Calcium-activated transient outward chloride current and phase 1 repolarization of swine ventricular action potential

Heterogeneity of cardiac tissue is an important factor determining the initiation and dynamics of cardiac arrhythmias. In this paper, we studied the effects of gradients of electrophysiological heterogeneity on reentrant excitation patterns using computer simulations. We investigated the dynamics of spiral waves in a two-dimensional sheet of cardiac tissue described by the Luo-Rudy phase 1 (LR1) ventricular action potential model. A gradient of action potential duration (APD) was imposed by gradually varying the local current density of K+ current or inward rectifying K+ current along one axis of the tissue sheet. We show that a gradient of APD resulted in spiral wave drift. This drift consisted of two components. The longitudinal (along the gradient) component was always directed toward regions of longer spiral wave period. The transverse (perpendicular to the gradient) component had a direction dependent on the direction of rotation of the spiral wave. We estimated the velocity of the drift as a function of the magnitude of the gradient and discuss its implications.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00084.2006 ◽

2006 ◽

Vol 291 (2) ◽

pp. H631-H637 ◽

Cited By ~ 21

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.2.h548 ◽

1996 ◽

Vol 271 (2) ◽

pp. H548-H561 ◽

Cited By ~ 38

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.

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