Nadolol Block of Nav1.5 Does Not Explain Its Efficacy in the Long QT Syndrome

Beta-adrenergic receptor antagonists (beta-blockers) are the therapy of choice for the long QT syndrome but their efficacy is not homogeneous: propranolol and nadolol are the most effective, whereas metoprolol is associated with more treatment failures. Propranolol has a blocking effect on the sodium current ("membrane-stabilizing" effect), and it has been hypothesized that the efficacy of nadolol might be due to a similar effect. Accordingly, we used whole-cell patch-clamp recording to assess propranolol, nadolol, and metoprolol block of wildtype or mutant cardiac sodium channels (Nav1.5) coexpressed with beta 1 subunit in tsA201 cells. Nadolol had a similar to 20% non-use-dependent blocking effect on peak sodium current and no effect on the persistent current evoked by the LQT3 mutant A1330D, whereas propranolol blocked Nav1.5 in a use-dependent manner and reduced A1330D persistent current. Metoprolol had no effect on either the peak or persistent current. Analysis of the biophysical properties of the channel revealed that both nadolol and propranolol cause hyperpolarizing shifts on voltage dependence of activation and steady-state inactivation, whereas metoprolol shifts only the activation curve. These results provide partial explanation for the differences between nadolol and metoprolol but do not explain the similar clinical efficacy of nadolol and propranolol.