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Selective Pharmacological Inhibition of the Pacemaker Channel Isoforms (HCN1-4) as New Possible Therapeutical Targets

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Abstract:

The pacemaker channel isoforms are encoded by the hyperpolarization-activated and cyclic nucleotide-gated (HCN) gene family and are responsible for diverse cellular functions including regulation of spontaneous activity in sino-atrial node cells and control of excitability in different types of neurons. Four channel isoforms exist (HCN1-HCN4). The hyperpolarization-activated cardiac pacemaker current (If) has an important role in the generation of the diastolic depolarization in the sino-atrial node, while its neuronal equivalent (Ih) is an important contributor to determination of resting membrane potential, and plays an important role in neuronal functions such as synaptic transmission, motor learning and generation of thalamic rhythms. Ivabradine is a novel, heart rate-lowering drug which inhibits the pacemaker (If) current in the heart with high selectivity and with minimal effect on haemodynamic parameters. Ivabradine is beneficial in patients with chronic stable angina pectoris equally to beta receptor blocker and calcium channel antagonist drugs. There is increasing interest to apply this drug in other fields of cardiology such as heart failure, myocardial infarction, cardiac arrhyhtmias. Heart rate reduction might improve clinical outcomes in heart failure. HCN upregulation presumably contributes to increased (If) and may play a role in ventricular and atrial arrhythmogenesis in heart failure. In the nervous system the HCN channels received attention in the research areas of neuropathic pain, epilepsy and understanding the mechanism of action of volatile anaesthetics. This article delineates that the pharmacological modulation of cardiac and neuronal HCN channels can serve current or future drug therapy and introduces some recently investigated HCN channel inhibitor compounds being potential candidates for development.





Keywords: HCN channel isoforms; arrhythmogenesis; clinical trials; heart rate; isoform-selective phenylalkylamines; ivabradine; myocardial ischaemia; neuropathic pain; pacemaker channel isoforms; sino-atrial node

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986711796642427

Publication date: August 1, 2011

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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