If in non-pacemaker cells: Role and pharmacological implications

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Abstract

Pacemaker channels play a major role in the generation of sinoatrial rhythmic activity. However, their expression is not confined to specialized myocardial cells, such as primary and subsidiary pacemakers. Electrophysiological and molecular data collected over the last ten years have demonstrated that f-channels are also present in non-pacemaker cardiomyocytes, and become upregulated in cardiac hypertrophy and failure. Mislocalized expression and/or overexpression of f-channels are a consequence of electrophysiological remodeling and, from a clinical point of view, may represent an arrhythmogenic mechanism in heart failure, a condition associated with a high risk for sudden cardiac death. The potential arrhythmogenic role of If and the availability of selective f-channel blockers cause If to be a suitable therapeutic target in heart disease.

Introduction

Pacemaker ionic channels help to endow some types of specialized cells (either cardiomyocytes, neurons, or smooth muscle cells) with an intrinsic rhythmic activity. In the mammalian cardiac sinus node, the pacemaker current, termed If, plays a crucial physiological role in setting the heart rate and sensing its autonomic control (see [1] in this issue). The role of f-channels in non-pacemaker cardiac cells has long been disregarded. This flaw was based on the assumption that If expression is limited to the sinus node region and other parts of the conduction system, i.e., those cells possessing a well-defined diastolic depolarization phase. This conviction was also fueled by the lack of molecular assays, since genes coding for f-channels have been cloned only recently. Notwithstanding this view, first electrophysiological and then molecular data demonstrated that HCN channels are also present in non-pacemaker tissues. In our laboratory, the hypothesis of a “pacemaker” current in ventricular cells arose from the observation of a clear-cut diastolic depolarization phase during intracellular recordings from papillary muscles of hypertrophied rat hearts [2]. Two facts excluded the interpretation of this phenomenon as an experimental artifact: first, diastolic depolarization was absent in non-hypertrophied muscles challenged with similar experimental conditions. Second, and most important, this diastolic depolarization phase was prone to be steepened by β-adrenoceptor (βAR) stimulation, which exerted – in the hypertrophied ventricular tissue namely – a striking proarrhythmic action [2]. As reviewed in the previous article by DiFrancesco [1], the autonomic control of heart rate in pacemaker cells is largely mediated by the presence of the funny current If which is specifically modulated by intracellular cAMP levels. Thus, we postulated that the sensitivity to catecholamines and the presence of a diastolic depolarization were due to an atypical If occurrence in diseased ventricular tissue. This article will review the present knowledge concerning the presence and pharmacological modulation of If in common ventricular and atrial myocytes.

Section snippets

If in non-pacemaker cardiac cells

In ventricular myocytes, If is abundantly expressed during fetal and neonatal life [3], [4], [5]. Moreover, in murine beating myocytes derived from embryonic stem cells (ESC), If is detected early during differentiation [6]. At some stage of their in situ (or in vitro, for ESC-derived cardiomyocytes) electrophysiological maturation toward adult ventricular phenotype, these cells lose their capacity to generate spontaneous activity. Both in mouse and rat hearts, this is accompanied by a

Biophysical and pharmacological properties of ventricular If

By definition, pacemaker channels are non-selective ionic channels, blocked by a millimolar concentration of cesium applied extracellularly. These are distinctive features of ventricular If, too. In fact, Fig. 3A and B demonstrates that the reversal potential, calculated by tail current analysis, is about −20 mV, matching a channel with mixed conductance for Na and K ions (PNa/PK  0.25), and that the current is completely blocked by extracellular cesium (Fig. 3B and inset). Channel selectivity (P

If as a marker of cardiac remodeling

Mislocalized expression and/or overexpression of cardiac HCN channels may represent an example of a general phenomenon, termed cardiac remodeling, which consists namely in the re-expression of fetal proteins [31]. The renin–angiotensin system plays a pivotal role in ventricular remodeling (for a review, see [32]). The chronic activation in this system, as occurs in hypertension, ischemic cardiomyopathy, diabetes, and many other cardiovascular diseases, results in an overproduction of

If inhibitors in non-pacemaker cells

If expression in non-pacemaker cells may have pharmacological and therapeutic implications. Among many well-known mechanisms, the efficacy of some drugs routinely used in ischemic cardiomyopathy or heart failure in reducing cardiac death, might be speculatively ascribed to a reduced If expression (ACE inhibitors, AT1 antagonists) or blockade of catecholamine action on this current (β-blockers). Selective 5-HT4 antagonists demonstrated antiarrhythmic properties in a pig model of atrial

Conclusions

Molecular identification of HCN subunits and their functional/molecular detection in the diseased ventricle attracted novel and unforeseen attention to pacemaker channels. In addition to the acute regulation of pacemaker currents, which adjusts beat-to-beat cardiac rate, long-term stimuli involved in cardiac remodeling can profoundly alter the properties of If in cardiomyocytes. Although the regulatory pathways which control f-channel expression remain to be elucidated, this phenomenon involves

Acknowledgments

Our original work was supported by grants from the Ministry of Education, University and Research and from Telethon.

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