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.
Highlights
Heart rate is a primary determinant of cardiac output, an index of myocardial work and myocardial oxygen demand, an index of ATP production rate
We found by measuring action potentials (APs) and ionic currents in single isolated sinoatrial nodal cells (SANC), that the IVA blockade is, less pronounced at physiological membrane potentials, i.e., those encompassing diastolic depolarization (DD) (~−60 mV)
inhibits the funny current (If) activation was calculated from the peak tail current 5 min after IVA application
Summary
Heart rate is a primary determinant of cardiac output, an index of myocardial work and myocardial oxygen demand, an index of ATP production rate. Clinical evidence has shown that an increase in heart rate in patients with ischemic heart diseases is associated with an increased cardiovascular morbidity and mortality (e.g., [1,2]), and that drugs which reduce the heart rate can improve myocardial pumping performance and energy balance efficiency. Recent clinical trials (for a review cf [3]) have shown that administration of ivabradine (IVA), a drug that inhibits If, i.e., an inward current activated by hyperpolarization of the cell membrane, is associated with a reduction in heart rate and reduction in morbidity and mortality in patients with cardiovascular diseases. The relative reduction in If in vitro by IVA, has been reported only at hyperpolarized membrane potentials, i.e., those more negative to the maximum diastolic potential (MDP), far from the physiological voltages over which If can contribute to spontaneous diastolic depolarization (DD) of the surface membrane in rabbit SANC [4,6]. Inhibition of funny-channels by IVA occurs only when they are open [4], i.e., when If is activated
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