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Updated: Nov 23, 2025
Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
Blockade of sodium‑calcium exchanger via ORM-10962 attenuates cardiac alternans
Jozefina Szlovák1, Jakub Tomek2, Xin Zhou3
1Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary.
Insights
Blocking the sodium-calcium exchanger (NCX) with ORM-10962 effectively reduces cardiac repolarization alternans and calcium transient alternans, offering a potential anti-arrhythmic strategy. This approach shows promise even in heart failure models where alternans risk is high.
Area of Science:
- Cardiac Electrophysiology
- Molecular Cardiology
- Pharmacology
Background:
- Repolarization alternans, characterized by oscillating action potential durations, contribute significantly to arrhythmogenic substrates.
- Current therapeutic strategies lack specific targeting for repolarization alternans, despite their role as arrhythmia precursors.
- The underlying mechanisms driving alternans remain incompletely understood, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate the hypothesis that blocking the sodium-calcium exchanger (NCX) can inhibit cardiac alternans.
- To evaluate the efficacy of the selective NCX blocker ORM-10962 in attenuating repolarization and calcium transient alternans.
- To elucidate the mechanisms by which NCX blockade affects alternans using experimental and computational methods.
Main Methods:
- Action potentials were measured in canine papillary muscle preparations using microelectrodes.
- Calcium transients were assessed in isolated ventricular myocytes using Fluo4-AM.
- Computer simulations were employed to gain mechanistic insights into the effects of ORM-10962.
Main Results:
- ORM-10962 significantly attenuated both action potential duration (APD) and calcium transient alternans.
- The drug's effect on APD alternans varied among different observed morphological types.
- ORM-10962 increased post-repolarization refractoriness, potentially via indirect reduction of L-type calcium current, and simulations indicated reduced sarcoplasmic reticulum release refractoriness.
Conclusions:
- Blockade of the sodium-calcium exchanger (NCX) with ORM-10962 is a viable strategy to inhibit calcium-driven cardiac alternans.
- The anti-alternans effect of NCX inhibition was demonstrated even in a computer model of heart failure, a condition with elevated alternans risk.
- Targeting NCX represents a promising anti-arrhythmic approach for specifically preventing alternans.
Abstract:
Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that blockade of the sodium‑calcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM from isolated ventricular myocytes paced to evoke alternans. Computer simulations were used to obtain insight into the drug's mechanisms of action. ORM-10962 attenuated cardiac alternans, both in action potential duration and calcium transient amplitude. Three morphological types of alternans were observed, with differential response to ORM-10962 with regards to APD alternans attenuation. Analysis of APD restitution indicates that calcium oscillations underlie alternans formation. Furthermore, ORM-10962 did not markedly alter APD restitution, but increased post-repolarization refractoriness, which may be mediated by indirectly reduced L-type calcium current. Computer simulations reproduced alternans attenuation via ORM-10962, suggesting that it is acts by reducing sarcoplasmic reticulum release refractoriness. This results from the ORM-10962-induced sodium‑calcium exchanger block accompanied by an indirect reduction in L-type calcium current. Using a computer model of a heart failure cell, we furthermore demonstrate that the anti-alternans effect holds also for this disease, in which the risk of alternans is elevated. Targeting NCX may therefore be a useful anti-arrhythmic strategy to specifically prevent calcium driven alternans.
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