Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node

2000 ◽  
Vol 279 (1) ◽  
pp. H397-H421 ◽  
Author(s):  
H. Zhang ◽  
A. V. Holden ◽  
I. Kodama ◽  
H. Honjo ◽  
M. Lei ◽  
...  
Keyword(s):  
Action Potential ◽  
Mathematical Models ◽  
Action Potentials ◽  
Phase 1 ◽  
Outward Current ◽  
Transient Outward Current ◽  
Dimensional Model ◽  
Peripheral Cell ◽  
One Dimensional ◽  
Sa Node

Mathematical models of the action potential in the periphery and center of the rabbit sinoatrial (SA) node have been developed on the basis of published experimental data. Simulated action potentials are consistent with those recorded experimentally: the model-generated peripheral action potential has a more negative takeoff potential, faster upstroke, more positive peak value, prominent phase 1 repolarization, greater amplitude, shorter duration, and more negative maximum diastolic potential than the model-generated central action potential. In addition, the model peripheral cell shows faster pacemaking. The models behave qualitatively the same as tissue from the periphery and center of the SA node in response to block of tetrodotoxin-sensitive Na+current, L- and T-type Ca2+ currents, 4-aminopyridine-sensitive transient outward current, rapid and slow delayed rectifying K+ currents, and hyperpolarization-activated current. A one-dimensional model of a string of SA node tissue, incorporating regional heterogeneity, coupled to a string of atrial tissue has been constructed to simulate the behavior of the intact SA node. In the one-dimensional model, the spontaneous action potential initiated in the center propagates to the periphery at ∼0.06 m/s and then into the atrial muscle at 0.62 m/s.

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.

Electrophysiological properties of neurons within the nucleus ambiguus of adult guinea pigs

1991 ◽  
Vol 66 (3) ◽  
pp. 744-761 ◽  
Author(s):  
S. M. Johnson ◽  
P. A. Getting
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Outward Current ◽  
Nucleus Ambiguus ◽  
Transient Outward Current ◽  
Maximum Magnitude ◽  
Action Potential Firing ◽  
Onset Of Action ◽  
Electrophysiological Properties ◽  
Single Action

1. The purpose of this study was to determine the electrophysiological properties of neurons within the region of the nucleus ambiguus (NA), an area that contains the ventral respiratory group. By the use of an in vitro brain stem slice preparation, intracellular recordings from neurons in this region (to be referred to as NA neurons, n = 235) revealed the following properties: postinhibitory rebound (PIR), delayed excitation (DE), adaptation, and posttetanic hyperpolarization (PTH). NA neurons were separated into three groups on the basis of their expression of PIR and DE: PIR cells (58%), DE cells (31%), and Non cells (10%). Non cells expressed neither PIR nor DE and no cells expressed both PIR and DE. 2. PIR was a transient depolarization that produced a single action potential or a burst of action potentials when the cell was released from hyperpolarization. In the presence of tetrodotoxin (TTX), the maximum magnitude of PIR was 7-12 mV. Under voltage-clamp conditions, hyperpolarizing voltage steps elicited a small inward current during the hyperpolarization and a small inward tail current on release from hyperpolarization. These currents, which mediate PIR, were most likely due to Q-current because they were blocked with extracellular cesium and were insensitive to barium. 3. DE was a delay in the onset of action potential firing when cells were hyperpolarized before application of depolarizing current. When cells were hyperpolarized to -90 mV for greater than or equal to 300 ms, maximum delays ranged from 150 to 450 ms. The transient outward current underlying DE was presumed to be A-current because of the current's activation and inactivation characteristics and its elimination by 4-aminopyridine (4-AP). 4. Adaptation was examined by applying depolarizing current for 2.0 s and measuring the frequency of evoked action potentials. Although there was a large degree of variability in the degree of adaptation, PIR cells tended to express less adaptation than DE and Non cells. Nearly three-fourths of all NA neurons adapted rapidly (i.e., 50% adaptation in less than 200 ms), but PIR cells tended to adapt faster than DE and Non cells. PTH after a train of action potentials was relatively rare and occurred more often in DE cells (43%) and Non cells (33%) than in PIR cells (13%). PTH had a magnitude of up to 18 mV and time constants that reflected the presence of one (1.7 +/- 1.4 s, mean +/- SD) or two components (0.28 +/- 0.13 and 4.1 +/- 2.2 s).(ABSTRACT TRUNCATED AT 400 WORDS)

Time course of postnatal changes in rat heart action potential and in transient outward current is different

1994 ◽  
Vol 267 (3) ◽  
pp. H1157-H1166 ◽  
Author(s):  
G. M. Wahler ◽  
S. J. Dollinger ◽  
J. M. Smith ◽  
K. L. Flemal
Keyword(s):  
Action Potential ◽  
Rat Heart ◽  
Action Potentials ◽  
Time Course ◽  
Outward Current ◽  
Transient Outward Current ◽  
Papillary Muscles ◽  
Isolated Cells ◽  
Time Courses ◽  
Action Potential Shortening

The rat ventricular action potential shortens after birth. The contribution of increases in the transient outward current (Ito) to postnatal action potential shortening was assessed by measuring Ito in isolated cells and by determining the effect of 2 mM 4-aminopyridine (4-AP) on the action potentials of papillary muscles. 4-AP had no effect on 1-day action potential duration at 25% repolarization (APD25), and 1-day cells had little Ito. In 8- to 10-day muscles, 4-AP caused a small, but significant, increase in APD25. Ito increased slightly between day 1 and days 8-10, but this increase was not significant. Most of the increase in Ito (79%) and in the response to 4-AP (64%) occurred between days 8-10 and adult; however, approximately 75% of the APD25 shortening took place by days 8-10. Thus, while Ito may contribute to repolarization in late neonatal and adult cells, the different time courses of action potential shortening and increases in Ito suggest that changes in Ito are unlikely to be responsible for most of the postnatal action potential shortening.

Transient outward current contributes to Wenckebach-like rhythms in isolated rabbit ventricular cells

1997 ◽  
Vol 273 (1) ◽  
pp. H1-H11 ◽  
Author(s):  
A. R. Yehia ◽  
A. Shrier ◽  
K. C. Lo ◽  
M. R. Guevara
Keyword(s):  
Action Potential ◽  
Potassium Current ◽  
Phase 1 ◽  
Outward Current ◽  
Transient Outward Current ◽  
Ionic Model ◽  
Recovery Interval ◽  
Ventricular Cells ◽  
Outward Potassium Current ◽  
Phase Phase

Wenckebach-like rhythms in isolated rabbit ventricular cells are characterized by beat-to-beat increments in action potential duration (APD) and latency, giving rise to a beat-to-beat decrease in the recovery interval and culminating in a skipped beat. These systematic APD changes are associated with a beat-to-beat decrease in the slope of the early repolarizing phase (phase 1) of the action potential, which is partially controlled by the transient outward potassium current (Ito). When Ito is blocked with 4-aminopyridine, periodic Wenckebach rhythms are replaced by aperiodic Wenckebach rhythms, in which the beat-to-beat changes in the slope of phase 1 and in APD disappear but the beat-to-beat increase in latency remains. A beat-to-beat decrease in Ito, paralleling the beat-to-beat changes in the slope of phase 1 and in APD, is seen in action-potential clamp experiments with Wenckebach rhythms previously recorded in the same cell. Simulations with an ionic model of Ito show cyclical changes in Ito consistent with the experimental data. These results demonstrate a key role for Ito in the generation of maintained periodic Wenckebach rhythms in isolated rabbit ventricular cells.

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.

Rate-dependent differences in dog epi- and endocardial monophasic action potential configuration in vivo

1991 ◽  
Vol 261 (5) ◽  
pp. H1387-H1391 ◽  
Author(s):  
P. M. Tande ◽  
E. Mortensen ◽  
H. Refsum
Keyword(s):  
Action Potential ◽  
Phase 1 ◽  
Outward Current ◽  
Ventricular Repolarization ◽  
Monophasic Action Potential ◽  
Transient Outward Current ◽  
Phase 2 ◽  
Lower Phase

A transient outward current (Ito), long considered to be a unique feature of Purkinje fiber tissue, has recently been demonstrated in dog ventricular tissue in vitro and most prominently in the epicardium. To investigate its possible contribution to ventricular repolarization in vivo, we recorded right ventricular endocardial and epicardial monophasic action potentials (MAP) simultaneously in pentobarbital-anesthetized open-chest dogs. Epicardial MAP had lower phase 1 than phase 2 amplitude at both spontaneous heart rate and paced cycle length of 300 and 400 ms. This "spike-and-dome" morphology of the epicardial MAP, possibly attributable to Ito, progressively disappeared at shorter extrastimulus intervals. In endocardium the phase 1 amplitude was always higher or equal to phase 2 amplitude and was not affected by shorter extrastimulus intervals. The action potential duration (APD) was shorter in epicardium than in endocardium. Both endocardial and epicardial APD shortened as the premature intervals were reduced, but the shortening was not parallel. The restitution curves converged so that, at the shortest intervals (160 ms), there were no longer any significant differences in APD between endocardium and epicardium. This study indicates that Ito contributes to ventricular repolarization in vivo, and most prominently in the epicardium. Unequal shortening of APD between endocardium and epicardium after progressively shorter diastolic intervals may thus partly result from uneven distribution of Ito across the ventricular wall.

Regional differences in rabbit atrial repolarization: importance of transient outward current

1994 ◽  
Vol 266 (2) ◽  
pp. H643-H649 ◽  
Author(s):  
A. Qi ◽  
J. A. Yeung-Lai-Wah ◽  
J. Xiao ◽  
C. R. Kerr
Keyword(s):  
Action Potential ◽  
Regional Differences ◽  
Phase 1 ◽  
Outward Current ◽  
Right Atrial ◽  
Resting Potential ◽  
Transient Outward Current ◽  
Phase 3 ◽  
Roof Area ◽  
Atrial Repolarization

Regional differences in rabbit atrial repolarization were investigated using a conventional microelectrode technique. A more rapid phase 1 repolarization (lower phase 1 amplitude) was seen in the left atrial (LA) roof area compared with the right atrial (RA) roof area: 54 +/- 10 vs. 82 +/- 6 mV at 1,000 ms (P < 0.001). In addition, action potential duration at 40 mV above the resting potential (APD40) was shorter in LA and was associated with a slower phase 3 repolarization rate. Furthermore, the recovery time constant of phase 1 amplitude at 500 ms was 0.9 +/- 0.2 s in LA and 3.5 +/- 1.5 s in RA (P < 0.001). Pacing cycle lengths (2,000, 1,500, 1,000, 800, and 500 ms) modulated phase 1 amplitude, APD40, and phase 3 rate in both regions. 4-Aminopyridine (4-AP; 1 mM), a selective transient outward current (I(to)) blocker, abolished cycle length dependence of the above action potential parameters and diminished the differences in electrophysiological properties between the two regions. 4-AP also flattened the restitution curve of phase 1 amplitude in both regions. In conclusion, the findings suggest that the different kinetics of I(to) play an important role in regional differences of atrial repolarization.

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.

Ito1 dictates behavior of ICl(Ca) during early repolarization of canine ventricle

1997 ◽  
Vol 273 (3) ◽  
pp. H1096-H1106 ◽  
Author(s):  
A. C. Zygmunt ◽  
D. C. Robitelle ◽  
G. T. Eddlestone
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Time Course ◽  
Ventricular Myocytes ◽  
Phase 1 ◽  
Potassium Conductance ◽  
Outward Current ◽  
Direct Result ◽  
Disulfonic Acid ◽  
Early Repolarization

The contributions of the 4-aminopyridine (4-AP)-sensitive transient outward potassium conductance (Ito1) and the calcium-activated chloride conductance (ICl(Ca)] to cardiac action potentials were investigated in canine ventricular myocytes. Action potentials or currents were recorded at 37 degrees C using standard whole cell or amphotericin B perforated-patch-clamp techniques. Inhibition of Ito1 by 1 mM 4-AP prolonged phase 1 repolarization, elevated the action potential notch, and depressed the plateau. Action potential voltage clamp revealed that 4-AP blocked a rapidly decaying outward current during phase 1 without affecting plateau or diastolic currents. These results suggested that depression of the plateau was not a direct result of Ito1 inhibition but followed from delayed phase 1 repolarization. Calcium current (ICa) at the peak of the action potential dome was reduced 60 +/- 4% when the rate of phase 1 repolarization was reduced. ICl(Ca) measured by action potential clamp reversed over the course of the action potential. Chloride fluxes associated with outward and inward components of the 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid-sensitive current were +130 +/- 17 and -184 +/- 20 (pA.ms)/pF, respectively. The effects of selective inhibition of ICl(Ca) on the action potential were dependent on the rate of early repolarization and the prominence of the notch. Inhibition of ICl(Ca) elevated the plateau and slightly abbreviated action potential duration when the notch was prominent. When repolarization was prolonged and the notch was shallow, inhibition of ICl(Ca) elevated the notch and the plateau and abbreviated duration. We have shown that Ito1 and ICl(Ca) contribute to canine ventricular action potentials. The extent of overlap between Ito1 and ICl(Ca) during the action potential is largely determined by the amplitude of Ito1 and the depth of the notch. Regional differences in the density of Ito1, or interventions that moderate phase 1 repolarization by reducing this current, will have considerable effect on the time course of ICa and calcium-dependent conductances.

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.

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