Pharmacological Basics of ƒ-Current Inhibition

Abstract

Elevated heart rate (HR) contributes to myocardial ischaemia, especially when coronary blood supply is restricted, and is recognised as an independent risk factor for increased morbidity and mortality. Heart beat is driven by cellular automaticity of pacemaker cells in the sinus node. The slow spontaneous diastolic depolarisation phase (phase 4) of the action potential is a unique feature of pacemaker cells that confers automaticity. The ƒ-current (Iƒ) determines the slope of the diastolic depolarisation and is modulated by the autonomic system, and thus plays a key role in the regulation of heart rate. Ivabradine is a novel selective use-dependent Iƒinhibitor which exerts a pure heart rate reduction in all animal species tested, without any direct effect on myocardial contractility and relaxation, cardiac output, coronary haemodynamics, blood pressure, peripheral resistance and cardiac conduction parameters and thus affords the advantage of preserving the haemodynamic adaptations occurring spontaneously in response to exercise. These features markedly differentiate ivabradine from current anti-anginal therapies. Ivabradine was demonstrated to exert cardioprotection both on ischaemic and stunned myocardium. Pharmacological inhibition of Iƒ by ivabradine thus represents a new and promising concept in the treatment of myocardial ischaemic diseases.