If inhibition: a novel mechanism of action

Aims: It is well established that the cardiac pacemaker ('funny', or I f) current plays an important role in the generation and autonomic modulation of cardiac rate by controlling the rate of diastolic depolarization. Here, the properties of If and the criteria that permit identification of If activation as the main mechanism responsible for diastolic depolarization are briefly summarized. The relationship between If inhibition by specific If channel blockers (rate-reducing agents) and reduction in pacemaker rate is also described. Methods and results: The If data reported here were collected from rabbit sinoatrial node cells that were isolated and patch-clamped. Cs + ions and, more efficiently, 'rate-reducing' agents block I f and reduce the steepness of diastolic depolarization and frequency in spontaneously active sinoatrial node myocytes. Ivabradine (Procoralan®; Servier, Neuilly-sur-Seine, France), a recently developed molecule, blocks If channels when they are open and preferentially when the current is outward. Conclusions: If controls the slope of diastolic depolarization and cardiac frequency, and its inhibition causes heart rate reduction. The current-dependent blockade of If with ivabradine leads to a specific and use-dependent, heart rate reducing effect that may have therapeutic applications in clinical settings.