The phenothiazine drugs inhibit hERG potassium channels

Area of Science:

• Pharmacology
• Cardiology
• Molecular Biology

Background:

• Cardiovascular adverse effects, including arrhythmias and sudden death, are common with phenothiazine drugs.
• Cardiac potassium channel blockade, particularly of the human ether-a-go-go-related gene (hERG) channel, is a primary mechanism for these serious consequences.
• The diverse pharmacological and structural nature of phenothiazines necessitates investigation into their specific effects on hERG channels.

Purpose of the Study:

• To investigate the effects of four distinct phenothiazine drugs (thioridazine, chlorpromazine, trifluoperazine, and perphenazine) on hERG channel activity.
• To determine the potency of these drugs in blocking hERG potassium channels.
• To characterize the mechanism of hERG channel inhibition by thioridazine.

Main Methods:

• HEK293 cells stably expressing hERG channels were utilized.
• Ion currents were measured using the patch-clamp technique.
• Inhibition constants (IC50) and voltage-dependence of channel block were determined for each drug.

Main Results:

• All four phenothiazine drugs tested blocked hERG potassium channels.
• Thioridazine exhibited the highest potency with an IC50 of 224 nM, followed by perphenazine (1003 nM), trifluoperazine (1406 nM), and chlorpromazine (1561 nM).
• Thioridazine's inhibition was voltage-dependent, significantly altering channel activation potentials, while other drugs showed no significant changes.

Conclusions:

• Thioridazine demonstrates significant hERG channel blockade, suggesting a higher risk for drug-induced arrhythmias compared to the other tested phenothiazines.
• The findings highlight the importance of evaluating individual phenothiazine drugs for their potential to inhibit hERG channels.
• Further research is warranted to understand the clinical implications of these hERG channel interactions for patient safety.