Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model

1998 ◽  
Vol 275 (1) ◽  
pp. H301-H321 ◽  
Author(s):  
Marc Courtemanche ◽  
Rafael J. Ramirez ◽  
Stanley Nattel
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Important Determinant ◽  
Outward Current ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Ionic Mechanisms

The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization

2000 ◽  
Vol 278 (3) ◽  
pp. H806-H817 ◽  
Author(s):  
Gary A. Gintant
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Inward Rectifier ◽  
Ventricular Repolarization ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Voltage Dependent

Although inactivation of the rapidly activating delayed rectifier current ( I Kr) limits outward current on depolarization, the role of I Kr (and recovery from inactivation) during repolarization is uncertain. To characterize I Krduring ventricular repolarization (and compare with the inward rectifier current, I K1), voltage-clamp waveforms simulating the action potential were applied to canine ventricular, atrial, and Purkinje myocytes. In ventricular myocytes, I Kr was minimal at plateau potentials but transiently increased during repolarizing ramps. The I Kr transient was unaffected by repolarization rate and maximal after 150-ms depolarizations (+25 mV). Action potential clamps revealed the I Kr transient terminating the plateau. Although peak I Kr transient density was relatively uniform among myocytes, potentials characterizing the peak transients were widely dispersed. In contrast, peak inward rectifier current ( I K1) density during repolarization was dispersed, whereas potentials characterizing I K1 defined a narrower (more negative) voltage range. In summary, rapidly activating I Kr provides a delayed voltage-dependent (and functionally time-independent) outward transient during ventricular repolarization, consistent with rapid recovery from inactivation. The heterogeneous voltage dependence of I Kr provides a novel means for modulating the contribution of this current during repolarization.

scholarly journals Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

2009 ◽  
Vol 296 (4) ◽  
pp. H1017-H1026 ◽  
Author(s):  
Keith F. Decker ◽  
Jordi Heijman ◽  
Jonathan R. Silva ◽  
Thomas J. Hund ◽  
Yoram Rudy
Keyword(s):  
Action Potential ◽  
Critical Role ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Valuable Insight ◽  
Rate Dependent ◽  
Limited Role ◽  
Wide Range ◽  
Ionic Mechanisms ◽  
Mechanistic Basis

Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current ( Ito1), the slow component of the delayed rectifier K+ current ( IKs), the L-type Ca2+ channel current ( ICa,L), and the Na+-K+ pump current ( INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca2+ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca2+ entry via ICa,L at fast rate drives increased Na+-Ca2+ exchanger Ca2+ extrusion and Na+ entry, which in turn increases Na+ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.

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.

Roles of outward potassium currents in the action potentials of guinea pig ureteral myocytes

1997 ◽  
Vol 273 (3) ◽  
pp. C962-C972 ◽  
Author(s):  
J. L. Sui ◽  
C. Y. Kao
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Outward Current ◽  
Membrane Conductance ◽  
Resting Potential ◽  
Delayed Rectifier ◽  
Inactivation Kinetics ◽  
Transient Outward Current ◽  
Delayed Rectifier Current ◽  
Fast Activation

Outward currents of freshly dissociated ureteral myocytes consist mainly of Ca(2+)-activated K+ current (IKCa) and a transient outward current (ITO). No delayed rectifier current was apparent. IKCa is small and nondecaying and fluctuates actively and irregularly. Blocking IKCa decreased resting membrane conductance and prolonged action potential plateaus, showing its roles in maintaining the resting potential and in repolarizing action potentials. It is also responsible for the membrane potential fluctuations on action potential plateaus. Neither 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride nor caffeine reduced the fluctuations in the outward current or in the action potentials, indicating that internal Ca2+ storage contributes little to the fluctuations. ITO has fast activation and inactivation kinetics with inactivation time constants of approximately 15 and 150 ms, respectively. Its highly negative voltage-availability relationship (V0.5 = -70.5 mV) suggests a low availability (< 5%) at normal resting potentials. It has only trivial effects on action potentials.

scholarly journals Contribution of L-type Ca2+current to electrical activity in sinoatrial nodal myocytes of rabbits

1999 ◽  
Vol 276 (3) ◽  
pp. H1064-H1077 ◽  
Author(s):  
E. Etienne Verheijck ◽  
Antoni C. G. van Ginneken ◽  
Ronald Wilders ◽  
Lennart N. Bouman
Keyword(s):  
Action Potential ◽  
Calcium Current ◽  
Sodium Current ◽  
Delayed Rectifier ◽  
Current Clamp ◽  
Patch Clamp Technique ◽  
Inward Current ◽  
Delayed Rectifier Current ◽  
Diastolic Depolarization ◽  
Recovery From Inactivation

The role of L-type calcium current ( I Ca,L) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit, with the use of the amphotericin-perforated patch-clamp technique. Nifedipine, at a concentration of 5 μM, was used to block I Ca,L. At this concentration, nifedipine selectively blocked I Ca,L for 81% without affecting the T-type calcium current ( I Ca,T), the fast sodium current, the delayed rectifier current ( I K), and the hyperpolarization-activated inward current. Furthermore, we did not observe the sustained inward current. The selective action of nifedipine on I Ca,L enabled us to determine the activation threshold of I Ca,L, which was around −60 mV. As nifedipine (5 μM) abolished spontaneous activity, we used a combined voltage- and current-clamp protocol to study the effects of I Ca,L blockade on repolarization and diastolic depolarization. This protocol mimics the action potential such that the repolarization and subsequent diastolic depolarization are studied in current-clamp conditions. Nifedipine significantly decreased action potential duration at 50% repolarization and reduced diastolic depolarization rate over the entire diastole. Evidence was found that recovery from inactivation of I Ca,L occurs during repolarization, which makes I Ca,L available already early in diastole. We conclude that I Ca,L contributes significantly to the net inward current during diastole and can modulate the entire diastolic depolarization.

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.

Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig

2013 ◽  
Vol 91 (4) ◽  
pp. 306-315 ◽  
Author(s):  
Oleg E. Osadchii
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Left Ventricular ◽  
Ventricular Repolarization ◽  
Monophasic Action Potential ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Left Ventricular Chamber ◽  
The Right

Quinidine is a class Ia Na+ channel blocker that prolongs cardiac repolarization owing to the inhibition of IKr, the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.

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.

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.

Sign in / Sign up

Export Citation Format

Share Document