Sympathetic activation enhances QT prolongation by quinidine

Introduction: Salt restriction results in endogenous sympathetic activation, and we previously showed that plasma concentrations of quinidine measured after oral drug administration are increased during a low-salt diet. However, it is not known whether, independent of effects on plasma concentration, the extent to which quinidine prolongs the QT interval also is modulated by changes in endogenous sympathetic activity. Methods and Results: In these studies, we evaluated quinidine concentration-QT relations during low-salt (10 mEq/day for 8 days) and high-salt (400 mEq/day for 8 days) diets, with or without beta blockade in normal volunteers. In the absence of beta blockade, the concentration producing a fixed (15%) increase in QTc was significantly lower with salt restriction: 1.2 ± 0.4 μg/mL (low salt) versus 2.2 ± 0.4 μg/mL (high salt) (P < 0.01). With beta blockade, this difference was abolished: 1.9 ± 0.3 μg/mL (low salt + beta blockade) versus 2.1 ± 0.3 μg/mL (high salt + beta blockade). QT morphologic abnormalities including bifid T waves and U waves were abolished with beta-adrenergic blockade. Conclusion: Sympathetic activation by a low-salt diet not only modulates drug disposition but also increases sensitivity to drug-induced QT prolongation.