The "funny" current (I f) inhibition by ivabradine at membrane potentials encompassing spontaneous depolarization in pacemaker cells

Yael Yaniv, Victor A. Maltsev, Bruce D. Ziman, Harold A. Spurgeon, Edward G. Lakatta

Research output: Contribution to journalArticle

Abstract

Recent clinical trials have shown that ivabradine (IVA), a drug that inhibits the funny current (If) in isolated sinoatrial nodal cells (SANC), decreases heart rate and reduces morbidity and mortality in patients with cardiovascular diseases. While IVA inhibits If, this effect has been reported at essentially unphysiological voltages, i.e., those more negative than the spontaneous diastolic depolarization (DD) between action potentials (APs). We tested the relative potency of IVA to block If over a wide range of membrane potentials, including those that encompass DD governing to the SANC spontaneous firing rate. A clinically relevant IVA concentration of 3 μM to single, isolated rabbit SANC slowed the spontaneous AP firing rate by 15%. During voltage clamp the maximal If was 18 ± 3 pA/pF (at ?120 mV) and the maximal If reduction by IVA was 60 ± 8% observed at ?92 ± 4 mV. At the maximal diastolic depolarization (∼?60 mV) If amplitude was only ?2.9 ± 0.4 pA/pF, and was reduced by only 41 ± 6% by IVA. Thus, If amplitude and its inhibition by IVA at physiologically relevant membrane potentials are substantially less than that at unphysiological (hyperpolarized) membrane potentials. This novel finding more accurately describes how IVA affects SANC function and is of direct relevance to numerical modeling of SANC automaticity.

Original languageEnglish (US)
Pages (from-to)8241-8254
Number of pages14
JournalMolecules
Volume17
Issue number7
DOIs
StatePublished - Jul 2012

Keywords

  • Arrhythmia
  • Pacemaker Ca clock
  • Pacemaker cell automaticity

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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