Rate dependency of delayed rectifier currents during the guinea‐pig ventricular action potential
The Journal of PhysiologyPublished 1 August 2001Open access
Marcella Rocchetti, Alessandra Besana, Georgina B. Gurrola, Lourival D. Possani, Antonio Zaza
Citations110
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
In spite of its complexity, the behaviour of IKr was accurately predicted by a numerical model based entirely on known kinetic properties of the current, and may be increased at fast heart rates, but this may occur through completely different mechanisms.
Abstract
1. The action potential clamp technique was exploited to evaluate the rate dependency of delayed rectifier currents (I(Kr) and I(Ks)) during physiological electrical activity. I(Kr) and I(Ks) were measured in guinea-pig ventricular myocytes at pacing cycle lengths (CL) of 1000 and 250 ms. 2. A shorter CL, with the attendant changes in action potential shape, was associated with earlier activation and increased magnitude of both I(Kr) and I(Ks). Nonetheless, the relative contributions of I(Kr) and I(Ks) to total transmembrane current were independent of CL. 3. Shortening of diastolic interval only (constant action potential shape) enhanced I(Ks), but not I(Kr). 4. I(Kr) was increased by a change in the action potential shape only (constant diastolic interval). 5. In ramp clamp experiments, I(Kr) amplitude was directly proportional to repolarization rate at values within the low physiological range ( 1.0 V s(-1) were associated with a reduced effect of I(Kr) block on APD. The effect of changes in repolarization rate was independent of CL and occurred in the presence of I(Ks) blockade. 7. In spite of its complexity, the behaviour of I(Kr) was accurately predicted by a numerical model based entirely on known kinetic properties of the current. 8. Both I(Kr) and I(Ks) may be increased at fast heart rates, but this may occur through completely different mechanisms. The mechanisms identified are such as to contribute to abnormal rate dependency of repolarization in prolonged repolarization syndromes.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
CellA mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel
2,439 Citations1995Michael C. Sanguinetti, Changan Jiang +2 more
The finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT, and that an additional subunit may be required for drug sensitivity.
CellA molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome
2,278 Citations1995Mark Curran, Igor Splawski +4 more
Nature GeneticsPositional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias
1,765 Citations1996Q. Wang, Mark Curran +15 more
The Journal of General PhysiologyTwo components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
1,472 Citations1990Michael C. Sanguinetti, Nancy K. Jurkiewicz
The magnitude of IKr was small relative to fully activated IKs, and the two currents were of similar magnitude when measured during a relatively short pulse protocol at membrane potentials typical of the plateau phase of cardiac action potentials.
CirculationLong QT Syndrome Patients With Mutations of the <i>SCN5A</i> and <i>HERG</i> Genes Have Differential Responses to Na <sup>+</sup> Channel Blockade and to Increases in Heart Rate
816 Citations1995Peter J. Schwartz, Silvia G. Priori +9 more
This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect, and it is suggested that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates.
Circulation ResearchRate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide.
521 Citations1993Nancy K. Jurkiewicz, Michael C. Sanguinetti
This work investigated the mechanism of APD prolongation using voltage-clamp techniques and found that sensitivity to block of IKr by dofetilide was rate independent, and the magnitude of neither IK1 nor IKR was dependent on the rate of the preceding train of depolarizations.
Circulation ResearchEvidence for Two Components of Delayed Rectifier K<sup>+</sup>Current in Human Ventricular Myocytes
464 Citations1996Gui‐Rong Li, Jianlin Feng +3 more
It is concluded that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent.
The Journal of General PhysiologyFast inactivation causes rectification of the IKr channel.
397 Citations1996Peter Spector, Mark Curran +3 more
The mechanism of rectification of HERG, the human cardiac delayed rectifier K+ channel, was studied after heterologous expression in Xenopus oocytes, showing voltage-gated fast inactivation and the resulting rectification are partly responsible for the prolonged plateau phase typical of ventricular action potentials.
Cardiovascular ResearchRapid and slow components of delayed rectifier current in human atrial myocytes
236 Citations1994Zhiguo Wang, Bernard Fermini +1 more
IK in human atrium shows kinetically distinguishable rapid and slow components that correspond to E-4031 sensitive and resistant currents, which have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs.
Cardiovascular ResearchEffects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes
226 Citations1998Ralph Bosch
293B is a selective IKs blocker, and the frequency dependence of APD prolongation caused by this Iks blocker is different from that caused by IKr blockade: 293B may be an interesting tool to study the physiologic role of IKS and the antiarrhythmic potential of I ks blockade.
European Heart JournalGenetic and molecular basis of cardiac arrhythmias Impact on clinical management
169 Citations1999Silvia G. Priori
The first and second parts of this article attempt to answer the questions on patient management, which include not only broad questions like ‘How can I establish (or better yet, rule out) a diagnosis?’ but also more specific issues such as ‘Should this patient undergo genetic testing? Where? How? And how can I interpret the results?'
The Journal of PhysiologyMechanism of receptor‐mediated modulation of the delayed outward potassium current in guinea‐pig ventricular myocytes.
166 Citations1990Kazuto Yazawa, Masaki Kameyama
It is concluded that beta‐adrenergic modulation of IK is mediated by cyclic AMP‐dependent phosphorylation but not by an increase in [Ca2+]i, that PKA and PKC enhance IK independently, and that acetylcholine antagonizes beta‐ adrenergic stimulation of Ik most probably by inhibiting adenylate cyclase.
The Journal of PhysiologyVoltage‐dependent inactivation of the human K<sup>+</sup> channel KvLQT1 is eliminated by association with minimal K<sup>+</sup> channel (minK) subunits
160 Citations1998Martin Tristani‐Firouzi, Michael C. Sanguinetti
Multiple open states, and a sequential gating model for KvLQT1 channel activation and inactivation are suggested, and the onset of inactivation was immediate and 10 times faster when in activation was reinduced following transient recovery of channels to the open state(s).
Drug SafetyThe QT Interval and Torsade de Pointes
155 Citations1999Arthur J. Moss
The QT interval on the electrocardiogram is the time from the onset of ventricular depolarisation to completion of repolarisation (the end of the T wave) and is influenced by heart rate, autonomic factors, electrolyte levels, gender and age.
American Journal of Physiology-Heart and Circulatory PhysiologyIntracellular Ca2+ and protein kinase C modulate K+ current in guinea pig heart cells
138 Citations1987Noritsugu Tohse, Masaki Kameyama +1 more
It is indicated that IK channels are modulated by Cai2+ not only through activation of PKC but also directly, and thereby the amplitude of IK was increased.
Pflügers Archiv - European Journal of PhysiologyTime course and voltage dependence of expressed HERG current compared with native ”rapid" delayed rectifier K current during the cardiac ventricular action potential
121 Citations1998Jules C. Hancox, Allan J. Levi +1 more
The correlation between the voltage dependence of HERG during the AP and the fully activated I-V relation indicates that the contribution of HerG/IKr to AP repolarisation is more significantly determined by the open-channel I-v relation, than the precise activation time course of the current.
The Journal of General PhysiologyTime-dependent outward current in guinea pig ventricular myocytes. Gating kinetics of the delayed rectifier.
107 Citations1990Jeffrey R. Balser, Paul B. Bennett +1 more
Results suggest that the cardiac delayed rectifier undergoes at least two major transitions between closed states before opening upon depolarization, and indicates that identical and independent gating particles should not be assumed for this K channel.
The FASEB JournalA toxin to nervous, cardiac, and endocrine ERG K <sup>+</sup> channels isolated from <i>Centruroides noxius</i> scorpion venom
102 Citations1999Georgina B. Gurrola, Barbara Rosati +7 more
This work isolated a peptide from the scorpion Centruroides noxius Hoffmann that has no sequence homologies with other toxins, and demonstrates that it specifically inhibits (IC50 = 16±1 nM) only ERG channels of different species and distinct histogenesis.
Pflügers Archiv - European Journal of PhysiologyIonic currents contributing to the action potential in single ventricular myocytes of the guinea pig studied with action potential clamp
94 Citations1990Th. Doerr, R. Denger +2 more
Experiments using caffeine as a tool to increase calcium release from the sarcoplasmic reticulum supported the idea that INaCa contributes to the plateau during the second half of the action potential and even lasts into diastole, whereas strong elevation of the intracellular [Ca]i during theaction potential additionally activated the non-specific cation channel.
Circulation ResearchSubcellular mechanism for Ca(2+)-dependent enhancement of delayed rectifier K+ current in isolated membrane patches of guinea pig ventricular myocytes.
80 Citations1994Junichi Nitta, Tetsushi Furukawa +3 more
Cardiac IK was enhanced by increases in [Ca2+]i at a physiological range via a calmodulin-dependent pathway, which did not involve a phosphorylation process.
Circulation ResearchDynamic Ca<sup>2+</sup>-Induced Inward Rectification of K<sup>+</sup>Current During the Ventricular Action Potential
68 Citations1998Antonio Zaza, Marcella Rocchetti +3 more
Ca2+-induced effects may represent only a small fraction of total IK1 rectification, but they are large enough to affect excitability and repolarization and contribute to facilitation of early afterdepolarizations by conditions increasing Ca2+ influx.
Pacing and Clinical ElectrophysiologyDifferential Response of QTU Interval to Exercise, Isoproterenol, and Atrial Pacing in Patients with Congenital Long QT Syndrome
63 Citations1991Wataru Shimizu, Tohru Ohe +2 more
The results suggest that sympathetic stimulation plays an important role in the QTU prolongation and marked TU wave complex abnormalities in patients with congenital long QT syndrome.
American Journal of Physiology-Heart and Circulatory PhysiologyCharacterization and functional consequences of delayed rectifier current transient in ventricular repolarization
53 Citations2000Gary A. Gintant
Molecular PharmacologyKvLQT1 Potassium Channel but Not IsK Is the Molecular Target fortrans-6-Cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane
46 Citations1997Gildas Loussouarn, Flavien Charpentier +4 more
The results show that the chromanol compound 293B is targeted to KvLQT1 channels but not to the IsK regulator, suggesting that the compound penetrated the cell to block the channel.
Biochemical and Biophysical Research CommunicationsAlteration of HERG Current Profile during the Cardiac Ventricular Action Potential, Following a Pore Mutation
31 Citations1998Jules C. Hancox, Harry J. Witchel +1 more
Measurements from Chinese Hamster Ovary cells transfected with HERG cDNA with a point-mutation (S631A) in the pore region provide a direct demonstration that rapid inactivation normally plays a critical role in determining both time-course and voltage dependence of HERG/I(Kr) -current during the cardiac ventricular AP.