Sympathetic activation enhances QT prolongation by quinidine

Area of Science:

• Cardiovascular Pharmacology
• Autonomic Nervous System Physiology

Background:

• Salt restriction activates the endogenous sympathetic nervous system.
• Previous studies indicated salt restriction increases plasma quinidine concentrations.
• The impact of sympathetic activity on quinidine's QT interval prolongation was unknown.

Purpose of the Study:

• To investigate whether sympathetic activity influences quinidine's QT prolongation, independent of plasma drug concentrations.
• To assess the effect of salt intake on quinidine concentration-QT interval relationships.
• To determine the role of beta-adrenergic blockade in modulating these effects.

Main Methods:

• Evaluated quinidine concentration-QT relations in normal volunteers on low-salt and high-salt diets.
• Administered diets for 8 days with varying salt intake (10 mEq/day vs. 400 mEq/day).
• Conducted studies with and without beta-adrenergic blockade.

Main Results:

• The quinidine concentration causing a 15% QTc increase was lower with salt restriction (1.2 microg/mL) versus high salt (2.2 microg/mL) without beta blockade (P < 0.01).
• This difference was abolished with beta blockade (low salt: 1.9 microg/mL; high salt: 2.1 microg/mL).
• QT morphologic abnormalities were eliminated by beta-adrenergic blockade.

Conclusions:

• Sympathetic activation from low-salt diets enhances sensitivity to drug-induced QT prolongation.
• This effect is mediated, in part, by sympathetic nervous system activity.
• Beta-adrenergic blockade mitigates quinidine-induced QT prolongation and associated waveform changes.