maco har log P y: r O la u p c e n s a A v Perez-Neut et al., Cardiol Pharmacol 2015, 4:2 c o c i e d r s a s Open Access C Cardiovascular Pharmacology: DOI: 10.4172/2329-6607.1000139 ISSN: 2329-6607 Review Article OpenOpen Access Access Current and Potential Antiarrhythmic Drugs Targeting Voltage-Gated Cardiac Ion Channels Mathew Perez-Neut, Vidhya Rao, Lauren Haar, Keith W Jones and Saverio Gentile* Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL USA Abstract Voltage-gated ion channels play a fundamental role in the generation and propagation of the cardiac action potential by acting synergistically to produce an ionic current across cellular membranes. Abnormalities of heart ion channel activities that lead to loss or gain of function (channelopathies) are often associated with disruption of the coordinated propagation of electrical activity of the cardiac myocytes and can generate fatal arrhythmogenesis. Drugs that act on cardiac ion channels have long been used to restore normal rhythm and conduction in patients affected by cardiac arrhythmias and offered to basic scientists the possibility to characterize distinct ion channel classes. This review will explore the mechanisms and role of the current anti-arrhythmic drugs used in the clinic, and discuss recent development on ion channel openers as potential anti-arrhythmic drugs. Abbreviations: VGIC: Voltage gated ion channels; VGKC: Voltage gated potassium channels; KCNQ: Potassium Channel, Voltage-Gated, KQT-like subfamily; KCNH: Potassium channel voltage gated subfamily H; ATP: Adenosine tri phosphate; hERG1: human Ether-à-go-go-Related Gene; SCN: Sodium channel, voltage gated; CACNA: Calcium channel, voltage gated [gene]; CaV: Calcium channel, voltage gated [protein]; RyR: Ryanodine receptor Introduction (outward flow of positive charges) determines the initial descending deflection of the cardiac action potential (phase 1) [16]. This event Voltage-gated ion channels (VGIC) are pore forming is followed by a plateau (phase 2) in which an inward Ca2+ currents transmembrane proteins which are ion permeable and gated by changes resulting from activation of L-type calcium channels [17-19] is balanced of transmembrane voltage [1]. Activities of VGIC are characterized by an outward K+ current upon activation of KCNQ and KCNH type + by defined parameters ranging from distinct ion selectivity (e.g. Na , potassium channels [16]. During this phase, cells accumulate Ca2+ that + 2+ - K , Ca or Cl ) to ionic direction (inward or outward ionic flow; is used in conjunction with ATP during the activation of the contractile currents). Opening and closing of VGIC specifically expressed in machinery (systole). cardiac myocytes generate and propagate the electric signal to shape the waveform of a cardiac action potential [2]. While there are some Finally, closure of the Ca2+ channels determines the initiation of differences in the shape of action potentials among different cell types repolarization that is progressively accelerated by the full activation found in the myocardium, the myocyte action potential is composed by of potassium channels such as the KCNH2 (hERG1) channels (phase 5 phases (4-0-1-2-3) [3]. 3) [16]. As the membrane potential repolarizes, several potassium channels close resulting in restoring the resting membrane potential. In the resting state, when the cardiac muscle is relaxed (diastole) the At this point, the funny Na+ channels can re-open until a new phase + + activity of several pumps and ion transporters including Na /K pumps 4 initiates. [4], Na+/Ca2+ exchanger [5] and K+ ion channels (inwardly rectifying) [6] accumulate ions in the cytoplasm against their electrochemical Aberrant cardiac ion channel activities can often be associated with gradient. This results in the generation of a negative membrane generation of an abnormal action potential that results in arrhythmias potential that peaks around -85/-95 mV (phase 4; resting membrane [20-23]. For example, malfunction of several ion channels including potential. The membrane potential at resting state is unstable and Na+, K+ or Cl+ channels can lead to a pathological retardation in the slowly depolarizes (moves towards positive values) due to the activity repolarization of the cardiac action potential. This phenomenon is of a specific member of the Na+ channel family (“funny” Na+ channels) detected as prolonged QT interval measured by electrocardiogram [7] through which sodium ions slowly cross the membrane (Na+ (Long QT Syndrome, LQT) [24], and is the lead culprit in polymorphic currents) until the membrane potentials reach a value that activates ventricular tachycardia—the classical arrhythmia (Table 1). + + the fast Na channel [8]. Consequently, the rapid Na entry quickly Antiarrhythmic drugs aim to abolish the electrophysiological depolarizes the cell membrane (phase 0) reaching up to values of +20/25 mV. At this membrane potential, the inactivation gate of the fast Na+ channels closes (inactivated state) producing an impermeable channel that can re-open only when the membrane potential reaches *Corresponding author: Saverio Gentile, Department of Molecular Pharmacology the values at rest [9]. This phenomenon underlines the initiation of the and Therapeutics, Loyola University Chicago, Maywood, IL USA, E-mail: refractory period during which the cardiac cell cannot elicit another [email protected] action potential. However, although in the refractory period, random Received: April 15, 2015; Accepted: May 04, 2015; Published: May 10, 2015 + failure of inactivation can lead to generation of a small Na current (late Citation: Perez-Neut M, Rao V, Haar L, Jones KW, Gentile S (2015) Current and current, INaL) that appears to contribute minimally in shaping the action Potential Antiarrhythmic Drugs Targeting Voltage-Gated Cardiac Ion Channels. Cardiol potential of a normal cardiac myocyte but may play an important role Pharmacol 4: 139. doi:10.4172/2329-6607.1000139 in a diseased heart [10-12]. Copyright: © 2015 Perez-Neut M et al. This is an open-access article distributed + under the terms of the Creative Commons Attribution License, which permits un- Closing of the Na channels in addition to the slow opening of restricted use, distribution, and reproduction in any medium, provided the original Cl- (inward flow of negative charges) [13-15] and potassium channels author and source are credited. Cardiol Pharmacol ISSN: 2329-6607 CPO, an open access journal Volume 4 • Issue 2 • 1000139 Citation: Perez-Neut M, Rao V, Haar L, Jones KW, Gentile S (2015) Current and Potential Antiarrhythmic Drugs Targeting Voltage-Gated Cardiac Ion Channels. Cardiol Pharmacol 4: 139. doi:10.4172/2329-6607.1000139 Page 2 of 7 mechanisms that are responsible for the cardiac arrhythmias. These drugs cause inhibition of membrane permeability to Na+ by acting as drugs can exhibit diverse properties according to their effects on the Na+ channel blockers, thereby decreasing rate/velocity/magnitude of targeted ion channels as they and can be channel blockers (ligands that the depolarization that occurs in phase 0 of the cardiac action potential block ionic flows), gating inhibitors (ligand that inhibit channel gating [36]. Since activity of Na+ channel determines the speed through which either by acting on ion channel activation or inactivation) or activators a cardiac action potential depolarizes inhibition of Na+ channels is a (ligands that activate ion channels by direct binding) [25,26]. common strategy used to correct disturbances of the heart rhythm in which the heart rate is abnormally increased (pathological tachycardia/ + Pharmacology of the Cardiac Na Channel tachyarrhythmia). Members of the Class I antiarrhythmic drugs are Nine genes in the human genome (SCN1A through SCN9A) divided into three different categories (1A, 1B, 1C) and are defined by + + the different degree of Na channel blockage. encode for Na channels α subunit proteins named Nav1.1 through Nav1.9 and 4 β subunits (SCN1B-SCN4B). Although mRNA for Procainamide or quinidine is Class IA antiarrhythmic drugs several Nav channels have been found in the human heart, the product indicated for the treatment of sustained ventricular fibrillation. The + + of the SCNA5 gene, Nav1.5, is considered the main Na channel effects of these Na channel blockers is reduction of cell excitability that determines excitability and electrical conduction velocity in the by increasing the threshold for the rapid depolarization during phase cardiac myocytes. This conclusion is centered on the observation that 0. Consequently, termination of the refractory period of the atria and mutations of the Nav1.5 channel that cause partial or complete loss of ventricles is delayed. However, these drugs can also be pro-arrhythmic Nav1.5 activity can cause a delay of depolarization during phase 0 of the and are contraindicated by the presence of prolonged QT [37]. action potential [27-31]. This is hypothesized to occur by enhancing I which can lead to an abnormal Ca2+ entry during phase 2 or phase Lidocaine is one of the most commonly used class IB NaL , + 3 upon reactivation of Ca2+ channels that has been related to clinically antiarrhythmic. This drug blocks Na channel in the conduction system relevant cardiac arrhythmias such as Brugada syndrome (Table 1) [32- and in the muscle cells of the heart causing inhibition of spontaneous 34] . depolarization during diastole [38,39]. Na 1.5 channel blockers Flecainide and Propafenone are examples of class IC