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.

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.

Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells

2001 ◽  
Vol 280 (3) ◽  
pp. H1075-H1080 ◽  
Author(s):  
Wei Han ◽  
Zhiguo Wang ◽  
Stanley Nattel
Keyword(s):  
Purkinje Cells ◽  
Voltage Dependence ◽  
Delayed Rectifier ◽  
Adrenergic Stimulation ◽  
Early Afterdepolarizations ◽  
Voltage Range ◽  
Delayed Rectifier Current ◽  
Whole Cell Patch Clamp ◽  
Cardiac Purkinje Cells

Although cardiac Purkinje cells (PCs) are believed to be the source of early afterdepolarizations generating ventricular tachyarrhythmias in long Q-T syndromes (LQTS), the ionic determinants of PC repolarization are incompletely known. To evaluate the role of the slow delayed rectifier current ( I Ks) in PC repolarization, we studied PCs from canine ventricular false tendons with whole cell patch clamp (37°C). Typical I Ks voltage- and time-dependent properties were noted. Isoproterenol enhanced I Ks in a concentration-dependent fashion (EC50 ∼ 30 nM), negatively shifted I Ks activation voltage dependence, and accelerated I Ks activation. Block of I Ks with 293B did not alter PC action potential duration (APD) in the absence of isoproterenol; however, in the presence of isoproterenol, 293B significantly prolonged APD. We conclude that, without β-adrenergic stimulation, I Ks contributes little to PC repolarization; however, β-adrenergic stimulation increases the contribution of I Ks by increasing current amplitude, accelerating I Ks activation, and shifting activation voltage toward the PC plateau voltage range. I Ks may therefore provide an important “braking” function to limit PC APD prolongation in the presence of β-adrenergic stimulation.

Patch-clamp recording in myenteric neurons of guinea pig small intestine

1992 ◽  
Vol 262 (6) ◽  
pp. G1074-G1078 ◽  
Author(s):  
L. V. Baidan ◽  
A. V. Zholos ◽  
M. F. Shuba ◽  
J. D. Wood
Keyword(s):  
Small Intestine ◽  
Patch Clamp ◽  
Guinea Pig ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Patch Clamp Recording ◽  
Myenteric Neurons ◽  
Delayed Rectifier Current ◽  
Outward Currents ◽  
Current Clamp Mode

The results of our research established the feasibility of applying patch-clamp methods in the study of the cellular neurophysiology of myenteric neurons enzymatically dissociated from adult guinea pig small intestine. Recording in current-clamp mode revealed two populations of neurons. One population discharged repetitively during depolarizing current pulses and displayed anodal-break excitation reminiscent of S/type 1 myenteric neurons. In the second population, spike discharge was limited to one or two spikes at the onset of depolarizing pulses and was similar to the behavior of AH/type 2 neurons. Recording in voltage-clamp mode revealed a complex of overlapping inward and outward whole cell currents. Fast and slow components of inward current were interpreted as sodium and calcium currents, respectively. Outward currents were blocked by cesium and consisted of components with properties of delayed rectifier current and A-type potassium current.

Impact of ionic current variability on human ventricular cellular electrophysiology

2009 ◽  
Vol 297 (4) ◽  
pp. H1436-H1445 ◽  
Author(s):  
Lucía Romero ◽  
Esther Pueyo ◽  
Martin Fink ◽  
Blanca Rodríguez
Keyword(s):  
Cardiac Electrophysiology ◽  
Slow Component ◽  
Ionic Current ◽  
Pump Current ◽  
Rate Dependence ◽  
Delayed Rectifier ◽  
Inactivation Kinetics ◽  
Model Parameters ◽  
Delayed Rectifier Current ◽  
The Impact

Abnormalities in repolarization and its rate dependence are known to be related to increased proarrhythmic risk. A number of repolarization-related electrophysiological properties are commonly used as preclinical biomarkers of arrhythmic risk. However, the variability and complexity of repolarization mechanisms make the use of cellular biomarkers to predict arrhythmic risk preclinically challenging. Our goal is to investigate the role of ionic current properties and their variability in modulating cellular biomarkers of arrhythmic risk to improve risk stratification and identification in humans. A systematic investigation into the sensitivity of the main preclinical biomarkers of arrhythmic risk to changes in ionic current conductances and kinetics was performed using computer simulations. Four stimulation protocols were applied to the ten Tusscher and Panfilov human ventricular model to quantify the impact of ±15 and ±30% variations in key model parameters on action potential (AP) properties, Ca2+ and Na+ dynamics, and their rate dependence. Simulations show that, in humans, AP duration is moderately sensitive to changes in all repolarization current conductances and in L-type Ca2+ current ( ICaL) and slow component of the delayed rectifier current ( IKs) inactivation kinetics. AP triangulation, however, is strongly dependent only on inward rectifier K+ current ( IK1) and delayed rectifier current ( IKr) conductances. Furthermore, AP rate dependence (i.e., AP duration rate adaptation and restitution properties) and intracellular Ca2+ and Na+ levels are highly sensitive to both ICaL and Na+/K+ pump current ( INaK) properties. This study provides quantitative insights into the sensitivity of preclinical biomarkers of arrhythmic risk to variations in ionic current properties in humans. The results show the importance of sensitivity analysis as a powerful method for the in-depth validation of mathematical models in cardiac electrophysiology.

Molecular basis of species-specific expression of repolarizing K+ currents in the heart

2003 ◽  
Vol 285 (4) ◽  
pp. H1641-H1649 ◽  
Author(s):  
Stephen Zicha ◽  
Isaac Moss ◽  
Bruce Allen ◽  
Andras Varro ◽  
Julius Papp ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Protein Expression ◽  
Guinea Pigs ◽  
Delayed Rectifier ◽  
Important Species ◽  
Α Subunit ◽  
Delayed Rectifier Current ◽  
Mrna Concentration ◽  
Subunit Expression ◽  
Species Specific

There are important species-specific differences in K+ current profiles and arrhythmia susceptibility, but interspecies comparisons of K+ channel subunit expression are lacking. We quantified voltage-gated K+ channel (Kv) subunit mRNA and protein in rabbits, guinea pigs, and humans. Kv1.4, Kv4.2, and Kv4.3 mRNA was present in rabbits but undetectable in guinea pigs. MinK mRNA concentration in guinea pigs was almost threefold greater versus humans and 20-fold versus rabbits. MinK protein expression in guinea pigs was almost twofold that in humans and sixfold that in rabbits. KvLQT1 mRNA concentration was greatest in humans, and protein expression in humans was increased by ∼2- and ∼7-fold compared with values in rabbits and guinea pigs, respectively. The ether-a-go-go-related gene (ERG1) mRNA was more concentrated in humans, but ERG1 protein expression could not be compared across species because of epitope sequence differences. We conclude that important interspecies differences in cardiac K+ channel subunit expression exist and may contribute to the following: 1) lack of a transient outward current in the guinea pig (α-subunit transcription absent in the guinea pig heart); 2) small slow delayed rectifier current and torsades de pointes susceptibility in the rabbit (low-level minK expression); and 3) large slow component of the delayed rectifier current in the guinea pig (strong minK expression).

scholarly journals Cell swelling has differential effects on the rapid and slow components of delayed rectifier potassium current in guinea pig cardiac myocytes.

1995 ◽  
Vol 106 (6) ◽  
pp. 1151-1170 ◽  
Author(s):  
S A Rees ◽  
J I Vandenberg ◽  
A R Wright ◽  
A Yoshida ◽  
T Powell
Keyword(s):  
Guinea Pig ◽  
Potassium Current ◽  
Mean Value ◽  
Cell Swelling ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Differential Effects ◽  
Delayed Rectifier Current ◽  
Delayed Rectifier Potassium Current ◽  
Ionic Conductances

Cell swelling has been shown to cause activation of a variety of cardiac sarcolemmal ionic conductances including potassium channels. The aim of this study was to investigate the effect of swelling on the two subtypes of delayed rectifier potassium current (IKr and IKs) in single guinea pig myocytes using the whole-cell configuration of the patch clamp technique. When the holding potential was set at -40 mV and stepped to +40 mV for 1 s under isoosmotic conditions (300 mOsm) a delayed rectifier current (IK) was activated (0.86 +/- 0.05 nA; n = 43). Switching to a hypoosmotic solution (200 mOsm) caused a rapid increase in IK to a mean value of 1.43 +/- 0.10 nA (p < 0.05; n = 43). The effect of swelling on the two subtypes of IK was studied by analysis of deactivating tail currents using an envelope of tails protocol (stepping from -40 to +40 mV for 18 different pulse durations between 50 ms and 2.9 s; n = 16). Swelling caused a decrease in current amplitude measured at the end of the pulse (and IKtail) at short durations (< or = 150 ms) however, when the pulse duration was > 1 s swelling caused a significant increase in current. Using a pulse protocol to measure IKr with minimal contamination by IKs (voltage step from -40 to -10 mV for 250 ms) a 50-100 pA current was elicited which could be completely blocked by dofetilide (0.2 microM; n = 3). Introduction of hypoosmotic solution caused a significant decrease in IKr and when dofetilide (0.2 or 1.0 microM) was introduced the current remaining was decreased further (p < 0.05; n = 5), but was not completely blocked, thus suggesting that swelling had decreased the ability of dofetilide to block IKr. Similar results were obtained over a range of dofetilide concentrations and with a second IKr blocker, La3+. In Ca(2+)-free external solutions, pulsing to -10 mV for 500 ms to measure IKr in the absence of IKs, and to +60 mV for 5 s (with 0.2 microM dofetilide) to evoke only IKs, it was clear that swelling significantly increased IKs (pulse and tail currents) and decreased IKr. In addition, when measured using the perforated patch method, swelling modulated IKt and IKs in a similar fashion. We conclude that swelling has differential effects on the subtypes of the classical cardiac IK, which may have important implications in our understanding of the mechanisms underlying ischaemia- and reperfusion-induced arrhythmogenesis.

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