Ivabradine

Dear Colleagues,

Ivabradine (IVA) is a novel specific heart rate (HR) lowering agent that acts in sinoatrial node (SAN) cells by selectively inhibiting the pacemaker I_f current in a dose–dependent manner by slowing the diastolic depolarization slope of SAN cells, and reducing HR at rest and during exercise with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction.

The cardiac pacemaker cells, the first cells which generate the electrical impulse and form SAN, have the specific  feature of spontaneous electrical activity generating repetitive action potentials at a specific controlled rate.

Among the different currents at the basis of the mechanisms contributing to electrical stimulus, the I_f current has a major role in providing pacemaking competence. Originally this current was described in the SAN the funny current and its properties in cardiac pacemaker cells have been the object of intense investigations. Funny channels underlie the cardiac pacemaker I_f current, originally described as an inward current activated on hyperpolarization to the diastolic range of voltages in SAN myocytes.

SAN cells can depolarize spontaneously. This depolarization is due to the movement of ions (sodium and potassium) across specialized membrane channels, which directly modulates the rate of spontaneous diastolic depolarization. The I_f current is important in the generation of pacemaking not only for diastolic–depolarization but also for its involvement in neurotransmitter–induced control of cardiac rate. It was shown since its first description that I_f mediates the acceleratory effect of adrenaline on pacemaker rate and a later study showed its strongly modulation by acetylcholine but with opposite action regard that of catecholamines.

The molecular basis of the I_f current and its related equivalent in non–cardiac cells I_f have been characterized by cloning a family of ionic channels, known as hyperpolarization–activated cyclic nucleotide–gated channels (HCN). Four isoforms of HCN have been identified, HCN_1–4 which show typical characteristics of pacemaker currents, activation on hyperpolarization, current carried by sodium and potassium ions, modulation by cyclic adenosine monophosphate and sensitivity to caesium.

Detailed patch–clamp studies in rabbit SAN cells have shown that the drug blocks I_f channels  and that it interacts with the channels from the intracellular side.³³ More recently, also in SAN cells, IVA has been shown to be an open channel blocker, indicating that it cannot reach its binding site when the channels are closed, and its blocking effect is current–dependent and is attenuated during very long hyperpolarized pulses (more than 20 seconds of hyperpolarization).

The possibility to modulate the I_f current offers new therapeutic options for the control of cardiac chronotropism. The development of molecules that interact specifically with funny channels is the basis of new pharmacological approaches to the management of HR. The aim of this Special Issue is to examinate the most important aspects will regard the synthesis, biological activities and pharmacokinetic-pharmacodynamic aspects.

Dr. Graziano Riccioni
Guest Editor