Contributions of a transient outward current to repolarization in human atrium

Conventional microelectrode recordings combined with enzymatic cell dispersion methods and a single microelectrode voltage-clamp technique were used to record transmembrane action potentials and ionic currents in isolated single myocytes and in excised segments of human right atrium. Recordings of the outward current(s), which is responsible for the resting potential and early repolarization of the action potential in human right atrium, consistently showed that this tissue has 1) a relatively small inwardly rectifying background potassium current (IK1) which generates the resting potential in mammalian ventricular tissue and Purkinje fibers, and 2) a large time- and voltage-dependent, but Ca2(+)-independent, transient outward current. A somewhat similar K+ current was originally described in neurons and recently has also been identified in a variety of mammalian cardiac tissues. As expected from previous work, this transient outward current in human atrium is blocked by 4-aminopyridine (4-AP; 0.5 mM) and exhibits time- and voltage-dependent inactivation and reactivation. Measurements of action potential shape changes and phasic tension as a function of stimulus frequency, or after 4-AP application, show that in human atrium this current can produce pronounced changes in both the early repolarization of the action potential and force generation.

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Action Potential Remodeling in the Human Right Atrium with Chronic Lone Atrial Fibrillation

Pacing and Clinical Electrophysiology ◽

10.1111/j.1540-8159.2000.tb00881.x ◽

2000 ◽

Vol 23 (6) ◽

pp. 960-965 ◽

Cited By ~ 17

Author(s):

TOSHIYUKI OSAKA ◽

ATSUSHIITOH ◽

ITSUO KODAMA

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Right Atrium ◽

Human Right ◽

Lone Atrial Fibrillation ◽

Human Right Atrium

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Characterization of a transient outward K+ current with inward rectification in canine ventricular myocytes

AJP Cell Physiology ◽

10.1152/ajpcell.1998.274.3.c577 ◽

1998 ◽

Vol 274 (3) ◽

pp. C577-C585 ◽

Cited By ~ 264

Author(s):

Gui-Rong Li ◽

Haiying Sun ◽

Stanley Nattel

Keyword(s):

Action Potential ◽

Ventricular Myocytes ◽

Reversal Potential ◽

Outward Current ◽

Equilibrium Potential ◽

Inward Rectification ◽

Transient Outward Current ◽

Membrane Excitability ◽

Voltage Dependent ◽

Patch Technique

The threshold potential for the classical depolarization-activated transient outward K+ current and Cl− current is positive to −30 mV. With the whole cell patch technique, a transient outward current was elicited in the presence of 5 mM 4-aminopyridine (4-AP) and 5 μM ryanodine at voltages positive to the K+ equilibrium potential in canine ventricular myocytes. The current was abolished by 200 μM Ba2+ or omission of external K+([Formula: see text]) and showed biexponential inactivation. The current-voltage relation for the peak of the transient outward component showed moderate inward rectification. The transient outward current demonstrated voltage-dependent inactivation (half-inactivation voltage: −43.5 ± 3.2 mV) and rapid, monoexponential recovery from inactivation (time constant: 13.2 ± 2.5 ms). The reversal potential responded to the changes in[Formula: see text] concentration. Action potential clamp revealed two phases of Ba2+-sensitive current during the action potential, including a large early transient component after the upstroke and a later outward component during phase 3 repolarization. The present study demonstrates that depolarization may elicit a Ba2+- and[Formula: see text]-sensitive, 4-AP-insensitive, transient outward current with inward rectification in canine ventricular myocytes. The properties of this K+ current suggest that it may carry a significant early outward current upon depolarization that may play a role in determining membrane excitability and action potential morphology.

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Regional differences in rabbit atrial repolarization: importance of transient outward current

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.2.h643 ◽

1994 ◽

Vol 266 (2) ◽

pp. H643-H649 ◽

Cited By ~ 5

Author(s):

A. Qi ◽

J. A. Yeung-Lai-Wah ◽

J. Xiao ◽

C. R. Kerr

Keyword(s):

Action Potential ◽

Regional Differences ◽

Phase 1 ◽

Outward Current ◽

Right Atrial ◽

Resting Potential ◽

Transient Outward Current ◽

Phase 3 ◽

Roof Area ◽

Atrial Repolarization

Regional differences in rabbit atrial repolarization were investigated using a conventional microelectrode technique. A more rapid phase 1 repolarization (lower phase 1 amplitude) was seen in the left atrial (LA) roof area compared with the right atrial (RA) roof area: 54 +/- 10 vs. 82 +/- 6 mV at 1,000 ms (P < 0.001). In addition, action potential duration at 40 mV above the resting potential (APD40) was shorter in LA and was associated with a slower phase 3 repolarization rate. Furthermore, the recovery time constant of phase 1 amplitude at 500 ms was 0.9 +/- 0.2 s in LA and 3.5 +/- 1.5 s in RA (P < 0.001). Pacing cycle lengths (2,000, 1,500, 1,000, 800, and 500 ms) modulated phase 1 amplitude, APD40, and phase 3 rate in both regions. 4-Aminopyridine (4-AP; 1 mM), a selective transient outward current (I(to)) blocker, abolished cycle length dependence of the above action potential parameters and diminished the differences in electrophysiological properties between the two regions. 4-AP also flattened the restitution curve of phase 1 amplitude in both regions. In conclusion, the findings suggest that the different kinetics of I(to) play an important role in regional differences of atrial repolarization.

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Decreased transient outward K+ current in ventricular myocytes from acromegalic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.260.3.h935 ◽

1991 ◽

Vol 260 (3) ◽

pp. H935-H942 ◽

Cited By ~ 2

Author(s):

X. P. Xu ◽

P. M. Best

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Time Course ◽

Ventricular Myocytes ◽

Outward Current ◽

Resting Potential ◽

Gh3 Cells ◽

Heart Weight ◽

Transient Outward Current ◽

Tumor Bearing

Cardiac hypertrophy and heart failure are common to acromegalic patients who have abnormally high serum growth hormone (GH). While the function of cardiac muscle is clearly affected by chronically elevated GH, the electrical activity of myocytes from hearts with GH-dependent hypertrophy has not been studied. We used adult, female Wistar-Furth rats with induced GH-secreting tumors to study the effect of excessive GH on ion channels of cardiac myocytes. GH-secreting tumors were induced by subcutaneous inoculation of GH3 cells. Eight weeks after inoculation, the rats had doubled their body weight and heart size compared with age-matched controls. There were no differences in either action potential amplitude or resting potential of right ventricular myocytes from control and tumor-bearing rats. However, action potential duration increased significantly in tumor-bearing rats; the time to 50% repolarization was 23 +/- 14 ms (n = 10) compared with 6.6 +/- 1.5 ms (n = 14) in controls. The prolongation of the action potential was mainly due to a decrease in density of a transient outward current (It,o) carried by K+. The normalized conductance for It,o decreased from 0.53 +/- 0.10 nS/pF (n = 25) in controls to 0.33 +/- 0.09 nS/pF (n = 26) in tumor-bearing rats. The decrease in It,o) and increase in heart weight occurred with a similar time course. The increased action potential duration prolongs Ca2+ influx through L-type Ca2+ channels in the tumor-bearing animals; this may be important in cardiovascular adaptation.

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Rat hippocampal neurons in culture: potassium conductances

Journal of Neurophysiology ◽

10.1152/jn.1984.51.6.1409 ◽

1984 ◽

Vol 51 (6) ◽

pp. 1409-1433 ◽

Cited By ~ 93

Author(s):

M. Segal ◽

J. L. Barker

Keyword(s):

Time Constant ◽

Hippocampal Neurons ◽

Outward Current ◽

Resting Potential ◽

Equilibrium Potential ◽

Transient Outward Current ◽

Current Response ◽

Normal Medium ◽

Inward Current ◽

Voltage Dependent

Two-electrode voltage-clamp methodology was used to analyze voltage-dependent ionic conductances in 81 rat hippocampal neurons grown in culture for 4-6 wk. Pyramidal and multipolar cells with 15- to 20-micron-diameter cell bodies were impaled with two independent KCl electrodes. The cells had resting potentials of -30 to -60 mV and an average input resistance of about 30 M omega. A depolarizing command applied to a cell maintained in normal medium invariably evoked a fast (2-10 ms) inward current that saturated the current-passing capacity of the system. This was blocked in a reversible manner by application of tetrodotoxin (TTX) (0.1-1.0 microM) near the recorded cell. In the presence of TTX, a depolarizing command evoked a rapidly rising (3-5 ms), rapidly decaying (25 ms) transient outward current reminiscent of "IA" reported in molluscan neurons. This was followed by a more slowly activating (approximately 100 ms) outward current response of greater amplitude that decayed with a time constant of about 2-3 s. These properties resemble those associated with the K+ conductance, IK, underlying delayed rectification described in many excitable membranes. IK was blocked by extracellular application of tetraethylammonium (TEA) but was insensitive to 4-aminopyridine (4-AP) at concentrations that effectively eliminated IA. IA, in turn, was only marginally depressed by TEA. Unlike IK, IA was completely inactivated when the membrane was held at potentials positive to -50 mV. Inactivation was completely removed by conditioning hyperpolarization at -90 mV. A brief hyperpolarizing pulse (10 ms) was sufficient to remove 95% of the inactivation. IA activated on commands to potentials more positive than -50 mV. The inversion potential of the ionic conductance underlying IA and IK was in the range of the K+ equilibrium potential, EK, as measured by the inversion of tail currents; and this potential was shifted in a depolarizing direction by elevated [K+]0. Thus, both current species reflect activation of membrane conductance to K+ ions. Hyperpolarizing commands from resting potentials revealed a time- and voltage-dependent slowly developing inward current in the majority of cells studied. This membrane current was observed in cells exhibiting "anomalous rectification" and was therefore labeled IAR. It was activated at potentials negative to -70 mV with a time constant of 100-200 ms and was not inactivated. A return to resting potential revealed a tail current that disappeared at about EK. IAR was blocked by extracellular CS+ and was enhanced by elevating [K+]0. It thus appears to be carried by inward movement of K+ ions.(ABSTRACT TRUNCATED AT 400 WORDS)

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Roles of outward potassium currents in the action potentials of guinea pig ureteral myocytes

AJP Cell Physiology ◽

10.1152/ajpcell.1997.273.3.c962 ◽

1997 ◽

Vol 273 (3) ◽

pp. C962-C972 ◽

Cited By ~ 8

Author(s):

J. L. Sui ◽

C. Y. Kao

Keyword(s):

Action Potential ◽

Action Potentials ◽

Outward Current ◽

Membrane Conductance ◽

Resting Potential ◽

Delayed Rectifier ◽

Inactivation Kinetics ◽

Transient Outward Current ◽

Delayed Rectifier Current ◽

Fast Activation

Outward currents of freshly dissociated ureteral myocytes consist mainly of Ca(2+)-activated K+ current (IKCa) and a transient outward current (ITO). No delayed rectifier current was apparent. IKCa is small and nondecaying and fluctuates actively and irregularly. Blocking IKCa decreased resting membrane conductance and prolonged action potential plateaus, showing its roles in maintaining the resting potential and in repolarizing action potentials. It is also responsible for the membrane potential fluctuations on action potential plateaus. Neither 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride nor caffeine reduced the fluctuations in the outward current or in the action potentials, indicating that internal Ca2+ storage contributes little to the fluctuations. ITO has fast activation and inactivation kinetics with inactivation time constants of approximately 15 and 150 ms, respectively. Its highly negative voltage-availability relationship (V0.5 = -70.5 mV) suggests a low availability (< 5%) at normal resting potentials. It has only trivial effects on action potentials.

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Slow inactivation of a TEA-sensitive K current in acutely isolated rat thalamic relay neurons

Journal of Neurophysiology ◽

10.1152/jn.1991.66.4.1316 ◽

1991 ◽

Vol 66 (4) ◽

pp. 1316-1328 ◽

Cited By ~ 45

Author(s):

J. R. Huguenard ◽

D. A. Prince

Keyword(s):

Steady State ◽

Membrane Potential ◽

Outward Current ◽

Resting Potential ◽

Transient Outward Current ◽

Voltage Range ◽

Voltage Dependent ◽

Kinetics Of ◽

K Currents ◽

Relay Neurons

1. Voltage-gated K currents were studied in relay neurons (RNs) acutely isolated from somatosensory (VB) thalamus of 7- to 14-day-old rats. In addition to a rapidly activated, transient outward current, IA, depolarizations activated slower K+ currents, which were isolated through the use of appropriate ionic and pharmacological conditions and measured via whole-cell voltage-clamp. 2. At least two slow components of outward current were observed, both of which were sensitive to changes in [K+]o, as expected for K conductances. The first, IK1, had an amplitude that was insensitive to holding potential and a relatively small conductance of 150 pS/pF. It was blocked by submillimolar levels of tetraethylammonium [TEA, 50%-inhibitory concentration (IC50 = 30 microM)] and 4-aminopyridine (4-AP, 40 microM). In the absence of intracellular Ca2+ buffering, the amplitude of IK1 was both larger and dependent on holding potential, as expected for a Ca(2+)-dependent current. Replacement of [Ca2+]o by Co2+ reduced IK1, although the addition of Cd2+ to Ca(2+)-containing solutions had no effect. 3. The second component, IK2, had a normalized conductance of 2.0 nS/pF and was blocked by millimolar concentrations of TEA (IC50 = 4 mM) but not by 4AP. The kinetics of IK2 were analogous to (but much slower than) those of IA in that both currents displayed voltage-dependent activation and voltage-independent inactivation. IK2 was not reduced by the addition of Cd2+ to Ca(2+)-containing solutions or by replacement of Ca2+ by Co2+. 4. IK2 had a more depolarized activation threshold than IA and attained peak amplitude with a latency of approximately 100 ms at room temperature. IK2 decay was nonexponential and could be described as the sum of two components with time constants (tau) near 1 and 10 s. 5. IK2 was one-half steady-state inactivated at a membrane potential of -63 mV, near the normal resting potential for these cells. The slope factor of the Boltzman function describing steady-state inactivation was 13 mV-1, which indicates that IK2 varies in availability across a broad voltage range between -100 and -20 mV. 6. Activation kinetics of IK2 were voltage dependent, with peak latency shifting from 300 to 50 ms in the voltage range -50 to +30 mV. Deinactivation and deactivation were also voltage dependent, in contrast to inactivation, which showed little dependence on membrane potential. Increase in temperature sped the kinetics of IK2, with temperature coefficient (Q10) values near 3 for activation and inactivation. Heating increased the amplitude of IK2 with a Q10 value near 2.(ABSTRACT TRUNCATED AT 400 WORDS)

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