Original articleMolecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long QT syndrome variant 3
Introduction
The long QT syndrome (LQTS) is a rare inherited disorder that is associated with an increased propensity to arrhythmogenic syncope, polymorphous ventricular tachycardia, and sudden cardiac death. To date at least 11 genes have been discovered that, when mutated, lead to LQTS, but LQTS variants 1–3 comprise the majority of documented genotyped LQTS to date [1], [2], [3]. LQT-1 and LQT-2, which are due to mutations in the potassium channel alpha subunits KCNQ1 and hERG respectively, make up approximately 80–90% of the genotyped cases whereas LQT-3, the variant due to mutations in SCN5A, the gene encoding the alpha subunit of the primary heart voltage-gated sodium channel, accounts for 5–8% of the known cases [4], [5]. In the absence of genetic information, beta-blockers are the first line treatment for this disorder [6]. However, because the triggers for cardiac events in LQTS have been shown to be gene and mutation specific, and because the biophysical mechanisms underlying different variants of LQTS have been shown to be diverse, the therapeutic strategies for managing LQTS in genotyped patients have also emerged using a gene-specific approach [1].
In the case of LQT-1, life-threatening events occur most frequently during periods of sympathetic activation, allowing this subset of patients to be effectively protected by the use of anti-adrenergic therapies including beta-blockers [7], [8]. Clinical studies thus far have shown that beta-blocker therapy is less effective in the treatment of LQT-2 and LQT-3 patients [6].
The prototypical LQT-3 mutation is characterized by a disruption in Na+ channel inactivation and a subsequent increase in inward current during the critical plateau phase of the cardiac action potential [9]. This mutation dependent inward current, termed late non-inactivating sodium current (INaL), has been shown to increase when channels are opened at slower frequencies [10]. Consistent with this idea, LQT-3 patients have an increased risk of fatal arrhythmia during periods of slow heart rate such as sleep due, at least in part, to a further increase in APD when heart rate slows [10], [11].
Na+ channel blockers such as mexiletine and flecainide, which are members of the local anesthetic (LA) family of drugs, are currently believed to be the most effective treatment for LQT-3 patients due to preferential inhibition of INaL [1], [12], [13]. Given LQT-3 patients increased risk of arrhythmia during periods of slowed heart rate, beta-blockers would seem to be a potentially harmful course of treatment because of the slowing of heart rate that accompanies reduced adrenergic input. As early as the 1960s, beta-blockers have been thought to have LA-like activity [14], [15], [16]. This property of beta-blockers, particularly propranolol, has been further supported by its anti-arrhythmic efficacy [17]. However, while this LA activity has long been appreciated its molecular basis as well as the potential impact of propranolol treatment in LQT-3 patients, particularly via block of mutation-altered INaL, have been largely unexamined. Recent computational modeling work has suggested that a closer experimental examination of beta-blocker activity on LQT-3 patients may be necessary [18].
Here we show that the beta-blockers propranolol and carvedilol, but not metoprolol, block sodium current in a manner similar to the blocking of LA drugs. We examine closely the effects of propranolol on WT NaV1.5 channels as well as a series of mutant channels. We demonstrate that propranolol efficacy is dependent on the inactivated state of the channel; that propranolol blocks late non-inactivating current more effectively than peak sodium current; and that mutation of the LA binding site greatly reduces the efficacy of propranolol block of NaV1.5 channels. Our results reveal the molecular basis of beta-blocker modulation of heart Na+ channels and indicate that, like local anesthetic drugs, beta-blocker effects on Na+ channels differ with drug structure and the biophysical properties of inactivation that depend on specific LQT-3 mutations.
Section snippets
Electrophysiology
Site-directed mutagenesis was done on NaV1.5 in pcDNA3.1 using the Quik Change site-directed mutagenesis kit (Stratagene). Whole cell recordings were made on Human Embryonic Kidney (HEK) 293 cells expressing WT and mutant NaV1.5 channels along with hβ1 subunits (Lipofectamine, Invitrogen) [19].
Patch clamp procedures were used with the following internal solution (in mM): 50 aspartic acid, 60 CsCl, 5 Na2ATP, 11 EGTA, 10 HEPES, 4.27 CaCl2 (resulting in a final [Ca2+]i of 100 nM), and 1 MgCl2, pH
Propranolol blocks wild type Na+ channels in a use-dependent manner: similarity to effects of local anesthetic drugs
In order to determine whether beta-blockers such as propranolol, block Na+ channel currents similarly to LAs, we first investigated the effects of propranolol on Na+ channels expressed in human embryonic kidney (HEK) cells transfected with wild type (WT) channels and the beta subunit hβ1 using whole cell patch clamp procedures. To facilitate the comparison of the properties of propranolol on sodium channels with those of previously studied LA molecules, we chose first to examine the
Discussion
Beta-blockers have become first-line prophylactic therapy for the management of LQTS. While this approach is highly successful for the treatment of patients with LQT-1, clinical evidence suggests that patients with mutations in SCN5A show little reduction in the frequency of cardiac events when treated with beta-blockers [6], [30]. In addition, there is significant evidence both at the channel level as well as the whole animal level that slow heart rates present an increased risk for
Acknowledgment
This work was supported by grants from the NIH (1R01 HL-56810-15 to RSK and TG HL087745 support for JRB).
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