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.

scholarly journals Isoform-specific Stimulation of Cardiac Na/K Pumps by Nanomolar Concentrations of Glycosides

2002 ◽  
Vol 119 (4) ◽  
pp. 297-312 ◽  
Author(s):  
Junyuan Gao ◽  
Randy S. Wymore ◽  
Yongli Wang ◽  
Glenn R. Gaudette ◽  
Irvin B. Krukenkamp ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Pump Current ◽  
Ion Accumulation ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Pump Activity ◽  
Specific Regulation ◽  
Stimulation Of

It is well-known that micromolar to millimolar concentrations of cardiac glycosides inhibit Na/K pump activity, however, some early reports suggested nanomolar concentrations of these glycosides stimulate activity. These early reports were based on indirect measurements in multicellular preparations, hence, there was some uncertainty whether ion accumulation/depletion rather than pump stimulation caused the observations. Here, we utilize the whole-cell patch-clamp technique on isolated cardiac myocytes to directly measure Na/K pump current (IP) in conditions that minimize the possibility of ion accumulation/depletion causing the observed effects. In guinea pig ventricular myocytes, nanomolar concentrations of dihydro-ouabain (DHO) caused an outward current that appeared to be due to stimulation of IP because of the following: (1) it was absent in 0 mM [K+]o, as was IP; (2) it was absent in 0 mM [Na+]i, as was IP; (3) at reduced [Na+]i, the outward current was reduced in proportion to the reduction in IP; (4) it was eliminated by intracellular vanadate, as was IP. Our previous work suggested guinea pig ventricular myocytes coexpress the α1- and α2-isoforms of the Na/K pumps. The stimulation of IP appears to be through stimulation of the high glycoside affinity α2-isoform and not the α1-isoform because of the following: (1) regulatory signals that specifically increased activity of the α2-isoform increased the amplitude of the stimulation; (2) regulatory signals that specifically altered the activity of the α1-isoform did not affect the stimulation; (3) changes in [K+]o that affected activity of the α1-isoform, but not the α2-isoform, did not affect the stimulation; (4) myocytes from one group of guinea pigs expressed the α1-isoform but not the α2-isoform, and these myocytes did not show the stimulation. At 10 nM DHO, total IP increased by 35 ± 10% (mean ± SD, n = 18). If one accepts the hypothesis that this increase is due to stimulation of just the α2-isoform, then activity of the α2-isoform increased by 107 ± 30%. In the guinea pig myocytes, nanomolar ouabain as well as DHO stimulated the α2-isoform, but both the stimulatory and inhibitory concentrations of ouabain were ∼10-fold lower than those for DHO. Stimulation of IP by nanomolar DHO was observed in canine atrial and ventricular myocytes, which express the α1- and α3-isoforms of the Na/K pumps, suggesting the other high glycoside affinity isoform (the α3-isoform) also was stimulated by nanomolar concentrations of DHO. Human atrial and ventricular myocytes express all three isoforms, but isoform affinity for glycosides is too similar to separate their activity. Nevertheless, nanomolar DHO caused a stimulation of IP that was very similar to that seen in other species. Thus, in all species studied, nanomolar DHO caused stimulation of IP, and where the contributions of the high glycoside affinity α2- and α3-isoforms could be separated from that of the α1-isoform, it was only the high glycoside affinity isoform that was stimulated. These observations support early reports that nanomolar concentrations of glycosides stimulate Na/K pump activity, and suggest a novel mechanism of isoform-specific regulation of IP in heart by nanomolar concentrations of endogenous ouabain-like molecules.

scholarly journals Inhibition of Na-K pump current in guinea pig ventricular myocytes by dihydroouabain occurs at high- and low-affinity sites.

1989 ◽  
Vol 64 (6) ◽  
pp. 1063-1069 ◽  
Author(s):  
D J Mogul ◽  
H H Rasmussen ◽  
D H Singer ◽  
R E Ten Eick
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Pump 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.

Delayed-rectifier potassium channel activity in isolated membrane patches of guinea pig ventricular myocytes

1991 ◽  
Vol 260 (4) ◽  
pp. H1390-H1393 ◽  
Author(s):  
K. B. Walsh ◽  
J. P. Arena ◽  
W. M. Kwok ◽  
L. Freeman ◽  
R. S. Kass
Keyword(s):  
Guinea Pig ◽  
Single Channel ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Time Dependent ◽  
Delayed Rectifier ◽  
Potential Range ◽  
Ammonium Compound ◽  
Channel Activity ◽  
Patch Clamp Technique

When the patch-clamp technique was used, a slowly activating, time-dependent outward current was identified in both cell-attached and excised membrane patches obtained from guinea pig ventricular myocytes. This macroscopic patch current was present in approximately 50% of patches studied and could be observed both in the presence and absence of unitary single channel activity (i.e., ATP-sensitive K+ channels). The time course of activation of the patch current resembled that of the whole cell delayed-rectifier K+ current (IK) recorded under similar ionic conditions, and the patch current and IK were activated over a similar membrane potential range. The time-dependent patch current could be eliminated when the Nernst potential for K+ equaled that of the pulse voltage. The patch current was inhibited by external addition of the tertiary ammonium compound LY 97241 (50 microM) and was augmented after internal application of the catalytic subunit of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (500 nM). Deactivating tail currents with kinetics similar to those of IK could be recorded to cell-attached and excised patches. Unitary single channel events underlying the time-dependent patch current could not be resolved despite various attempts to increase single channel conductance. Thus our results suggest that a major component of delayed rectification in guinea pig ventricular cells is due to the activity of a high-density, extremely low conductance K+ channel.

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.

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.

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