Cardiac pacemaker I(f) current and its inhibition by heart rate-reducing agents.

The 'funny' (I(f)) current, first described by Brown et al. in 1979 in pacemaker myocytes, is an inward current that slowly activates on hyperpolarization to the diastolic range of voltages. Extensive work has amply demonstrated its involvement in the generation of spontaneous activity. The extent of current activation determines the slope of diastolic depolarization and hence of pacemaker rate. Since I(f) is under cyclic adenosine monophosphate (cAMP)-mediated control by beta-adrenergic and muscarinic stimulation, this mechanism underlies neurotransmitter modulation of cardiac rate and is therefore of fundamental physiological relevance. Their key role in pacemaking makes f-channels a natural target for drugs aiming at regulation of pacemaker activity and cardiac rate. Both in the past and more recently, rate-reducing drugs that slow pacemaker activity by decreasing the rate of diastolic depolarization have been developed. These drugs act as specific f-channel inhibitors. One of the latest such molecules developed, ivabradine, has a highly specific inhibitory action on f-channels, which atypically depends on the current flow across the channel. These specific properties make the I(f) inhibition by ivabradine 'use-dependent,' a therapeutically beneficial property. Investigation of the interaction between rate-reducing molecules and specific regions of hyperpolarization-activated, cyclic nucleotidegated (HCN) channels, the molecular components of native f-channels, will provide new strategies for more specific and efficient drug design. This short review addresses the major basic properties of cardiac f-channels, with a focus on the mode of action of f-channel inhibitors and on its possible molecular interpretation.