Heart rate lowering by inhibition of the pacemaker current: a new therapeutic perspective in cardiovascular disease.

Several studies have demonstrated that resting heart rate is an important correlate of cardiovascular and all-cause mortality and that the mortality benefit of some cardiovascular drugs seems to be related in part to their heart rate-lowering effects. Since the currently available classes of drugs with heart-rate lowering effect (e.g. beta-blockers and calcium channel antagonists) also exert multiple structural and functional actions on the cardiovascular system, which may be in some cases undesired, the introduction of a new class of agents exclusively affecting the pacemaker activity of the sinus node is of particular interest. The first molecule of this class - sinus node modulators or I(f)-current inhibitors - to reach clinical application is ivabradine. Cardiac pacemaker cells generate a spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised level towards the threshold level for initiating a subsequent action potential, generating rhythmic action potentials that propagate through the heart and trigger myocardial contraction. The I(f) current is an inward ionic current that determines the slope of diastolic depolarisation, which in turn controls the heart beating rate. Extensive work has amply demonstrated its involvement in the generation of spontaneous activity. The molecular basis of the generation of the pacemaker current was landmarked by the cloning of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, which constitute the structural units of the f-channels. This review addresses the major basic properties of cardiac f-channels, with a focus on the mode of action of I(f)-current inhibitors and outlines the therapeutic implications of the existing research data.