A new family of drugs has been developed with the aim of specifically reducing the heart rate by directly interfering with the currents involved in the generation of the pacemaking mechanism of the sinoatrial node. The I_f current is one of the currents contributing to the pacemaker diastolic depolarization and plays an important role in the autonomic modulation of the sinus rate. The channels carrying this current have been identified and form the family of hyperpolarization-activated and cyclic nucleotide-gated channels (HCN). The most selective heart rate reducing drugs are open HCN channel blockers. Like other drugs blocking voltage-dependent channels, the I_f blocking drugs act in positive charged form from the inside of the cell. When the channel is open and the electrical gradient favors the entry of the drug into the channel pore, there is binding to a blocking site within the channel. At negative membrane potentials with inward current crossing the channel, unbinding of the drug takes place and there is relief from block. These drugs, by blocking the I_f current in an use-dependent way, induce a limited and frequency-depending slowing of the heart rate. Buy this Article