Abstract 505: Propranolol Block of Human Cardiac Sodium Channels is Enhanced by SCN5A Mutations in Long-QT Syndrome Type 3
Propranolol is a widely-used, nonselective β-adrenergic receptor antagonist with proven efficacy in reducing mortality after myocardial infarction and in the congenital long-QT syndrome (LQTS). At plasma concentrations exceeding those required for β-adrenergic receptor inhibition, propranolol also exhibits antiarrhythmic (“membrane stabilizing”) effects that are not fully explained by β-blockade. Previous in vitro studies suggested that propranolol may have local anesthetic effects on cardiac sodium channels but there has been no direct proof of this hypothesis. We directly tested the effects of propranolol on recombinant human cardiac sodium channels (NaV1.5 encoded by SCN5A) using whole-cell patch-clamp recording of channels heterologously expressed in tsA201 cells. Propranolol exerted tonic and use-dependent block of NaV1.5 channels with IC50 values of 37.6μM and 2.9μM, respectively. During depolarizing pulse trains (−10mV, 1Hz) 3μM propranolol reduced initial peak current 10.4±2.5% (tonic block) and reduced steady-state current 52.2±3.7% (use-dependent block). By contrast, nadolol (10μM), which lacks “membrane stabilizing” effects, did not exhibit tonic or use-dependent block of NaV1.5 (peak current reduced <2.5% at 1Hz). We also tested the effects of the stereoisomer (R)-propranolol which does not block β-adrenergic receptors but does exert anti-arrhythmic effects in humans. 1μM (R)-propranolol blocks steady-state peak current 32.2±2.3% during 1Hz pulse trains similar to 1μM racemic propranolol (35.6±2.8%). Finally, we tested the effects of propranolol on specific SCN5A mutations associated with LQTS. We observed that delKPQ and R1623Q mutants exhibited significantly enhanced (~2-fold greater) use-dependent block by propranolol as compared to wild-type NaV1.5. In summary, propranolol and (R)-propranolol block human cardiac sodium channels in a dose-dependent manner and this may help explain the β-receptor independent antiarrhythmic effects of these drugs. We also show that certain mutations associated with LQTS exhibit enhanced sensitivity to propranolol, a potential mechanism whereby some patients may have greater benefit from β-blockers that have membrane stabilizing properties.