The “Funny” Current (I(f)) Inhibition by Ivabradine at Membrane Potentials Encompassing Spontaneous Depolarization in Pacemaker Cells

Recent clinical trials have shown that ivabradine (IVA), a drug that inhibits the funny current (I(f)) in isolated sinoatrial nodal cells (SANC), decreases heart rate and reduces morbidity and mortality in patients with cardiovascular diseases. While IVA inhibits I(f), 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 I(f) 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 I(f) was 18 ± 3 pA/pF (at −120 mV) and the maximal I(f) reduction by IVA was 60 ± 8% observed at −92 ± 4 mV. At the maximal diastolic depolarization (~−60 mV) I(f) amplitude was only −2.9 ± 0.4 pA/pF, and was reduced by only 41 ± 6% by IVA. Thus, I(f) 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.