Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide

Abstract

Na+ channel blockers such as flecainide have found renewed usefulness in the diagnosis and treatment of two clinical syndromes arising from inherited mutations in SCN5A, the gene encoding the α subunit of the cardiac voltage–gated Na+ channel. The Brugada syndrome (BrS) and the LQT-3 variant of the Long QT syndrome are caused by disease-linked SCN5A mutations that act to change functional and pharmacological properties of the channel. Here we have explored a set of SCN5A mutations linked both to BrS and LQT-3 to determine what disease-modified channel properties underlie distinct responses to the Na+ channel blocker flecainide. We focused on flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB). Our results indicate that mutation-induced changes in the voltage-dependence of channel availability (inactivation) may act as determinants of flecainide block. The data further indicate that UDB by flecainide requires channel opening, but is not likely due to open channel block. Rather, flecainide appears to interact with inactivation states that follow depolarization-induced channel opening, and mutation-induced changes in channel inactivation will alter flecainide block independent of the disease to which the mutation is linked. Analysis of flecainide block of mutant channels linked to these rare disorders has provided novel insight into the molecular determinants of drug action.

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

“…A likely explanation is that AZD7009 binds to and inhibits the Nav1.5 channel in its inactivated state and that channel opening is required for the drug molecule to access the binding site. A similar block mechanism has been described for flecainide, which, like AZD7009, has a high pKa and is thus charged to a large extent at physiologic pH Liu et al, 2002).…”

Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor

“…Flecainide is a well‐characterized UDB of Na + channels (Liu et al ., 2002; Liu et al ., 2003). More recently, flecainide has emerged as an effective therapeutic agent for the treatment of CPVT both in combination with conventional β‐adrenoceptor blockade (van der Werf et al ., 2011; van der Werf et al ., 2012; Watanabe et al ., 2013) and as a monotherapy (Napolitano, 2016; Padfield et al ., 2016).…”

“…Crucially, the consequence of flecainide interaction with the Na + channel differs from that with RyR2 channels in one very important way; although, access to the flecainide binding site in Na + channels requires the channel to be open, once bound, flecainide interacts preferentially with the inactivated closed conformation of the channel, prolonging this state, thereby limiting the channel's availability for further activation (Liu et al ., 2002). This limited egress of flecainide from the Na + channel facilitates the accumulation of block (or use‐dependence) with repetitive depolarizations of the cell (Liu et al ., 2003).…”

“…Flecainide is a well‐characterized blocker of sarcolemmal Na + channels (Liu et al ., 2002; Liu et al ., 2003) and K + channels (Follmer and Colatsky, 1990; Paul et al ., 2002). In addition, flecainide has been shown to be effective in the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), and its action has been attributed to an ability to reduce inappropriate release of Ca 2 + from the sarcoplasmic reticulum (SR) by directly blocking open cardiac ryanodine receptor (RyR2) channels (Watanabe et al ., 2009; Hilliard et al ., 2010).…”

Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model

“…Furthermore, analysis of the experimental data suggested that the predominant pathway for lidocaine binding to the Na ϩ channel is provided by the preopen state of the channel (14,18). The assumption that ranolazine does not unbind from the inactivated state and is effectively trapped in the channel after accessing the binding site via the preopen/open state has previously been shown to be essential for the use-dependent block by flecainide (7).…”