended on external Zn ion concentrations. The action potentials were suppressed by specific Ca-channel inhibitors such as Co2+, La3+ and Verapamil, but they were resistant to Na-channel inhibitor, tetrodotoxin, even at 30 microM. It is concluded that these action potentials are generated by Zn ions permeating Ca channels in snail neuronal membrane. On the basis of Hagiwara and Takahashi's (S. Hagiwara & K. Takahashi, 1967, J. Gen. Physiol. 50:583) model of Ca channels, it is inferred that Zn ions are 5 to 10 times stronger in affinity to Ca channels than Ca ions, but 10 to 20 times less permeable.

  1. Youth Participatory Action Research and Educational Transformation: The Potential of Intertextuality as a Methodological Tool

    ERIC Educational Resources Information Center

    Bertrand, Melanie

    2016-01-01

    In this article, Melanie Bertrand explores the potential of using the concept of intertextuality--which captures the way snippets of written or spoken text from one source become incorporated into other sources--in the study and practice of youth participatory action research (YPAR). Though this collective and youth-centered form of research…

  2. Ca2+ involvement in the action potential generation of myenteric neurones in the rat oesophagus.

    PubMed

    De Laet, A; Cornelissen, W; Adriaensen, D; Van Bogaert, P-P; Scheuermann, D W; Timmermans, J-P

    2002-04-01

    Intracellular recordings were used to study the physiological behaviour of rat oesophageal myenteric neurones, which are embedded in striated muscle. Injection of depolarizing pulses evoked action potentials with a clear 'shoulder' in all neurones. This shoulder disappeared under low Ca2+/high Mg2+ conditions. Tetrodotoxin (TTX; 1 micromol L-1) did not impede spike firing, whereas under combined TTX and low Ca2+/high Mg2+ conditions the action potentials were completely abolished, indicating that TTX- resistant action potentials are mediated by a Ca2+ current. Further experiments with omega-conotoxin GVIA (100 nmol L-1) revealed that these Ca2+ currents enter the cell via N-type voltage-activated Ca2+ channels (see also accompanying paper). Tetraethylammonium (10 mmol L-1) caused broadening of the action potentials, which probably resulted from prolonged Ca2+ influx due to blockade of the delayed rectifier K+ channel. Although Ca2+ appears to be involved in the spike generation of all rat oesophageal myenteric neurones, only a minority (14%) shows a slow afterhyperpolarization. Thus, no strict correlation exists between the presence of a shoulder and a slow afterhyperpolarization. Furthermore, morphological identification of 25 of the impaled neurones revealed that there was no strict correlation between morphology and electrophysiological behaviour. Consequently, rat oesophageal myenteric neurones appear to differ in several aspects from myenteric neurones in smooth muscle regions of the gastrointestinal tract.

  3. The Transformative Potential of Action Research and ICT in the Second Language (L2) Classroom

    ERIC Educational Resources Information Center

    Farren, Margaret; Crotty, Yvonne; Kilboy, Laura

    2015-01-01

    This study shows the transformative potential of action research and information and communications technology (ICT) in the second language (L2) classroom. Two enquiries from teacher-researchers are detailed in the article. Their engagement in a collaborative professional development Masters programme was pivotal in designing and implementing ICT…

  4. Viewing Objects and Planning Actions: On the Potentiation of Grasping Behaviours by Visual Objects

    ERIC Educational Resources Information Center

    Makris, Stergios; Hadar, Aviad A.; Yarrow, Kielan

    2011-01-01

    How do humans interact with tools? Gibson (1979) suggested that humans perceive directly what tools afford in terms of meaningful actions. This "affordances" hypothesis implies that visual objects can potentiate motor responses even in the absence of an intention to act. Here we explore the temporal evolution of motor plans afforded by common…

  5. Ecstasy and methamphetamine elicit action potential bursts via different mechanisms in a central snail neuron.

    PubMed

    Lin, Pei-Lin; Tsai, Ming-Cheng; Lu, Guan-Ling; Lu, Dah-Yuu; Chuang, Chieh-Min; Yang, Han-Yin; Huang, Shiang-Suo; Chen, Yi-Hung

    2010-01-01

    This study sought to determine the effects of (+) methamphetamine (METH) and its ring-substituted analog (+/-)3,4-methylenedioxymethamphetamine (MDMA; ecstasy) on electrophysiological behavior and their relationships to second messenger systems in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. Extracellular application of MDMA at 1mM and METH at 3mM elicited action potential bursts that were not blocked after immersing the neurons in Ca(2+)-free solution. Notably, MDMA- (1mM) elicited action potential bursts were blocked by pretreatment with the protein kinase C (PKC) inhibitors chelerythrine (20 microM) and Ro 31-8220 (20 microM), but not by the PKA inhibitors KT-5720 (10 microM) and H89 (10 microM). The PKC activator phorbol 12,13-dibutyrate (PDBu; 3 microM), but not the PKA activator forskolin (50 microM), facilitated the induction of bursts elicited by MDMA at a lower concentration (0.3mM). In contrast, METH- (3mM) elicited action potential bursts were blocked by pretreatment with KT-5720 (10 microM) and H89 (10 microM), but not by chelerythrine (20 microM) and Ro 31-8220 (20 microM). Forskolin (50 microM), but not PDBu (3 microM) facilitated the induction of bursts elicited by METH at a lower concentration (1mM). Tetraethylammonium chloride (TEA), a blocker of the delayed rectifying K(+) current (I(KD)), did not elicit bursts at a concentration of 5mM but did facilitate the induction of action potential bursts elicited by both METH and MDMA. Voltage clamp studies revealed that both METH and MDMA decreased the TEA-sensitive I(KD) of the RP4 neuron. Forskolin (50 microM) or dibutyryl cAMP (1mM), a membrane-permeable cAMP analog, alone did not elicit action potential bursts. However, co-administration with forskolin (50 microM) and TEA (5mM) or co-administration with dibutyryl cAMP (1mM) and TEA (50mM) elicited action potential bursts in the presence of the PKC inhibitor chelerythrine (20 microM). Similarly, PDBu (10 microM) or phorbol

  6. Dependence of transient and residual calcium dynamics on action-potential patterning during neuropeptide secretion.

    PubMed

    Muschol, M; Salzberg, B M

    2000-09-15

    Secretion of the neuropeptide arginine vasopressin (AVP) from the neurohypophysis is optimized by short phasic bursts of action potentials with a mean intraburst frequency around 10 Hz. Several hypotheses, most prominently action-potential broadening and buildup of residual calcium, have been proposed to explain this frequency dependence of AVP release. However, how either of these mechanisms would optimize release at any given frequency remains an open question. We have addressed this issue by correlating the frequency-dependence of intraterminal calcium dynamics and AVP release during action-potential stimulation. By monitoring the intraterminal calcium changes with low-affinity indicator dyes and millisecond time resolution, the signal could be dissected into three separate components: rapid Ca(2+) rises (Delta[Ca(2+)](tr)) related to action-potential depolarization, Ca(2+) extrusion and/or uptake, and a gradual increase in residual calcium (Delta[Ca(2+)](res)) throughout the stimulus train. Action-potential stimulation modulated all three components in a manner dependent on both the stimulation frequency and number of stimuli. Overall, the cumulative Delta[Ca(2+)](tr) amplitude initially increased with f(Stim) and then rapidly deteriorated, with a maximum around f(Stim)

  7. Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects

    PubMed Central

    Lou, Yu; Buchanan, Ann M.; Chen, Shuguang; Ford, Susan L.; Gould, Elizabeth; Margolis, David; Spreen, William R.

    2016-01-01

    Abstract A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization. PMID:27162089

  8. Arrhythmogenic remodelling of activation and repolarization in the failing human heart.

    PubMed

    Holzem, Katherine M; Efimov, Igor R

    2012-11-01

    Heart failure is a major cause of disability and death worldwide, and approximately half of heart failure-related deaths are sudden and presumably due to ventricular arrhythmias. Patients with heart failure have been shown to be at 6- to 9-fold increased risk of sudden cardiac death compared to the general population. (AHA. Heart Disease and Stroke Statistics-2003 Update. Heart and Stroke Facts. Dallas, TX: American Heart Association; 2002) Thus, electrophysiological remodelling associated with heart failure is a leading cause of disease mortality and has been a major investigational focus examined using many animal models of heart failure. While these studies have provided an important foundation for understanding the arrhythmogenic pathophysiology of heart failure, the need for corroborating studies conducted on human heart tissue has been increasingly recognized. Many human heart studies of conduction and repolarization remodelling have now been published and shed some light on important, potentially arrhythmogenic, changes in human heart failure. These studies are being conducted at multiple experimental scales from isolated cells to whole-tissue preparations and have provided insight into regulatory mechanisms such as decreased protein expression, alternative mRNA splicing of ion channel genes, and defective cellular trafficking. Further investigations of heart failure in the human myocardium will be essential for determining possible therapeutic targets to prevent arrhythmia in heart failure and for facilitating the translation of basic research findings to the clinical realm.

  9. Toward a system to measure action potential on mice brain slices with local magnetoresistive probes

    SciTech Connect

    Amaral, J.; Cardoso, S.; Freitas, P. P.; Sebastiao, A. M.

    2011-04-01

    This work combines an electrophysiological system with a magnetoresistive chip to measure the magnetic field created by the synaptic/action potential currents. The chip, with 15 spin valve sensors, was designed to be integrated in a recording chamber for submerged mice brain slices used for synaptic potential measurements. Under stimulation (rectangular pulses of 0.1 ms every 10 s) through a concentric electrode placed near the CA3/CA1 border of the hippocampus, the spin valve sensor readout signals with 20 {mu}V amplitude and a pulse length of 20 to 30 ms were recorded only in the pyramidal cell bodies region and can be interpreted as being derived from action potentials/currents.

  10. Toward a system to measure action potential on mice brain slices with local magnetoresistive probes

    NASA Astrophysics Data System (ADS)

    Amaral, J.; Cardoso, S.; Freitas, P. P.; Sebastião, A. M.

    2011-04-01

    This work combines an electrophysiological system with a magnetoresistive chip to measure the magnetic field created by the synaptic/action potential currents. The chip, with 15 spin valve sensors, was designed to be integrated in a recording chamber for submerged mice brain slices used for synaptic potential measurements. Under stimulation (rectangular pulses of 0.1 ms every 10 s) through a concentric electrode placed near the CA3/CA1 border of the hippocampus, the spin valve sensor readout signals with 20 μV amplitude and a pulse length of 20 to 30 ms were recorded only in the pyramidal cell bodies region and can be interpreted as being derived from action potentials/currents.

  11. The influence of regional anaesthesia and local anaesthetics on cardiac repolarization.

    PubMed

    Biernawska, Jowita; Kaźmierczak, Jarosław; Kotfis, Katarzyna; Żukowski, Maciej

    2016-01-01

    The normal function of the heart muscle is the result of electro-mechanic and hemodynamic coupling. Modification of the structure and activity of ion channels within the cardiomyocytes may induce cardiac arrhythmias. Electrophysiological mechanisms of arrhythmia, generated by a prolonged period of repolarization, result either from conduction disturbances (reentry mechanism) and/or the induction of beats (early after-depolarizations). Local anaesthetic drug deposition does not affect the repolarization period, as long as the concentration of the free drug in the plasma does not reach the critical value to cause toxic effects in the cardiomyocytes. When analyzing the effect of regional anaesthesia on the repolarization period it is essential to acknowledge the activity or blockade of adrenergic fibres. Blocking the sympathetic fibres', including level T1 to T4, leads to a shortening of the QT interval and a reduction of QT dispersion. Adrenergic blockade as a result of spinal anaesthesia causes severe adrenergic activity above the level of the block and therefore prolongs repolarization. Stellate ganglion block on the right side causes a significant prolongation of the QT interval and QT dispersion. Regardless of the reasons for prolongation of the repolarization period (congenital or acquired), vigilance is required within the perioperative anaesthetic management of a patient, so as not to lead to the occurrence of ventricular arrhythmias. Regional anaesthesia techniques and properly used local anaesthetic drugs are regarded as being safe in these patients.

  12. Early repolarization: a rare primary arrhythmic syndrome and common modifier of arrhythmic risk.

    PubMed

    Roberts, Jason D; Gollob, Michael H

    2013-07-01

    Despite longstanding beliefs, early repolarization is not always a benign electrocardiographic observation. Its association with increased arrhythmic events has been observed in 2 strikingly different groups of individuals, retrospectively in young subjects with idiopathic ventricular fibrillation and in long-term cohort studies from the general population. This form of primary electrical disease is now referred to as the early repolarization syndrome and has mechanistically been demonstrated to occur secondary to a transmural gradient of early cellular repolarization, resulting in the presence of an ST-elevation pattern and J-waves merged within or offset from the terminal QRS complex. In addition to creating a milieu of increased arrhythmic risk in isolation, an increasing number of studies have highlighted that the presence of early repolarization and J-waves may provide a baseline electrical substrate that modifies the risk of malignant arrhythmias in other clinical settings, such as acute myocardial ischemia. The challenge ahead lies in discerning when early repolarization may represent an ominous ECG marker, as opposed to a benign entity.

  13. [Mechanism of induction and termination of ventricular fibrillation--significance of dispersion of ventricular repolarization].

    PubMed

    Behrens, S; Zabel, M; Franz, M R; Schultheiss, H P

    2000-12-01

    It has been known for many years that ventricular fibrillation may be induced and terminated by electrical field stimuli. Recent experimental studies have shown that both fibrillation and defibrillation have a common electrophysiologic mechanism that is based on the interaction between the electrical field stimulus and ventricular repolarization. Ventricular fibrillation will be induced if the field stimulus is applied with the area of vulnerability, this area of vulnerability is defined two dimensionally by the shock coupling interval and shock strength, and is modified by the configuration of the shock. A field shock that is applied within the area of vulnerability causes heterogeneity of ventricular repolarization immediately after the shock (postshock dispersion), thereby enabling the development of circuit movements and reentry, and resulting in ventricular fibrillation. High energy shocks, however, that are applied above the area of vulnerability (i.e., above the upper limit of vulnerability) will not induce ventricular fibrillation due to homogeneous prolongation of repolarization and a resulting small postshock dispersion. In analogy, ventricular fibrillation will continue after unsuccessful low-energy defibrillation shocks due to high postshock dispersion, whereas a high-energy shock will synchronize ventricular repolarization, thereby causing small postshock dispersion and termination of ventricular fibrillation. This paper describes the relation between fibrillation, defibrillation and ventricular repolarization based on experimental findings. A possible clinical application of these findings is that the upper limit of vulnerability may be used as a surrogate for the defibrillation threshold. Thus, defibrillation threshold testing may not be necessary during future implantations of automatic cardioverter defibrillators.

  14. The effect of adrenaline on the temperature dependency of cardiac action potentials in pink salmon Oncorhynchus gorbuscha.

    PubMed

    Ballesta, S; Hanson, L M; Farrell, A P

    2012-04-01

    Using sharp electrode impalement, action potentials recorded from atrial and ventricular tissue of pink salmon Oncorhynchus gorbuscha generally decreased in duration with increasing test temperature (6, 10, 16 and 20° C). Stimulation of the tissue using 500 nM adrenaline had no significant effect on the duration of the atrial action potential at any test temperature but lengthened the ventricular action potential by ~17%.

  15. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve.

    PubMed

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC50 values of 1.2 and 1.5mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC50=0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  16. Simple techniques suitable for student use to record action potentials from the frog heart.

    PubMed

    Yoshida, S

    2001-12-01

    Demonstrating action potentials during class experiments is very educational for science students. It is not easy, however, to obtain a stable intracellular recording of action potentials from the conventionally used skeletal muscle cells, because the tip of a glass microelectrode often comes out or breaks due to muscle contraction. Here, I present a much simpler recording method using a flexible polyethylene electrode with a wide orifice (approximately 1 mm) for a bullfrog heart beating on automaticity. Extracellular recordings of action potentials (electrocardiogram) can be obtained by placing an electrode on the cardiac surface, and transmembrane potentials can be obtained by rupturing the membrane with negative pressure, i.e., whole cell configuration. Once attached to the heart by suction, the polyethylene electrode does not easily come off during contraction of the heart. Perfusion of the heart via the postcaval vein offers us opportunities for observing the effects of either changing ionic compositions of solutions or applying drugs. The techniques shown here provide a simple and convenient way to perform a variety of class experiments.

  17. Event-related potentials reveal early activation of body part representations in action concept comprehension.

    PubMed

    Lu, Aitao; Liu, Jing; Zhang, John X

    2012-03-09

    With tasks involving action concept comprehension, many fMRI studies have reported brain activations in sensori-motor regions specific to effectors of the referent action. There is relatively less evidence whether such activations reflect early semantic access or late conceptual re-processing. Here we recorded event-related potentials when participants recognized noun-verb pairs. For Congruent pairs, the verb was the one most commonly associated with the noun (e.g., football-kick). Compared with a control condition, verbs in Congruent pairs showed priming effects in the time windows of 100-150 ms and 210-260 ms. Such activation seems to be specific to body part but not other aspects of the action as similar priming effect was also found when the noun and verb involved different actions though sharing the same body part (e.g., football-jump), documenting for the first time the early activation of body part representations in action concept comprehension.

  18. Evidence that the compound action potential (CAP) from the auditory nerve is a stationary potential generated across dura mater.

    PubMed

    Brown, Daniel J; Patuzzi, Robert B

    2010-08-01

    We have investigated the generation of the compound action potential (CAP) from the auditory nerve of guinea pigs. Responses to acoustic tone-bursts were recorded from the round window (RW), throughout the cochlear fluids, from the surface of the cochlear nucleus, from the central end of the auditory nerve after removal of the cochlear nucleus, from the scalp vertex, and from the contralateral ear. Responses were compared before, during and after experimental manipulations including pharmacological blockade of the auditory nerve, section of the auditory nerve, section of the efferent nerves, removal of the cochlear nucleus, and focal cooling of the cochlear nerve and/or cochlear nucleus. Regardless of the waveform changes occurring with these manipulations, the responses were similar in waveform but inverted polarity across the internal auditory meatus. The CAP waveforms were very similar before and after removal of the cochlear nucleus, apart from transient changes that could last many minutes. This suggests that the main CAP components are generated entirely by the eighth nerve. Based on previous studies and a clear understanding of the generation of extracellular potentials, we suggest that the early components in the responses recorded from the round window, from the cochlear fluids, from the surface of the cochlear nucleus, or from the scalp are a far-field or stationary potential, generated when the circulating action currents associated with each auditory neurone encounters a high extracellular resistance as it passes through the dura mater.

  19. Excitatory amino acids acting on metabotropic glutamate receptors broaden the action potential in hippocampal neurons.

    PubMed

    Hu, G Y; Storm, J F

    1991-12-24

    Activation of metabotropic glutamate receptors (mGluRs, QP or ACPD receptors) has recently been shown to cause depolarization, blockade of the slow after-hyperpolarization and depression of calcium currents in hippocampal pyramidal cells. Here, we report evidence for a new mGluR-mediated effect: slowing of the spike repolarization in CA1 cells in rat hippocampal slices. During blockade of the ionotropic glutamate receptors, the mGluR agonists trans-1-amino-cyclopentyl-1,3-dicarboxylate (t-ACPD), quisqualate or L-glutamate caused spike broadening. In contrast, the ionotropic receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) was ineffective. The spike broadening may act in concert with the other mGluR effects, e.g. by further increasing the influx of Ca2+ ions which, in turn, may contribute to synaptic modulation.

  20. Modeling the attenuation and failure of action potentials in the dendrites of hippocampal neurons.

    PubMed Central

    Migliore, M

    1996-01-01

    We modeled two different mechanisms, a shunting conductance and a slow sodium inactivation, to test whether they could modulate the active propagation of a train of action potentials in a dendritic tree. Computer simulations, using a compartmental model of a pyramidal neuron, suggest that each of these two mechanisms could account for the activity-dependent attenuation and failure of the action potentials in the dendrites during the train. Each mechanism is shown to be in good qualitative agreement with experimental findings on somatic or dendritic stimulation and on the effects of hyperpolarization. The conditions under which branch point failures can be observed, and a few experimentally testable predictions, are presented and discussed. PMID:8913580

  1. Regulation of cough and action potentials by voltage-gated Na channels.

    PubMed

    Carr, Michael J

    2013-10-01

    The classical role ascribed to voltage-gated Na channels is the conduction of action potentials. Some excitable tissues such as cardiac muscle and skeletal muscle predominantly express a single voltage-gated Na channels isoform. Of the nine voltage-gated Na channels, seven are expressed in neurons, of these Nav 1.7, 1.8 and 1.9 are expressed in sensory neurons including vagal sensory neurons that innervate the airways and initiate cough. Nav 1.7 and Nav 1.9 are of particular interest as they represent two extremes in the functional diversity of voltage-gated Na channels. Voltage-gated Na channel isoforms expressed in airway sensory neurons produce multiple distinct Na currents that underlie distinct aspects of sensory neuron function. The interaction between voltage-gated Na currents underlies the characteristic ability of airway sensory nerves to encode encounters with irritant stimuli into action potential discharge and evoke the cough reflex.

  2. FHF-independent conduction of action potentials along the leak-resistant cerebellar granule cell axon

    PubMed Central

    Dover, Katarzyna; Marra, Christopher; Solinas, Sergio; Popovic, Marko; Subramaniyam, Sathyaa; Zecevic, Dejan; D'Angelo, Egidio; Goldfarb, Mitchell

    2016-01-01

    Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. Here, we report several unanticipated passive and active properties of the cerebellar granule cell's unmyelinated axon. Whereas spike initiation at the axon initial segment relies on sodium channel (Nav)-associated fibroblast growth factor homologous factor (FHF) proteins to delay Nav inactivation, distal axonal Navs show little FHF association or FHF requirement for high-frequency transmission, velocity and waveforms of conducting action potentials. In addition, leak conductance density along the distal axon is estimated as <1% that of somatodendritic membrane. The faster inactivation rate of FHF-free Navs together with very low axonal leak conductance serves to minimize ionic fluxes and energetic demand during repetitive spike conduction and at rest. The absence of FHFs from Navs at nodes of Ranvier in the central nervous system suggests a similar mechanism of current flux minimization along myelinated axons. PMID:27666389

  3. Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites.

    PubMed

    Bakkum, Douglas J; Frey, Urs; Radivojevic, Milos; Russell, Thomas L; Müller, Jan; Fiscella, Michele; Takahashi, Hirokazu; Hierlemann, Andreas

    2013-01-01

    Axons are traditionally considered stable transmission cables, but evidence of the regulation of action potential propagation demonstrates that axons may have more important roles. However, their small diameters render intracellular recordings challenging, and low-magnitude extracellular signals are difficult to detect and assign. Better experimental access to axonal function would help to advance this field. Here we report methods to electrically visualize action potential propagation and network topology in cortical neurons grown over custom arrays, which contain 11,011 microelectrodes and are fabricated using complementary metal oxide semiconductor technology. Any neuron lying on the array can be recorded at high spatio-temporal resolution, and simultaneously precisely stimulated with little artifact. We find substantial velocity differences occurring locally within single axons, suggesting that the temporal control of a neuron's output may contribute to neuronal information processing.

  4. Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes.

    PubMed

    Gluais, Pascale; Bastide, Michèle; Caron, Jacques; Adamantidis, Monique

    2002-05-31

    Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1-3 microM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03-0.3 microM) reduced significantly the current density of the delayed rectifier current and at 30 microM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.

  5. Real-time imaging of action potentials in nerves using changes in birefringence

    PubMed Central

    Badreddine, Ali H.; Jordan, Tomas; Bigio, Irving J.

    2016-01-01

    Polarized light can be used to measure the electrical activity associated with action potential propagation in nerves, as manifested in simultaneous dynamic changes in their intrinsic optical birefringence. These signals may serve as a tool for minimally invasive neuroimaging in various types of neuroscience research, including the study of neuronal activation patterns with high spatiotemporal resolution. A fast linear photodiode array was used to image propagating action potentials in an excised portion of the lobster walking leg nerve. We show that the crossed-polarized signal (XPS) can be reliably imaged over a ≥2 cm span in our custom nerve chamber, by averaging multiple-stimulation signals, and also in single-scan real-time “movies”. This demonstration paves the way toward utilizing changes in the optical birefringence to image more complex neuronal activity in nerve fibers and other organized neuronal tissue. PMID:27231635

  6. A mathematical model of action potential in cells of vascular plants.

    PubMed

    Sukhov, Vladimir; Vodeneev, Vladimir

    2009-12-01

    A mathematical model of action potential (AP) in vascular plants cells has been worked out. The model takes into account actions of plasmalemma ion transport systems (K(+), Cl(-) and Ca(2+) channels; H(+)- and Ca(2+)-ATPases; 2H(+)/Cl(-) symporter; and H(+)/K(+) antiporter), changes of ion concentrations in the cell and in the extracellular space, cytoplasmic and apoplastic buffer capacities and the temperature dependence of active transport systems. The model of AP simulates a stationary level of the membrane potential and ion concentrations, generation of AP induced by electrical stimulation and gradual cooling and the impact of external Ca(2+) for AP development. The model supports a hypothesis about participation of H(+)-ATPase in AP generation.

  7. Monophasic action potentials in a patient with multiform ventricular tachycardia without QT prolongation.

    PubMed Central

    Emori, T; Ohe, T; Shimomura, K

    1993-01-01

    A 41 year old woman had multiform ventricular tachycardia without QT prolongation. Monophasic action potentials were recorded from the right ventricle during the attacks of multiform ventricular tachycardia and effective refractory periods were examined at the same sites. There was no abnormal hump to suggest early afterdepolarisation in the monophasic action potentials, but there was dispersion of the effective refractory period in the right ventricle (80 ms). Stimulation from the right ventricular apex, where the effective refractory period was shortest, reproducibly induced multiform ventricular tachycardia. Two weeks after admission, when her condition was stable, multiform ventricular tachycardia could not be induced and the dispersion of the effective refractory period in the right ventricle was 20 ms. PMID:8489870

  8. Antisense suppression of potassium channel expression demonstrates its role in maturation of the action potential.

    PubMed

    Vincent, A; Lautermilch, N J; Spitzer, N C

    2000-08-15

    A developmental increase in delayed rectifier potassium current (I(Kv)) in embryonic Xenopus spinal neurons is critical for the maturation of excitability and action potential waveform. Identifying potassium channel genes that generate I(Kv) is essential to understanding the mechanisms by which they are controlled. Several Kv genes are upregulated during embryogenesis in parallel with increases in I(Kv) and produce delayed rectifier current when heterologously expressed, indicating that they could encode channels underlying this current. We used antisense (AS) cRNA to test the contribution of xKv3.1 to the maturation of I(Kv), because xKv3.1 AS appears to suppress specifically heterologous expression of potassium current by xKv3.1 mRNA. The injection of xKv3.1 AS into embryos reduces endogenous levels of xKv3.1 mRNA in the developing spinal cord and reduces the amplitude and rate of activation of I(Kv) in 40% of cultured neurons, similar to the percentage of neurons in which endogenous xKv3.1 transcripts are detected. The current in these mature neurons resembles that at an earlier stage of differentiation before the appearance of xKv3.1 mRNA. Furthermore, AS expression increases the duration of the action potential in 40% of the neurons. No change in voltage-dependent calcium current is observed, suggesting that the decrease in I(Kv) is sufficient to account for lengthening of the action potential. Computer-simulated action potentials incorporating observed reductions in amplitude and rate of activation of I(Kv) exhibit an increase in duration similar to that observed experimentally. Thus xKv3.1 contributes to the maturation of I(Kv) in a substantial percentage of these developing spinal neurons.

  9. SHAPING OF ACTION POTENTIALS BY TYPE I AND TYPE II BK CHANNELS

    PubMed Central

    Jaffe, David B.; Wang, Bin; Brenner, Robert

    2011-01-01

    The BK channel is a Ca2+ and voltage-gated conductance responsible for shaping action potential waveforms in many types of neurons. Type II BK channels are differentiated from type I channels by their pharmacology and slow gating kinetics. The β4 accessory subunit confers type II properties on BK α subunits. Empirically derived properties of BK channels, with and without the β4 accessory subunit, were obtained using a heterologous expression system under physiological ionic conditions. These data were then used to study how BK channels alone (type I) and with the accessory β4 subunit (type II) modulate action potential properties in biophysical neuron models. Overall, the models support the hypothesis that it is the slower kinetics provided by the β4 subunit that endows the BK channel with type II properties, which leads to broadening of action potentials and, secondarily, to greater recruitment of SK channels reducing neuronal excitability. Two regions of parameter space distinguished type II and type I effects; one where the range of BK-activating Ca2+ was high (>20 µM) and the other where BK-activating Ca2+ was low (~0.4–1.2 µM). The latter required an elevated BK channel density, possibly beyond a likely physiological range. BK-mediated sharpening of the spike waveform associated with the lack of the β4 subunit was sensitive to the properties of voltage-gated Ca2+ channels due to electrogenic effects on spike duration. We also found that depending on Ca2+ dynamics, type II BK channels may have the ability to contribute to the medium AHP, a property not generally ascribed to BK channels, influencing the frequency-current relationship. Finally, we show how the broadening of action potentials conferred by type II BK channels can also indirectly increase the recruitment of SK-type channels decreasing the excitability of the neuron. PMID:21723921

  10. Activity dependence of action potential duration in rat supraoptic neurosecretory neurones recorded in vitro.

    PubMed

    Bourque, C W; Renaud, L P

    1985-06-01

    Action potential durations, measured at one-third peak amplitude, were examined during intracellular recordings in 134 supraoptic nucleus neurones maintained in vitro in perfused hypothalamic explants. Spike durations ranged between 1.2 and 3.9 ms and were dependent on firing frequency. Shortest measurements (1.74 +/- 0.03 ms; mean +/- S.E. of mean) were obtained during relative quiescence, i.e. less than or equal to 0.5 Hz. A gradual increase in firing frequency through continuous injection of depolarizing current prolonged spike duration, with maximum levels (2.68 +/- 0.05 ms) achieved at 20 Hz. When interspike interval variability was eliminated and firing was more precisely regulated by brief 15-20 ms intracellular current pulses given at pre-determined frequencies, a proportional relationship between increasing spike duration and firing frequency was retained but the change in spike duration at frequencies between 2 and 10 Hz was less pronounced. Once action potentials had achieved the long duration configuration, their return to the shorter duration took place gradually during any succeeding silent interval with a time constant of 4.9 s. Action potential broadening occurred progressively and was most pronounced at the onset of spontaneous or current-induced bursts. In thirty-six phasically active neurones, spike broadening at the onset of a burst was concurrent with the presence of 5-10 consecutive short (less than or equal to 100 ms) interspike intervals; thereafter, despite a greater than 50% reduction in firing frequency, action potential durations remained prolonged throughout the burst. In all of nineteen cells tested, frequency-dependent changes in spike duration were reversibly decreased or blocked by Cd2+, Co2+ and Mn2+, or when CaCl2 was exchanged for equimolar amounts of EGTA in the perfusion medium. These observations indicate that a Ca2+ conductance contributes to frequency- and firing-pattern-dependent changes in spike duration in rat supraoptic

  11. Application of the optical method in experimental cardiology: action potential and intracellular calcium concentration measurement.

    PubMed

    Ronzhina, M; Cmiel, V; Janoušek, O; Kolářová, J; Nováková, M; Babula, P; Provazník, I

    2013-01-01

    It has been shown that, in addition to conventional contact electrode techniques, optical methods using fluorescent dyes can be successfully used for cardiac signal measurement. In this review, the physical and technical fundamentals of the method are described, as well as the properties of the most common systems for measuring action potentials and intracellular calcium concentration. Special attention is paid to summarizing limitations and trends in developing this method.

  12. ER Stress-Mediated Signaling: Action Potential and Ca2+ as Key Players

    PubMed Central

    Bahar, Entaz; Kim, Hyongsuk; Yoon, Hyonok

    2016-01-01

    The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca2+) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca2+ regulates cell death both at the early and late stages of apoptosis. Severe Ca2+ dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca2+ (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca2+ and action potential in ER stress-mediated apoptosis. PMID:27649160

  13. Action potential characteristics of demyelinated rat sciatic nerve following application of 4-aminopyridine.

    PubMed

    Targ, E F; Kocsis, J D

    1986-01-15

    The sciatic nerves of rats were demyelinated by microinjection of lysophosphatidylcholine. A variety of abnormalities such as conduction slowing and block were present. Application of the potassium channel blocker 4-aminopyridine (4-AP) to the lesion site, led to an increase in area of the compound action potential recorded across the site of demyelination. Single axon recordings revealed three types of changes that may account for the 4-AP-induced increase in the compound response. One group showed broadening of the action potential. Other axons showed hyperexcitability following 4-AP, as manifest by spontaneous firing and multiple spike discharge following a single stimulus. In some of the axons studied, 4-AP led to overcoming of conduction block. Although many axons showed increased excitability properties in the presence of 4-AP, the frequency-following ability of the axons was reduced, and the absolute refractory period of the axons was increased. These results indicate that pharmacological blockade of potassium channels with 4-AP not only leads to action potential broadening in demyelinated axons, but to a variety of excitability changes. These heterogeneous effects of 4-AP should be considered in the rationale for its clinical use.

  14. Concept of relative variability of cardiac action potential duration and its test under various experimental conditions.

    PubMed

    Magyar, János; Kistamás, Kornél; Váczi, Krisztina; Hegyi, Bence; Horváth, Balázs; Bányász, Tamás; Nánási, Péter P; Szentandrássy, Norbert

    2016-01-01

    Beat-to-beat variability of action potential duration (short-term variability, SV) is an intrinsic property of mammalian myocardium. Since the majority of agents and interventions affecting SV may modify also action potential duration (APD), we propose here the concept of relative SV (RSV), where changes in SV are normalized to changes in APD and these data are compared to the control SV-APD relationship obtained by lengthening or shortening of action potentials by inward and outward current injections. Based on this concept the influence of the several experimental conditions like stimulation frequency, temperature, pH, redox-state and osmolarity were examined on RSV in canine ventricular myocytes using sharp microelectrodes. RSV was increased by high stimulation frequency (cycle lengths <0.7 s), high temperature (above 37ºC), oxidative agents (H2O2), while it was decreased by reductive environment. RSV was not affected by changes in pH (within the range of 6.4-8.4) and osmolarity of the solution (between 250-350 mOsm). The results indicate that changes in beat-to-beat variability of APD must be evaluated exclusively in terms of RSV; furthermore, some experimental conditions, including the stimulation frequency, redox-state and temperature have to be controlled strictly when analyzing alterations in the short-term variability of APD.

  15. TASK-1 Channels May Modulate Action Potential Duration of Human Atrial Cardiomyocytes

    PubMed Central

    Limberg, Sven H.; Netter, Michael F.; Rolfes, Caroline; Rinné, Susanne; Schlichthörl, Günter; Zuzarte, Marylou; Vassiliou, Timon; Moosdorf, Rainer; Wulf, Hinnerk; Daut, Jürgen; Sachse, Frank B.; Decher, Niels

    2011-01-01

    Background/Aims: Atrial fibrillation is the most common arrhythmia in the elderly, and potassium channels with atrium-specific expression have been discussed as targets to treat atrial fibrillation. Our aim was to characterize TASK-1 channels in human heart and to functionally describe the role of the atrial whole cell current ITASK-1. Methods and Results: Using quantitative PCR, we show that TASK-1 is predominantly expressed in the atria, auricles and atrio-ventricular node of the human heart. Single channel recordings show the functional expression of TASK-1 in right human auricles. In addition, we describe for the first time the whole cell current carried by TASK-1 channels (ITASK-1) in human atrial tissue. We show that ITASK-1 contributes to the sustained outward current IKsus and that ITASK-1 is a major component of the background conductance in human atrial cardiomyocytes. Using patch clamp recordings and mathematical modeling of action potentials, we demonstrate that modulation of ITASK-1 can alter human atrial action potential duration. Conclusion: Due to the lack of ventricular expression and the ability to alter human atrial action potential duration, TASK-1 might be a drug target for the treatment of atrial fibrillation. PMID:22178873

  16. [Influence of pacing site on myocardial transmural dispersion of repolarization in intact normal and dilated cardiomyopathy dogs].

    PubMed

    Bai, Rong; Pu, Jun; Liu, Nian; Lu, Jia-Gao; Zhou, Qiang; Ruan, Yan-Fei; Niu, Hui-Yan; Wang, Lin

    2003-12-25

    In order to verify the hypothesis that left ventricular epicardial (LV-Epi) pacing and biventricular (BiV) pacing unavoidably influence the myocardial electrophysiological characters and may result in high risk of malignant ventricular arrhythmia, we calculated, in both normal mongrel dogs and dog models with rapid-right-ventricular-pacing induced dilated cardiomyopathy congestive heart failure (DCM-CHF), the monophasic action potential duration (MAPD) and the transmural dispersion of repolarization (TDR) in intracardiac electrogram together with the QT interval and T(peak)-T(end) (T(p(-T(e)) interval in surface electrocardiogram (ECG) during LV-Epi and BiV pacing, compared with those during right ventricular endocardial (RV-Endo) pacing. To prepare the DCM-CHF dog model, rapid right ventricular pacing (250 bpm) was performed for 23.6+/-2.57 days to the dog. All the normal and DCM-CHF dogs were given radio frequency catheter ablation (RFCA) to His bundle with the guide of X-ray fluoroscopy. After the RFCA procedures, the animals were under the situation of complete atrioventricular block so that the canine heart rates could be voluntarily controlled in the following experiments. After a thoracotomy, ECG and monophasic action potentials (MAP) of subendocardial, subepicardial and mid-layer myocardium were recorded synchronously in 8 normal and 5 DCM-CHF dogs during pacing from endocardium of RV apex (RV-Endo), epicardium of LV anterior wall (LV-Epi) and simultaneously both of the above (biventricular, BiV), the later was similar to the ventricular resynchronization therapy to congestive heart failure patients in clinic. The Tp-Te) meant the interval from the peak to the end of T wave, which was a representative index of TDR in surface ECG. The TDR was defined as the difference between the longest and the shortest MAPD of subendocardial, subepicardial and mid-layer myocardium. Our results showed that in normal dogs, pacing participating of LV (LV-Epi, BiV) prolonged

  17. Carbon nanotube multi-electrode array chips for noninvasive real-time measurement of dopamine, action potentials, and postsynaptic potentials.

    PubMed

    Suzuki, Ikuro; Fukuda, Mao; Shirakawa, Keiichi; Jiko, Hideyasu; Gotoh, Masao

    2013-11-15

    Multi-electrode arrays (MEAs) can be used for noninvasive, real-time, and long-term recording of electrophysiological activity and changes in the extracellular chemical microenvironment. Neural network organization, neuronal excitability, synaptic and phenotypic plasticity, and drug responses may be monitored by MEAs, but it is still difficult to measure presynaptic activity, such as neurotransmitter release, from the presynaptic bouton. In this study, we describe the development of planar carbon nanotube (CNT)-MEA chips that can measure both the release of the neurotransmitter dopamine as well as electrophysiological responses such as field postsynaptic potentials (fPSPs) and action potentials (APs). These CNT-MEA chips were fabricated by electroplating the indium-tin oxide (ITO) microelectrode surfaces. The CNT-plated ITO electrode exhibited electrochemical response, having much higher current density compared with the bare ITO electrode. Chronoamperometric measurements using these CNT-MEA chips detected dopamine at nanomolar concentrations. By placing mouse striatal brain slices on the CNT-MEA chip, we successfully measured synaptic dopamine release from spontaneous firings with a high S/N ratio of 62. Furthermore, APs and fPSPs were measured from cultured hippocampal neurons and slices with high temporal resolution and a 100-fold greater S/N ratio. Our CNT-MEA chips made it possible to measure neurotransmitter dopamine (presynaptic activities), postsynaptic potentials, and action potentials, which have a central role in information processing in the neuronal network. CNT-MEA chips could prove useful for in vitro studies of stem cell differentiation, drug screening and toxicity, synaptic plasticity, and pathogenic processes involved in epilepsy, stroke, and neurodegenerative diseases.

  18. T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex.

    PubMed

    Deleuze, Charlotte; David, François; Béhuret, Sébastien; Sadoc, Gérard; Shin, Hee-Sup; Uebele, Victor N; Renger, John J; Lambert, Régis C; Leresche, Nathalie; Bal, Thierry

    2012-08-29

    The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.

  19. Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction.

    PubMed

    Jabr, Rita I; Hatch, Fiona S; Salvage, Samantha C; Orlowski, Alejandro; Lampe, Paul D; Fry, Christopher H

    2016-11-01

    Cardiac arrhythmias are associated with raised intracellular [Ca(2+)] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca(2+)-dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca(2+)-dependent phosphatase, calcineurin. Intracellular [Ca(2+)] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2.Raised [Ca(2)(+)]i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca(2+)]i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca(2+)-independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca(2+)]i. PP2A had no role. Conduction velocity was reduced by raised [Ca(2+)]i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca(2+)] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1.

  20. ACTION-SPACE CLUSTERING OF TIDAL STREAMS TO INFER THE GALACTIC POTENTIAL

    SciTech Connect

    Sanderson, Robyn E.; Helmi, Amina; Hogg, David W.

    2015-03-10

    We present a new method for constraining the Milky Way halo gravitational potential by simultaneously fitting multiple tidal streams. This method requires three-dimensional positions and velocities for all stars to be fit, but does not require identification of any specific stream or determination of stream membership for any star. We exploit the principle that the action distribution of stream stars is most clustered when the potential used to calculate the actions is closest to the true potential. Clustering is quantified with the Kullback-Leibler Divergence (KLD), which also provides conditional uncertainties for our parameter estimates. We show, for toy Gaia-like data in a spherical isochrone potential, that maximizing the KLD of the action distribution relative to a smoother distribution recovers the input potential. The precision depends on the observational errors and number of streams; using K III giants as tracers, we measure the enclosed mass at the average radius of the sample stars accurate to 3% and precise to 20%-40%. Recovery of the scale radius is precise to 25%, biased 50% high by the small galactocentric distance range of stars in our mock sample (1-25 kpc, or about three scale radii, with mean 6.5 kpc). 20-25 streams with at least 100 stars each are required for a stable confidence interval. With radial velocities (RVs) to 100 kpc, all parameters are determined with ∼10% accuracy and 20% precision (1.3% accuracy for the enclosed mass), underlining the need to complete the RV catalog for faint halo stars observed by Gaia.

  1. Environmental Asthma Reduction Potential Estimates for Selected Mitigation Actions in Finland Using a Life Table Approach

    PubMed Central

    Rumrich, Isabell Katharina; Hänninen, Otto

    2015-01-01

    Aims: To quantify the reduction potential of asthma in Finland achievable by adjusting exposures to selected environmental factors. Methods: A life table model for the Finnish population for 1986–2040 was developed and Years Lived with Disability caused by asthma and attributable to the following selected exposures were estimated: tobacco smoke (smoking and second hand tobacco smoke), ambient fine particles, indoor dampness and mould, and pets. Results: At baseline (2011) about 25% of the total asthma burden was attributable to the selected exposures. Banning tobacco was the most efficient mitigation action, leading to 6% reduction of the asthma burden. A 50% reduction in exposure to dampness and mould as well as a doubling in exposure to pets lead each to a 2% reduction. Ban of urban small scale wood combustion, chosen as a mitigation action to reduce exposure to fine particles, leads to a reduction of less than 1% of the total asthma burden. Combination of the most efficient mitigation actions reduces the total asthma burden by 10%. A more feasible combination of mitigation actions leads to 6% reduction of the asthma burden. Conclusions: The adjustment of environmental exposures can reduce the asthma burden in Finland by up to 10%. PMID:26067987

  2. Potentiation of antimalarial drug action by chlorpheniramine against multidrug-resistant Plasmodium falciparum in vitro.

    PubMed

    Nakornchai, Sunan; Konthiang, Phattanapong

    2006-09-01

    Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the 3H-hypoxanthine incorporation. Chlorphenirame inhibited P. falciparum K1 and T9/94 growth with IC50 values of 136.0+/-40.2 microM and 102.0+/-22.6 microM respectively. A combination of antimalarial drug and chlorpheniramine was tested against resistant P. falciparum in vitro. Isobologram analysis showed that chlorpheniramine exerts marked synergistic action on chloroquine against P. falciparum K1 and T9/94. Chlorpheniramine also potentiated antimalarial action of mefloquine, quinine or pyronaridine against both of the resistant strains of P. falciparum. However, chlorpheniramine antagonism with artesunate was obtained in both P. falciparum K1 and T9/94. The results in this study indicate that antihistaminic drugs may be promising candidates for potentiating antimalarial drug action against drug resistant malarial parasites.

  3. The real-time link between person perception and action: brain potential evidence for dynamic continuity.

    PubMed

    Freeman, Jonathan B; Ambady, Nalini; Midgley, Katherine J; Holcomb, Phillip J

    2011-01-01

    Using event-related potentials, we investigated how the brain extracts information from another's face and translates it into relevant action in real time. In Study 1, participants made between-hand sex categorizations of sex-typical and sex-atypical faces. Sex-atypical faces evoked negativity between 250 and 550 ms (N300/N400 effects), reflecting the integration of accumulating sex-category knowledge into a coherent sex-category interpretation. Additionally, the lateralized readiness potential revealed that the motor cortex began preparing for a correct hand response while social category knowledge was still gradually evolving in parallel. In Study 2, participants made between-hand eye-color categorizations as part of go/no-go trials that were contingent on a target's sex. On no-go trials, although the hand did not actually move, information about eye color partially prepared the motor cortex to move the hand before perception of sex had finalized. Together, these findings demonstrate the dynamic continuity between person perception and action, such that ongoing results from face processing are immediately and continuously cascaded into the motor system over time. The preparation of action begins based on tentative perceptions of another's face before perceivers have finished interpreting what they just saw.

  4. The real-time link between person perception and action: Brain potential evidence for dynamic continuity

    PubMed Central

    Freeman, Jonathan B.; Ambady, Nalini; Midgley, Katherine J.; Holcomb, Phillip J.

    2010-01-01

    Using event-related potentials, we investigated how the brain extracts information from another’s face and translates it into relevant action in real-time. In Study 1, participants made between-hand sex categorizations of sex-typical and sex-atypical faces. Sex-atypical faces evoked negativity between 250-550 ms (N300/N400 effects), reflecting the integration of accumulating sex-category knowledge into a coherent sex-category interpretation. Additionally, the lateralized readiness potential (LRP) revealed that the motor cortex began preparing for a correct hand response while social category knowledge was still gradually evolving in parallel. In Study 2, participants made between-hand eye-color categorizations as part of go/no-go trials that were contingent on a target’s sex. On no-go trials, although the hand did not actually move, information about eye color partially prepared the motor cortex to move the hand before perception of sex had finalized. Together, these findings demonstrate the dynamic continuity between person perception and action, such that ongoing results from face processing are immediately and continuously cascaded into the motor system over time. The preparation of action begins based on tentative perceptions of another’s face before perceivers have finished interpreting what they just saw. PMID:20602284

  5. A novel anionic conductance affects action potential duration in isolated rat ventricular myocytes.

    PubMed

    Spencer, C I; Uchida, W; Kozlowski, R Z

    2000-01-01

    Effects of extracellular anions were studied in electrophysiological experiments on freshly isolated rat ventricular myocytes. Under current-clamp, action potential duration (APD) was prolonged by reducing the extracellular Cl(-) concentration and shortened by replacement of extracellular Cl(-) with I(-). Under voltage-clamp, membrane potential steps or ramps evoked an anionic background current (I(AB)) carried by either Cl(-), Br(-), I(-) or NO(3)(-). Activation of I(AB) was Ca(2+)- and cyclic AMP-independent, and was unaffected by cell shrinkage. I(AB) was insensitive to stilbene and fenamate anion transport blockers at concentrations that inhibit Ca(2+)-, cyclic AMP- and swelling-activated Cl(-) currents in ventricular cells of other mammals. These results suggest that I(AB) may be carried by a novel class of Cl(-) channel. Correlation of anion substitution experiments on membrane current and action potentials revealed that I(AB) could play a major role in controlling rat ventricular APD. These findings have important implications for those studying cardiac Cl(-) channels as potential targets for novel antiarrythmic agents.

  6. Constraining the Galactic potential via action-based distribution functions for mono-abundance stellar populations

    NASA Astrophysics Data System (ADS)

    Ting, Yuan-Sen; Rix, Hans-Walter; Bovy, Jo; van de Ven, Glenn

    2013-09-01

    We present a rigorous and practical way of constraining the Galactic potential based on the phase-space information for many individual stars. Such an approach is needed to dynamically model the data from ongoing spectroscopic surveys of the Galaxy and in the future Gaia. This approach describes the orbit distribution of stars by a family of parametrized distribution function (DF) proposed by McMillan and Binney, which are based on actions. We find that these parametrized DFs are flexible enough to capture well the observed phase-space distributions of individual abundance-selected Galactic subpopulations of stars (`mono-abundance populations') for a disc-like gravitational potential, which enables independent dynamical constraints from each of the Galactic mono-abundance populations. We lay out a statistically rigorous way to constrain the Galactic potential parameters by constructing the joint likelihood of potential and DF parameters, and subsequently marginalizing over the DF parameters. This approach explicitly incorporates the spatial selection function inherent to all Galactic surveys, and can account for the uncertainties of the individual position-velocity observations. On that basis, we study the precision of the parameters of the Galactic potential that can be reached with various sample sizes and realistic spatial selection functions. By creating mock samples from the DF, we show that, even under a restrictive and realistic spatial selection function, given a two-parameter gravitational potential, one can recover the true potential parameters to a few per cent with sample sizes of a few thousands. The assumptions of axisymmetry, of DFs that are smooth in the actions and of no time variation remain important limitations in our current study.

  7. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.

    PubMed

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S; Klyachko, Vitaly A

    2013-02-20

    Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.

  8. Ventricular Repolarization Evaluation From Surface ECG for Identification of the Patients With Increased Myocardial Electrical Instability

    DTIC Science & Technology

    2007-11-02

    interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy . Circulation 1997, 96:1557-1565 [17...temporal variability already appears at early stages of the disease. So, Berger et al [16] demonstrated in ischemic and non-ischemic dilated ... cardiomyopathy patients that significantly greater QTV prevailed among minimally symptomatic patients with little or no further increase among the patients

  9. [Malignant fascicular ventricular tachycardia degenerating into ventricular fibrillation in a patient with early repolarization syndrome].

    PubMed

    Kane, Ad; Defaye, P; Jacon, P; Mbaye, A; Machecourt, J

    2012-08-01

    A 45-year-old man was hospitalized for syncope due to fascicular ventricular tachycardia degenerating into ventricular fibrillation (VF). The electrocardiogram showed an early repolarization syndrome. The arrhythmia was repetitive and disappeared after oral hydroquinidine. An implantable cardioverter-defibrillator (ICD) was implanted; subsequently, the patient was arrhythmia free at 9 months follow-up.

  10. In vivo neuronal action potential recordings via three-dimensional microscale needle-electrode arrays

    PubMed Central

    Fujishiro, Akifumi; Kaneko, Hidekazu; Kawashima, Takahiro; Ishida, Makoto; Kawano, Takeshi

    2014-01-01

    Very fine needle-electrode arrays potentially offer both low invasiveness and high spatial resolution of electrophysiological neuronal recordings in vivo. Herein we report the penetrating and recording capabilities of silicon-growth-based three-dimensional microscale-diameter needle-electrodes arrays. The fabricated needles exhibit a circular-cone shape with a 3-μm-diameter tip and a 210-μm length. Due to the microscale diameter, our silicon needles are more flexible than other microfabricated silicon needles with larger diameters. Coating the microscale-needle-tip with platinum black results in an impedance of ~600 kΩ in saline with output/input signal amplitude ratios of more than 90% at 40 Hz–10 kHz. The needles can penetrate into the whisker barrel area of a rat's cerebral cortex, and the action potentials recorded from some neurons exhibit peak-to-peak amplitudes of ~300 μVpp. These results demonstrate the feasibility of in vivo neuronal action potential recordings with a microscale needle-electrode array fabricated using silicon growth technology. PMID:24785307

  11. Stretch-induced excitation and action potential changes of single cardiac cells.

    PubMed

    Riemer, Tara L; Tung, Leslie

    2003-01-01

    Mechanoelectric coupling (MEC) has been studied extensively in the heart at the tissue and organ levels, but to only a limited extent in single cells because of the technical challenges. New results are presented in which MEC was studied in 57 single frog ventricular myocytes that were held on both ends by glass holding pipettes. Axial stretch was applied either by displacement of the pipettes, or by a glass fiber around which the cell was wrapped, that was displaced in a pulsatile or sinusoidal fashion. Electrical activity of the cell was monitored either by active contraction, by intracellular action potentials, or by focal extracellular potentials. Of more than 350 stretches applied to 57 cells with amplitudes ranging from 3% to 35%, only 4 cases of mechanically induced stimulation were observed. In 252 stretches applied to 32 cells in which action potential duration (APD) was measured, no change >20% was observed, except in 3 cells in which APD increased by >100%, and in 2 cells with extended triggered activity. Thus, in contrast to studies in intact tissue, single frog ventricular myocytes are generally insensitive to direct axial stretch. However, robust mechanosensitive responses were observed in 7 of 57 ( approximately 12%) cells. The results of other single cell studies are reviewed, and the significance of differences in tissue-level and single cell results is discussed.

  12. Effects of bath resistance on action potentials in the squid giant axon: myocardial implications.

    PubMed Central

    Wu, J; Wikswo, J P

    1997-01-01

    This study presents a simplified version of the quasi-one-dimensional theory (Wu, J., E. A. Johnson, and J. M. Kootsey. 1996. A quasi-one-dimensional theory for anisotropic propagation of excitation in cardiac muscle. Biophys. J. 71:2427-2439) with two components of the extracellular current, along and perpendicular to the axis, and a simulation and its experimental confirmation for the giant axon of the squid. By extending the one-dimensional core conductor cable equations, this theory predicts, as confirmed by the experiment, that the shapes of the intracellular and the extracellular action potentials are related to the resistance of the bath. Such a result was previously only expected by the field theories. The correlation between the shapes of the intracellular and the extracellular potentials of the giant axon of the squid resembles that observed during the anisotropic propagation of excitation in cardiac muscle. Therefore, this study not only develops a quasi-one-dimensional theory for a squid axon, but also provides one possible factor contributing to the anisotropic propagation of action potentials in cardiac muscle. PMID:9370430

  13. An Excel-based implementation of the spectral method of action potential alternans analysis.

    PubMed

    Pearman, Charles M

    2014-12-01

    Action potential (AP) alternans has been well established as a mechanism of arrhythmogenesis and sudden cardiac death. Proper interpretation of AP alternans requires a robust method of alternans quantification. Traditional methods of alternans analysis neglect higher order periodicities that may have greater pro-arrhythmic potential than classical 2:1 alternans. The spectral method of alternans analysis, already widely used in the related study of microvolt T-wave alternans, has also been used to study AP alternans. Software to meet the specific needs of AP alternans analysis is not currently available in the public domain. An AP analysis tool is implemented here, written in Visual Basic for Applications and using Microsoft Excel as a shell. This performs a sophisticated analysis of alternans behavior allowing reliable distinction of alternans from random fluctuations, quantification of alternans magnitude, and identification of which phases of the AP are most affected. In addition, the spectral method has been adapted to allow detection and quantification of higher order regular oscillations. Analysis of action potential morphology is also performed. A simple user interface enables easy import, analysis, and export of collated results.

  14. Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

    PubMed Central

    Trenor, Beatriz; Cardona, Karen; Saiz, Javier; Rajamani, Sridharan; Belardinelli, Luiz; Giles, Wayne R.

    2013-01-01

    Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or “late” component of the Na+ current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na+ and Ca2+ currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity. PMID:24146650

  15. Action potentials and amphetamine release antipsychotic drug from dopamine neuron synaptic VMAT vesicles

    PubMed Central

    Tucker, Kristal R.; Block, Ethan R.; Levitan, Edwin S.

    2015-01-01

    Based on lysotracker red imaging in cultured hippocampal neurons, antipsychotic drugs (APDs) were proposed to accumulate in synaptic vesicles by acidic trapping and to be released in response to action potentials. Because many APDs are dopamine (DA) D2 receptor (D2R) antagonists, such a mechanism would be particularly interesting if it operated in midbrain DA neurons. Here, the APD cyamemazine (CYAM) is visualized directly by two-photon microscopy in substantia nigra and striatum brain slices. CYAM accumulated slowly into puncta based on vacuolar H+-ATPase activity and dispersed rapidly upon dissipating organelle pH gradients. Thus, CYAM is subject to acidic trapping and released upon deprotonation. In the striatum, Ca2+-dependent reduction of the CYAM punctate signal was induced by depolarization or action potentials. Striatal CYAM overlapped with the dopamine transporter (DAT). Furthermore, parachloroamphetamine (pCA), acting via vesicular monoamine transporter (VMAT), and a charged VMAT, substrate 1-methyl-4-phenylpyridinium (MPP+), reduced striatal CYAM. In vivo CYAM administration and in vitro experiments confirmed that clinically relevant CYAM concentrations result in vesicular accumulation and pCA-dependent release. These results show that some CYAM is in DA neuron VMAT vesicles and suggests a new drug interaction in which amphetamine induces CYAM deprotonation and release as a consequence of the H+ countertransport by VMAT that accompanies vesicular uptake, but not by inducing exchange or acting as a weak base. Therefore, in the striatum, APDs are released with DA in response to action potentials and an amphetamine. This synaptic corelease is expected to enhance APD antagonism of D2Rs where and when dopaminergic transmission occurs. PMID:26216995

  16. Neuronal Competition for Action Potential Initiation Sites in a Circuit Controlling Simple Learning

    PubMed Central

    Cruz, Georgina E.; Sahley, Christie L.; Muller, Kenneth J.

    2007-01-01

    The spatial and temporal patterns of action potential initiations were studied in a behaving leech preparation to determine the basis of increased firing that accompanies sensitization, a form of non-associative learning requiring the S-interneurons. Little is known at the network level about mechanisms of behavioral sensitization. The S-interneurons, one in each ganglion and linked by electrical synapses with both neighbors to form a chain, are interposed between sensory and motor neurons. In sensitized preparations the strength of shortening is related to S-cell firing, which itself is the result of impulses initiating in several S-cells. Because the S-cells, as independent initiation sites, all contribute to activity in the chain, it was hypothesized that during sensitization, increased multi-site activity increased the chain's firing rate. However, it was found that during sensitization, the single site with the largest initiation rate, the S-cell in the stimulated segment, suppressed initiations in adjacent ganglia. Experiments showed this was both because (1) it received the earliest, greatest input and (2) the delayed synaptic input to the adjacent S-cells coincided with the action potential refractory period. A compartmental model of the S-cell and its inputs showed that a simple, intrinsic mechanism of inexcitability after each action potential may account for suppression of impulse initiations. Thus, a non-synaptic competition between neurons alters synaptic integration in the chain. In one mode, inputs to different sites sum independently, whereas in another, synaptic input to a single site precisely specifies the overall pattern of activity. PMID:17644266

  17. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.

    PubMed

    Yue, L; Feng, J; Gaspo, R; Li, G R; Wang, Z; Nattel, S

    1997-10-01

    Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3 +/- 2 seconds in sham-operated dogs to 3060 +/- 707 seconds in dogs after 42 days of pacing, P < .001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca2+ current, or Ca(2+)-dependent Cl- current. In contrast, the densities of transient outward current (Ito) and L-type Ca2+ current (ICa) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in ICa. We conclude that sustained atrial tachycardia reduces Ito and ICa, that the reduced ICa decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial

  18. The optimal distance between two electrode tips during recording of compound nerve action potentials in the rat median nerve.

    PubMed

    Li, Yongping; Lao, Jie; Zhao, Xin; Tian, Dong; Zhu, Yi; Wei, Xiaochun

    2014-01-15

    The distance between the two electrode tips can greatly influence the parameters used for recording compound nerve action potentials. To investigate the optimal parameters for these recordings in the rat median nerve, we dissociated the nerve using different methods and compound nerve action potentials were orthodromically or antidromically recorded with different electrode spacings. Compound nerve action potentials could be consistently recorded using a method in which the middle part of the median nerve was intact, with both ends dissociated from the surrounding fascia and a ground wire inserted into the muscle close to the intact part. When the distance between two stimulating electrode tips was increased, the threshold and supramaximal stimulating intensity of compound nerve action potentials were gradually decreased, but the amplitude was not changed significantly. When the distance between two recording electrode tips was increased, the amplitude was gradually increased, but the threshold and supramaximal stimulating intensity exhibited no significant change. Different distances between recording and stimulating sites did not produce significant effects on the aforementioned parameters. A distance of 5 mm between recording and stimulating electrodes and a distance of 10 mm between recording and stimulating sites were found to be optimal for compound nerve action potential recording in the rat median nerve. In addition, the orthodromic compound action potential, with a biphasic waveform that was more stable and displayed less interference (however also required a higher threshold and higher supramaximal stimulus), was found to be superior to the antidromic compound action potential.

  19. The Healthy Bus project in Denmark: need for an action potential assessment.

    PubMed

    Poulsen, Kjeld B

    2004-06-01

    Research over the last 50 years has repeatedly documented that bus drivers are exposed to several physical and psychological risk factors, which are associated with health problems in the form of heart, musculo-skeletal and stomach disease, and increased coronary mortality. So why has there been little action to improve the situation when it is so obviously indicated by such assessments? This article describes the long and complex process that has made it possible to launch almost 200 interventions among the 3500 municipal bus drivers in Copenhagen. Using a participative action research design, new evidence was gathered by broadening the traditional work environmental scope to lifestyle, health issues and private matters. Comparing this updated needs assessment with a national reference population, it was found that drivers were often still worse off. Again, simply presenting new evidence did not seem to lead to changes and further work is needed to empower the stakeholders so that they can commit to start making effective interventions. It is concluded that every needs assessment has to be supplemented with an evaluation of the action potential.

  20. Effects of K(+) channel openers on spontaneous action potentials in detrusor smooth muscle of the guinea-pig urinary bladder.

    PubMed

    Takagi, Hiroaki; Hashitani, Hikaru

    2016-10-15

    The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM). A higher concentration of NS1619 (30μM) hyperpolarized the membrane and abolished action potential firing. NS309 (10μM) and SKA31 (100μM), small conductance Ca(2+)-activated K(+) (SK) channel openers, dramatically increased the duration of the after-hyperpolarization and then abolished action potential firing in an apamin (100nM)-sensitive manner. Flupirtine (10μM), a Kv7 channel opener, inhibited action potential firing without hyperpolarizing the membrane in a manner sensitive to XE991 (10μM), a Kv7 channel blocker. BRL37344 (10μM), a β3-adrenceptor agonist, or rolipram (10nM), a phosphodiesterase 4 inhibitor, also inhibited action potential firing. A higher concentration of rolipram (100nM) hyperpolarized the DSM and abolished the action potentials. IbTX (100nM) prevented the rolipram-induced blockade of action potentials but not the hyperpolarization. BK and Kv7 channels appear to predominantly contribute to the stabilization of DSM excitability. Spare SK channels could be pharmacologically activated to suppress DSM excitability. BK channels appear to be involved in the cyclic AMP-induced inhibition of action potentials but not the membrane hyperpolarization.

  1. Three-dimensional mapping and regulation of action potential propagation in nanoelectronics innervated tissues

    PubMed Central

    Dai, Xiaochuan; Zhou, Wei; Gao, Teng; Liu, Jia; Lieber, Charles M.

    2016-01-01

    Real-time mapping and manipulation of electrophysiology in three-dimensional (3D) tissues could impact broadly fundamental scientific and clinical studies, yet realization lacks effective methods. Here we introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and sub-millisecond time-resolution. Real-time extracellular action potential (AP) recordings reveal quantitative maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topology of 3D conducting pathways in developing cardiac tissues, and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. We further demonstrate simultaneous multi-site stimulation and mapping to manipulate actively the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacology and electronic therapeutics. PMID:27347837

  2. Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe.

    PubMed

    Jin, Lei; Han, Zhou; Platisa, Jelena; Wooltorton, Julian R A; Cohen, Lawrence B; Pieribone, Vincent A

    2012-09-06

    Monitoring neuronal electrical activity using fluorescent protein-based voltage sensors has been limited by small response magnitudes and slow kinetics of existing probes. Here we report the development of a fluorescent protein voltage sensor, named ArcLight, and derivative probes that exhibit large changes in fluorescence intensity in response to voltage changes. ArcLight consists of the voltage-sensing domain of Ciona intestinalis voltage-sensitive phosphatase and super ecliptic pHluorin that carries the point mutation A227D. The fluorescence intensity of ArcLight A242 decreases by 35% in response to a 100 mV depolarization when measured in HEK293 cells, which is more than five times larger than the signals from previously reported fluorescent protein voltage sensors. We show that the combination of signal size and response speed of these new probes allows the reliable detection of single action potentials and excitatory potentials in individual neurons and dendrites.

  3. Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues

    NASA Astrophysics Data System (ADS)

    Dai, Xiaochuan; Zhou, Wei; Gao, Teng; Liu, Jia; Lieber, Charles M.

    2016-09-01

    Real-time mapping and manipulation of electrophysiology in three-dimensional (3D) tissues could have important impacts on fundamental scientific and clinical studies, yet realization is hampered by a lack of effective methods. Here we introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and a submillisecond temporal resolution. Real-time extracellular action potential (AP) recordings reveal quantitative maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topology of 3D conducting pathways in developing cardiac tissues and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. We further demonstrate simultaneous multisite stimulation and mapping to actively manipulate the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacology and electronic therapeutics.

  4. Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues.

    PubMed

    Dai, Xiaochuan; Zhou, Wei; Gao, Teng; Liu, Jia; Lieber, Charles M

    2016-09-01

    Real-time mapping and manipulation of electrophysiology in three-dimensional (3D) tissues could have important impacts on fundamental scientific and clinical studies, yet realization is hampered by a lack of effective methods. Here we introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and a submillisecond temporal resolution. Real-time extracellular action potential (AP) recordings reveal quantitative maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topology of 3D conducting pathways in developing cardiac tissues and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. We further demonstrate simultaneous multisite stimulation and mapping to actively manipulate the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacology and electronic therapeutics.

  5. Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials.

    PubMed

    Radivojevic, Milos; Jäckel, David; Altermatt, Michael; Müller, Jan; Viswam, Vijay; Hierlemann, Andreas; Bakkum, Douglas J

    2016-08-11

    A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs.

  6. Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials

    NASA Astrophysics Data System (ADS)

    Radivojevic, Milos; Jäckel, David; Altermatt, Michael; Müller, Jan; Viswam, Vijay; Hierlemann, Andreas; Bakkum, Douglas J.

    2016-08-01

    A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs.

  7. The Influence of Glutamate on Axonal Compound Action Potential In Vitro

    PubMed Central

    Abouelela, Ahmed; Wieraszko, Andrzej

    2016-01-01

    Background Our previous experiments demonstrated modulation of the amplitude of the axonal compound action potential (CAP) by electrical stimulation. To verify assumption that glutamate released from axons could be involved in this phenomenon, the modification of the axonal CAP induced by glutamate was investigated. Objectives The major objective of this research is to verify the hypothesis that axonal activity would trigger the release of glutamate, which in turn would interact with specific axonal receptors modifying the amplitude of the action potential. Methods Segments of the sciatic nerve were exposed to exogenous glutamate in vitro, and CAP was recorded before and after glutamate application. In some experiments, the release of radioactive glutamate analog from the sciatic nerve exposed to exogenous glutamate was also evaluated. Results The glutamate-induced increase in CAP was blocked by different glutamate receptor antagonists. The effect of glutamate was not observed in Ca-free medium, and was blocked by antagonists of calcium channels. Exogenous glutamate, applied to the segments of sciatic nerve, induced the release of radioactive glutamate analog, demonstrating glutamate-induced glutamate release. Immunohistochemical examination revealed that axolemma contains components necessary for glutamatergic neurotransmission. Conclusion The proteins of the axonal membrane can under the influence of electrical stimulation or exogenous glutamate change membrane permeability and ionic conductance, leading to a change in the amplitude of CAP. We suggest that increased axonal activity leads to the release of glutamate that results in changes in the amplitude of CAPs. PMID:28077958

  8. Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates

    PubMed Central

    Thiede, Joshua M.; Kordus, Shannon L.; Turman, Breanna J.; Buonomo, Joseph A.; Aldrich, Courtney C.; Minato, Yusuke; Baughn, Anthony D.

    2016-01-01

    The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents. PMID:27905500

  9. From damage response to action potentials: early evolution of neural and contractile modules in stem eukaryotes

    PubMed Central

    Brunet, Thibaut; Arendt, Detlev

    2016-01-01

    Eukaryotic cells convert external stimuli into membrane depolarization, which in turn triggers effector responses such as secretion and contraction. Here, we put forward an evolutionary hypothesis for the origin of the depolarization–contraction–secretion (DCS) coupling, the functional core of animal neuromuscular circuits. We propose that DCS coupling evolved in unicellular stem eukaryotes as part of an ‘emergency response’ to calcium influx upon membrane rupture. We detail how this initial response was subsequently modified into an ancient mechanosensory–effector arc, present in the last eukaryotic common ancestor, which enabled contractile amoeboid movement that is widespread in extant eukaryotes. Elaborating on calcium-triggered membrane depolarization, we reason that the first action potentials evolved alongside the membrane of sensory-motile cilia, with the first voltage-sensitive sodium/calcium channels (Nav/Cav) enabling a fast and coordinated response of the entire cilium to mechanosensory stimuli. From the cilium, action potentials then spread across the entire cell, enabling global cellular responses such as concerted contraction in several independent eukaryote lineages. In animals, this process led to the invention of mechanosensory contractile cells. These gave rise to mechanosensory receptor cells, neurons and muscle cells by division of labour and can be regarded as the founder cell type of the nervous system. PMID:26598726

  10. Biorealistic cardiac cell culture platforms with integrated monitoring of extracellular action potentials

    PubMed Central

    Trantidou, Tatiana; Terracciano, Cesare M.; Kontziampasis, Dimitrios; Humphrey, Eleanor J.; Prodromakis, Themistoklis

    2015-01-01

    Current platforms for in vitro drug development utilize confluent, unorganized monolayers of heart cells to study the effect on action potential propagation. However, standard cell cultures are of limited use in cardiac research, as they do not preserve important structural and functional properties of the myocardium. Here we present a method to integrate a scaffolding technology with multi-electrode arrays and deliver a compact, off-the-shelf monitoring platform for growing biomimetic cardiac tissue. Our approach produces anisotropic cultures with conduction velocity (CV) profiles that closer resemble native heart tissue; the fastest impulse propagation is along the long axis of the aligned cardiomyocytes (CVL) and the slowest propagation is perpendicular (CVT), in contrast to standard cultures where action potential propagates isotropically (CVL ≈ CVT). The corresponding anisotropy velocity ratios (CVL/CVT = 1.38 – 2.22) are comparable with values for healthy adult rat ventricles (1.98 – 3.63). The main advantages of this approach are that (i) it provides ultimate pattern control, (ii) it is compatible with automated manufacturing steps and (iii) it is utilized through standard cell culturing protocols. Our platform is compatible with existing read-out equipment and comprises a prompt method for more reliable CV studies. PMID:26053434

  11. Action-potential-independent GABAergic tone mediated by nicotinic stimulation of immature striatal miniature synaptic transmission.

    PubMed

    Liu, Zhi; Otsu, Yo; Vasuta, Cristina; Nawa, Hiroyuki; Murphy, Timothy H

    2007-08-01

    Stimulation of presynaptic nicotinic acetylcholine receptors (nAChRs) increases the frequency of miniature excitatory synaptic activity (mEPSCs) to a point where they can promote cell firing in hippocampal CA3 neurons. We have evaluated whether nicotine regulation of miniature synaptic activity can be extended to inhibitory transmission onto striatal medium spiny projection neurons (MSNs) in acute brain slices. Bath application of micromolar nicotine typically induced 12-fold increases in the frequency of miniature inhibitory synaptic currents (mIPSCs). Little effect was observed on the amplitude of mIPSCs or mEPSCs under these conditions. Nicotine stimulation of mIPSCs was dependent on entry of extracellular calcium because removal of calcium from perfusate was able to block its action. To assess the potential physiological significance of the nicotine-stimulated increase in mIPSC frequency, we also examined the nicotine effect on evoked IPSCs (eIPSCs). eIPSCs were markedly attenuated by nicotine. This effect could be attributed to two potential mechanisms: transmitter depletion due to extremely high mIPSC rates and/or a reduction in presynaptic excitability associated with nicotinic depolarization. Treatment with low concentrations of K(+) was able to in part mimic nicotine's stimulatory effect on mIPSCs and inhibitory effect on eIPSCs. Current-clamp recordings confirmed a direct depolarizing action of nicotine that could dampen eIPSC activity leading to a switch to striatal inhibitory synaptic transmission mediated by tonic mIPSCs.

  12. Amphetamine augments action potential-dependent dopaminergic signaling in the striatum in vivo.

    PubMed

    Ramsson, Eric S; Covey, Daniel P; Daberkow, David P; Litherland, Melissa T; Juliano, Steven A; Garris, Paul A

    2011-06-01

    Amphetamine (AMPH) is thought to disrupt normal patterns of action potential-dependent dopaminergic signaling by depleting dopamine (DA) vesicular stores and promoting non-exocytotic DA efflux. Voltammetry in brain slices concurrently demonstrates these key drug effects, along with competitive inhibition of neuronal DA uptake. Here, we perform comparable kinetic and voltammetric analyses in vivo to determine whether AMPH acts qualitatively and quantitatively similar in the intact brain. Fast-scan cyclic voltammetry measured extracellular DA in dorsal and ventral striata of urethane-anesthetized rats. Electrically evoked recordings were analyzed to determine K(m) and V(max) for DA uptake and vesicular DA release, while background voltammetric current indexed basal DA concentration. AMPH (0.5, 3, and 10 mg/kg i.p.) robustly increased evoked DA responses in both striatal subregions. The predominant contributor to these elevated levels was competitive uptake inhibition, as exocytotic release was unchanged in the ventral striatum and only modestly decreased in the dorsal striatum. Increases in basal DA levels were not detected. These results are consistent with AMPH augmenting action potential-dependent dopaminergic signaling in vivo across a wide, behaviorally relevant dose range. Future work should be directed at possible causes for the distinct in vitro and in vivo pharmacology of AMPH.

  13. Applications of control theory to the dynamics and propagation of cardiac action potentials.

    PubMed

    Muñoz, Laura M; Stockton, Jonathan F; Otani, Niels F

    2010-09-01

    Sudden cardiac arrest is a widespread cause of death in the industrialized world. Most cases of sudden cardiac arrest are due to ventricular fibrillation (VF), a lethal cardiac arrhythmia. Electrophysiological abnormalities such as alternans (a beat-to-beat alternation in action potential duration) and conduction block have been suspected to contribute to the onset of VF. This study focuses on the use of control-systems techniques to analyze and design methods for suppressing these precursor factors. Control-systems tools, specifically controllability analysis and Lyapunov stability methods, were applied to a two-variable Karma model of the action-potential (AP) dynamics of a single cell, to analyze the effectiveness of strategies for suppressing AP abnormalities. State-feedback-integral (SFI) control was then applied to a Purkinje fiber simulated with the Karma model, where only one stimulating electrode was used to affect the system. SFI control converted both discordant alternans and 2:1 conduction block back toward more normal patterns, over a wider range of fiber lengths and pacing intervals compared with a Pyragas-type chaos controller. The advantages conferred by using feedback from multiple locations in the fiber, and using integral (i.e., memory) terms in the controller, are discussed.

  14. Supernormal Conduction and Suppression of Spatially Discordant Alternans of Cardiac Action Potentials

    PubMed Central

    Jing, Linyuan; Agarwal, Anuj; Patwardhan, Abhijit

    2016-01-01

    Spatially discordant alternans (DA) of action potential durations (APD) is thought to be more pro-arrhythmic than concordant alternans. Super normal conduction (SNC) has been reported to suppress formation of DA. An increase in conduction velocity (CV) as activation rate increases, i.e., a negative CV restitution, is widely considered as hallmark of SNC. Our aim in this study is to show that it is not an increase in CV for faster rates that prevents formation of DA, rather, it is the ratio of the CV for the short relative to the long activation that is critical in DA suppression. To illustrate this subtlety, we simulated this phenomenon using two approaches; (1) by using the standard, i.e., S1S2 protocol to quantify restitution and disabling the slow inactivation gate j of the sodium current (INa), and (2) by using the dynamic, i.e., S1S1 protocol for quantification of restitution and increasing INa at different cycle lengths (CL). Even though both approaches produced similar CV restitution curves, DA was suppressed only during the first approach, where the CV of the short of the long-short action potential (AP) pattern was selectively increased. These results show that negative CV restitution, which is considered characteristic of SNC, per se, is not causal in suppressing DA, rather, the critical factor is a change in the ratio of the velocities of the short and the long APs. PMID:26779035

  15. Applications of Control Theory to the Dynamics and Propagation of Cardiac Action Potentials

    PubMed Central

    Muñoz, Laura M.; Stockton, Jonathan F.; Otani, Niels F.

    2011-01-01

    Sudden cardiac arrest is a widespread cause of death in the industrialized world. Most cases of sudden cardiac arrest are due to ventricular fibrillation (VF), a lethal cardiac arrhythmia. Electrophysiological abnormalities such as alternans (a beat-to-beat alternation in action potential duration) and conduction block have been suspected to contribute to the onset of VF. This study focuses on the use of control-systems techniques to analyze and design methods for suppressing these precursor factors. Control-systems tools, specifically controllability analysis and Lyapunov stability methods, were applied to a two-variable Karma model of the action-potential (AP) dynamics of a single cell, to analyze the effectiveness of strategies for suppressing AP abnormalities. State-feedback-integral (SFI) control was then applied to a Purkinje fiber simulated with the Karma model, where only one stimulating electrode was used to affect the system. SFI control converted both discordant alternans and 2:1 conduction block back toward more normal patterns, over a wider range of fiber lengths and pacing intervals compared with a Pyragas-type chaos controller. The advantages conferred by using feedback from multiple locations in the fiber, and using integral (i.e., memory) terms in the controller, are discussed. PMID:20407833

  16. Frequency-dependent inhibition of antidromic hippocampal compound action potentials by anti-convulsants.

    PubMed

    Teriakidis, Adrianna; Brown, Jon T; Randall, Andrew

    2006-01-01

    Using rat hippocampal slices, extracellularly recorded antidromic compound action potentials (cAP) were produced in CA1 pyramidal cell populations by electrical stimulation of the alveus at 0.5 Hz. These responses were additionally examined across a range of stimulus frequencies between 0.5 and 100 Hz. Anticonvulsant drugs in clinical use were applied via perfusion of the recording chamber. Three anticonvulsants produced a concentration-dependent inhibition of the cAP evoked at low frequency (0.5 Hz). The following IC(50) values were observed: lamotrigine, 210 microM (interpolated); carbamazepine, 210 microM (interpolated); phenytoin, 400 microM (extrapolated). The extent of inhibition produced was increased when trains of 30 cAPs were evoked at frequencies > or 30 Hz. This frequency dependence was quantified by measuring a response integral for a range of compound concentrations. Three other compounds valproate (5 mM), topiramate (500 microM) and levetiracetam (500 microM) produced no clear effect at any stimulus frequency tested. Using this simple neurophysiological assay it has been possible to compare the use-dependent inhibition of hippocampal action potentials by a range of anticonvulsants, providing a useful adjunct to patch clamp studies of such molecules at Na(+) channels. There is no clear correlation between the activity in this model and the clinical efficacy of these drugs in different forms of epilepsy.

  17. The use of sensory action potential to evaluate inferior alveolar nerve damage after orthognathic surgery.

    PubMed

    Calabria, Francesca; Sellek, Lucy; Gugole, Fabio; Trevisiol, Lorenzo; Trevisol, Lorenzo; Bertolasi, Laura; D'Agostino, Antonio

    2013-03-01

    To assess and monitor the common event of neurosensory disturbance to the inferior alveolar nerve (IAN) after bilateral sagittal split osteotomy, we used clinical sensory tests and neurophysiologic test sensory action potentials. The diagnostic value of these tests was evaluated by comparing them with the degree of nerve damage reported by patients. Fourteen patients undergoing bilateral sagittal split osteotomy were analyzed preoperatively and 2 years postoperatively. Patients were evaluated bilaterally for positive and negative symptoms: light touch sensation, paraesthesia, hyperesthesia, and dysaesthesia; a "sensation score" was then calculated for each patient. Patients were also asked if they would be willing to repeat the procedure knowing the sensation loss they had now. Next, the right and left IAN were evaluated using sensory action potential and correlated with the other results. Before surgery, the medium latency difference between left and right was lower compared with postsurgery, with all patients having some deficit. The reduction in medium amplitude of 67% after the intervention was statistically significant. The frequency of abnormal findings in the electrophysiologic tests indicating IAN injury correlated with subjective sensory alteration. All patients said that they would repeat the surgery. Electrophysiologic testing is recommended for the evaluation of nerve dysfunction and seems a sensitive method for accurately assessing postsurgical nerve conduction.

  18. Effects of acoustic noise on the auditory nerve compound action potentials evoked by electric pulse trains.

    PubMed

    Nourski, Kirill V; Abbas, Paul J; Miller, Charles A; Robinson, Barbara K; Jeng, Fuh-Cherng

    2005-04-01

    This study investigated the effects of acoustic noise on the auditory nerve compound action potentials in response to electric pulse trains. Subjects were adult guinea pigs, implanted with a minimally invasive electrode to preserve acoustic sensitivity. Electrically evoked compound action potentials (ECAP) were recorded from the auditory nerve trunk in response to electric pulse trains both during and after the presentation of acoustic white noise. Simultaneously presented acoustic noise produced a decrease in ECAP amplitude. The effect of the acoustic masker on the electric probe was greatest at the onset of the acoustic stimulus and it was followed by a partial recovery of the ECAP amplitude. Following cessation of the acoustic noise, ECAP amplitude recovered over a period of approximately 100-200 ms. The effects of the acoustic noise were more prominent at lower electric pulse rates (interpulse intervals of 3 ms and higher). At higher pulse rates, the ECAP adaptation to the electric pulse train alone was larger and the acoustic noise, when presented, produced little additional effect. The observed effects of noise on ECAP were the greatest at high electric stimulus levels and, for a particular electric stimulus level, at high acoustic noise levels.

  19. Modulation of action potential and calcium signaling by levetiracetam in rat sensory neurons.

    PubMed

    Ozcan, Mete; Ayar, Ahmet

    2012-06-01

    Levetiracetam (LEV), a new anticonvulsant agent primarily used to treat epilepsy, has been used in pain treatment but the cellular mechanism of this action remains unclear. This study aimed to investigate effects of LEV on the excitability and membrane depolarization-induced calcium signaling in isolated rat sensory neurons using the whole-cell patch clamp and fura 2-based ratiometric Ca(2+)-imaging techniques. Dorsal root ganglia (DRG) were excised from neonatal rats, and cultured following enzymatic and mechanical dissociation. Under current clamp conditions, acute application of LEV (30 µM, 100 µM and 300 µM) significantly increased input resistance and caused the membrane to hyperpolarize from resting membrane potential in a dose-dependent manner. Reversal potentials of action potential (AP) after hyperpolarising amplitudes were shifted to more negative, toward to potassium equilibrium potentials, after application of LEV. It also caused a decrease in number of APs in neurons fired multiple APs in response to prolonged depolarization. Fura-2 fluorescence Ca(2+) imaging protocols revealed that HiK(+) (30 mM)-induced intracellular free Ca(2+) ([Ca(2+)](i)) was inhibited to 97.8 ± 4.6% (n = 17), 92.6 ± 4.8% (n = 17, p < 0.01) and 89.1 ± 5.1% (n = 18, p < 0.01) after application of 30 µM, 100 µM and 300 µM LEV (respectively), without any significant effect on basal levels of [Ca(2+)](i). This is the first evidence for the effect of LEV on the excitability of rat sensory neurons through an effect which might involve activation of potassium channels and inhibition of entry of Ca(2+), providing new insights for cellular mechanism(s) of LEV in pain treatment modalities.

  20. Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats.

    PubMed

    Liu, Xiaowen; Murali, Sangita G; Holst, Jens J; Ney, Denise M

    2009-11-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral protein component, casein, soy, or whey protein, potentiates the intestinal growth response to GLP-2 in rats with PN-induced mucosal hypoplasia. Rats received PN and continuous intravenous infusion of GLP-2 (100 microg/kg/day) for 7 days. Six EN groups received PN+GLP-2 for days 1-3 and partial PN+GLP-2 plus EN for days 4-7. EN was provided by ad libitum intake of a semielemental liquid diet with different protein sources: casein, hydrolyzed soy, whey protein concentrate (WPC), and hydrolyzed WPC+casein. Controls received PN+GLP-2 alone. EN induced significantly greater jejunal sucrase activity and gain of body weight, and improved feed efficiency compared with PN+GLP-2 alone. EN induced greater ileal proglucagon expression, increased plasma concentration of bioactive GLP-2 by 35%, and reduced plasma dipeptidyl peptidase IV (DPP-IV) activity compared with PN+GLP-2 alone, P < 0.05. However, only whey protein, and not casein or soy, potentiated the ability of GLP-2 to reverse PN-induced mucosal hypoplasia and further increase ileal villus height, crypt depth, and mucosa cellularity compared with PN+GLP-2 alone, P < 0.05. The ability of whey protein to induce greater mucosal surface area was associated with decreased DPP-IV activity in ileum and colon compared with casein, soy, or PN+GLP-2 alone, P < 0.05. In conclusion, whey protein potentiates the action of GLP-2 to reverse PN-induced mucosal hypoplasia in association with decreased intestinal DPP-IV activity.

  1. Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats

    PubMed Central

    Liu, Xiaowen; Murali, Sangita G.; Holst, Jens J.

    2009-01-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral protein component, casein, soy, or whey protein, potentiates the intestinal growth response to GLP-2 in rats with PN-induced mucosal hypoplasia. Rats received PN and continuous intravenous infusion of GLP-2 (100 μg/kg/day) for 7 days. Six EN groups received PN+GLP-2 for days 1–3 and partial PN+GLP-2 plus EN for days 4–7. EN was provided by ad libitum intake of a semielemental liquid diet with different protein sources: casein, hydrolyzed soy, whey protein concentrate (WPC), and hydrolyzed WPC+casein. Controls received PN+GLP-2 alone. EN induced significantly greater jejunal sucrase activity and gain of body weight, and improved feed efficiency compared with PN+GLP-2 alone. EN induced greater ileal proglucagon expression, increased plasma concentration of bioactive GLP-2 by 35%, and reduced plasma dipeptidyl peptidase IV (DPP-IV) activity compared with PN+GLP-2 alone, P < 0.05. However, only whey protein, and not casein or soy, potentiated the ability of GLP-2 to reverse PN-induced mucosal hypoplasia and further increase ileal villus height, crypt depth, and mucosa cellularity compared with PN+GLP-2 alone, P < 0.05. The ability of whey protein to induce greater mucosal surface area was associated with decreased DPP-IV activity in ileum and colon compared with casein, soy, or PN+GLP-2 alone, P < 0.05. In conclusion, whey protein potentiates the action of GLP-2 to reverse PN-induced mucosal hypoplasia in association with decreased intestinal DPP-IV activity. PMID:19776251

  2. Back-propagating action potentials in pyramidal neurons: a putative signaling mechanism for the induction of Hebbian synaptic plasticity.

    PubMed

    Colbert, C M

    2001-01-01

    A hallmark of synaptic plasticity is the associative, or Hebbian, nature of its induction. By associative, we mean that the timing relationships between activity of the pre- and postsynaptic elements of a synapse determine whether synaptic strengths are modified. lt is well-established that associativity results, in large part, from the dual requirements for activation of the N-methyl-D-aspartate receptor-ionophore, namely presynaptic neurotransmitter release and postsynaptic depolarization. However, the specific dendritic events that provide the postsynaptic depolarization have been relatively unexplored. Increasing evidence suggests that back-propagating (i.e., antidromic) Na(+) action potentials provide the necessary postsynaptic depolarization to allow induction of associative synaptic plasticities. In hippocampal CAI and neocortical layer V pyramidal neurons, these action potentials provide much greater levels of dendritic depolarization than would be expected from synaptic currents alone. Moreover, they provide a relatively brief and synchronous depolarization throughout the dendritic arbor, allowing timing relationships to more directly reflect pre- and postsynaptic cell firing. Interestingly, certain properties of the back-propagating actions potentials differ from axonal or somatic action potentials in ways that seem to reflect their function. For example, the all-or-none property of action potential amplitude does not hold in the dendrites. In this review we discuss the back-propagating action potential as a dendritic signal that provides information to synapses about the firing state of the postsynaptic neuron. First, we consider the evidence that action potentials propagate back from the axon. Second, we describe the characteristics of the back-propagating action potential in terms of interactions of its underlying ionic currents. Third, we describe how these properties contribute to the timing aspects of the induction of long-term potentiation. Finally

  3. Resistance to action potential depression of a rat axon terminal in vivo.

    PubMed

    Sierksma, Martijn C; Borst, J Gerard G

    2017-04-03

    The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.

  4. Nonlinear Dynamic Modeling of Neuron Action Potential Threshold During Synaptically Driven Broadband Intracellular Activity

    PubMed Central

    Roach, Shane M.; Song, Dong; Berger, Theodore W.

    2012-01-01

    Activity-dependent variation of neuronal thresholds for action potential (AP) generation is one of the key determinants of spike-train temporal-pattern transformations from presynaptic to postsynaptic spike trains. In this study, we model the nonlinear dynamics of the threshold variation during synaptically driven broadband intracellular activity. First, membrane potentials of single CA1 pyramidal cells were recorded under physiologically plausible broadband stimulation conditions. Second, a method was developed to measure AP thresholds from the continuous recordings of membrane potentials. It involves measuring the turning points of APs by analyzing the third-order derivatives of the membrane potentials. Four stimulation paradigms with different temporal patterns were applied to validate this method by comparing the measured AP turning points and the actual AP thresholds estimated with varying stimulation intensities. Results show that the AP turning points provide consistent measurement of the AP thresholds, except for a constant offset. It indicates that 1) the variation of AP turning points represents the nonlinearities of threshold dynamics; and 2) an optimization of the constant offset is required to achieve accurate spike prediction. Third, a nonlinear dynamical third-order Volterra model was built to describe the relations between the threshold dynamics and the AP activities. Results show that the model can predict threshold accurately based on the preceding APs. Finally, the dynamic threshold model was integrated into a previously developed single neuron model and resulted in a 33% improvement in spike prediction. PMID:22156947

  5. The Belem Framework for Action: Harnessing the Power and Potential of Adult Learning and Education for a Viable Future

    ERIC Educational Resources Information Center

    Adult Learning, 2012

    2012-01-01

    This article presents the Belem Framework for Action. This framework focuses on harnessing the power and potential of adult learning and education for a viable future. This framework begins with a preamble on adult education and towards lifelong learning.

  6. Pattern-dependent Role of NMDA receptors in Action Potential Generation: Consequences on ERK Activation

    PubMed Central

    Zhao, Meilan; Adams, J. Paige

    2005-01-01

    Synaptic long-term potentiation is maintained through gene transcription, but how the nucleus is recruited remains controversial. Activation of extracellular-signal regulated kinases 1 and 2 (ERKs) with synaptic stimulation has been shown to require NMDA receptors (NMDARs), yet stimulation intensities sufficient to recruit action potentials (APs) also appear to be required. This has led us to ask the question whether NMDARs are necessary for AP generation as they relate to ERK activation. To test this, we examined the effects of NMDAR blockade on APs induced with synaptic stimulation using whole-cell current clamp recordings from CA1 pyramidal cells in hippocampal slices. NMDAR antagonists were found to potently inhibit APs generated with 5 and 100 Hz synaptic stimulation. Blockade of APs, and ERK activation, could be overcome with the addition of the GABA-A antagonist bicuculline, indicating that APs are sufficient to activate signals such as ERK in the nucleus and throughout the neuron in the continued presence of NMDAR antagonists. Interestingly, no effects of the NMDAR antagonists were observed when theta-burst stimulation (TBS) was used. This resistance to the antagonists is conferred by temporal summation during the bursts. These results clarify findings from a previous study showing that ERK activation induced with TBS is resistant to APV, in contrast to that induced with 5 Hz or 100 Hz stimulation, which is sensitive. By showing that NMDAR blockade inhibits AP generation, we demonstrate that a major role NMDARs play in cell-wide and nuclear ERK activation is through their contribution to action potential generation. PMID:16049179

  7. Calcium-dependent but action potential-independent BCM-like metaplasticity in the hippocampus.

    PubMed

    Hulme, Sarah R; Jones, Owen D; Ireland, David R; Abraham, Wickliffe C

    2012-05-16

    The Bienenstock, Cooper and Munro (BCM) computational model, which incorporates a metaplastic sliding threshold for LTP induction, accounts well for experience-dependent changes in synaptic plasticity in the visual cortex. BCM-like metaplasticity over a shorter timescale has also been observed in the hippocampus, thus providing a tractable experimental preparation for testing specific predictions of the model. Here, using extracellular and intracellular electrophysiological recordings from acute rat hippocampal slices, we tested the critical BCM predictions (1) that high levels of synaptic activation will induce a metaplastic state that spreads across dendritic compartments, and (2) that postsynaptic cell-firing is the critical trigger for inducing that state. In support of the first premise, high-frequency priming stimulation inhibited subsequent long-term potentiation and facilitated subsequent long-term depression at synapses quiescent during priming, including those located in a dendritic compartment different to that of the primed pathway. These effects were not dependent on changes in synaptic inhibition or NMDA/metabotropic glutamate receptor function. However, in contrast to the BCM prediction, somatic action potentials during priming were neither necessary nor sufficient to induce the metaplasticity effect. Instead, in broad agreement with derivatives of the BCM model, calcium as released from intracellular stores and triggered by M1 muscarinic acetylcholine receptor activation was critical for altering subsequent synaptic plasticity. These results indicate that synaptic plasticity in stratum radiatum of CA1 can be homeostatically regulated by the cell-wide history of synaptic activity through a calcium-dependent but action potential-independent mechanism.

  8. Toxin detection based on action potential shape analysis using a realistic mathematical model of differentiated NG108-15 cells

    PubMed Central

    Mohan, Dinesh K; Molnar, Peter; Hickman, James J.

    2010-01-01

    The NG108-15 neuroblastoma / glioma hybrid cell line has been frequently used for toxin detection, pharmaceutical screening and as a whole-cell biosensor. However, detailed analysis of its action potentials during toxin or drug administration has not been accomplished previously using patch clamp electrophysiology. In order to explore the possibility of identifying toxins based on their effect on the shape of intracellularly or extracellularly detected action potentials, we created a computer model of the action potential generation of this cell type. To generate the experimental data to validate the model, voltage dependent sodium, potassium and high-threshold calcium currents, as well as action potentials, were recorded from NG108-15 cells with conventional whole-cell patch-clamp methods. Based on the classic Hodgkin-Huxley formalism and the linear thermodynamic description of the rate constants, ion-channel parameters were estimated using an automatic fitting method. Utilizing the established parameters, action potentials were generated in the model and were optimized to represent the actual recorded action potentials to establish baseline conditions. To demonstrate the applicability of the method for toxin detection and discrimination, the effect of tetrodotoxin (a sodium channel blocker) and tefluthrin (a pyrethroid that is a sodium channel opener) were studied. The two toxins affected the shape of the action potentials differently and their respective effects were identified based on the changes in the fitted parameters. Our results represent one of the first steps to establish a complex model of NG108-15 cells for quantitative toxin detection based on action potential shape analysis of the experimental results. PMID:16460924

  9. Action potential initiation in the peripheral terminals of cold-sensitive neurones innervating the guinea-pig cornea.

    PubMed

    Carr, Richard W; Pianova, Svetlana; McKemy, David D; Brock, James A

    2009-03-15

    The site at which action potentials initiate within the terminal region of unmyelinated sensory axons has not been resolved. Combining recordings of nerve terminal impulses (NTIs) and collision analysis, the site of action potential initiation in guinea-pig corneal cold receptors was determined. For most receptors (77%), initiation mapped to a point in the time domain that was closer to the nerve terminal than to the site of electrical stimulation at the back of the eye. Guinea-pig corneal cold receptors are Adelta-neurones that lose their myelin sheath at the point where they enter the cornea, and therefore their axons conduct more slowly within the cornea. Allowing for this inhomogeneity in conduction speed, the resulting spatial estimates of action potential initiation sites correlated with changes in NTI shape predicted by simulation of action potentials initiating within a nerve terminal. In some receptors, more than one NTI shape was observed. Simulations of NTI shape suggest that the origin of differing NTI shapes result from action potentials initiating at different, spatially discrete, locations within the nerve terminal. Importantly, the relative incidence of NTI shapes resulting from action potential initiation close to the nerve termination increased during warming when nerve activity decreased, indicating that the favoured site of action potential initiation shifts toward the nerve terminal when it hyperpolarizes. This finding can be explained by a hyperpolarization-induced relief of Na(+) channel inactivation in the nerve terminal. The results provide direct evidence that the molecular entities responsible for stimulus transduction and action potential initiation reside in parallel with one another in the unmyelinated nerve terminals of cold receptors.

  10. Neural mechanisms underlying immediate and final action goals in object use reflected by slow wave brain potentials.

    PubMed

    van Schie, Hein T; Bekkering, Harold

    2007-05-07

    Event-related brain potentials were used to study the neural mechanisms underlying goal-directed object use distinguishing between processes supporting immediate and final action goals during action planning and execution. Subjects performed a grasping and transportation task in which actions were cued either with the immediate action goal (the part of the object to grasp) or with the final action goal of the movement (the end position for transportation). Slow wave potentials dissociated between processes supporting immediate and final goals: reaching for the object was accompanied by the development of a parietal-occipital slow wave that peaked in congruency with the grasping event, whereas transport of the object towards the final goal location was found accompanied by slow wave components developing over left frontal regions with a peak towards the movement end. Source localization of cueing differences indicated activation centered around the parieto-occipital sulcus during reaching of the immediate action goal, followed by enhanced activation in the anterior prefrontal cortex during transport to the final action goal. These results suggest the existence of separate neural controllers for immediate and final action goals during the execution of goal-directed actions with objects.

  11. Intracellular recordings of action potentials by an extracellular nanoscale field-effect transistor

    NASA Astrophysics Data System (ADS)

    Duan, Xiaojie; Gao, Ruixuan; Xie, Ping; Cohen-Karni, Tzahi; Qing, Quan; Choe, Hwan Sung; Tian, Bozhi; Jiang, Xiaocheng; Lieber, Charles M.

    2012-03-01

    The ability to make electrical measurements inside cells has led to many important advances in electrophysiology. The patch clamp technique, in which a glass micropipette filled with electrolyte is inserted into a cell, offers both high signal-to-noise ratio and temporal resolution. Ideally, the micropipette should be as small as possible to increase the spatial resolution and reduce the invasiveness of the measurement, but the overall performance of the technique depends on the impedance of the interface between the micropipette and the cell interior, which limits how small the micropipette can be. Techniques that involve inserting metal or carbon microelectrodes into cells are subject to similar constraints. Field-effect transistors (FETs) can also record electric potentials inside cells, and because their performance does not depend on impedance, they can be made much smaller than micropipettes and microelectrodes. Moreover, FET arrays are better suited for multiplexed measurements. Previously, we have demonstrated FET-based intracellular recording with kinked nanowire structures, but the kink configuration and device design places limits on the probe size and the potential for multiplexing. Here, we report a new approach in which a SiO2 nanotube is synthetically integrated on top of a nanoscale FET. This nanotube penetrates the cell membrane, bringing the cell cytosol into contact with the FET, which is then able to record the intracellular transmembrane potential. Simulations show that the bandwidth of this branched intracellular nanotube FET (BIT-FET) is high enough for it to record fast action potentials even when the nanotube diameter is decreased to 3 nm, a length scale well below that accessible with other methods. Studies of cardiomyocyte cells demonstrate that when phospholipid-modified BIT-FETs are brought close to cells, the nanotubes can spontaneously penetrate the cell membrane to allow the full-amplitude intracellular action potential to be

  12. Potential Mechanisms of Action in the Treatment of Social Impairment and Disorganization in Adolescents with ADHD

    PubMed Central

    Evans, Steven W.; Schultz, Brandon K.; Zoromski, Allison K.

    2014-01-01

    Two important domains that can be impaired in adolescents with ADHD are organization and social functioning; however, the development of interventions to target these areas in adolescents is in the early stages. Currently, small efficacy trials are beginning to be used to conduct preliminary tests on the proposed mechanisms of action for these interventions. These two studies examined the efficacy of organization and social functioning interventions for adolescents with ADHD, as well as the potential mechanisms of action for each intervention. Results from the organization intervention provide support for a significant relationship between performance on the organization checklist and overall GPA; however, there was no meaningful pattern of relationships between achieving mastery of the organization tasks and grades within quarter. Further, results from the social functioning intervention support a moderate relationship between performance on process measures of response to the intervention and outcome measures of social functioning. Results of this study provide implications for modifications to the measures and intervention procedures in future research. PMID:24748901

  13. FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK channels

    PubMed Central

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A.; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S.; Klyachko, Vitaly A.

    2013-01-01

    SUMMARY Loss of FMRP causes Fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation-independent and are mediated selectively by BK channels via interaction of FMRP with BK channel’s regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology. PMID:23439122

  14. Electrophysiological Motor Unit Number Estimation (MUNE) Measuring Compound Muscle Action Potential (CMAP) in Mouse Hindlimb Muscles.

    PubMed

    Arnold, W David; Sheth, Kajri A; Wier, Christopher G; Kissel, John T; Burghes, Arthur H; Kolb, Stephen J

    2015-09-25

    Compound muscle action potential (CMAP) and motor unit number estimation (MUNE) are electrophysiological techniques that can be used to monitor the functional status of a motor unit pool in vivo. These measures can provide insight into the normal development and degeneration of the neuromuscular system. These measures have clear translational potential because they are routinely applied in diagnostic and clinical human studies. We present electrophysiological techniques similar to those employed in humans to allow recordings of mouse sciatic nerve function. The CMAP response represents the electrophysiological output from a muscle or group of muscles following supramaximal stimulation of a peripheral nerve. MUNE is an electrophysiological technique that is based on modifications of the CMAP response. MUNE is a calculated value that represents the estimated number of motor neurons or axons (motor control input) supplying the muscle or group of muscles being tested. We present methods for recording CMAP responses from the proximal leg muscles using surface recording electrodes following the stimulation of the sciatic nerve in mice. An incremental MUNE technique is described using submaximal stimuli to determine the average single motor unit potential (SMUP) size. MUNE is calculated by dividing the CMAP amplitude (peak-to-peak) by the SMUP amplitude (peak-to-peak). These electrophysiological techniques allow repeated measures in both neonatal and adult mice in such a manner that facilitates rapid analysis and data collection while reducing the number of animals required for experimental testing. Furthermore, these measures are similar to those recorded in human studies allowing more direct comparisons.

  15. Cancer Driver Log (CanDL): Catalog of Potentially Actionable Cancer Mutations.

    PubMed

    Damodaran, Senthilkumar; Miya, Jharna; Kautto, Esko; Zhu, Eliot; Samorodnitsky, Eric; Datta, Jharna; Reeser, Julie W; Roychowdhury, Sameek

    2015-09-01

    Massively parallel sequencing technologies have enabled characterization of genomic alterations across multiple tumor types. Efforts have focused on identifying driver mutations because they represent potential targets for therapy. However, because of the presence of driver and passenger mutations, it is often challenging to assign the clinical relevance of specific mutations observed in patients. Currently, there are multiple databases and tools that provide in silico assessment for potential drivers; however, there is no comprehensive resource for mutations with functional characterization. Therefore, we created an expert-curated database of potentially actionable driver mutations for molecular pathologists to facilitate annotation of cancer genomic testing. We reviewed scientific literature to identify variants that have been functionally characterized in vitro or in vivo as driver mutations. We obtained the chromosome location and all possible nucleotide positions for each amino acid change and uploaded them to the Cancer Driver Log (CanDL) database with associated literature reference indicating functional driver evidence. In addition to a simple interface, the database allows users to download all or selected genes as a comma-separated values file for incorporation into their own analysis pipeline. Furthermore, the database includes a mechanism for third-party contributions to support updates for novel driver mutations. Overall, this freely available database will facilitate rapid annotation of cancer genomic testing in molecular pathology laboratories for mutations.

  16. Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

    PubMed Central

    Li, Wentao; Xu, Haoliang; Testai, Fernando D.

    2016-01-01

    Fingolimod (FTY720) is an orally bio-available immunomodulatory drug currently approved by the FDA for the treatment of multiple sclerosis. Currently, there is a significant interest in the potential benefits of FTY720 on stroke outcomes. FTY720 and the sphingolipid signaling pathway it modulates has a ubiquitous presence in the central nervous system and both rodent models and pilot clinical trials seem to indicate that the drug may improve overall functional recovery in different stroke subtypes. Although the precise mechanisms behind these beneficial effects are yet unclear, there is evidence that FTY720 has a role in regulating cerebrovascular responses, blood–brain barrier permeability, and cell survival in the event of cerebrovascular insult. In this article, we critically review the data obtained from the latest laboratory findings and clinical trials involving both ischemic and hemorrhagic stroke, and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke. PMID:27617002

  17. Control and Plasticity of the Presynaptic Action Potential Waveform at Small CNS Nerve Terminals

    PubMed Central

    Hoppa, Michael B.; Gouzer, Geraldine; Armbruster, Moritz; Ryan, Timothy A.

    2014-01-01

    SUMMARY The steep dependence of exocytosis on Ca2+ entry at nerve terminals implies that voltage control of both Ca2+ channel opening and the driving force for Ca2+ entry are powerful levers in sculpting synaptic efficacy. Using fast, genetically encoded voltage indicators in dissociated primary neurons, we show that at small nerve terminals K+ channels constrain the peak voltage of the presynaptic action potential (APSYN) to values much lower than those at cell somas. This key APSYN property additionally shows adaptive plasticity: manipulations that increase presynaptic Ca2+ channel abundance and release probability result in a commensurate lowering of the APSYN peak and narrowing of the waveform, while manipulations that decrease presynaptic Ca2+ channel abundance do the opposite. This modulation is eliminated upon blockade of Kv3.1 and Kv1 channels. Our studies thus reveal that adaptive plasticity in the APSYN waveform serves as an important regulator of synaptic function. PMID:25447742

  18. Na+ current in presynaptic terminals of the crayfish opener cannot initiate action potentials

    PubMed Central

    2015-01-01

    Action potential (AP) propagation in presynaptic axons of the crayfish opener neuromuscular junction (NMJ) was investigated by simultaneously recording from a terminal varicosity and a proximal branch. Although orthodromically conducting APs could be recorded in terminals with amplitudes up to 70 mV, depolarizing steps in terminals to −20 mV or higher failed to fire APs. Patch-clamp recordings did detect Na+ current (INa) in most terminals. The INa exhibited a high threshold and fast activation rate. Local perfusion of Na+-free saline showed that terminal INa contributed to AP waveform by slightly accelerating the rising phase and increasing the peak amplitude. These findings suggest that terminal INa functions to “touch up” but not to generate APs. PMID:26561611

  19. Boron-doped nanocrystalline diamond microelectrode arrays monitor cardiac action potentials.

    PubMed

    Maybeck, Vanessa; Edgington, Robert; Bongrain, Alexandre; Welch, Joseph O; Scorsone, Emanuel; Bergonzo, Philippe; Jackman, Richard B; Offenhäusser, Andreas

    2014-02-01

    The expansion of diamond-based electronics in the area of biological interfacing has not been as thoroughly explored as applications in electrochemical sensing. However, the biocompatibility of diamond, large safe electrochemical window, stability, and tunable electronic properties provide opportunities to develop new devices for interfacing with electrogenic cells. Here, the fabrication of microelectrode arrays (MEAs) with boron-doped nanocrystalline diamond (BNCD) electrodes and their interfacing with cardiomyocyte-like HL-1 cells to detect cardiac action potentials are presented. A nonreductive means of structuring doped and undoped diamond on the same substrate is shown. The resulting BNCD electrodes show high stability under mechanical stress generated by the cells. It is shown that by fabricating the entire surface of the MEA with NCD, in patterns of conductive doped, and isolating undoped regions, signal detection may be improved up to four-fold over BNCD electrodes passivated with traditional isolators.

  20. Action potential evoked transmitter release in central synapses: insights from the developing calyx of Held

    PubMed Central

    2009-01-01

    Chemical synapses are the fundamental units that mediate communication between neurons in the mammalian brain. In contrast to the enormous progress made in mapping out postsynaptic contributions of receptors, scaffolding structures and receptor trafficking to synaptic transmission and plasticity, the small size of nerve terminals has largely precluded direct analyses of presynaptic modulation of excitability and transmitter release in central synapses. Recent studies performed in accessible synapses such as the calyx of Held, a giant axosomatic synapse in the sound localization circuit of the auditory brainstem, have provided tremendous insights into how central synapses regulate the dynamic gain range of synaptic transmission. This review will highlight experimental evidence that resolves several long-standing issues with respect to intricate interplays between the waveform of action potentials, Ca2+ currents and transmitter release and further conceptualize their relationships in a physiological context with theoretical models of the spatial organization of voltage-gated Ca2+ channels and synaptic vesicles at release sites. PMID:19939269

  1. A Shab potassium channel contributes to action potential broadening in peptidergic neurons.

    PubMed

    Quattrocki, E A; Marshall, J; Kaczmarek, L K

    1994-01-01

    We have cloned the gene for a potassium channel, Aplysia Shab, that is expressed in the bag cell neurons of Aplysia. The voltage dependence and kinetics of the Aplysia Shab current in oocytes match those of IK2, one of the two delayed rectifiers in these neurons. Like IK2, but in contrast with other members of the Shab subfamily, the Aplysia Shab current inactivates within several hundred milliseconds. This inactivation occurs by a process whose properties do not match those previously described for C-type and N-type mechanisms. Neither truncation of the N-terminus nor block by tetraethylammonium alters the time course of inactivation. By incorporating the characteristics of Aplysia Shab into a computational model, we have shown how this current contributes to the normal enhancement of action potentials that occurs in the bag cell neurons at the onset of neuropeptide secretion.

  2. Action potential shape change in an electrically coupled network during propagation: a computer simulation.

    PubMed

    Buckingham, Steven D; Spencer, Andrew N

    2008-06-01

    We applied compartmental computer modeling to test a model of spike shape change in the jellyfish, Polyorchis penicillatus, to determine whether adaptive spike shortening can be attributed to the inactivation properties of a potassium channel. We modeled the jellyfish outer nerve-ring as a continuous linear segment, using ion channel and membrane properties derived in earlier studies. The model supported action potentials that shortened as they propagated away from the site of initiation and this was found to be largely independent of potassium channel inactivation. Spike broadening near the site of initiation was found to be due to a depolarization plateau that collapsed as two spikes spread from the point of initiation. The lifetime of this plateau was found to depend critically on the inward current flux and the space constant of the membrane. These data suggest that the spike shape changes may be due not only to potassium channel inactivation, but also to the passive properties of the membrane.

  3. Neuronal adaptation involves rapid expansion of the action potential initiation site

    PubMed Central

    Scott, Ricardo S.; Henneberger, Christian; Padmashri, Ragunathan; Anders, Stefanie; Jensen, Thomas P.; Rusakov, Dmitri A.

    2014-01-01

    Action potential (AP) generation is the key to information-processing in the brain. Although APs are normally initiated in the axonal initial segment, developmental adaptation or prolonged network activity may alter the initiation site geometry thus affecting cell excitability. Here we find that hippocampal dentate granule cells adapt their spiking threshold to the kinetics of the ongoing dendrosomatic excitatory input by expanding the AP-initiation area away from the soma while also decelerating local axonal spikes. Dual-patch soma–axon recordings combined with axonal Na+ and Ca2+ imaging and biophysical modelling show that the underlying mechanism involves distance-dependent inactivation of axonal Na+ channels due to somatic depolarization propagating into the axon. Thus, the ensuing changes in the AP-initiation zone and local AP propagation could provide activity-dependent control of cell excitability and spiking on a relatively rapid timescale. PMID:24851940

  4. Experimental and theoretical description of higher order periods in cardiac tissue action potential duration

    NASA Astrophysics Data System (ADS)

    Herndon, Conner; Fenton, Flavio; Uzelac, Ilija

    Much theoretical, experimental, and clinical research has been devoted to investigating the initiation of cardiac arrhythmias by alternans, the first period doubling bifurcation in the duration of cardiac action potentials. Although period doubling above alternans has been shown to exist in many mammalian hearts, little is understood about their emergence or behavior. There currently exists no physiologically correct theory or model that adequately describes and predicts their emergence in stimulated tissue. In this talk we present experimental data of period 2, 4, and 8 dynamics and a mathematical model that describes these bifurcations. This model extends current cell models through the addition of memory and includes spatiotemporal nonlinearities arising from cellular coupling by tissue heterogeneity.

  5. Inhomogeneity of action potential waveshape assists frequency entrainment of cardiac pacemaker cells.

    PubMed

    Cloherty, S L; Lovell, N H; Celler, B G; Dokos, S

    2001-10-01

    In this paper, we have employed ionic models of sinoatrial node cells to investigate the synchronization of a pair of coupled cardiac pacemaker cells from central and peripheral regions of the sinoatrial node. The free-running cycle length of the cell models was perturbed using two independent techniques and the minimum coupling conductance required to achieve frequency entrainment was used to assess the relative ease with which various cell pairs achieve entrainment. The factors effecting entrainment were further investigated using single-cell models paced with an artificial biphasic coupling current. Our simulation results suggest that dissimilar cell types, those with largely different upstroke velocities entrain more easily, that is, they require less coupling conductance to achieve 1:1 frequency entrainment. We, therefore, propose that regional variation in action-potential waveshape within the sinoatrial node assists frequency synchronization in vivo.

  6. Distributed computing for membrane-based modeling of action potential propagation.

    PubMed

    Porras, D; Rogers, J M; Smith, W M; Pollard, A E

    2000-08-01

    Action potential propagation simulations with physiologic membrane currents and macroscopic tissue dimensions are computationally expensive. We, therefore, analyzed distributed computing schemes to reduce execution time in workstation clusters by parallelizing solutions with message passing. Four schemes were considered in two-dimensional monodomain simulations with the Beeler-Reuter membrane equations. Parallel speedups measured with each scheme were compared to theoretical speedups, recognizing the relationship between speedup and code portions that executed serially. A data decomposition scheme based on total ionic current provided the best performance. Analysis of communication latencies in that scheme led to a load-balancing algorithm in which measured speedups at 89 +/- 2% and 75 +/- 8% of theoretical speedups were achieved in homogeneous and heterogeneous clusters of workstations. Speedups in this scheme with the Luo-Rudy dynamic membrane equations exceeded 3.0 with eight distributed workstations. Cluster speedups were comparable to those measured during parallel execution on a shared memory machine.

  7. Effects of lead acetate on guinea pig - cochear microphonics, action potential, and motor nerve conduction velocity

    SciTech Connect

    Yamamura, K.; Maehara, N.; Terayama, K.; Ueno, N.; Kohyama, A.; Sawada, Y.; Kishi, R.

    1987-04-01

    Segmental demyelination and axonal degeneration of motor nerves induced by lead exposure is well known in man, and animals. The effect of lead acetate exposure to man may involve the cranial nerves, since vertigo and sensory neuronal deafness have been reported among lead workers. However, there are few reports concerning the dose-effects of lead acetate both to the peripheral nerve and the cranial VII nerve with measurement of blood lead concentration. The authors investigated the effects of lead acetate to the cochlea and the VIII nerve using CM (cochlear microphonics) and AP (action potential) of the guinea pigs. The effects of lead acetate to the sciatic nerve were measured by MCV of the sciatic nerve with measurement of blood lead concentration.

  8. BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus.

    PubMed

    Bukalo, Olena; Lee, Philip R; Fields, R Douglas

    2016-12-02

    Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation.

  9. Sequential dissection of multiple ionic currents in single cardiac myocytes under action potential-clamp

    PubMed Central

    Banyasz, Tamas; Horvath, Balazs; Jian, Zhong; Izu, Leighton T.; Chen-Izu, Ye

    2011-01-01

    The cardiac action potential (AP) is shaped by myriad ionic currents. In this study we develop an innovative AP-clamp Sequential Dissection technique to enable recording of multiple ionic currents in the single cell under AP-clamp. This new technique presents a significant step beyond the traditional way of recording only one current in any one cell. The ability to measure many currents in a single cell has revealed two hitherto unknown characteristics of the ionic currents in cardiac cells: coordination of currents within a cell and large variation of currents between cells. Hence, the AP-clamp Sequential Dissection method provides a unique and powerful tool for studying individual cell electrophysiology. PMID:21215755

  10. Sequential dissection of multiple ionic currents in single cardiac myocytes under action potential-clamp.

    PubMed

    Banyasz, Tamas; Horvath, Balazs; Jian, Zhong; Izu, Leighton T; Chen-Izu, Ye

    2011-03-01

    The cardiac action potential (AP) is shaped by myriad ionic currents. In this study, we develop an innovative AP-clamp Sequential Dissection technique to enable the recording of multiple ionic currents in the single cell under AP-clamp. This new technique presents a significant step beyond the traditional way of recording only one current in any one cell. The ability to measure many currents in a single cell has revealed two hitherto unknown characteristics of the ionic currents in cardiac cells: coordination of currents within a cell and large variation of currents between cells. Hence, the AP-clamp Sequential Dissection method provides a unique and powerful tool for studying individual cell electrophysiology.

  11. Mannan Oligosaccharides in Nursery Pig Nutrition and Their Potential Mode of Action

    PubMed Central

    Halas, Veronika; Nochta, Imre

    2012-01-01

    Simple Summary The aim of the paper is to provide a review of mannan oligosaccharide products in relation to their growth promoting effect and mode of action. Mannan oligosaccharide products maintain intestinal integrity and the digestive and absorptive function of the gut in the post-weaning period in pigs and enhance disease resistance by promoting antigen presentation. We find that dietary supplementation has growth promoting effects in pigs kept in a poor hygienic environment, while the positive effect of MOS is not observed in healthy pig herds with high hygienic standards. Abstract Mannan oligosaccharides (MOSs) are often referred to as one of the potential alternatives for antimicrobial growth promoters. The aim of the paper is to provide a review of mannan oligosaccharide products in relation to their growth promoting effect and mode of action based on the latest publications. We discuss the dietary impact of MOSs on (1) microbial changes, (2) morphological changes of gut tissue and digestibility of nutrients, and (3) immune response of pigs after weaning. Dietary MOSs maintain the intestinal integrity and the digestive and absorptive function of the gut in the post-weaning period. Recent results suggest that MOS enhances the disease resistance in swine by promoting antigen presentation facilitating thereby the shift from an innate to an adaptive immune response. Accordingly, dietary MOS supplementation has a potential growth promoting effect in pigs kept in a poor hygienic environment, while the positive effect of MOS is not observed in healthy pig herds with high hygienic standards that are able to maintain a high growth rate after weaning. PMID:26486920

  12. Effects of norfluoxetine on the action potential and transmembrane ion currents in canine ventricular cardiomyocytes.

    PubMed

    Magyar, János; Szentandrássy, Norbert; Bányász, Tamás; Kecskeméti, Valéria; Nánási, Péter P

    2004-09-01

    Norfluoxetine is the most important active metabolite of the widely used antidepressant compound fluoxetine. Although the cellular electrophysiological actions of fluoxetine are well characterized in cardiac cells, little is known about the effects of its metabolite. In this study, therefore, the effects of norfluoxetine on action potential (AP) configuration and transmembrane ion currents were studied in isolated canine cardiomyocytes using the whole cell configuration of patch clamp techniques. Micromolar concentrations of norfluoxetine (1-10 microM) modified AP configuration: amplitude and duration of the AP and maximum velocity of depolarization were decreased in addition to depression of the plateau and elimination of the incisura of AP. Voltage clamp experiments revealed a concentration-dependent suppression of both L-type Ca(2+) current, I(Ca) (EC(50)=1.13+/-0.08 microM) and transient outward K(+) current, I(to) (EC(50)=1.19+/-0.17 microM) having Hill coefficients close to unity. The midpoint potential of the steady-state inactivation of I(Ca) was shifted from -20.9+/-0.75 mV to -27.7+/-1.35 mV by 3 microM norfluoxetine ( P<0.05, n=7). No such shift in the steady-state inactivation curve was observed in the case of I(to). Similarly, norfluoxetine caused no change in the steady-state current-voltage relationship of the membrane or in the density of the inward rectifier K(+) current, I(K1). All these effects of norfluoxetine developed rapidly and were fully reversible. Comparing present results with those obtained previously with fluoxetine, it can be concluded that norfluoxetine displays stronger suppression of cardiac ion channels than fluoxetine. Consequently, the majority of the cardiac side effects observed during fluoxetine treatment are likely to be attributed to its metabolite norfluoxetine.

  13. 12-lead electrocardiogram features of arrhythmic risk: A focus on early repolarization

    PubMed Central

    Rizzo, Caterina; Monitillo, Francesco; Iacoviello, Massimo

    2016-01-01

    The 12-lead electrocardiogram (ECG) is still the most used tool in cardiology clinical practice. Considering its easy accessibility, low cost and the information that it provides, it remains the starting point for diagnosis and prognosis. More specifically, its ability to detect prognostic markers for sudden cardiac death due to arrhythmias by identifying specific patterns that express electrical disturbances of the heart muscle, which may predispose to malignant arrhythmias, is universally recognized. Alterations in the ventricular repolarization process, identifiable on a 12-lead ECG, play a role in the genesis of ventricular arrhythmias in different cardiac diseases. The aim of this paper is to focus the attention on a new marker of arrhythmic risk, the early repolarization pattern in order to highlight the prognostic role of the 12-lead ECG. PMID:27621772

  14. Traditional and novel electrocardiographic conduction and repolarization markers of sudden cardiac death.

    PubMed

    Tse, Gary; Yan, Bryan P

    2016-10-04

    Sudden cardiac death, frequently due to ventricular arrhythmias, is a significant problem globally. Most affected individuals do not arrive at hospital in time for medical treatment. Therefore, there is an urgent need to identify the most-at-risk patients for insertion of prophylactic implantable cardioverter defibrillators. Clinical risk markers derived from electrocardiography are important for this purpose. They can be based on repolarization, including corrected QT (QTc) interval, QT dispersion (QTD), interval from the peak to the end of the T-wave (Tpeak - Tend), (Tpeak - Tend)/QT, T-wave alternans (TWA), and microvolt TWA. Abnormal repolarization properties can increase the risk of triggered activity and re-entrant arrhythmias. Other risk markers are based solely on conduction, such as QRS duration (QRSd), which is a surrogate marker of conduction velocity (CV) and QRS dispersion (QRSD) reflecting CV dispersion. Conduction abnormalities in the form of reduced CV, unidirectional block, together with a functional or a structural obstacle, are conditions required for circus-type or spiral wave re-entry. Conduction and repolarization can be represented by a single parameter, excitation wavelength (λ = CV × effective refractory period). λ is an important determinant of arrhythmogenesis in different settings. Novel conduction-repolarization markers incorporating λ include Lu et al.' index of cardiac electrophysiological balance (iCEB: QT/QRSd), [QRSD× (Tpeak - Tend)/QRSd] and [QRSD × (Tpeak - Tend)/(QRSd × QT)] recently proposed by Tse and Yan. The aim of this review is to provide up to date information on traditional and novel markers and discuss their utility and downfalls for risk stratification.

  15. Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels

    PubMed Central

    Dubó, Sebastián; Gallegos, David; Cabrera, Lissette; Sobrevia, Luis; Zúñiga, Leandro; González, Marcelo

    2016-01-01

    Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction. On the other hand, electrical remodeling in cardiomyocytes is considered a key factor in heart failure progression associated to diabetes mellitus. This generates a challenge to understand the specific role of insulin and the pathways involved in cardiac function. Studies on isolated mammalian cardiomyocytes have shown prolongated action potential in ventricular repolarization phase that produces a long QT interval, which is well explained by attenuation in the repolarizing potassium currents in cardiac ventricles. Impaired insulin signaling causes specific changes in these currents, such a decrease amplitude of the transient outward K+ (Ito) and the ultra-rapid delayed rectifier (IKur) currents where, together, a reduction of mRNA and protein expression levels of α-subunits (Ito, fast; Kv 4.2 and IKs; Kv 1.5) or β-subunits (KChIP2 and MiRP) of K+ channels involved in these currents in a MAPK mediated pathway process have been described. These results support the hypothesis that lack of insulin signaling can produce an abnormal repolarization in cardiomyocytes. Furthermore, the arrhythmogenic potential due to reduced Ito current can contribute to an increase in the incidence of sudden death in heart failure. This review aims to show, based on pathophysiological models, the regulatory function that would have insulin in vascular system and in cardiac electrophysiology. PMID

  16. Potential of an outranking multi-criteria approach to support the participatory assessment of land management actions.

    PubMed

    Ocampo-Melgar, Anahí; Bautista, Susana; Edward deSteiguer, J; Orr, Barron J

    2016-12-07

    We evaluated the potential of an outranking Multi-Criteria Decision Analysis approach for assisting in the participatory assessment of dryland management actions implemented in the San Simon watershed, in southeastern Arizona, USA. We compared an outranking-facilitated assessment of actions with a simple and direct (baseline) ranking of the same actions by the participating stakeholders in terms of: 1) internal homogeneity of each assessment approach, (2) similarity of individual assessments between methods, and (3) effects of the use of implicit/explicit assessment criteria. The actions assessed combined various management approaches, including livestock management (rotation, resting), vegetation management (grass seeding, brush control), and hydraulic structures (dams, dykes). The outranking-facilitated assessment discriminated better between actions and reduced the variability of results between individual stakeholders as compared with the direct ranking of actions. In general, the two assessments significantly differed in the relative preference of the five management actions assessed, yet both assessments identified rotational grazing combined with vegetation management (grass seeding and brush control) as the most preferred management action in the study area. The comparative analysis revealed inconsistencies between the use of implicit and explicit assessment criteria. Our findings highlight the opportunities offered by outranking approaches to help capture, structure, and make explicit stakeholder perspectives in the framework of a participatory environmental assessment process, which may facilitate the understanding of the multiple preferences involved. The outranking integration process, which resembles a voting procedure, proved simple and transparent, with potential for contributing to stakeholder engagement and trust in participatory assessment.

  17. Role of dendritic spines in action potential backpropagation: a numerical simulation study.

    PubMed

    Tsay, David; Yuste, Rafael

    2002-11-01

    Two remarkable aspects of pyramidal neurons are their complex dendritic morphologies and the abundant presence of spines, small structures that are the sites of excitatory input. Although the channel properties of the dendritic shaft membrane have been experimentally probed, the influence of spine properties in dendritic signaling and action potential propagation remains unclear. To explore this we have performed multi-compartmental numerical simulations investigating the degree of consistency between experimental data on dendritic channel densities and backpropagation behavior, as well as the necessity and degree of influence of excitable spines. Our results indicate that measured densities of Na(+) channels in dendritic shafts cannot support effective backpropagation observed in apical dendrites due to suprathreshold inactivation. We demonstrate as a potential solution that Na(+) channels in spines at higher densities than those measured in the dendritic shaft can support extensive backpropagation. In addition, clustering of Na(+) channels in spines appears to enhance their effect due to their unique morphology. Finally, we show that changes in spine morphology significantly influence backpropagation efficacy. These results suggest that, by clustering sodium channels, spines may serve to control backpropagation.

  18. Seasonal acclimatization of the cardiac action potential in the Arctic navaga cod (Eleginus navaga, Gadidae).

    PubMed

    Hassinen, Minna; Abramochkin, Denis V; Vornanen, Matti

    2014-04-01

    Freshwater fishes of north-temperate latitudes adjust electrical excitability of the heart to seasonal temperature changes by changing expression levels of ion channel isoforms. However, little is known about thermal responses of action potential (AP) in the hearts of marine polar fishes. To this end, we examined cardiac AP in the atrial myocardium of the Arctic navaga cod (Eleginus navaga) from the White Sea (Russia) acclimatized to winter (March) and summer (September) seasons. Acute increases in temperature from 4 to 10 °C were associated with increases in heart rate, maximum velocity of AP upstroke and negative resting membrane potential, while duration of AP was shortened in both winter-acclimatized and summer-acclimatized navaga hearts. In winter, there was a compensatory shortening (41.1%) of atrial AP duration and this was associated with a strong increase in transcript expression of Erg K(+) channels, known to produce the rapid component of the delayed rectifier K(+) current, I(Kr). Smaller increases were found in the expression of Kir2.1 channels that produce the inward rectifier K(+) current, I(K1). These findings indicate that the heart of navaga cod has a good acclimatory capacity in electrical excitation of cardiac myocytes, which enables cardiac function in the cold-eurythermal waters of the subarctic White Sea.

  19. Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials

    PubMed Central

    Radivojevic, Milos; Jäckel, David; Altermatt, Michael; Müller, Jan; Viswam, Vijay; Hierlemann, Andreas; Bakkum, Douglas J.

    2016-01-01

    A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs. PMID:27510732

  20. Human neural tuning estimated from compound action potentials in normal hearing human volunteers

    NASA Astrophysics Data System (ADS)

    Verschooten, Eric; Desloovere, Christian; Joris, Philip X.

    2015-12-01

    The sharpness of cochlear frequency tuning in humans is debated. Evoked otoacoustic emissions and psychophysical measurements suggest sharper tuning in humans than in laboratory animals [15], but this is disputed based on comparisons of behavioral and electrophysiological measurements across species [14]. Here we used evoked mass potentials to electrophysiologically quantify tuning (Q10) in humans. We combined a notched noise forward masking paradigm [9] with the recording of trans tympanic compound action potentials (CAP) from masked probe tones in awake human and anesthetized monkey (Macaca mulatta). We compare our results to data obtained with the same paradigm in cat and chinchilla [16], and find that CAP-Q10values in human are ˜1.6x higher than in cat and chinchilla and ˜1.3x higher than in monkey. To estimate frequency tuning of single auditory nerve fibers (ANFs) in humans, we derive conversion functions from ANFs in cat, chinchilla, and monkey and apply these to the human CAP measurements. The data suggest that sharp cochlear tuning is a feature of old-world primates.

  1. Zinc-related actions of sublethal levels of benzalkonium chloride: Potentiation of benzalkonium cytotoxicity by zinc.

    PubMed

    Mitani, Tsuyoshi; Elmarhomy, Ahmed Ibrahim Elhossany; Dulamjav, Luvsandorj; Anu, Enkhtumur; Saitoh, Shohei; Ishida, Shiro; Oyama, Yasuo

    2017-04-25

    Benzalkonium chloride (BZK) is a common preservative used in pharmaceutical and personal care products. ZnCl2 was recently reported to significantly potentiate the cytotoxicity of some biocidal compounds. In the present study, therefore, we compared the cytotoxic potency of BZK and then further studied the Zn(2+)-related actions of the most cytotoxic agent among BZK, using flow cytometric techniques with appropriate fluorescent probes in rat thymocytes. Cytotoxicity of benzylcetyldimethylammonium (BZK-C16) was more potent that those of benzyldodecyldimethylammonium and benzyldimethyltetradecylammonium. ZnCl2 (1-10 μM) significantly potentiated the cytotoxicity of BZK-C16 at a sublethal concentration (1 μM). The co-treatment of cells with 3 μM ZnCl2 and 1 μM BZK-C16 increased the population of both living cells with phosphatidylserine exposed on membrane surfaces and dead cells. BZK-C16 at 0.3-1.0 μM elevated intracellular Zn(2+) levels by increasing Zn(2+) influx, and augmented the cytotoxicity of 100 μM H2O2. Zn(2+) is concluded to facilitate the toxicity of BZK. We suggest that the toxicity of BZK is determined after taking extracellular (plasma) and/or environmental Zn(2+) levels into account.

  2. Glutamate induces series of action potentials and a decrease in circumnutation rate in Helianthus annuus.

    PubMed

    Stolarz, Maria; Król, Elzbieta; Dziubińska, Halina; Kurenda, Andrzej

    2010-03-01

    Reports concerning the function of glutamate (Glu) in the electrical and movement phenomena in plants are scarce. Using the method of extracellular measurement, we recorded electrical potential changes in the stem of 3-week-old Helianthus annuus L. plants after injection of Glu solution. Simultaneously, circumnutation movements of the stem were measured with the use of time-lapse images. Injection of Glu solution at millimolar (200, 50, 5 mM) concentrations in the basal part of the stem evoked a series of action potentials (APs). The APs appeared in the site of injection and in different parts of the stem and were propagated acropetally and/or basipetally along the stem. Glu injection also resulted in a transient, approximately 5-h-long decrease in the stem circumnutation rate. The APs initiated and propagating in the sunflower stem after Glu injection testify the existence of a Glu perception system in vascular plants and suggest its involvement in electrical, long-distance signaling. Our experiments also demonstrated that Glu is a factor affecting circumnutation movements.

  3. A fluorescent, genetically-encoded voltage probe capable of resolving action potentials.

    PubMed

    Barnett, Lauren; Platisa, Jelena; Popovic, Marko; Pieribone, Vincent A; Hughes, Thomas

    2012-01-01

    There is a pressing need in neuroscience for genetically-encoded, fluorescent voltage probes that can be targeted to specific neurons and circuits to allow study of neural activity using fluorescent imaging. We created 90 constructs in which the voltage sensing portion (S1-S4) of Ciona intestinalis voltage sensitive phosphatase (CiVSP) was fused to circularly permuted eGFP. This led to ElectricPk, a probe that is an order of magnitude faster (taus ~1-2 ms) than any currently published fluorescent protein-based voltage probe. ElectricPk can follow the rise and fall of neuronal action potentials with a modest decrease in fluorescence intensity (~0.7% ΔF/F). The probe has a nearly linear fluorescence/membrane potential response to both hyperpolarizing and depolarizing steps. This is the first probe based on CiVSP that captures the rapid movements of the voltage sensor, suggesting that voltage probes designed with circularly permuted fluorescent proteins may have some advantages.

  4. Amplitudes of sural and radial sensory nerve action potentials in orthodromic and antidromic studies in children.

    PubMed

    Melendrez, J L; MacMillan, L J; Vajsar, J

    1998-01-01

    Several previous studies of adults have reported that the amplitudes of the sural and superficial radial nerve action potentials (SN and SRN SNAP respectively) are larger with antidromic than with orthodromic recordings. However, this difference has not been documented in children. This study evaluated the amplitudes of SN and SRN SNAPs obtained with antidromic and orthodromic recordings in children with and without neuropathy and compared these data with findings in adults. The SN or SRN or both of 10 neurologically normal children, 6 children with neuropathy and 7 healthy adults were studied with surface stimulation and recording. The position of the stimulating and recording electrodes for the orthodromic recordings was the reverse of that for the antidromic recordings. Peak-to-peak SNAP amplitudes were measured and analyzed. The mean of the SRN SNAP amplitude was significantly higher with the antidromic than the orthodromic technique for the first and third groups (p < 0.05). The mean SN SNAP amplitude was higher in the three groups, but not statistically significant when the data for the children and adult normal groups were combined and reanalyzed (p < 0.05). Consistent responses were obtained with both techniques. However, the antidromic technique was superior to the orthodromic technique because of the greater amplitude of responses. We recommend the use of the antidromic technique because of its greater amplitudes, ease of use and potential reduction of discomfort to the patient.

  5. Calcium Transients Closely Reflect Prolonged Action Potentials in iPSC Models of Inherited Cardiac Arrhythmia

    PubMed Central

    Spencer, C. Ian; Baba, Shiro; Nakamura, Kenta; Hua, Ethan A.; Sears, Marie A.F.; Fu, Chi-cheng; Zhang, Jianhua; Balijepalli, Sadguna; Tomoda, Kiichiro; Hayashi, Yohei; Lizarraga, Paweena; Wojciak, Julianne; Scheinman, Melvin M.; Aalto-Setälä, Katriina; Makielski, Jonathan C.; January, Craig T.; Healy, Kevin E.; Kamp, Timothy J.; Yamanaka, Shinya; Conklin, Bruce R.

    2014-01-01

    Summary Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca2+]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca2+]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca2+. Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca2+]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na+-Ca2+ exchange. These results suggest that LQTS mutations act partly on cytosolic Ca2+ cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site. PMID:25254341

  6. The fibrogenic actions of lung fibroblast-derived urokinase: a potential drug target in IPF

    PubMed Central

    Schuliga, Michael; Jaffar, Jade; Harris, Trudi; Knight, Darryl A; Westall, Glen; Stewart, Alastair G

    2017-01-01

    The role of urokinase plasminogen activator (uPA) in idiopathic pulmonary fibrosis (IPF) remains unclear. uPA-generated plasmin has potent fibrogenic actions involving protease activated receptor-1 (PAR-1) and interleukin-6 (IL-6). Here we characterize uPA distribution or levels in lung tissue and sera from IPF patients to establish the mechanism of its fibrogenic actions on lung fibroblasts (LFs). uPA immunoreactivity was detected in regions of fibrosis including fibroblasts of lung tissue from IPF patients (n = 7). Serum uPA levels and activity were also higher in IPF patients (n = 18) than controls (n = 18) (P < 0.05), being negatively correlated with lung function as measured by forced vital capacity (FVC) %predicted (P < 0.05). The culture supernatants of LFs from IPF patients, as compared to controls, showed an increase in plasmin activity after plasminogen incubation (5–15 μg/mL), corresponding with increased levels of uPA and IL-6 (n = 5–6, P < 0.05). Plasminogen-induced increases in plasmin activity and IL-6 levels were attenuated by reducing uPA and/or PAR-1 expression by RNAi. Plasmin(ogen)-induced mitogenesis was also attenuated by targeting uPA, PAR-1 or IL-6. Our data shows uPA is formed in active regions of fibrosis in IPF lung and contributes to LF plasmin generation, IL-6 production and proliferation. Urokinase is a potential target for the treatment of lung fibrosis. PMID:28139758

  7. Sympathetic activity–associated periodic repolarization dynamics predict mortality following myocardial infarction

    PubMed Central

    Rizas, Konstantinos D.; Nieminen, Tuomo; Barthel, Petra; Zürn, Christine S.; Kähönen, Mika; Viik, Jari; Lehtimäki, Terho; Nikus, Kjell; Eick, Christian; Greiner, Tim O.; Wendel, Hans P.; Seizer, Peter; Schreieck, Jürgen; Gawaz, Meinrad; Schmidt, Georg; Bauer, Axel

    2014-01-01

    Background. Enhanced sympathetic activity at the ventricular myocardium can destabilize repolarization, increasing the risk of death. Sympathetic activity is known to cluster in low-frequency bursts; therefore, we hypothesized that sympathetic activity induces periodic low-frequency changes of repolarization. We developed a technique to assess the sympathetic effect on repolarization and identified periodic components in the low-frequency spectral range (≤0.1 Hz), which we termed periodic repolarization dynamics (PRD). Methods. We investigated the physiological properties of PRD in multiple experimental studies, including a swine model of steady-state ventilation (n = 7) and human studies involving fixed atrial pacing (n = 10), passive head-up tilt testing (n = 11), low-intensity exercise testing (n = 11), and beta blockade (n = 10). We tested the prognostic power of PRD in 908 survivors of acute myocardial infarction (MI). Finally, we tested the predictive values of PRD and T-wave alternans (TWA) in 2,965 patients undergoing clinically indicated exercise testing. Results. PRD was not related to underlying respiratory activity (P < 0.001) or heart-rate variability (P = 0.002). Furthermore, PRD was enhanced by activation of the sympathetic nervous system, and pharmacological blockade of sympathetic nervous system activity suppressed PRD (P ≤ 0.005 for both). Increased PRD was the strongest single risk predictor of 5-year total mortality (hazard ratio 4.75, 95% CI 2.94–7.66; P < 0.001) after acute MI. In patients undergoing exercise testing, the predictive value of PRD was strong and complementary to that of TWA. Conclusion. We have described and identified low-frequency rhythmic modulations of repolarization that are associated with sympathetic activity. Increased PRD can be used as a predictor of mortality in survivors of acute MI and patients undergoing exercise testing. Trial registration. ClinicalTrials.gov NCT00196274. Funding. This study was funded by

  8. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease.

    PubMed

    Williams, Robert J; Spencer, Jeremy P E

    2012-01-01

    There is increasing evidence that the consumption of flavonoid-rich foods can beneficially influence normal cognitive function. In addition, a growing number of flavonoids have been shown to inhibit the development of Alzheimer disease (AD)-like pathology and to reverse deficits in cognition in rodent models, suggestive of potential therapeutic utility in dementia. The actions of flavonoid-rich foods (e.g., green tea, blueberry, and cocoa) seem to be mediated by the direct interactions of absorbed flavonoids and their metabolites with a number of cellular and molecular targets. For example, their specific interactions within the ERK and PI3-kinase/Akt signaling pathways, at the level of receptors or kinases, have been shown to increase the expression of neuroprotective and neuromodulatory proteins and increase the number of, and strength of, connections between neurons. Concurrently, their effects on the vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Additional mechanisms have been suggested for the ability of flavonoids to delay the initiation of and/or slow the progression of AD-like pathology and related neurodegenerative disorders, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation) or disrupt amyloid β aggregation and effects on amyloid precursor protein processing through the inhibition of β-secretase (BACE-1) and/or activation of α-secretase (ADAM10). Together, these processes act to maintain the number and quality of synaptic connections in key brain regions and thus flavonoids have the potential to prevent the progression of neurodegenerative pathologies and to promote cognitive performance.

  9. Averaging methods for extracting representative waveforms from motor unit action potential trains.

    PubMed

    Malanda, Armando; Navallas, Javier; Rodriguez-Falces, Javier; Rodriguez-Carreño, Ignacio; Gila, Luis

    2015-08-01

    In the context of quantitative electromyography (EMG), it is of major interest to obtain a waveform that faithfully represents the set of potentials that constitute a motor unit action potential (MUAP) train. From this waveform, various parameters can be determined in order to characterize the MUAP for diagnostic analysis. The aim of this work was to conduct a thorough, in-depth review, evaluation and comparison of state-of-the-art methods for composing waveforms representative of MUAP trains. We evaluated nine averaging methods: Ensemble (EA), Median (MA), Weighted (WA), Five-closest (FCA), MultiMUP (MMA), Split-sweep median (SSMA), Sorted (SA), Trimmed (TA) and Robust (RA) in terms of three general-purpose signal processing figures of merit (SPMF) and seven clinically-used MUAP waveform parameters (MWP). The convergence rate of the methods was assessed as the number of potentials per MUAP train (NPM) required to reach a level of performance that was not significantly improved by increasing this number. Test material comprised 78 MUAP trains obtained from the tibialis anterioris of seven healthy subjects. Error measurements related to all SPMF and MWP parameters except MUAP amplitude descended asymptotically with increasing NPM for all methods. MUAP amplitude showed a consistent bias (around 4% for EA and SA and 1-2% for the rest). MA, TA and SSMA had the lowest SPMF and MWP error figures. Therefore, these methods most accurately preserve and represent MUAP physiological information of utility in clinical medical practice. The other methods, particularly WA, performed noticeably worse. Convergence rate was similar for all methods, with NPM values averaged among the nine methods, which ranged from 10 to 40, depending on the waveform parameter evaluated.

  10. Back-Propagation of Physiological Action Potential Output in Dendrites of Slender-Tufted L5A Pyramidal Neurons

    PubMed Central

    Grewe, Benjamin F.; Bonnan, Audrey; Frick, Andreas

    2009-01-01

    Pyramidal neurons of layer 5A are a major neocortical output type and clearly distinguished from layer 5B pyramidal neurons with respect to morphology, in vivo firing patterns, and connectivity; yet knowledge of their dendritic properties is scant. We used a combination of whole-cell recordings and Ca2+ imaging techniques in vitro to explore the specific dendritic signaling role of physiological action potential patterns recorded in vivo in layer 5A pyramidal neurons of the whisker-related ‘barrel cortex’. Our data provide evidence that the temporal structure of physiological action potential patterns is crucial for an effective invasion of the main apical dendrites up to the major branch point. Both the critical frequency enabling action potential trains to invade efficiently and the dendritic calcium profile changed during postnatal development. In contrast to the main apical dendrite, the more passive properties of the short basal and apical tuft dendrites prevented an efficient back-propagation. Various Ca2+ channel types contributed to the enhanced calcium signals during high-frequency firing activity, whereas A-type K+ and BKCa channels strongly suppressed it. Our data support models in which the interaction of synaptic input with action potential output is a function of the timing, rate and pattern of action potentials, and dendritic location. PMID:20508744

  11. Mechanism of potassium efflux and action potential shortening during ischaemia in isolated mammalian cardiac muscle.

    PubMed Central

    Gasser, R N; Vaughan-Jones, R D

    1990-01-01

    1. Ischaemia was simulated in the isolated sheep cardiac Purkinje fibre and guinea-pig papillary muscle by immersing the preparations in paraffin oil. Ion-selective microelectrodes recorded potassium (Ks+) and pH (pHs) in the thin film of Tyrode solution trapped at the fibre surface while other microelectrodes recorded intracellular pH (pHi), membrane potential and action potentials (AP) (evoked by field stimulation), or membrane current (two-microelectrode voltage clamp in shortened Purkinje fibres). Twitch tension was also monitored. The paraffin oil model reproduced the salient characteristics of myocardial ischaemia, i.e. a decrease of twitch tension; a decrease of pHi and pHs; a rise in Ks+ (by 2-3 mM); a depolarization of diastolic membrane potential; considerable shortening of the AP (up to 30% within 4 min). 2. The sulphonylurea compounds, glibenclamide (200 microM) and tolbutamide (1 mM), known inhibitors of the KATP channel, completely blocked the ischaemic rise of Ks+ and prevented AP shortening. Ischaemic tension decline was notably less pronounced in the presence of sulphonylureas. 3. The ischaemic increase of slope conductance (Purkinje fibre) was prevented by 1 mM-tolbutamide and 200 microM-glibenclamide. 4. Sulphonylureas did not affect resting membrane potential, the AP or the current-voltage relationship under non-ischaemic conditions (this also indicates that ischaemic Ks+ accumulation is not fuelled by the background K+ current [iK1] which was shown, as expected, to be Ba2+ sensitive). 5. In a normally perfused preparation, reducing intracellular ATP by inhibiting glycolysis with 2-deoxyglucose (DOG) produced a similar AP shortening plus a membrane hyperpolarization, both of which were inhibited by tolbutamide or glibenclamide. The AP shortening was not related uniquely to the fall of pHi observed under these conditions since experimentally reducing pHi (by reducing pHo in the absence of DOG) lengthened rather than shortened the AP. 6. The

  12. Characterization of action potential-evoked calcium transients in mouse postganglionic sympathetic axon bundles.

    PubMed

    Jackson, V M; Trout, S J; Brain, K L; Cunnane, T C

    2001-11-15

    1. Action potential-evoked Ca(2+) transients in postganglionic sympathetic axon bundles in mouse vas deferens have been characterized using confocal microscopy and Ca(2+) imaging. 2. Axonal Ca(2+) transients were tetrodotoxin sensitive. The amplitude depended on both the frequency of stimulation and the number of stimuli in a train. 3. Removal of extracellular Ca(2+) abolished the Ca(2+) transient. Cd(2+)(100 microM) inhibited the Ca(2+) transient by 78 +/- 10 %. The N-type Ca(2+) channel blocker omega-conotoxin GVIA (0.1 microM) reduced the amplitude by -35 +/-4 %, whereas nifedipine (10 microM; L-type) and omega-conotoxin MVIIC (0.1 microM; P/Q type) were ineffective. 4. Caffeine (10 mM), ryanodine (10 microM), cyclopiazonic acid (30 microM) or CCCP (10 microM) had no detectable effects. 5. Blockade of large and small conductance Ca(2+)-dependent K+ channels with iberiotoxin (0.1 microM) and apamin (1 microM), respectively, or Ca(2+)-dependent Cl(-) channels by niflumic acid (100 microM) did not alter Ca(2+) transients. 6. In contrast, the non-specific K+ channel blockers tetraethylammonium (10 mM) and 4-aminopyridine (10 mM) markedly increased the amplitude of the Ca(2+) transient. Blockade of delayed rectifiers and A-like K+ channels, by tityustoxin-K (alpha) (0.1 microM) and pandinustoxin-K (alpha) (10 nM), respectively, also increased the Ca(2+) transient amplitude. 7. Thus, Ca(2+) transients are evoked by Na(+)-dependent action potentials in axons. These transients originate mainly from Ca(2+) entry through voltage-dependent Ca(2+) channels (80 % Cd(2+) sensitive of which 40 % was attributable to N-type). Twenty per cent of the Ca(2+) transient was not due to Ca(2+) entry through voltage-gated Ca(2+) channels. Intracellular stores and mitochondria were not involved in the generation of the transient. Ca(2+) transients are modulated by A-like K+ channels and delayed rectifiers (possibly K(V)1.2) but not by Ca(2+)-activated ion channels.

  13. Actions of the digitalis analogue strophanthidin on action potentials and L-type calcium current in single cells isolated from the rabbit atrioventricular node.

    PubMed Central

    Hancox, J. C.; Levi, A. J.

    1996-01-01

    1. The atrioventricular node (AVN) of the heart is vital to normal cardiac function and is a major site of antiarrhythmic drug action. This study describes the effects of the cardiac glycoside analogue strophanthidin on spontaneous action potentials and L-type calcium current recorded from single AVN cells isolated from the rabbit heart. 2. With a standard KCl-based internal dialysis solution, exposure to 50 microM strophanthidin produced a progressive depolarization of the maximum diastolic potential and a reduction in action potential amplitude and upstroke velocity. Sustained application resulted in the loss of action potentials and occurrence of spontaneous 'bell-shaped' depolarizations. 3. Cells were whole-cell voltage clamped at -40 mV and depolarizing voltage clamps applied. With a standard KCl-based internal dialysis solution, exposure to 50 microM strophanthidin caused a large reduction of ICa,L at all potentials between -30 and +40 mV (n = 4). At + 10 mV, the mean ICa,L amplitude was reduced from -232 +/- 65 pA to -48 +/- 26 pA (P < 0.05; 1 test; n = 5 cells). 4. To record ICa,L more selectively, cells were dialysed with a Cs-based pipette solution. A short strophanthidin exposure reduced ICa,L amplitude from -250 +/- 31 pA to -88 +/- 19 pA (P < 0.001; n = 8 cells). For both KCl and CsCl-based solutions it was observed that sustained exposure to strophanthidin for several minutes caused spontaneous inward fluctuations in the membrane current record similar to the 'ITI' (arrhythmogenic oscillatory transient inward) current shown for other cardiac cells. 5. When the calcium chelator BAPTA was added to the pipette solution (10 mM), the reduction in ICa,L by strophanthidin was largely eliminated (P > 0.1), and no spontaneous inward current fluctuations were observed after sustained exposure to strophanthidin (n = 8 cells). 6. When external Ca in the perfusate was replaced with Ba, strophanthidin did not significantly reduce the Ba current through L

  14. Motor Unit Number Estimation and Motor Unit Action Potential Analysis in Carpal Tunnel Syndrome

    PubMed Central

    Sohn, Min Kyun; Jee, Sung Ju; Kim, Young-Jae; Shin, Hyun-Dae

    2011-01-01

    Objective To evaluate the clinical significance of motor unit number estimation (MUNE) and quantitative analysis of motor unit action potential (MUAP) in carpal tunnel syndrome (CTS) according to electrophysiologic severity, ultrasonographic measurement and clinical symptoms. Method We evaluated 78 wrists of 45 patients, who had been diagnosed with CTS and 42 wrists of 21 healthy controls. Median nerve conduction studies, amplitude and duration of MUAP, and the MUNE of the abductor pollicis brevis were measured. The cross sectional area (CSA) of the median nerve at the pisiform and distal radioulnar joint level was determined by high resolution ultrasonography. Clinical symptom of CTS was assessed using the Boston Carpal Tunnel Questionnaire (BCTQ). Results The MUNE, the amplitude and the duration of MUAP of the CTS group were significantly different from those found in the control group. The area under the ROC curve was 0.944 for MUNE, 0.923 for MUAP amplitude and 0.953 for MUAP duration. MUNE had a negative correlation with electrophysiologic stage of CTS, amplitude and duration of MUAP, CSA at pisiform level, and the score of BCTQ. The amplitude and duration of MUAP had a positive correlation with the score of BCTQ. The electrophysiologic stage was correlated with amplitude but not with the duration of MUAP. Conclusion MUNE, amplitude and duration of MUAP are useful tests for diagnosis of CTS. In addition, the MUNE serves as a good indicator of CTS severity. PMID:22506210

  15. Adhesion to Carbon Nanotube Conductive Scaffolds Forces Action-Potential Appearance in Immature Rat Spinal Neurons

    PubMed Central

    Toma, Francesca Maria; Calura, Enrica; Rizzetto, Lisa; Carrieri, Claudia; Roncaglia, Paola; Martinelli, Valentina; Scaini, Denis; Masten, Lara; Turco, Antonio; Gustincich, Stefano; Prato, Maurizio; Ballerini, Laura

    2013-01-01

    In the last decade, carbon nanotube growth substrates have been used to investigate neurons and neuronal networks formation in vitro when guided by artificial nano-scaled cues. Besides, nanotube-based interfaces are being developed, such as prosthesis for monitoring brain activity. We recently described how carbon nanotube substrates alter the electrophysiological and synaptic responses of hippocampal neurons in culture. This observation highlighted the exceptional ability of this material in interfering with nerve tissue growth. Here we test the hypothesis that carbon nanotube scaffolds promote the development of immature neurons isolated from the neonatal rat spinal cord, and maintained in vitro. To address this issue we performed electrophysiological studies associated to gene expression analysis. Our results indicate that spinal neurons plated on electro-conductive carbon nanotubes show a facilitated development. Spinal neurons anticipate the expression of functional markers of maturation, such as the generation of voltage dependent currents or action potentials. These changes are accompanied by a selective modulation of gene expression, involving neuronal and non-neuronal components. Our microarray experiments suggest that carbon nanotube platforms trigger reparative activities involving microglia, in the absence of reactive gliosis. Hence, future tissue scaffolds blended with conductive nanotubes may be exploited to promote cell differentiation and reparative pathways in neural regeneration strategies. PMID:23951361

  16. The central action of salbutamol, a beta-agonist with a potential antidepressant activity.

    PubMed

    Przegalinski, E; Baran, L; Kedrek, G

    1980-01-01

    The pharmacological profile of salbutamol, an agonist of beta-adrenergic receptors and a potential antidepressant drug, and its effect on the central serotonin system were studied. It was found that salbutamol either had no effect, or, at higher doses, inhibited the spontaneous activity of mice and rats; it did not influence significantly either the produced by amphetamine locomotor stimulation (in mice and rats) or amphetamine stereotype (in rats). Salbutamol while not affecting body temperature of normal mice reversed hypothermia but not ptosis induced by reserpine, and counteracted the hypothermic action of apomorphine in mice. It neither affected the spiperone-induced catalepsy nor was active in the behavioural despair test in rats. Salbutamol had no effect either, on the fenfluramine-induced hyperthermia in rabbits, on the 5-hydroxytryptophan-induced head twitch reaction in mice, on the tryptamine-induced clonic convulsions of forepaw in rats on the flexor reflex in spinal rats, or on the quipazine- or fenfluramine-induced stimulation of this reflex. The above findings indicate that the pharmacological profile of salbutamol resembles that of classical imipramine-like antidepressant drugs to a very small extent and it does not affect the central serotonergic transmission.

  17. A new three-variable mathematical model of action potential propagation in cardiac tissue.

    NASA Astrophysics Data System (ADS)

    Fenton, Flavio; Karma, Alain

    1996-03-01

    Modeling the electrical activity of the heart, and the complex signaling patterns which underly dangerous arrhythmias such as tachycardia and fibrillation, requires a quantitative model of action potential (AP) propagation. At present, there exist detailed ionic models of the Hodgkin-Huxley form that accurately reproduce dynamical features of the AP at a single cell level (e.g. Luo-Rudy, 1994). However, such models are not computationally tractable to study propagation in two and three-dimensional tissues of many resistively coupled cells. At the other extreme, there exists generic models of excitable media, such as the well-known FitzHugh-Nagumo model, which are only qualitative and do not reproduce essential dynamical features of cardiac AP. A new three-variable model is introduced which bridges the gap between these two types of models. It reproduces quantitatively important `mesoscopic' dynamical properties which are specific to cardiac AP, namely restitution and dispersion. At the same time, it remains computationally tractable and makes it possible to study the effect of these properties on the initiation, dynamics, and stability of complex reentrant excitations in two and three dimensions. Preliminary numerical results of the effect of restitution and dispersion on two-dimensional reentry (i.e. spiral waves) are presented.

  18. 'Action potential-like' ST elevation following pseudo-Wellens' electrocardiogram.

    PubMed

    Oksuz, Fatih; Sensoy, Baris; Sen, Fatih; Celik, Ethem; Ozeke, Ozcan; Maden, Orhan

    2015-01-01

    Coronary artery vasospasm is an important cause of chest pain syndromes that can lead to myocardial infarction, ventricular arrhythmias, and sudden death. In 1959, Prinzmetal et al described a syndrome of nonexertional chest pain with ST-segment elevation on electrocardiography. Persistent angina is challenging, and repeated coronary angioplasty may be required in this syndrome. Calcium antagonists are extremely effective in treating and preventing coronary spasm, and may provide long-lasting relief for the patient. Whereas the Wellens' syndrome is characterized by symmetrically inverted T-waves with preserved R waves in the precordial leads suggestive of impending myocardial infarction due to a critical proximal left anterior descending stenosis, the pseudo-Wellens' syndrome caused by coronary artery spasm has also rarely been reported in literature. We present a pseudo-Wellens syndrome as a cause of vasospastic angina, and a diffuse ST segment elavation on electrocardiogram resembling the Greek letter lambda, called also 'action potential-like' ECG in a patient with vasospastic-type Printzmetal angina.

  19. Effects of stochastic channel gating and distribution on the cardiac action potential.

    PubMed

    Lemay, Mathieu; de Lange, Enno; Kucera, Jan P

    2011-07-21

    Ion channels exhibit stochastic conformational changes determining their gating behavior. In addition, the process of protein turnover leads to a natural variability of the number of membrane and gap junctional channels. Nevertheless, in computational models, these two aspects are scarcely considered and their impacts are largely unknown. We investigated the effects of stochastic current fluctuations and channel distributions on action potential duration (APD), intercellular conduction delays (ICDs) and conduction blocks using a modified ventricular cell model (Rudy et al.) with Markovian formulations of the principal ion currents (to simulate their stochastic open-close gating behavior) and with channel counts drawn from Poisson distributions (to simulate their natural variability). In single cells, APD variability (coefficient of variation: 1.6% at BCL=1000ms) was essentially caused by stochastic channel gating of I(Ks), persistent I(Na) and I(Ca,L). In cell strands, ICD variability induced by stochastic channel gating and Poissonian channel distributions was low under normal conditions. Nonetheless, at low intercellular coupling levels, Poissonian gap junctional channel distribution resulted in a large ICD variability (coefficient of variation >20%), highly heterogeneous conduction patterns and conduction blocks. Therefore, the stochastic behavior of current fluctuations and channel distributions can contribute to the heterogeneity of conduction patterns and to conduction block, as observed previously in experiments in cardiac tissue with altered intercellular coupling.

  20. Direction-Selective Circuitry in Rat Retina Develops Independently of GABAergic, Cholinergic and Action Potential Activity

    PubMed Central

    He, Shigang

    2011-01-01

    The ON-OFF direction selective ganglion cells (DSGCs) in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience. PMID:21573161

  1. Multifocal fluorescence microscope for fast optical recordings of neuronal action potentials.

    PubMed

    Shtrahman, Matthew; Aharoni, Daniel B; Hardy, Nicholas F; Buonomano, Dean V; Arisaka, Katsushi; Otis, Thomas S

    2015-02-03

    In recent years, optical sensors for tracking neural activity have been developed and offer great utility. However, developing microscopy techniques that have several kHz bandwidth necessary to reliably capture optically reported action potentials (APs) at multiple locations in parallel remains a significant challenge. To our knowledge, we describe a novel microscope optimized to measure spatially distributed optical signals with submillisecond and near diffraction-limit resolution. Our design uses a spatial light modulator to generate patterned illumination to simultaneously excite multiple user-defined targets. A galvanometer driven mirror in the emission path streaks the fluorescence emanating from each excitation point during the camera exposure, using unused camera pixels to capture time varying fluorescence at rates that are ∼1000 times faster than the camera's native frame rate. We demonstrate that this approach is capable of recording Ca(2+) transients resulting from APs in neurons labeled with the Ca(2+) sensor Oregon Green Bapta-1 (OGB-1), and can localize the timing of these events with millisecond resolution. Furthermore, optically reported APs can be detected with the voltage sensitive dye DiO-DPA in multiple locations within a neuron with a signal/noise ratio up to ∼40, resolving delays in arrival time along dendrites. Thus, the microscope provides a powerful tool for photometric measurements of dynamics requiring submillisecond sampling at multiple locations.

  2. Motor unit action potential conduction velocity estimated from surface electromyographic signals using image processing techniques.

    PubMed

    Soares, Fabiano Araujo; Carvalho, João Luiz Azevedo; Miosso, Cristiano Jacques; de Andrade, Marcelino Monteiro; da Rocha, Adson Ferreira

    2015-09-17

    In surface electromyography (surface EMG, or S-EMG), conduction velocity (CV) refers to the velocity at which the motor unit action potentials (MUAPs) propagate along the muscle fibers, during contractions. The CV is related to the type and diameter of the muscle fibers, ion concentration, pH, and firing rate of the motor units (MUs). The CV can be used in the evaluation of contractile properties of MUs, and of muscle fatigue. The most popular methods for CV estimation are those based on maximum likelihood estimation (MLE). This work proposes an algorithm for estimating CV from S-EMG signals, using digital image processing techniques. The proposed approach is demonstrated and evaluated, using both simulated and experimentally-acquired multichannel S-EMG signals. We show that the proposed algorithm is as precise and accurate as the MLE method in typical conditions of noise and CV. The proposed method is not susceptible to errors associated with MUAP propagation direction or inadequate initialization parameters, which are common with the MLE algorithm. Image processing -based approaches may be useful in S-EMG analysis to extract different physiological parameters from multichannel S-EMG signals. Other new methods based on image processing could also be developed to help solving other tasks in EMG analysis, such as estimation of the CV for individual MUs, localization and tracking of innervation zones, and study of MU recruitment strategies.

  3. Computer Simulations Support a Morphological Contribution to BDNF Enhancement of Action Potential Generation

    PubMed Central

    Hiester, Brian G.; Jones, Kevin R.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates both action potential (AP) generation and neuron morphology. However, whether BDNF-induced changes in neuron morphology directly impact AP generation is unclear. We quantified BDNF’s effect on cultured cortical neuron morphological parameters and found that BDNF stimulates dendrite growth and addition of dendrites while increasing both excitatory and inhibitory presynaptic inputs in a spatially restricted manner. To gain insight into how these combined changes in neuron structure and synaptic input impact AP generation, we used the morphological parameters we gathered to generate computational models. Simulations suggest that BDNF-induced neuron morphologies generate more APs under a wide variety of conditions. Synapse and dendrite addition have the greatest impact on AP generation. However, subtle alterations in excitatory/inhibitory synapse ratio and strength have a significant impact on AP generation when synaptic activity is low. Consistent with these simulations, BDNF rapidly enhances spontaneous activity in cortical cultures. We propose that BDNF promotes neuron morphologies that are intrinsically more efficient at translating barrages of synaptic activity into APs, which is a previously unexplored aspect of BDNF’s function. PMID:27683544

  4. Frequency decoding of periodically timed action potentials through distinct activity patterns in a random neural network

    NASA Astrophysics Data System (ADS)

    Reichenbach, Tobias; Hudspeth, A. J.

    2012-11-01

    Frequency discrimination is a fundamental task of the auditory system. The mammalian inner ear, or cochlea, provides a place code in which different frequencies are detected at different spatial locations. However, a temporal code based on spike timing is also available: action potentials evoked in an auditory-nerve fiber by a low-frequency tone occur at a preferred phase of the stimulus—they exhibit phase locking—and thus provide temporal information about the tone's frequency. Humans employ this temporal information for discrimination of low frequencies. How might such temporal information be read out in the brain? Here we employ statistical and numerical methods to demonstrate that recurrent random neural networks in which connections between neurons introduce characteristic time delays, and in which neurons require temporally coinciding inputs for spike initiation, can perform sharp frequency discrimination when stimulated with phase-locked inputs. Although the frequency resolution achieved by such networks is limited by the noise in phase locking, the resolution for realistic values reaches the tiny frequency difference of 0.2% that has been measured in humans.

  5. Telemetry system for reliable recording of action potentials from freely moving rats.

    PubMed

    Hawley, Emerson S; Hargreaves, Eric L; Kubie, John L; Rivard, Bruno; Muller, Robert U

    2002-01-01

    Recording single cells from alert rats currently requires a cable to connect brain electrodes to the acquisition system. If no cable were necessary, a variety of interesting experiments would become possible, and the design of other experiments would be simplified. To eliminate the need for a cable we have developed a one-channel radiotelemetry system that is easily carried by a rat. This system transmits a signal that is reliable, highly accurate and can be detected over distances of > or = 20 m. The mobile part of the system has three components: (1) a headstage with built-in amplifiers that plugs into the connector for the electrode array on the rat's head; the headstage also incorporates a light-emitting diode (LED) used to track the rat's position; (2) a backpack that contains the transmitter and batteries (2 N cells); the backpack also provides additional amplification of the single cell signals; and (3) a short cable that connects the headstage to the backpack; the cable supplies power to the headstage amplifiers and the LED, and carries the physiological signals from the headstage to the backpack. By using a differential amplifier and recording between two brain microelectrodes the system can transmit action potential activity from two nearly independent sources. In a future improvement, two transmitters with different frequencies would be used telemeter signals from four microelectrodes simultaneously.

  6. Loss of Saltation and Presynaptic Action Potential Failure in Demyelinated Axons

    PubMed Central

    Hamada, Mustafa S.; Popovic, Marko A.; Kole, Maarten H. P.

    2017-01-01

    In cortical pyramidal neurons the presynaptic terminals controlling transmitter release are located along unmyelinated axon collaterals, far from the original action potential (AP) initiation site, the axon initial segment (AIS). Once initiated, APs will need to reliably propagate over long distances and regions of geometrical inhomogeneity like branch points (BPs) to rapidly depolarize the presynaptic terminals and confer temporally precise synaptic transmission. While axon pathologies such as demyelinating diseases are well established to impede the fidelity of AP propagation along internodes, to which extent myelin loss affects propagation along BPs and axon collaterals is not well understood. Here, using the cuprizone demyelination model, we performed optical voltage-sensitive dye (VSD) imaging from control and demyelinated layer 5 pyramidal neuron axons. In the main axon, we find that myelin loss switches the modality of AP propagation from rapid saltation towards a slow continuous wave. The duration of single AP waveforms at BPs or nodes was, however, only slightly briefer. In contrast, by using two-photon microscopy-guided loose-seal patch recordings from axon collaterals we revealed a presynaptic AP broadening in combination with a reduced velocity and frequency-dependent failure. Finally, internodal myelin loss was also associated with de novo sprouting of axon collaterals starting from the primary (demyelinated) axon. Thus, the loss of oligodendrocytes and myelin sheaths bears functional consequences beyond the main axon, impeding the temporal fidelity of presynaptic APs and affecting the functional and structural organization of synaptic connectivity within the neocortex. PMID:28289377

  7. Sensitivity analysis of potential events affecting the double-shell tank system and fallback actions

    SciTech Connect

    Knutson, B.J.

    1996-09-27

    Sensitivity analyses were performed for fall-back positions (i.e., management actions) to accommodate potential off-normal and programmatic change events overlaid on the waste volume projections and their uncertainties. These sensitivity analyses allowed determining and ranking tank system high-risk parameters and fall- back positions that will accommodate the respective impacts. This quantification of tank system impacts shows periods where tank capacity is sensitive to certain variables that must be carefully managed and/or evaluated. Identifying these sensitive variables and quantifying their impact will allow decision makers to prepare fall-back positions and focus available resources on the highest impact parameters where technical data are needed to reduce waste projection uncertainties. For noncomplexed waste, the period of capacity vulnerability occurs during the years of single-shell tank (SST) retrieval (after approximately 2009) due to the sensitivity to several variables. Ranked by importance these variables include the pretreatment rate and 200-East SST solids transfer volume. For complexed waste, the period of capacity vulnerability occurs during the period after approximately 2005 due to the sensitivity to several variables. Ranked by importance these variables include the pretreatment rate. 200-East SST solids transfer volume. complexed waste reduction factor using evaporation, and 200-west saltwell liquid porosity.

  8. Wavelet transform for real-time detection of action potentials in neural signals.

    PubMed

    Quotb, Adam; Bornat, Yannick; Renaud, Sylvie

    2011-01-01

    We present a study on wavelet detection methods of neuronal action potentials (APs). Our final goal is to implement the selected algorithms on custom integrated electronics for on-line processing of neural signals; therefore we take real-time computing as a hard specification and silicon area as a price to pay. Using simulated neural signals including APs, we characterize an efficient wavelet method for AP extraction by evaluating its detection rate and its implementation cost. We compare software implementation for three methods: adaptive threshold, discrete wavelet transform (DWT), and stationary wavelet transform (SWT). We evaluate detection rate and implementation cost for detection functions dynamically comparing a signal with an adaptive threshold proportional to its SD, where the signal is the raw neural signal, respectively: (i) non-processed; (ii) processed by a DWT; (iii) processed by a SWT. We also use different mother wavelets and test different data formats to set an optimal compromise between accuracy and silicon cost. Detection accuracy is evaluated together with false negative and false positive detections. Simulation results show that for on-line AP detection implemented on a configurable digital integrated circuit, APs underneath the noise level can be detected using SWT with a well-selected mother wavelet, combined to an adaptive threshold.

  9. A regenerative microchannel device for recording multiple single-unit action potentials in awake, ambulatory animals.

    PubMed

    Srinivasan, Akhil; Tipton, John; Tahilramani, Mayank; Kharbouch, Adel; Gaupp, Eric; Song, Chao; Venkataraman, Poornima; Falcone, Jessica; Lacour, Stéphanie P; Stanley, Garrett B; English, Arthur W; Bellamkonda, Ravi V

    2016-02-01

    Despite significant advances in robotics, commercially advanced prosthetics provide only a small fraction of the functionality of the amputated limb that they are meant to replace. Peripheral nerve interfacing could provide a rich controlling link between the body and these advanced prosthetics in order to increase their overall utility. Here, we report on the development of a fully integrated regenerative microchannel interface with 30 microelectrodes and signal extraction capabilities enabling evaluation in an awake and ambulatory rat animal model. In vitro functional testing validated the capability of the microelectrodes to record neural signals similar in size and nature to those that occur in vivo. In vitro dorsal root ganglia cultures revealed striking cytocompatibility of the microchannel interface. Finally, in vivo, the microchannel interface was successfully used to record a multitude of single-unit action potentials through 63% of the integrated microelectrodes at the early time point of 3 weeks. This marks a significant advance in microchannel interfacing, demonstrating the capability of microchannels to be used for peripheral nerve interfacing.

  10. Effects of aminoglycoside antibiotics on calcium action potentials and calcium channel currents.

    PubMed

    Suarez-Kurtz, G

    1989-01-01

    The author reviews work from his laboratory on the effects of neomycin and streptomycin on the Ca(2+)-dependent electrogenesis of crustacean muscle fibers and on two distinct Ca2+ channel currents of pituitary cells. The data indicate that these aminoglycosides inhibit the graded electrogenesis and the action potentials of crustacean muscle; these effects are accompanied by inhibition of tension development upon membrane depolarization. Increasing the extracellular Ca2+ concentration reverses the aminoglycoside-induced blockade of the Ca(2+)-dependent electrogenesis of the muscle fibers. Neomycin blocked both the transient (T-type) and the slowly-inactivating (L-type) Ca2+ currents of clonal pituitary GH3 cells, studied with the whole cell modality of the patch clamp technique. The blockade of these currents was not modulated by activation or inactivation of the channels. Neomycin inhibited also the currents conveyed by Na+ through the slowly-inactivating Ca2+ in cells equilibrated with Ca(2+)-free media. Interpretation of these data led to the suggestion that the blockade of Ca2+ currents by neomycin (and other aminoglycosides) cannot be explained by competition with Ca2+ ions for binding to high affinity transition sites within the Ca2+ channel path.

  11. Covariation of axon initial segment location and dendritic tree normalizes the somatic action potential

    PubMed Central

    Hamada, Mustafa S.; Goethals, Sarah; de Vries, Sharon I.; Brette, Romain

    2016-01-01

    In mammalian neurons, the axon initial segment (AIS) electrically connects the somatodendritic compartment with the axon and converts the incoming synaptic voltage changes into a temporally precise action potential (AP) output code. Although axons often emanate directly from the soma, they may also originate more distally from a dendrite, the implications of which are not well-understood. Here, we show that one-third of the thick-tufted layer 5 pyramidal neurons have an axon originating from a dendrite and are characterized by a reduced dendritic complexity and thinner main apical dendrite. Unexpectedly, the rising phase of somatic APs is electrically indistinguishable between neurons with a somatic or a dendritic axon origin. Cable analysis of the neurons indicated that the axonal axial current is inversely proportional to the AIS distance, denoting the path length between the soma and the start of the AIS, and to produce invariant somatic APs, it must scale with the local somatodendritic capacitance. In agreement, AIS distance inversely correlates with the apical dendrite diameter, and model simulations confirmed that the covariation suffices to normalize the somatic AP waveform. Therefore, in pyramidal neurons, the AIS location is finely tuned with the somatodendritic capacitive load, serving as a homeostatic regulation of the somatic AP in the face of diverse neuronal morphologies. PMID:27930291

  12. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model.

    PubMed

    Courtemanche, M; Ramirez, R J; Nattel, S

    1998-07-01

    The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

  13. Quantitative weight of evidence to assess confidence in potential modes of action.

    PubMed

    Becker, Richard A; Dellarco, Vicki; Seed, Jennifer; Kronenberg, Joel M; Meek, Bette; Foreman, Jennifer; Palermo, Christine; Kirman, Chris; Linkov, Igor; Schoeny, Rita; Dourson, Michael; Pottenger, Lynn H; Manibusan, Mary K

    2017-02-20

    The evolved World Health Organization/International Programme on Chemical Safety mode of action (MOA) framework provides a structure for evaluating evidence in pathways of causally linked key events (KE) leading to adverse health effects. Although employed globally, variability in use of the MOA framework has led to different interpretations of the sufficiency of evidence in support of hypothesized MOAs. A proof of concept extension of the MOA framework is proposed for scoring confidence in the supporting data to improve scientific justification for MOA use in characterizing hazards and selecting dose-response extrapolation methods for specific chemicals. This involves selecting hypothesized MOAs, and then, for each MOA, scoring the weight of evidence (WOE) in support of causality for each KE using evolved Bradford Hill causal considerations (biological plausibility, essentiality, dose-response concordance, consistency, and analogy). This early proof of concept method is demonstrated by comparing two potential MOAs (mutagenicity and peroxisome proliferator activated receptor-alpha) for clofibrate, a rodent liver carcinogen. Quantitative confidence scoring of hypothesized MOAs is shown to be useful in characterizing the likely operative MOA. To guide method refinement and future confidence scoring for a spectrum of MOAs, areas warranting further focus and lessons learned, including the need to incorporate a narrative discussion of the weights used in the evaluation and an overall evaluation of the plausibility of the outcome, are presented.

  14. Low Somatic Sodium Conductance Enhances Action Potential Precision in Time-Coding Auditory Neurons.

    PubMed

    Yang, Yang; Ramamurthy, Bina; Neef, Andreas; Xu-Friedman, Matthew A

    2016-11-23

    Auditory nerve fibers encode sounds in the precise timing of action potentials (APs), which is used for such computations as sound localization. Timing information is relayed through several cell types in the auditory brainstem that share an unusual property: their APs are not overshooting, suggesting that the cells have very low somatic sodium conductance (gNa). However, it is not clear how gNa influences temporal precision. We addressed this by comparing bushy cells (BCs) in the mouse cochlear nucleus with T-stellate cells (SCs), which do have normal overshooting APs. BCs play a central role in both relaying and refining precise timing information from the auditory nerve, whereas SCs discard precise timing information and encode the envelope of sound amplitude. Nucleated-patch recording at near-physiological temperature indicated that the Na current density was 62% lower in BCs, and the voltage dependence of gNa inactivation was 13 mV hyperpolarized compared with SCs. We endowed BCs with SC-like gNa using two-electrode dynamic clamp and found that synaptic activity at physiologically relevant rates elicited APs with significantly lower probability, through increased activation of delayed rectifier channels. In addition, for two near-simultaneous synaptic inputs, the window of coincidence detection widened significantly with increasing gNa, indicating that refinement of temporal information by BCs is degraded by gNa Thus, reduced somatic gNa appears to be an adaption for enhancing fidelity and precision in time-coding neurons.

  15. Optical magnetic detection of single-neuron action potentials using quantum defects in diamond

    PubMed Central

    Barry, John F.; Turner, Matthew J.; Schloss, Jennifer M.; Glenn, David R.; Song, Yuyu; Lukin, Mikhail D.; Park, Hongkun; Walsworth, Ronald L.

    2016-01-01

    Magnetic fields from neuronal action potentials (APs) pass largely unperturbed through biological tissue, allowing magnetic measurements of AP dynamics to be performed extracellularly or even outside intact organisms. To date, however, magnetic techniques for sensing neuronal activity have either operated at the macroscale with coarse spatial and/or temporal resolution—e.g., magnetic resonance imaging methods and magnetoencephalography—or been restricted to biophysics studies of excised neurons probed with cryogenic or bulky detectors that do not provide single-neuron spatial resolution and are not scalable to functional networks or intact organisms. Here, we show that AP magnetic sensing can be realized with both single-neuron sensitivity and intact organism applicability using optically probed nitrogen-vacancy (NV) quantum defects in diamond, operated under ambient conditions and with the NV diamond sensor in close proximity (∼10 µm) to the biological sample. We demonstrate this method for excised single neurons from marine worm and squid, and then exterior to intact, optically opaque marine worms for extended periods and with no observed adverse effect on the animal. NV diamond magnetometry is noninvasive and label-free and does not cause photodamage. The method provides precise measurement of AP waveforms from individual neurons, as well as magnetic field correlates of the AP conduction velocity, and directly determines the AP propagation direction through the inherent sensitivity of NVs to the associated AP magnetic field vector. PMID:27911765

  16. Multifocal Fluorescence Microscope for Fast Optical Recordings of Neuronal Action Potentials

    PubMed Central

    Shtrahman, Matthew; Aharoni, Daniel B.; Hardy, Nicholas F.; Buonomano, Dean V.; Arisaka, Katsushi; Otis, Thomas S.

    2015-01-01

    In recent years, optical sensors for tracking neural activity have been developed and offer great utility. However, developing microscopy techniques that have several kHz bandwidth necessary to reliably capture optically reported action potentials (APs) at multiple locations in parallel remains a significant challenge. To our knowledge, we describe a novel microscope optimized to measure spatially distributed optical signals with submillisecond and near diffraction-limit resolution. Our design uses a spatial light modulator to generate patterned illumination to simultaneously excite multiple user-defined targets. A galvanometer driven mirror in the emission path streaks the fluorescence emanating from each excitation point during the camera exposure, using unused camera pixels to capture time varying fluorescence at rates that are ∼1000 times faster than the camera’s native frame rate. We demonstrate that this approach is capable of recording Ca2+ transients resulting from APs in neurons labeled with the Ca2+ sensor Oregon Green Bapta-1 (OGB-1), and can localize the timing of these events with millisecond resolution. Furthermore, optically reported APs can be detected with the voltage sensitive dye DiO-DPA in multiple locations within a neuron with a signal/noise ratio up to ∼40, resolving delays in arrival time along dendrites. Thus, the microscope provides a powerful tool for photometric measurements of dynamics requiring submillisecond sampling at multiple locations. PMID:25650920

  17. Effects of terpineol on the compound action potential of the rat sciatic nerve.

    PubMed

    Moreira, M R; Cruz, G M; Lopes, M S; Albuquerque, A A; Leal-Cardoso, J H

    2001-10-01

    Terpineol, a volatile terpenoid alcohol of low toxicity, is widely used in the perfumery industry. It is an important chemical constituent of the essential oil of many plants with widespread applications in folk medicine and in aromatherapy. The effects of terpineol on the compound action potential (CAP) of rat sciatic nerve were studied. Terpineol induced a dose-dependent blockade of the CAP. At 100 microM, terpineol had no demonstrable effect. At 300 microM terpineol, peak-to-peak amplitude and conduction velocity of CAP were significantly reduced at the end of 180-min exposure of the nerve to the drug, from 3.28 +/- 0.22 mV and 33.5 +/- 7.05 m/s, respectively, to 1.91 +/- 0.51 mV and 26.2 +/- 4.55 m/s. At 600 microM, terpineol significantly reduced peak-to-peak amplitude and conduction velocity from 2.97 +/- 0.55 mV and 32.8 +/- 3.91 m/s to 0.24 +/- 0.23 mV and 2.72 +/- 2.72 m/s, respectively (N = 5). All these effects developed slowly and were reversible upon 180-min washout.

  18. Adhesion to carbon nanotube conductive scaffolds forces action-potential appearance in immature rat spinal neurons.

    PubMed

    Fabbro, Alessandra; Sucapane, Antonietta; Toma, Francesca Maria; Calura, Enrica; Rizzetto, Lisa; Carrieri, Claudia; Roncaglia, Paola; Martinelli, Valentina; Scaini, Denis; Masten, Lara; Turco, Antonio; Gustincich, Stefano; Prato, Maurizio; Ballerini, Laura

    2013-01-01

    In the last decade, carbon nanotube growth substrates have been used to investigate neurons and neuronal networks formation in vitro when guided by artificial nano-scaled cues. Besides, nanotube-based interfaces are being developed, such as prosthesis for monitoring brain activity. We recently described how carbon nanotube substrates alter the electrophysiological and synaptic responses of hippocampal neurons in culture. This observation highlighted the exceptional ability of this material in interfering with nerve tissue growth. Here we test the hypothesis that carbon nanotube scaffolds promote the development of immature neurons isolated from the neonatal rat spinal cord, and maintained in vitro. To address this issue we performed electrophysiological studies associated to gene expression analysis. Our results indicate that spinal neurons plated on electro-conductive carbon nanotubes show a facilitated development. Spinal neurons anticipate the expression of functional markers of maturation, such as the generation of voltage dependent currents or action potentials. These changes are accompanied by a selective modulation of gene expression, involving neuronal and non-neuronal components. Our microarray experiments suggest that carbon nanotube platforms trigger reparative activities involving microglia, in the absence of reactive gliosis. Hence, future tissue scaffolds blended with conductive nanotubes may be exploited to promote cell differentiation and reparative pathways in neural reg