Quinidine-induced inhibition of transient outward current in cardiac muscle

1987 ◽  
Vol 253 (3) ◽  
pp. H704-H708 ◽  
Author(s):  
Y. Imaizumi ◽  
W. R. Giles
Keyword(s):  
Action Potential ◽  
Antiarrhythmic Agent ◽  
Sodium Current ◽  
Single Cells ◽  
Outward Current ◽  
Cell Voltage ◽  
Rabbit Heart ◽  
Transient Outward Current ◽  
K Current ◽  
Therapeutic Doses

Quinidine is frequently used as a class I antiarrhythmic agent in the management of cardiac rhythm disturbances. It depresses the rapid initial depolarization of the action potential by blocking the sodium current, INa. In addition, quinidine increases the duration of the action potential and lengthens the refractory period. We have used a whole cell voltage-clamp technique to study the ionic mechanism underlying the lengthening of the action potential in single cells from the atrium and ventricle of the rabbit heart. Our data show that quinidine at therapeutic doses (3-10 microM) is a potent and selective inhibitor of a transient outward current, which controls the early repolarization of the action potential. In contrast, neither the calcium current, ICa, nor the time-independent background K+ current, IK1, is changed significantly by 10 microM quinidine. The reduction in the transient outward current can explain the lengthening of action potential and provides new insight into the mechanism of action of quinidine as an antiarrhythmic agent.

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.

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.

Transient outward current in young and adult diseased human atria

1993 ◽  
Vol 265 (4) ◽  
pp. H1466-H1470 ◽  
Author(s):  
J. Mansourati ◽  
B. Le Grand
Keyword(s):  
Action Potential ◽  
Developmental Change ◽  
Single Cells ◽  
Young Patients ◽  
Outward Current ◽  
Cell Voltage ◽  
Transient Outward Current ◽  
Normal Cells ◽  
Outward Currents ◽  
The Difference

In human atrial fibers, the action potential undergoes a major developmental change in shape in the months immediately after birth. Transient potassium outward currents, which may affect the shape of the action potential, have been studied using a whole cell voltage-clamp technique with single cells from the atria of young patients aged 3-60 mo. Transient outward current (I(to)) amplitude was measured as the difference between the peak current and the steady-state outward current (I(late)) at the end of the voltage step. The density of I(to) was significantly reduced in adult diseased cells (n = 18) compared with normal cells (n = 21) in a large range of potential and absent in young diseased cells (n = 13). Furthermore, the I(late) recorded in young cells was significantly greater (23.7 +/- 5.74 pA/pF at 60 mV) than in adult normal cells (12.71 +/- 2.25 pA/pF at 60 mV), whereas I(late) was not significantly different between both groups of adult cells. Nevertheless, a 4-aminopyridine-sensitive I(to) has been recorded in young cells. A decrease in the frequency of clamp steps (from 0.1 to 0.01 Hz) did not reactivate a I(to) in young cells. This absence of 4-aminopyridine-sensitive Ito in young cells probably results from either a normal developmental change of this current or from pathological alterations like those described in adult diseased atria.

A novel effect of norepinephrine on cardiac cells is mediated by alpha 1-adrenoceptors

1989 ◽  
Vol 256 (5) ◽  
pp. H1500-H1504 ◽  
Author(s):  
D. Fedida ◽  
Y. Shimoni ◽  
W. R. Giles
Keyword(s):  
Action Potential ◽  
Outward Current ◽  
Cardiac Cells ◽  
Transient Outward Current ◽  
Adrenergic Stimulation ◽  
Inotropic Effects ◽  
Alpha Adrenoceptor ◽  
Rate Dependent ◽  
Alpha Adrenoceptor Agonists ◽  
K Current

In the heart, alpha-adrenergic agonists have long been known to produce a positive inotropic effect that is rate dependent and associated with action potential prolongation but is not accompanied by adenosine 3',5'-cyclic monophosphate (cAMP) elevation. The ionic mechanism of these effects is unknown. We report that a transient outward K+ current, a major determinant of plateau duration in rabbit and human atria, is strongly inhibited by norepinephrine and the alpha-adrenoceptor agonists methoxamine and phenylephrine. These effects of alpha-stimulation can be blocked by prazosin. The reduction in the transient outward current substantially slows action potential repolarization. These results can explain the regional and species-dependent positive inotropic effects of alpha-adrenergic stimulation in the heart and give important new insight into the autonomic regulation of cardiac function. In addition, reduction in this repolarizing current during the enhanced alpha-adrenergic responsiveness of myocardial ischemia may be a factor in the genesis of arrhythmias produced by catecholamines.

scholarly journals In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes

2007 ◽  
Vol 292 (1) ◽  
pp. H56-H65 ◽  
Author(s):  
Stefania Vecchietti ◽  
Eleonora Grandi ◽  
Stefano Severi ◽  
Ilaria Rivolta ◽  
Carlo Napolitano ◽  
...  
Keyword(s):  
Action Potential ◽  
Cell Model ◽  
Sodium Current ◽  
Outward Current ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Dependent Manner ◽  
St Segment Elevation ◽  
Rate Dependent ◽  
Surface Ecg

The effects of two SCN5A mutations (Y1795C, Y1795H), previously identified in one Long QT syndrome type 3 (LQT3) and one Brugada syndrome (BrS) families, were investigated by means of numerical modeling of ventricular action potential (AP). A Markov model capable of reproducing a wild-type as well as a mutant sodium current ( INa) was identified and was included into the Luo-Rudy ventricular cell model for action potential (AP) simulation. The characteristics of endocardial, midmyocardial, and epicardial cells were reproduced by differentiating the transient outward current ( ITO) and the ratio of slow delayed rectifier potassium ( IKs) to rapid delayed rectifier current ( IKr). Administration of flecainide and mexiletine was simulated by appropriately modifying INa, calcium current ( ICa), ITO, and IKr. Y1795C prolonged AP in a rate-dependent manner, and early afterdepolarizations (EADs) appeared during bradycardia in epicardial and midmyocardial cells; flecainide and mexiletine shortened AP and abolished EADs. Y1795H resulted in minimal changes in the APs; flecainide but not mexiletine induced APs heterogeneity across the ventricular wall that accounts for the ST segment elevation induced by flecainide in Y1795H carriers. The AP abnormalities induced by Y1795H and Y1795C can explain the clinically observed surface ECG phenotype. For the first time by modeling the effects of flecainide and mexiletine, we are able to gather mechanistic insights on the response to drugs administration observed in affected patients.

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.

K+ currents in rabbit esophageal muscularis mucosae

1993 ◽  
Vol 264 (5) ◽  
pp. G1001-G1007 ◽  
Author(s):  
H. I. Akbarali
Keyword(s):  
Single Cells ◽  
Outward Current ◽  
Cell Voltage ◽  
Resting Potential ◽  
Delayed Rectifier ◽  
Muscularis Mucosae ◽  
Whole Cell ◽  
Electrophysiological Properties ◽  
Perforated Patch ◽  
K Current

Single cells were obtained from esophageal muscularis mucosae of the rabbit using enzymatic dispersion. Their electrophysiological properties were studied with both conventional whole cell and nystatin-perforated patch techniques. The latter technique was used to prevent "washout" of intracellular constituents and to maintain endogenous buffering of Ca2+. The average resting potential of these cells was -54 +/- 3.2 mV in the conventional recording and -51 +/- 4.4 mV in perforated patch recordings. In the current-clamp mode, regenerative responses were consistently observed in perforated patch recordings, but not when conventional whole cell gigaseal methods were used. Conventional whole cell voltage-clamp methods revealed outward currents on depolarization from a holding potential of -70 mV. These currents were inhibited by extracellular tetraethylammonium (TEA, 5-10 mM) and CoCl2 (4 mM), indicating that the predominant outward current is a Ca(2+)-activated K+ current. In the presence of TEA, inward Ca2+ currents were unmasked. In contrast, when the nystatin-perforated patch technique was used, depolarizations resulted in a net inward current followed by an outward current. The outward current was inhibited by CoCl2 (2 mM) and TEA (5 mM) to the same extent as in conventional recordings. A second component of K+ current was observed in both types of recordings when extracellular Ca2+ influx was abolished and also in the presence of TEA. This slowly activating persistent K+ current resembled a delayed rectifier K+ current. These studies show that the rabbit tunica muscularis mucosal cells possess voltage-activated Ca2+ and K+ channels as well as the capability to elicit action potentials.

Chloride conductance pathways in heart

1991 ◽  
Vol 261 (3) ◽  
pp. C399-C412 ◽  
Author(s):  
J. R. Hume ◽  
R. D. Harvey
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Cardiac Muscle ◽  
Action Potential Duration ◽  
Historical Perspective ◽  
Outward Current ◽  
Resting Membrane Potential ◽  
Transient Outward Current ◽  
K Current ◽  
Cl Conductance

Nonelectrogenic movement of Cl- is believed to be responsible for the active accumulation of intracellular Cl- in cardiac muscle. The electro-neutral pathways underlying this nonpassive distribution of Cl- are believed to include Cl(-)-HCO3- exchange, Na(+)-dependent cotransport (operating as Na(+)-Cl- and Na(+)-K(+)-2Cl- cotransport), and K(+)-Cl- cotransport. The electrogenic movement of Cl- in cardiac muscle is particularly interesting from a historical perspective. Until recently, there was some doubt as to whether Cl- carried any current in the heart. Early microelectrode experiments indicated that a Cl- conductance probably played an important role in regulating action potential duration and resting membrane potential. Subsequent voltage-clamp experiments identified a repolarizing, transient outward current that was believed to be conducted by Cl-, yet further investigation suggested that this transient outward current was more likely a K+ current, not a Cl- current. This left some doubt as to whether Cl- played any role in regulating membrane potential in cardiac muscle. More recent studies, however, have identified a highly selective Cl- conductance that is regulated by intracellular adenosine 3',5'-cyclic monophosphate, and it appears that this Cl- current may play an important role in the regulation of action potential duration and resting membrane potential.

I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium

1996 ◽  
Vol 271 (2) ◽  
pp. H548-H561 ◽  
Author(s):  
J. M. Di Diego ◽  
Z. Q. Sun ◽  
C. Antzelevitch
Keyword(s):  
Action Potential ◽  
Phase 1 ◽  
Outward Current ◽  
Disulfonic Acid ◽  
Transient Outward Current ◽  
Pharmacological Agents ◽  
Whole Cell Patch Clamp ◽  
Chloride Channel Blocker ◽  
The Right ◽  
Basic Cycle Length

Transmural heterogeneities of repolarizing currents underlie prominent differences in the electrophysiology and pharmacology of ventricular epicardial, endocardial, and M cells in a number of species. The degree to which heterogeneities exist between the right and left ventricles is not well appreciated. The present study uses standard microelectrode and whole cell patch-clamp techniques to contrast the electrophysiological characteristics and pharmacological responsiveness of tissues and myocytes isolated from right (RVE) and left canine ventricular epicardium (LVE). RVE and LVE studied under nearly identical conditions displayed major differences in the early repolarizing phases of the action potential. The magnitude of phase 1 in RVE was nearly threefold that in LVE: 28.7 +/- 6.2 vs. 10.6 +/- 4.1 mV (basic cycle length = 2,000 ms). Phase 1 in RVE was also more sensitive to alterations of the stimulation rate and to 4-aminopyridine (4-AP), suggesting a much greater contribution of the transient outward current (I(to) 1) in RVE than in LVE. The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable. At +70 mV, RVE myocytes displayed peak I(to) 1 densities between 28 and 37 pA/pF. LVE myocytes included cells with similar I(to) 1 densities (thought to represent subsurface cells) but also cells with much smaller current levels (thought to represent surface cells). Average peak I(to) 1 density was significantly smaller in LVE than in RVE at voltages more than or equal to +10 mV. Our data point to prominent differences in the magnitude of the I(to) 1-mediated action potential notch in cells at the surface of RVE compared with the LVE and suggest that important distinctions may exist in the response of these two tissues to pharmacological agents and pathophysiological states, as previously demonstrated for epicardium and endocardium. Our findings also suggest that a calcium-activated outward current contributes to the early repolarization phase in RVE and LVE and that the influence of this current, although small, is more important in the left ventricle.

scholarly journals Charge Movement Associated with the Opening and Closing of the Activation Gates of the Na Channels

1974 ◽  
Vol 63 (5) ◽  
pp. 533-552 ◽  
Author(s):  
Clay M. Armstrong ◽  
Francisco Bezanilla
Keyword(s):  
Time Course ◽  
Sodium Current ◽  
Close Association ◽  
Outward Current ◽  
Transient Outward Current ◽  
Activation Process ◽  
Charge Movement ◽  
Gating Current ◽  
Dipolar Molecules ◽  
Opening And Closing

The sodium current (INa) that develops after step depolarization of a voltage clamped squid axon is preceded by a transient outward current that is closely associated with the opening of the activation gates of the Na pores. This "gating current" is best seen when permeant ions (Na and K) are replaced by relatively impermeant ones, and when the linear portion of capacitative current is eliminated by adding current from positive steps to that from exactly equal negative ones. During opening of the Na pores gating current is outward, and as the pores close there is an inward tail of current that decays with approximately the same time-course as INa recorded in Na-containing medium. Both outward and inward gating current are unaffected by tetrodotoxin (TTX). Gating current is capacitative in origin, the result of relatively slow reorientation of charged or dipolar molecules in a suddenly altered membrane field. Close association with the Na activation process is clear from the time-course of gating current, and from the fact that three procedures that reversibly block INa also block gating current: internal perfusion with Zn2+, prolonged depolarization of the membrane, and inactivation of INa with a short positive prepulse.

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