Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson, Frida; Andersson, Birgit; Duker, Göran; Jacobson, Ingemar; Carlsson, Leif

doi:10.1016/j.ejphar.2006.11.040

Cited by 49 publications

(43 citation statements)

References 134 publications

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“…This idea is supported by another long-held explanation for these mechanistic differences, which posits that these compounds can interact favourably with distinct conformations within the binding site for local anaesthetics and anti-arrhythmic drugs, thus using an overlapping receptor site but employing distinct molecular interactions. In the case of flecainide, the interaction likely occurs with the open state, whereas lidocaine prefers the inactivated conformation 13,[51][52][53] . Our results, therefore, provide a starting point to define a chemical identity to the multiple highaffinity sites within the sodium channel receptor, each representing a valid drug target with different outcomes on heart rhythms.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

et al. 2011

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Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.

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Section: Discussionmentioning

confidence: 99%

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

et al. 2011

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“…The time scale bar applies to all traces. ported experimentally (12,18,26). The AP triangulation is strongly determined by the K ϩ conductances (i K1 and i Kr ) and Na ϩ /K ϩ exchanger conductance (G NaK ; Fig.…”

Section: Rabbit Purkinje Ap and Its Dependence With Extracellular Kmentioning

confidence: 99%

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

Corrias

Giles

Rodríguez

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Corrias A, Giles W, Rodriguez B. Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers. Am J Physiol Heart Circ Physiol 300: H1806-H1813, 2011. First published February 18, 2011 doi:10.1152/ajpheart.01170.2010.-Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K ϩ current and rapid delayed rectifier K ϩ current block as well as late Na ϩ current increase result in significant AP changes. However, enhanced L-type Ca 2ϩ current (iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics. electrophysiology; Purkinje; early afterdepolarization; arrhythmia FOR DECADES, PURKINJE FIBERS have been implicated in the initiation of lethal cardiac arrhythmias such as ventricular fibrillation and Torsades de Pointes in a variety of clinical situations. In patients with congenital long QT syndrome or Brugada syndrome, for example, the Purkinje-myocardial interface is often the location where ventricular fibrillation initiated (15). Adverse side effects of drugs belonging to a broad range of categories are important factors that have long been associated with arrhythmogenesis. Regulatory agencies have identified Purkinje fibers as an important tool in preclinical assessment of drug safety. Both the Food and Drug Administration and the European Medicines Agency recommend the Purkinje fiber assay for in vitro electrophysiological studies as valuable for assessing potential arrhythmogenicity of a tested compound (41). Aubert et al. (2) have specifically evaluated the rabbit Purkinj...

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“…These results are compatible with the increased refractoriness reported for conduction system cells with respect to working cardiomyocytes. However, the effective refractory period (ERP) of Purkinje fibers has only been determined in ex vivo preparations (15,45,(48)(49)(50)(51) or inferred using intracavital microelectrodes to deliver electrical pulses to an area that includes, but is not limited to, the conduction system (23-25, 52, 53). We thus performed noninvasive epicardial optical programmed stimulation to determine selectively the ERP of Purkinje fibers and that of the working cardiomyocytes in vivo.…”

Section: Direct Optogenetic Assessment Of Purkinje Fiber Function In mentioning

confidence: 99%

Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2

Zaglia

Pianca

Borile

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

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Extrasystoles lead to several consequences, ranging from uneventful palpitations to lethal ventricular arrhythmias, in the presence of pathologies, such as myocardial ischemia. The role of working versus conducting cardiomyocytes, as well as the tissue requirements (minimal cell number) for the generation of extrasystoles, and the properties leading ectopies to become arrhythmia triggers (topology), in the normal and diseased heart, have not been determined directly in vivo. Here, we used optogenetics in transgenic mice expressing ChannelRhodopsin-2 selectively in either cardiomyocytes or the conduction system to achieve cell typespecific, noninvasive control of heart activity with high spatial and temporal resolution. By combining measurement of optogenetic tissue activation in vivo and epicardial voltage mapping in Langendorffperfused hearts, we demonstrated that focal ectopies require, in the normal mouse heart, the simultaneous depolarization of at least 1,300-1,800 working cardiomyocytes or 90-160 Purkinje fibers. The optogenetic assay identified specific areas in the heart that were highly susceptible to forming extrasystolic foci, and such properties were correlated to the local organization of the Purkinje fiber network, which was imaged in three dimensions using optical projection tomography. Interestingly, during the acute phase of myocardial ischemia, focal ectopies arising from this location, and including both Purkinje fibers and the surrounding working cardiomyocytes, have the highest propensity to trigger sustained arrhythmias. In conclusion, we used cell-specific optogenetics to determine with high spatial resolution and cell type specificity the requirements for the generation of extrasystoles and the factors causing ectopies to be arrhythmia triggers during myocardial ischemia.optogenetics | heart | Purkinje fiber | arrhythmia | cardiac ectopies A berrant heartbeats, caused by the ectopic depolarization of a group of cardiomyocytes, are associated with a wide range of consequences, from the commonly experienced feeling of "palpitation" to the triggering of potentially lethal ventricular arrhythmias in diseased hearts. Physiological conduction of normal heartbeats is orchestrated by the interaction of at least two functionally and anatomically distinct populations of cardiomyocytes: the working cardiomyocytes and the conduction system (i.e., Purkinje fibers at the ventricular level) (1). The electrotonic coupling of myocardial cells protects the heart from abnormal excitation and allows the effect of spontaneous activity in sparse cardiomyocytes to be "sunk" by the surrounding myocardium. As a result, a minimal "critical" number of cardiomyocytes needs to simultaneously depolarize to prevail over such a protective mechanism and generate conducted beats (2-5). When this occurs, the source-sink mismatch (abnormal depolarization current/ myocardial electrotonic sink) is focally overcome, resulting in a premature ventricular contraction (PVC) that, in the presence of arrhythmogenic substrates, may e...

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Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Cited by 49 publications

References 134 publications

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2

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