The pacemaker channel and its modulation by ageing, development, and disease: physiopathological and pharmacological implications.

The susceptibility to cardiac arrhythmias increased dramatically during ageing, both for the prevalence of atrial fibrillation, and the development of myocardial hypertrophy and failure, which predispose to life-threatening ventricular arrhythmias. Understanding the role of arrhythmogenic mechanisms may help to promote the development of novel therapeutics. Single human ventricular and atrial myocytes consistently show the occurrence of the pacemaker current If, whose electrophysiological and pharmacological properties resemble those of the f channel expressed in cardiac pacemakers. In the ventricle, If is almost fully activated by negative steps close to the physiological resting potential and is increased by catecholamines through the stimulation of ß-adrenoceptors. Interestingly, the density and maximal specific conductance of this current is significantly higher in myocytes from ischemic cardiomyopathic hearts than in control or dilated cardiomyopathic hearts, thus suggesting that the etiology of the disease may influence the over-expression of the f channel. Likely If over-expression represents an example of a general phenomenon occurring in myocardial hypertrophy and failure, i.e. cell re-entry into a fetal program. Indeed, If density is higher in rat neonatal rat ventricular cardiomyocytes, progressively decreases during post-natal growth. Switching on/off the gene(s) encoding for the If may depend on several factors (e.g, angiotensin II, endothelin I), acting during physiological growth or pathological hypertrophy. If is constitutively expressed in the majority of atrial myocytes isolated from normal human right appendages; at variance with ventricular cells, its activation occurs at voltages more negative than the physiological resting potential of atrial cells. However, ß-adrenoceptor, 5HT4-receptor and natriuretic peptide receptor (NP-R) stimulation may shift the activation curve of If, thus increasing its contribution to the diastolic phase of the atrial action potential. If may represent an arrhythmogenic mechanism in human cells; thus, pharmacological interventions able to prevent disease-induced over-expression of the channel, to antagonize catecholamine or serotonin stimulation of its activation or to selectively block the channel may act as antiarrhythmic agents in heart disease.