If current inhibition: cellular basis and physiology

The slow diastolic depolarization phase in cardiac pacemaker cells is the electrical basis of cardiac automaticity. The hyperpolarization-activated current (I(f)) is one of the key mechanisms underlying diastolic depolarization. Particularly, I(f) is unique in being activated on membrane hyperpolarization following the repolarization phase of the action potential. I(f) has adapted biophysical properties and voltage-dependent gating to initiate pacemaker activity. I(f) possibly constitutes the first voltage-dependent trigger of the diastolic depolarization. For these reasons, I(f) is a natural pharmacological target for controlling heart rate in cardiovascular disease. In this view, I(f) inhibitors have been developed in the past, yet the only molecule to have reached the clinical development is ivabradine. At the cellular level, the remarkable success of ivabradine is to be ascribed to its relatively high affinity for f-channels. Furthermore, ivabradine is the most I(f)-specific inhibitor known to date, since moderate inhibition of other voltage-dependent ionic currents involved in automaticity can be observed only at very high concentrations of ivabradine, more than one order of magnitude from that inhibiting I(f). Finally, the mechanism of block of f-channels by ivabradine has particularly favorable properties in light of controlling heart rate under variable physiological conditions. In this article, we will discuss how I(f) inhibition by ivabradine can lead to reduction of heart rate. To this aim, we will comment on the role of I(f) in cardiac automaticity and on the mechanism of action of ivabradine on f-channels. Some aspects of the cardiac pacemaker mechanism that improve the degree of security of ivabradine will also be highlighted.