Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy

1997 ◽  
Vol 272 (6) ◽  
pp. H2833-H2842 ◽  
Author(s):  
J. K. Lee ◽  
I. Kodama ◽  
H. Honjo ◽  
T. Anno ◽  
K. Kamiya ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Hypertrophy ◽  
Ventricular Myocytes ◽  
Early Stage ◽  
Weight Ratio ◽  
Outward Current ◽  
Transient Outward Current ◽  
Significant Difference ◽  
And Control ◽  
Action Potential Configuration

Sequential changes in action potential configuration, 4-amino-pyridine-sensitive transient outward current (Ito), and L-type calcium current (ICa) in association with hypertrophy were investigated in ventricular myocytes from rats with monocrotaline (MCT)-induced pulmonary hypertension. The tissue weight ratio of right ventricle (RV) to left ventricle plus septum 14 and 28 days after a subcutaneous injection of MCT increased by 29.7 and 77.2%, respectively. Action potential duration (APD) of RV cells from MCT rats increased progressively, prolonged by 73.2 and 92.2% on days 14 and 28, respectively. The current density of Ito in RV cells from MCT rats on day 14 (32.5 +/- 4.5 pA/pF, n = 13) was significantly larger than in controls (26.8 +/- 4.5 pA/pF, n = 8; P < 0.05). On day 28, however, Ito density in MCT rats (15.3 +/- 4.6 pA/pF, n = 9) was significantly less than in controls (27.3 +/- 4.2 pA/pF, n = 10; P < 0.05). There were no differences in the voltage dependence of steady-state activation and inactivation of Ito between MCT and control rats. ICa density in MCT rats on day 14 (15.7 +/- 2.6 pA/pF, n = 10) was significantly larger than in controls (10.0 +/- 2.3 pA/pF, n = 10; P < 0.05), but there was no significant difference in Ito density between MCT rats (8.3 +/- 3.7 pA/pF, n = 10) and controls (11.6 +/- 3.0 pA/pF, n = 10) on day 28. These findings suggest that hypertrophy of mammalian hearts may cause stage-dependent changes in Ito and ICa density of ventricular myocytes. The APD prolongation in the early stage of hypertrophy may be caused mainly by an increase in ICa density, whereas the APD prolongation in the late stage may be ascribed to a reduction in Ito density.

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.

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.

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.

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.

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.

Developmental changes of action potential configuration and I(to) in canine epicardium

1995 ◽  
Vol 268 (6) ◽  
pp. H2513-H2521 ◽  
Author(s):  
L. M. Pacioretty ◽  
R. F. Gilmour
Keyword(s):  
Action Potential ◽  
Time Constant ◽  
Action Potential Duration ◽  
Phase 1 ◽  
Outward Current ◽  
Ionic Currents ◽  
Developmental Changes ◽  
Transient Outward Current ◽  
Rapid Phase ◽  
Action Potential Configuration

Developmental changes of the transient outward current (I(to)) and action potential configuration were determined in canine epicardium ranging in age from fetal to 60 wk. The contributions of I(to) to rapid initial repolarization and to terminal repolarization were estimated by measuring the amplitude of phase 1 of the action potential and action potential duration, respectively. Phase 1 amplitude decreased progressively from fetal to 40 wk and remained constant thereafter. Action potential duration decreased from fetal to 2 wk, increased to 20 wk, and tended to decrease thereafter. Peak I(to) at +40 mV increased progressively from 2 to 60 wk. However, I(to) density was less at 2-10 wk than at 20-60 wk. The time constant of decay of I(to) increased with age from 2 to 60 wk, whereas the steady-state voltage dependence of inactivation did not vary with age. The time constant for the initial rapid phase of recovery from inactivation decreased from 2 to 10 wk and remained constant thereafter. The time constant for the more slowly evolving phase did not vary with age. The observation that the age-dependent reduction in phase 1 amplitude did not necessarily coincide with significant increases in I(to) density suggests that maturation of other ionic currents or transport mechanisms may contribute to developmental alterations of phase 1 repolarization.

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

1991 ◽  
Vol 260 (3) ◽  
pp. H935-H942 ◽  
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.

Effect of simulated Ito on guinea pig and canine ventricular action potential morphology

2006 ◽  
Vol 291 (2) ◽  
pp. H631-H637 ◽  
Author(s):  
Min Dong ◽  
Xiaoyin Sun ◽  
Astrid A. Prinz ◽  
Hong-Sheng Wang
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Phase 1 ◽  
Outward Current ◽  
Transient Outward Current ◽  
Ventricular Cells ◽  
Perforated Patch Clamp ◽  
Ventricular Action Potential

The transient outward current ( Ito) is a major repolarizing current in the heart. Marked reduction of Ito density occurs in heart failure and is accompanied by significant action potential duration (APD) prolongation. To understand the species-dependent role of Ito in regulating the ventricular action potential morphology and duration, we introduced simulated Ito conductance in guinea pig and canine endocardial ventricular myocytes using the dynamic clamp technique and perforated patch-clamp recordings. The effects of simulated Ito in both types of cells were complex and biphasic, separated by a clear density threshold of ∼40 pA/pF. Below this threshold, simulated Ito resulted in a distinct phase 1 notch and had little effect on or moderately prolonged the APD. Ito above the threshold resulted in all-or-none repolarization and precipitously reduced the APD. Qualitatively, these results agreed with our previous studies in canine ventricular cells using whole cell recordings. We conclude that 1) contrary to previous gene transfer studies involving the Kv4.3 current, the response of guinea pig ventricular myocytes to a fully inactivating Ito is similar to that of canine ventricular cells and 2) in animals such as dogs that have a broad cardiac action potential, Ito does not play a major role in setting the APD.

Modulation of electrical heterogeneity by compensated hypertrophy in rat left ventricle

1997 ◽  
Vol 272 (3) ◽  
pp. H1078-H1086 ◽  
Author(s):  
A. M. Gomez ◽  
J. P. Benitah ◽  
D. Henzel ◽  
A. Vinet ◽  
P. Lorente ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Regional Distribution ◽  
Outward Current ◽  
Left Ventricular ◽  
Transient Outward Current ◽  
Abdominal Aortic ◽  
Cell Current ◽  
Normal Rat

Modulation of the regional distribution of the action potential by left ventricular hypertrophy and the role of the L-type Ca2+ current (I(Ca)) and transient outward current (I(to)) in the action potential duration (APD) were investigated in normal and hypertrophied rat ventricular myocytes from the apex (A), septum (S) and left ventricular free wall (FW) by using whole cell current- and voltage-clamp techniques. Hypertrophy was induced by abdominal aortic constriction. In control cells, the APD measured at 20% repolarization (APD20) assumed the shortest values in the A and the longest in the S, whereas FW cells showed intermediate values. Hypertrophy significantly prolonged the APD20 and increased APD variability within the A and FW regions but did not modify the APD in S cells. Analysis of the APD, I(Ca), and I(to) at the instant of 20% repolarization in the same cell showed that in control cells the shortest APD20 was associated with a prominent I(to) in the A and FW, whereas the long APD20 was identified with a lower I(to) in S myocytes. Hypertrophy-induced prolongation ofAPD20 was associated with a reduction in the I(to) in the A and FW. Significant correlations could be established between the APD20 and the "net current," defined as the algebraic addition of I(to) and I(Ca) in the A and FW control groups but not in the control S or hypertrophied cells whatever their origin. Our results indicate that interregional APD heterogeneity is lost while intraregional APD variability is increased in the A and FW during the hypertrophic process. These effects are largely due to a change in the balance between the I(Ca) and I(to), which is a major contributing factor to the heterogeneity of the initial phase of repolarization in the normal rat ventricle.

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