If channels in the pacemaker activity of the sino-atrial node

Heartbeat is initiated by specialized pacemaker cells generating spontaneous impulses in the sino-atrial node (SAN). Twenty years ago DiFrancesco described a current that underlay the diastolic depolarization phase and drove membrane potential towards a threshold where a new action potential starts. This pacemaker current has been named I-f f for "funny current" since it activates upon membrane hyperpolarization rather than depolarization, opposite to the most voltage-gated channels. Furthermore, the current is directly modulated by cyclic adenosine monophosphate through a mechanism independent of phosphorylation. Genes encoding for I-f have been cloned quite recently and named hyperpolarization-activated cyclic nucleotide-gated channels (HCN). The HCN family comprises four isoforms (HCN 1-4). In the SAN, HCN4 is the most highly expressed isoform but HCN1 and HCN2 have also been detected. I-f modulation is important for controlling cardiac rhythm: the complete block results in a reduction of SAN rate by approximately 20 to 30%. In the last years several drugs able to block the I-f channels have been studied. I-f is blocked by organic substances like zatebradine and analogues. Ivabradine is a zatebradine analog that selectively blocks I-f without affecting other ionic currents that underlie cardiac action potential; thus, it acts specifically on SAN and does not present negative inotropic effects like calcium channel blockers or beta-Mockers. Ivabradine blocks the HCN channel when it is open; ivabradine crosses the cell membrane and exerts its blocking action by interacting within the pore loop. At present, ivabradine is the only I-f Mocker approved for clinical use.