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If inhibition: a novel mechanism of action

D. DiFrancesco*

Department of General Physiology and Biochemistry, Laboratory of Molecular Physiology and Neurobiology, Milan, Italy

* Dario DiFrancesco, Department of General Physiology and Biochemistry, Laboratory of Molecular Physiology and Neurobiology, via Celoria 26, 20133 Milano, Italy.

Abstract

Aims It is well established that the cardiac pacemaker (‘funny’, or If) 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 and the criteria that permit identification of activation as the main mechanism responsible for diastolic depolarization are briefly summarized. The relationship between inhibition by specific 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-reduding’ agents block 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 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 with ivabradine leads to a specific and use-dependent, heart rate reducing effect that may have therapeutic applications in clinical settings.

Key Words: Cardiac rate • Funny current • blockers • Pacemaker • Sinoatrial node


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