Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes

1995 ◽  
Vol 269 (4) ◽  
pp. H1288-H1296 ◽  
Author(s):  
D. W. Wang ◽  
T. Kiyosue ◽  
S. Shigematsu ◽  
M. Arita
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Slow Component ◽  
Outward Current ◽  
Cell Voltage ◽  
Transient Outward Current ◽  
Inactivation Curve ◽  
Ionic Mechanisms ◽  
In Cells

Ionic mechanisms related to the prolongation of cardiac action potential in rats with chronic diabetes mellitus were studied using whole cell voltage-clamp techniques. Diabetes was induced by injection of streptozotocin (STZ; 65 mg/kg body wt) into the tail vein, and ventricular myocytes were isolated from STZ-injected rats (24-30 wk) and from age-matched normal rats. The current densities of transient outward current (Ito), a steady-state outward current, and L-type Ca2+ current (ICa) were significantly smaller in cells from diabetic animals. In addition, the kinetics of Ito of diabetic cells were modified. 1) The decay of Ito was well fitted by a sum of two exponential components in normal cells; there was only one (slow) component in the diabetic cells. 2) The steady-state inactivation curve of Ito in diabetic cells shifted by 5 mV in the negative direction. 3) Recovery from inactivation of Ito was slower in cells from diabetic animals. These alterations in Ito and the steady-state outward current can account for most of the action potential prolongation heretofore documented. The decrease of ICa may possibly be related to the depressed contraction seen in chronic diabetic mellitus.

Involvement of anion channel(s) in the modulation of the transient outward K+ channel in rat ventricular myocytes

2004 ◽  
Vol 287 (1) ◽  
pp. C163-C170 ◽  
Author(s):  
Xiao-Gang Lai ◽  
Jun Yang ◽  
Shi-Sheng Zhou ◽  
Jun Zhu ◽  
Gui-Rong Li ◽  
...  
Keyword(s):  
Steady State ◽  
Ventricular Myocytes ◽  
Ionic Current ◽  
Outward Current ◽  
Anion Channel ◽  
K Channel ◽  
Transient Outward Current ◽  
Inactivation Curve ◽  
Phalloidin Staining ◽  
Steady State Inactivation

The cardiac Ca2+-independent transient outward K+ current ( Ito), a major repolarizing ionic current, is markedly affected by Cl− substitution and anion channel blockers. We reexplored the mechanism of the action of anions on Ito by using whole cell patch-clamp in single isolated rat cardiac ventricular myocytes. The transient outward current was sensitive to blockade by 4-aminopyridine (4-AP) and was abolished by Cs+ substitution for intracellular K+. Replacement of most of the extracellular Cl− with less permeant anions, aspartate (Asp−) and glutamate (Glu−), markedly suppressed the current. Removal of external Na+ or stabilization of F-actin with phalloidin did not significantly affect the inhibitory action of less permeant anions on Ito. In contrast, the permeant Cl− substitute Br− did not markedly affect the current, whereas F− substitution for Cl− induced a slight inhibition. The Ito elicited during Br− substitution for Cl− was also sensitive to blockade by 4-AP. The ability of Cl− substitutes to induce rightward shifts of the steady-state inactivation curve of Ito was in the following sequence: NO3− > Cl− ≈ Br− > gluconate− > Glu− > Asp−. Depolymerization of actin filaments with cytochalasin D (CytD) induced an effect on the steady-state inactivation of Ito similar to that of less permeant anions. Fluorescent phalloidin staining experiments revealed that CytD-pretreatment significantly decreased the intensity of FITC-phalloidin staining of F-actin, whereas Asp− substitution for Cl− was without significant effect on the intensity. These results suggest that the Ito channel is modulated by anion channel(s), in which the actin cytoskeleton may be implicated.

Differences in outward currents between neonatal and adult rabbit ventricular cells

1994 ◽  
Vol 266 (3) ◽  
pp. H1184-H1194 ◽  
Author(s):  
J. Sanchez-Chapula ◽  
A. Elizalde ◽  
R. Navarro-Polanco ◽  
H. Barajas
Keyword(s):  
Action Potential ◽  
Papillary Muscle ◽  
Action Potential Duration ◽  
Outward Current ◽  
Stimulation Frequency ◽  
Transient Outward Current ◽  
Adult Rabbit ◽  
Outward Currents ◽  
Recovery From Inactivation ◽  
In Cells

In adult rabbit ventricular preparations, action potential duration is significantly increased when stimulation frequency is increased from 0.1 to 1.0 Hz. In neonatal preparations, a similar change in stimulation frequency produced no significant increase in action potential duration. To identify the ionic basis for this difference, we studied different outward currents in single myocytes from papillary muscle and from epicardial tissue of adult and neonatal rabbits. The densities of the outward currents in neonatal cells were about one-half of the current density in adult cells. The density of the voltage-activated transient outward current (I(to1)) was smaller in cells from papillary muscle than in cells from epicardium in adult and newborn rabbits. We found major differences in the kinetic behavior of I(to1) between adult and neonatal cells: 1) the rate of apparent inactivation was faster in neonatal cells, and 2) the recovery from inactivation was significantly faster in neonatal cells, with a time constant of 113 vs. 1,356 ms. We propose that this marked difference in the recovery from inactivation of I(to1) is the basis for the difference in frequency dependence of action potential duration.

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.

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 Passive properties and membrane currents of canine ventricular myocytes.

1987 ◽  
Vol 90 (5) ◽  
pp. 671-701 ◽  
Author(s):  
G N Tseng ◽  
R B Robinson ◽  
B F Hoffman
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Cardiac Cells ◽  
Membrane Currents ◽  
Membrane Properties ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Fast Kinetics

The membrane potential and membrane currents of single canine ventricular myocytes were studied using either single microelectrodes or suction pipettes. The myocytes displayed passive membrane properties and an action potential configuration similar to those described for multicellular dog ventricular tissue. As for other cardiac cells, in canine ventricular myocytes: (a) an inward rectifier current plays an important role in determining the resting membrane potential and repolarization rate; (b) a tetrodotoxin-sensitive Na current helps maintain the action potential plateau; and (c) the Ca current has fast kinetics and a large amplitude. Unexpected findings were the following: (a) in approximately half of the myocytes, there is a transient outward current composed of two components, one blocked by 4-aminopyridine and the other by Mn or caffeine; (b) there is clearly a time-dependent outward current (delayed rectifier current) that contributes to repolarization; and (c) the relationship of maximum upstroke velocity of phase 0 to membrane potential is more positive and steeper than that observed in cardiac tissues from Purkinje fibers.

Tedisamil inactivates transient outward K+ current in rat ventricular myocytes

1989 ◽  
Vol 257 (5) ◽  
pp. H1746-H1749 ◽  
Author(s):  
I. D. Dukes ◽  
M. Morad
Keyword(s):  
Ventricular Myocytes ◽  
Sodium Current ◽  
Outward Current ◽  
Cell Voltage ◽  
Transient Outward Current ◽  
Dependent Manner ◽  
Rat Ventricular Myocytes ◽  
K Current ◽  
New Type ◽  
Inwardly Rectifying

The action of tedisamil, a new bradycardiac agent with antiarrhythmic properties, was investigated in single rat ventricular myocytes using the whole cell voltage-clamp technique. Under current clamp conditions, 1-20 microM tedisamil caused marked prolongations of the action potential. Over the same concentration range, in voltage-clamped myocytes, tedisamil suppressed the transient outward current (ito) and enhanced its inactivation in a dose-dependent manner. The half-maximal dose for the effect of tedisamil on ito was approximately 6 microM. Tedisamil had no significant effects on the inwardly rectifying potassium current and calcium current but did suppress the sodium current at concentrations greater than 20 microM. Our findings suggest that tedisamil represents a new type of antiarrhythmic agent that primarily suppresses the transient outward K+ current.

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.

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