Molecular regulation and pharmacology of pacemaker channels.

The spontaneous activity of cardiac tissue originates in specialized pacemaker cells in the sino-atrial node that generate autonomous rhythmic electrical impulses. A number of regions in the brain are also able to generate spontaneous rhythmic activity to control and regulate important physiological functions. The generation of pacemaker potentials relies on a complex interplay between different types of currents carried by cation channels. Among these currents, the hyperpolarization-activated current (termed I(f), cardiac pacemaker "funny" current, and I(h) in neurons) is the major component contributing to the initiation of cardiac and neuronal excitability and to the modulation of this excitability by neurotransmitters and hormones. I(f) is an inward current activated by hyperpolarization of the membrane potential and by intracellular cyclic nucleotides such as cAMP. The identification at the end of the 1990s of a family of mammalian genes that encode for four Hyperpolarization-activated Cyclic Nucleotide-gated channels, HCN1-4, has made analysis of the location of these channels and the study of their biophysical properties an obtainable goal. As a result, specific agents have been developed for their ability to selectively reduce heart rate by lowering cardiac pacemaker activity where f-channels are their main natural target. These drugs include alinidine, zatebradine, cilobradine, ZD-7288 and ivabradine. Recent data indicate that pharmacological tools such as W7 and genistein, which have been used to identify some intracellular pathways involved in ionic channel modulation, also have the ability to inhibit I(f) directly. This opens new perspectives for the future development of other specific rhythm-lowering agents.