Azimilide Causes Reverse Rate-Dependent Block While Reducing Both Components of Delayed-Rectifier Current in Canine Ventricular Myocytes

1998 ◽  
Vol 31 (6) ◽  
pp. 945-953 ◽  
Author(s):  
Gary A. Gintant
Keyword(s):  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Delayed Rectifier Current

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.

Temperature-dependent expression of sarcolemmal K+ currents in rainbow trout atrial and ventricular myocytes

2002 ◽  
Vol 282 (4) ◽  
pp. R1191-R1199 ◽  
Author(s):  
Matti Vornanen ◽  
Ari Ryökkynen ◽  
Antti Nurmi
Keyword(s):  
Rainbow Trout ◽  
Cardiac Myocytes ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Temperature Acclimation ◽  
Delayed Rectifier ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Delayed Rectifier Current ◽  
Ventricular Cells

Temperature has a strong influence on the excitability and the contractility of the ectothermic heart that can be alleviated in some species by temperature acclimation. The molecular mechanisms involved in the temperature-induced improvement of cardiac contractility and excitability are, however, still poorly known. The present study examines the role of sarcolemmal K+ currents from rainbow trout ( Oncorhynchus mykiss) cardiac myocytes after thermal acclimation. The two major K+ conductances of the rainbow trout cardiac myocytes were identified as the Ba2+-sensitive background inward rectifier current ( I K1) and the E-4031-sensitive delayed rectifier current ( I Kr). In atrial cells, the density of I K1 is very low and the density of I Kr is remarkably high. The opposite is true for ventricular cells. Acclimation to cold (4°C) modified the two K+ currents in opposite ways. Acclimation to cold increases the density of I Kr and depresses the density of I K1. These changes in repolarizing K+ currents alter the shape of the action potential, which is much shorter in cold-acclimated than warm-acclimated (17°C) trout. These results provide the first concrete evidence that K+channels of trout cardiac myocytes are adaptable units that provide means to regulate cardiac excitability and contractility as a function of temperature.

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.

TransmembraneI Ca contributes to rate-dependent changes of action potentials in human ventricular myocytes

1999 ◽  
Vol 276 (1) ◽  
pp. H98-H106 ◽  
Author(s):  
Gui-Rong Li ◽  
Baofeng Yang ◽  
Jianlin Feng ◽  
Ralph F. Bosch ◽  
Michel Carrier ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Slow Component ◽  
Cell Voltage ◽  
High Rate ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Ventricular Cells ◽  
The Right

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current ( I Ca) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I Ca was decreased by 34 ± 3% from 0.5 to 2 Hz ( P < 0.01), and I Ca had recovery time constants of 65 ± 12 and 683 ± 39 ms at −80 mV. Action potential clamp demonstrated a decreasing contribution of I Ca during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+current ( I Ks) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I Ks is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.

SUPPRESSION OF CELLULAR ALTERNANS IN GUINEA PIG VENTRICULAR MYOCYTES WITH LQT2: INSIGHTS FROM THE LUO–RUDY MODEL

2007 ◽  
Vol 17 (02) ◽  
pp. 381-425 ◽  
Author(s):  
VLADIMIR E. BONDARENKO ◽  
RANDALL L. RASMUSSON
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Chaotic Behavior ◽  
Heart Diseases ◽  
Pump Current ◽  
Delayed Rectifier ◽  
Drug Induced ◽  
Delayed Rectifier Current ◽  
Model Control ◽  
Pump Activity

Genetic and drug-induced abnormalities of cardiac repolarization have been linked to fatal arrhythmias. These arrhythmias result from a complex interaction of the remaining currents during excitation and repolarization. In this review, we examine recent advancement in investigations of genetic heart diseases and mechanisms of arrhythmia generation. We also present our simulation of repolarization during rapid pacing for different levels of block of the rapid delayed rectifier current, I Kr , and pharmacological interventions using the Luo–Rudy model. Control simulations showed the development of alternans at a basic cycle length (BCL) of 131 ms. Two levels of I Kr block were simulated corresponding to type 2 of familial long QT syndrome, LQT2. At 100% I Kr block, the threshold BCL for the appearance of alternans increased to 145 ms and for shorter cycle lengths showed increasingly complex patterns of periodic and chaotic behavior. We examined the potential of other currents to correct this complex behavior. Improvement of the threshold for bifurcation as a function of BCL was achieved by: (1) 100% block of a nonspecific Ca 2+-activated current; (2) 15% block of L-type Ca 2+ current; (3) 20% increase of Na +/ K + pump current; (4) 50% increase of SERCA2 pump activity. Conversely, increased L-type Ca 2+ current, decreased Na +/ K + pump current, or decreased SERCA2 pump activity increased the threshold BCL. Modification of several other currents had little effect. Alternans and chaotic activity develop at fast pacing rates in model guinea pig ventricular myocytes through a sequence of bifurcations. We elucidated mechanisms that modify the development of alternans which may provide novel targets for treatment of patients with LQT2.

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.

Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes

2004 ◽  
Vol 286 (6) ◽  
pp. H2342-H2351 ◽  
Author(s):  
Fei Hua ◽  
David C. Johns ◽  
Robert F. Gilmour
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Cell Types ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Rate Dependent ◽  
Whole Cell Patch Clamp ◽  
The Difference ◽  
Viable Approach ◽  
Electrical Alternans

Suppression of electrical alternans may be antiarrhythmic. Our previous computer simulations have suggested that increasing the rapid component of the delayed rectifier K+ current ( IKr) suppresses alternans. To test this hypothesis, IKr in isolated canine ventricular myocytes was increased by infection with an adenovirus containing the gene for the pore-forming domain of IKr [human ether-a-go-go gene (HERG)]. With the use of the perforated or whole cell patch-clamp technique, action potentials recorded at different pacing cycle lengths (CLs) were applied to the myocytes as the command waveforms. HERG infection markedly increased peak IKr during the action potential (from 0.54 ± 0.03 pA/pF in control to 3.60 ± 0.81 pA/pF). Rate-dependent alterations of peak IKr were similar for freshly isolated myocytes and HERG-infected myocytes. In both cell types, IKr increased when CL decreased from 1,000 to 500 ms and then decreased progressively as CL decreased further. During alternans at CL = 170 ms, peak IKr was larger for the short than for the long action potential for both groups, but the difference in peak IKr was larger for HERG-infected myocytes. The voltage at which peak IKr occurred was significantly less negative in HERG-infected myocytes, in association with shifts of the steady-state voltage-dependent activation and inactivation curves to less negative potentials. Pacing at short CL induced stable alternans in freshly isolated myocytes and in cultured myocytes without HERG infection, but not in HERG-infected myocytes. These data support the idea that increasing IKr may be a viable approach to suppressing electrical alternans.

scholarly journals Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species

2012 ◽  
Vol 302 (5) ◽  
pp. H1023-H1030 ◽  
Author(s):  
Thomas O'Hara ◽  
Yoram Rudy
Keyword(s):  
Guinea Pig ◽  
Drug Response ◽  
Cellular Level ◽  
Quantitative Comparison ◽  
Rate Dependence ◽  
Delayed Rectifier ◽  
Adrenergic Stimulation ◽  
Early Afterdepolarizations ◽  
Rate Dependent ◽  
Delayed Rectifier Current

Explanations for arrhythmia mechanisms at the cellular level are usually based on experiments in nonhuman myocytes. However, subtle electrophysiological differences between species may lead to different rhythmic or arrhythmic cellular behaviors and drug response given the nonlinear and highly interactive cellular system. Using detailed and quantitatively accurate mathematical models for human, dog, and guinea pig ventricular action potentials (APs), we simulated and compared cell electrophysiology mechanisms and response to drugs. Under basal conditions (absence of β-adrenergic stimulation), Na+/K+-ATPase changes secondary to Na+ accumulation determined AP rate dependence for human and dog but not for guinea pig where slow delayed rectifier current ( IKs) was the major rate-dependent current. AP prolongation with reduction of rapid delayed rectifier current ( IKr) and IKs (due to mutations or drugs) showed strong species dependence in simulations, as in experiments. For humans, AP prolongation was 80% following IKr block. It was 30% for dog and 20% for guinea pig. Under basal conditions, IKs block was of no consequence for human and dog, but for guinea pig, AP prolongation after IKs block was severe. However, with β-adrenergic stimulation, IKs played an important role in all species, particularly in AP shortening at fast rate. Quantitative comparison of AP repolarization, rate-dependence mechanisms, and drug response in human, dog, and guinea pig revealed major species differences (e.g., susceptibility to arrhythmogenic early afterdepolarizations). Extrapolation from animal to human electrophysiology and drug response requires great caution.

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