In silico assessment of drug safety in human heart applied to late sodium current blockers

Trénor, Beatriz; Gomis-Tena, Julio; Cardona, Karen; Romero, Lucía; Rajamani, Sridharan; Belardinelli, Luiz; Giles, Wayne R.; Sáiz, Javier

doi:10.4161/chan.24905

Cited by 29 publications

(30 citation statements)

References 78 publications

(154 reference statements)

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“…The underlying biophysical mechanism(s) involves the non-linear interactions of the small overlapping Ca 2+ channel—and Na + /Ca 2+ —exchanger mediated currents in this range of membrane potentials (Madhvani et al, 2011, for review see Fink et al, 2006). The altered AP waveform and related pro- or anti-arrhythmic effects are sometimes described in terms of an altered “repolarization reserve” at defined time-points of early or late repolarization (Wu et al, 2009; Varró and Baczkó, 2011; Trenor et al, 2013). …”

Section: Resultsmentioning

confidence: 99%

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Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

Trénor¹,

Cardona²,

Sáiz³

et al. 2013

Front. Physiol.

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Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or “late” component of the Na+ current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na+ and Ca2+ currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.

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Section: Resultsmentioning

confidence: 99%

“…Trenor et al, 2013). This maneuver was based on the fact that the recommended adult dosage level for ranolazine is in the 3–8 μM range (Belardinelli et al, 2006).…”

Section: Methodsmentioning

confidence: 98%

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

Trénor¹,

Cardona²,

Sáiz³

et al. 2013

Front. Physiol.

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“…These findings suggest that it is not solely a progressive increase in [Na + ] i per se that is the main trigger for pro-arrhythmic changes in the ventricular myocardium. Instead, it is likely that the extraordinary efficacy of I Na-L as a current source (or initiator) for pro-arrhythmia in human ventricles is ‘indirect’ as has been pointed out previously [14,20,22,23]. …”

Section: Introductionmentioning

confidence: 94%

“…In turn, these changes in [Na + ] i could alter the dynamic balance and/or longer-term homeostatic capacity of one or more of the Na + -dependent regulatory mechanisms summarized above. It is also now well recognized that (mainly as a consequence of the very high resistance state of the cardiac myocyte during the entire duration of the action potential plateau) the I Na-L can significantly change the action potential waveform, and may also alter cell-to-cell electrotonic communication [14,22,23]. …”

Section: Introductionmentioning

confidence: 99%

“…In addition, the diabetic myocardium often exhibits an enhanced Na + current as a consequence of changes in tyrosine phosphorylase activity in both Type I and Type II diabetes [29,30]. This increased net inward current produces important changes in the safety factor for action potential repolarization and alters the repolarization reserve [20,22]. The immediate and direct consequences of an increase in I Na-L include a significant lengthening of the action potential duration, sometimes accompanied by (for example in the case of Purkinje tissue) a change in the height of the plateau of the action potential [17,31].…”

Section: Introductionmentioning

confidence: 99%

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Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes

2016

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The slowly inactivating or late Na+ current, INa-L, can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to INa-L significantly increases intracellular Na+, [Na+]i; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+/Ca2+ exchange. These changes increase intracellular Ca2+, [Ca2+]i; which may further enhance INa-L due to calmodulin-dependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O’Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2+]i homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na+]i even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na+]i when INa-L was increased. Based on our simulations, the major short-term effect of markedly augmenting INa-L is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, ICa-L. Furthermore, this action potential prolongation does not contribute to [Na+]i increase.

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Cardiac Sodium Current (Na _v 1.5)

Gintant

2015

Methods and Principles in Medicinal Chemistry

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Whole-cell patch-clamp analysis revealed a resting membrane potential of-60 mV in primary osteoblasts and in the MG-63 osteoblast-like cells. Depolarisation-induced action potentials were characterised by duration of 60 ms, a minimal peak-to-peak distance of 180 ms, a threshold value of-20 mV and a repolarisation between the spikes to-45 mV. Expressed channels were characterised by application of voltage pulses between-150 mV and 90 mV in 10 mV steps, from a holding potential of-40 mV. Voltages below-60 mV induced an inward current. Depolarising voltages above-30 mV evoked two currents: (i) a fast activated and inactivated inward current at voltages between-30 and 30 mV, and (ii) a delayed-activated outward current that was induced by voltages above-30 mV. Electrophysiological and pharmacological parameters indicated that hyperpolarisation activated strongly rectifying K + (K ir) channels, whereas depolarisation activated tetrodotoxin sensitive voltage gated Na + (Na v) channels as well as delayed, slowly activated, non-inactivating, and tetraethylammonium sensitive voltage gated K + (K v)

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In silico assessment of drug safety in human heart applied to late sodium current blockers

Abstract: (2013) In silico assessment of drug safety in human heart applied to late sodium current blockers, Channels, 7:4, 249-262,

Cited by 29 publications

References 78 publications

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes

Cardiac Sodium Current (Na _v 1.5)

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In silico assessment of drug safety in human heart applied to late sodium current blockers

Abstract: (2013) In silico assessment of drug safety in human heart applied to late sodium current blockers, Channels, 7:4, 249-262,

Cited by 29 publications

References 78 publications

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes

Cardiac Sodium Current (Na v 1.5)

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Cardiac Sodium Current (Na _v 1.5)