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Beta-adrenergic receptor antagonists (-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 wild-type or mutant cardiac sodium channels (Nav1.5) coexpressed with 1 subunit in tsA201 cells. Nadolol had a ∼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 Nav1.5in 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.

Objective: To gain some insight on the lesser arrhythmogenic properties of PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride] compared with digoxin, we compared modulation of intracellular Ca2+dynamics by the two agents. Methods: SERCA (sarcoplasmic reticulum Ca2+-ATPase) activity and Ca2+leak rate were measured in sarcoplasmic reticulum (SR) vesicles from guinea pig ventricles. Membrane current, intracellular Ca2+, and twitch amplitude were evaluated in guinea pig ventricular myocytes with or without blockade of the Na+/Ca2+exchanger. Results: In SR vesicles, PST2744 (30–300 nM), but not digoxin, increased SERCA activity; digoxin only (≥0.1 nM) increased SR Ca2+leak. In myocytes with blocked Na+/Ca2+exchanger, Ca2+reloading of caffeine-depleted SR was enhanced by PST2744 and slightly inhibited by digoxin. In myocytes with functioning Na+/Ca2+exchanger, both agents increased diastolic Ca2+, SR Ca2+content, the gain of Ca2+-induced Ca2+release, the rate of cytosolic Ca2+decay, twitch amplitude, and relaxation rate. Consistent with the observations in SR vesicles, the effects on SR Ca2+content and Ca2+decay rate were significantly larger for PST2744 than for digoxin. Conclusions: In isolated SR vesicles, PST2744 and digoxin directly affected SR function in opposite ways; this could be reproduced in myocytes during Na+/Ca2+exchanger blockade. Under physiological conditions (functioning Na+/Ca2+exchanger), the two agents affected Ca2+dynamics in the same direction, as expected by their Na+/K+pump inhibition; however, differential SR modulation was still expressed by quantitative differences. Thus, the more favorable inotropy-to-toxicity ratio previously described for PST2744 appears to be associated with direct SERCA stimulation and/or lack of enhancement of Ca2+leak.