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

1998 ◽  
Vol 274 (3) ◽  
pp. C577-C585 ◽  
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.

Isoproterenol activates a chloride current, not the transient outward current, in rabbit ventricular myocytes

1989 ◽  
Vol 257 (6) ◽  
pp. C1177-C1181 ◽  
Author(s):  
R. D. Harvey ◽  
J. R. Hume
Keyword(s):  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Outward Current ◽  
Chloride Current ◽  
Equilibrium Potential ◽  
K Channel ◽  
Transient Outward Current ◽  
Induced Current ◽  
Adrenergic Stimulation ◽  
Rabbit Ventricular Myocytes

The effects of beta-adrenergic stimulation on the Ca2(+)-insensitive transient outward current (Ito) in rabbit ventricular myocytes were examined. Exposure to isoproterenol (ISO; 1 microM) activated a time-dependent current at positive membrane potentials. To determine whether this ISO-induced current was associated with Ito, sensitivity to the K+ channel antagonist, 3,4-diaminopyridine (DAP; 200 microM) was compared before and after exposure to ISO. The DAP-sensitive current was not enhanced by ISO, suggesting that the ISO-induced current was not a component of Ito. Ito and the ISO-induced current could also be dissociated by changing the membrane holding potential. Positive holding potentials, which produced significant inactivation of Ito, had little effect on the ISO-induced membrane current. Furthermore, the ISO-induced current could be observed when K+ was replaced by Cs+. The reversal potential of the ISO-induced current agreed with the predicted Cl- equilibrium potential, and exposure to Cl(-)-free extracellular solutions eliminated the response to ISO. Therefore, we conclude that ISO does not directly activate Ito in rabbit ventricular myocytes, but instead, activates a time-independent chloride current (ICl) similar to that recently described in guinea pig ventricular myocytes and shown to be regulated by adenylate cyclase (R. D. Harvey and J. R. Hume. Science Wash. DC 244: 983-985, 1989).

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

2000 ◽  
Vol 278 (3) ◽  
pp. H806-H817 ◽  
Author(s):  
Gary A. Gintant
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Inward Rectifier ◽  
Ventricular Repolarization ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Voltage Dependent

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 Krduring 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.

Intracellular calcium activates a chloride current in canine ventricular myocytes

1994 ◽  
Vol 267 (5) ◽  
pp. H1984-H1995 ◽  
Author(s):  
A. C. Zygmunt
Keyword(s):  
Potassium Current ◽  
Ventricular Myocytes ◽  
Single Cells ◽  
Reversal Potential ◽  
Outward Current ◽  
Chloride Current ◽  
Disulfonic Acid ◽  
Transient Outward Current ◽  
Triggered Arrhythmias ◽  
Inward Currents

The contribution of chloride and potassium to the 4-aminopyridine (4-AP)-resistant transient outward current was investigated in dog cardiac myocytes. Whole cell currents were recorded at 37 degrees C in single cells dissociated from epicardial and midmyocardial regions of the canine ventricle. Sodium-calcium exchange current and voltage-dependent transient outward potassium current (IA) were blocked in sodium-free solutions containing 2 mM 4-AP; sodium channels were inactivated by the -50-mV holding potential. When patch pipettes contained 0.4–0.8 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, voltage-clamp steps over the range -20 to +50 mV activated an inward calcium current (ICa) and a Ca(2+)-activated chloride current [ICl(Ca)]. ICl(Ca) was blocked by 200 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, 1 mM 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), or reduction of external chloride. Independent of the presence of potassium, the reversal potential of the SITS-sensitive current varied with extracellular chloride, as predicted for a chloride-selective conductance. The bell-shaped current-voltage relation of ICl(Ca) has a threshold of -20 mV and a peak at +40 mV. No evidence could be found for a Ca(2+)-activated potassium current or a Ca(2+)-activated nonspecific cation current under these conditions. ICl(Ca) contributed to oscillatory inward currents at diastolic potentials in cells superfused by isoproterenol and high Ca2+, suggesting a role for this current in triggered arrhythmias associated with delayed afterdepolarizations. In the normal heart, ICl(Ca) is likely to contribute to rate- and rhythm-dependent repolarization of the cardiac action potential.

Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes

2000 ◽  
Vol 278 (2) ◽  
pp. E302-E307 ◽  
Author(s):  
Zhuo-Qian Sun ◽  
Kaie Ojamaa ◽  
William A. Coetzee ◽  
Michael Artman ◽  
Irwin Klein
Keyword(s):  
Action Potential ◽  
Cardiac Electrophysiology ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Mechanisms Of Action ◽  
Transient Outward Current ◽  
Prolonged Action ◽  
Electrophysiological Properties ◽  
Whole Cell Patch Clamp ◽  
Prolonged Action Potential Duration

Thyroid hormones play an important role in cardiac electrophysiology through both genomic and nongenomic mechanisms of action. The effects of triiodothyronine (T3) on the electrophysiological properties of ventricular myocytes isolated from euthyroid and hypothyroid rats were studied using whole cell patch clamp techniques. Hypothyroid ventricular myocytes showed significantly prolonged action potential duration (APD90) compared with euthyroid myocytes, APD90 of 151 ± 5 vs. 51 ± 8 ms, respectively. Treatment of hypothyroid ventricular myocytes with T3 (0.1 μM) for 5 min significantly shortened APD by 24% to 115 ± 10 ms. T3 similarly shortened APD in euthyroid ventricular myocytes, but only in the presence of 4-aminopyridine (4-AP), an inhibitor of the transient outward current ( I to), which prolonged the APD by threefold. Transient outward current ( I to) was not affected by the acute application of T3 to either euthyroid or hypothyroid myocytes; however, I to density was significantly reduced in hypothyroid compared with euthyroid ventricular myocytes.

Role of chloride currents in repolarizing rabbit atrial myocytes

1995 ◽  
Vol 268 (5) ◽  
pp. H1992-H2002 ◽  
Author(s):  
Z. Wang ◽  
B. Fermini ◽  
J. Feng ◽  
S. Nattel
Keyword(s):  
Action Potential ◽  
Reversal Potential ◽  
Outward Current ◽  
Cell Voltage ◽  
Disulfonic Acid ◽  
Transient Outward Current ◽  
Atrial Myocytes ◽  
Atrial Cells ◽  
K Current

Rabbit atrial cells manifest a prominent transient outward K+ current (Ito1), but this current recovers slowly from inactivation and is unlikely to be important at physiological rates (3-5 Hz). Depolarization of rabbit atrial cells also elicits a transient Ca(2+)-dependent outward Cl- current (Ito2). To compare the relative magnitude of these transient outward currents at various rates, we applied whole cell voltage-clamp techniques to isolated rabbit atrial myocytes. Whereas peak Ito1 exceeded Ito2 at slow rates (0.1 Hz), Ito1 was strongly reduced as rate was increased (by 97 +/- 2%, mean +/- SE, at 4 Hz), while Ito2 was slightly reduced (by 28 +/- 4%, 4 Hz). The reversal potential of transient outward tail currents at 0.07 Hz was -49 +/- 9 mV, while at 2.5 Hz the reversal potential became -18 +/- 7 mV (calculated Cl- reversal potential -18 mV). The addition of the Cl- transport blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 150 microM) or the replacement of external Cl- with methanesulfonate inhibited a large part of the transient outward current elicited by depolarization at 4 Hz. DIDS and Cl- replacement increased action potential duration in both single rabbit atrial cells and multicellular rabbit atrial preparations. We conclude that the Ca(2+)-dependent Cl- current is substantially larger than the transient K+ current at physiological rates in the rabbit and is likely to play a more important role in action potential repolarization than the latter current in this tissue in vivo.

Ca2+-activated Cl− current can be triggered by Na+ current-induced SR Ca2+ release in rabbit ventricle

1999 ◽  
Vol 277 (4) ◽  
pp. H1467-H1477 ◽  
Author(s):  
Hui Sun ◽  
Denis Chartier ◽  
Stanley Nattel ◽  
Normand Leblanc
Keyword(s):  
Ventricular Myocytes ◽  
Physiological Role ◽  
Reversal Potential ◽  
Outward Current ◽  
External Solution ◽  
Rabbit Heart ◽  
Transient Outward Current ◽  
Release Mechanism ◽  
Patch Clamp Technique ◽  
Reverse Mode

The Ca2+-activated Cl− current [ I Cl(Ca)] contributes to the repolarization of the cardiac action potential under physiological conditions. I Cl(Ca) is known to be primarily activated by Ca2+release from the sarcoplasmic reticulum (SR). L-type Ca2+ current [ I Ca(L)] represents the major trigger for Ca2+ release in the heart. Recent evidence, however, suggests that Ca2+ entry via reverse-mode Na+/Ca2+exchange promoted by voltage and/or Na+ current ( I Na) may also play a role. The purpose of this study was to test the hypothesis that I Cl(Ca) can be induced by I Na in the absence of I Ca(L). Macroscopic currents and Ca2+transients were measured using the whole cell patch-clamp technique in rabbit ventricular myocytes loaded with Indo-1. Nicardipine (10 μM) abolished I Ca(L)at a holding potential of −75 mV as tested in Na+-free external solution. In the presence of 131 mM external Na+and in the absence of I Ca(L), a 4-aminopyridine-resistant transient outward current was recorded in 64 of 81 cells accompanying a phasic Ca2+ transient. The current reversed at −42.0 ± 1.3 mV ( n = 6) and at +0.3 ± 1.4 mV ( n = 6) with 21 and 141 mM of internal Cl−, respectively, similar to the predicted reversal potential with low intracellular Cl− concentration ([Cl−]i) (−47.8 mV) and high [Cl−]i(−1.2 mV). Niflumic acid (100 μM) inhibited the current without affecting the Ca2+ signal ( n = 8). Both the current and Ca2+ transient were abolished by 10 mM caffeine ( n = 6), 10 μM ryanodine ( n = 3), 30 μM tetrodotoxin ( n = 9), or removal of extracellular Ca2+( n = 6). These properties are consistent with those of I Cl(Ca)previously described in mammalian cardiac myocytes. We conclude that 1) I Cl(Ca) can be recorded in the absence of I Ca(L), and 2) I Na-induced SR Ca2+ release mechanism is also present in the rabbit heart and may play a physiological role in activating the Ca2+-sensitive membrane Cl− conductance.

Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice

2007 ◽  
Vol 292 (2) ◽  
pp. C968-C973 ◽  
Author(s):  
Christian Pott ◽  
Xiaoyan Ren ◽  
Diana X. Tran ◽  
Ming-Jim Yang ◽  
Scott Henderson ◽  
...  
Keyword(s):  
Action Potential ◽  
Computer Model ◽  
Knockout Mice ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Transient Outward Current ◽  
Decay Kinetics ◽  
Interacting Protein ◽  
Major Mechanism ◽  
Qt Intervals

In cardiac-specific Na+-Ca2+ exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type Ca2+ current ( ICa), provides a critical mechanism for the maintenance of Ca2+ homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in Na+-Ca2+ exchanger knockout mice: reduced transsarcolemmal Ca2+ flux. Circ Res 97: 1288–1295, 2005). To investigate the mechanism that underlies the accelerated AP repolarization, we recorded the transient outward current ( Ito) in patch-clamped myocytes isolated from wild-type (WT) and NCX KO mice. Peak Ito was increased by 78% and decay kinetics were slowed in KO vs. WT. Consistent with increased Ito, ECGs from KO mice exhibited shortened QT intervals. Expression of the Ito-generating K+ channel subunit Kv4.2 and the K+ channel interacting protein was increased in KO. We used a computer model of the murine AP (Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, and Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287: 1378–1403, 2004) to determine the relative contributions of increased Ito, reduced ICa, and reduced NCX current ( INCX) on the shape and kinetics of the AP. Reduction of ICa and elimination of INCX had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when Ito was increased in the computer model. Thus, the increase in Ito, and not the reduction of ICa or INCX, is likely to be the major mechanism of AP shortening in KO myocytes. The upregulation of Ito may comprise an important regulatory mechanism to limit Ca2+ influx via a reduction of AP duration, thus preventing Ca2+ overload in situations of reduced myocyte Ca2+ extrusion capacity.

Effects of myocardial hypertrophy on transient outward current

1994 ◽  
Vol 266 (5) ◽  
pp. H1738-H1745 ◽  
Author(s):  
Q. Li ◽  
E. C. Keung
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Action Potential Duration ◽  
Time Course ◽  
Myocardial Hypertrophy ◽  
Pressure Overload ◽  
Reversal Potential ◽  
Outward Current ◽  
Transient Outward Current ◽  
The Difference

In the one-clip, two-kidney model of hypertensive rat, a gradual chronic pressure overload is imposed on the heart. Myocardial hypertrophy resulting from such pressure overload is associated with an increased but slower inactivating L-type calcium current and prolongation of action potential duration. Voltage clamp experiments in a variety of excitable tissues indicate that a 4-aminopyridine-sensitive transient outward current (Ito) plays an important role in regulating the action potential duration. Accordingly, we studied Ito in single adult cardiac myocytes enzymatically isolated from hypertrophied left ventricles of the renovascular hypertensive (HBP) rat hearts using the whole cell patch-clamp method. The current densities (normalized to cell capacitative surface area) measured at the early transient peak Ito, at the steady state, and as the difference between the transient peak and the steady state were larger in HBP cells (n = 23) than in control (Ctrl) cells (n = 20) (P < 0.05). There was no difference in the Ito reversal potential between Ctrl (-60.9 +/- 1.9 mV, mean +/- SE; n = 16) and HBP (-63.7 +/- 2.6 mV; n = 19) cells. The observed increase in Ito amplitude was not due to an increase in the number of channels available for activation or in the fraction of channels activated because there were no statistical differences in the membrane potential at which one-half of the Ito channels are activated (V0.5) for the steady-state activation and inactivation curves between Ctrl and HBP cells. The time course of inactivation of Ito was described by a double-exponential function.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Diverse Ionic Currents and Electrical Activity of Cultured Myenteric Neurons From the Guinea Pig Proximal Colon

2000 ◽  
Vol 83 (3) ◽  
pp. 1253-1263 ◽  
Author(s):  
Fivos Vogalis ◽  
Kirk Hillsley ◽  
Terence K. Smith
Keyword(s):  
Patch Clamp ◽  
Guinea Pig ◽  
Action Potential ◽  
Action Potentials ◽  
Outward Current ◽  
Proximal Colon ◽  
Equilibrium Potential ◽  
Transient Outward Current ◽  
Myenteric Neurons ◽  
Fast Transient

The aim of this study was to perform a patch-clamp analysis of myenteric neurons from the guinea pig proximal colon. Neurons were enzymatically dispersed, cultured for 2–7 days, and recorded from using whole cell patch clamp. The majority of cells fired phasically, whereas about one-quarter of the neurons fired in a tonic manner. Neurons were divided into three types based on the currents activated. The majority of tonically firing neurons lacked an A-type current, but generated a large fast transient outward current that was associated with the rapid repolarizing phase of an action potential. The fast transient outward current was dependent on calcium entry and was blocked by tetraethylammonium. Cells that expressed both an A-type current and a fast transient outward current were mostly phasic. Depolarization of these cells to suprathreshold potentials from less than −60 mV failed to trigger action potentials, or action potentials were only triggered after a delay of >50 ms. However, depolarizations from more positive potentials triggered action potentials with minimal latency. Neurons that expressed neither the A-type current or the fast transient outward current were all phasic. Sixteen percent of neurons were similar to AH/type II neurons in that they generated a prolonged afterhyperpolarization following an action potential. The current underlying the prolonged afterhyperpolarization showed weak inward rectification and had a reversal potential near the potassium equilibrium potential. Thus cultured isolated myenteric neurons of the guinea pig proximal colon retain many of the diverse properties of intact neurons. This preparation is suitable for further biophysical and molecular characterization of channels expressed in colonic myenteric neurons.

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