Pacemaker channels in the heart: physiology, pathology and pharmacology.

"Funny" (f) channels underlie the cardiac "pacemaker" If current, an inward current activated on hyperpolarization to voltages that are in the diastolic range of sino-atrial node cells. The degree of current activation determines the slope of diastolic depolarization, and hence heart rate; If being directly modulated by cAMP, underlies the regulation of cardiac rate by - adrenergic and muscarinic stimulation . If is also present in non automatic cardiac tissue. Electrophysiological and molecular data demonstrated that f-channels are present in ventricular cardiomyocytes. In cardiac hypertrophy and failure, If current density and/or mRNA levels of f-channels are increased compared with controls. Over -expression of f-channels in non-pacemaker cells may represent an arrhythmogenic mechanism in heart failure. Inhibition of the pacemaker If current to induce a direct and selective decrease in heart rate represents an attractive therapeutic approach for coronary artery disease. Substances acting as selective f-channel inhibitors, such as ivabradine, will be useful in treating diseases such as chronic angina and heart failure and will help to assess the potential arrhythmogenic role of If in heart disease.