Pentamidine reduces hERG expression to prolong the QT interval

Area of Science:

• Pharmacology
• Cardiology
• Molecular Biology

Background:

• Pentamidine is an antiprotozoal agent known to cause QT prolongation and arrhythmias.
• The precise ionic mechanism underlying pentamidine-induced cardiac events remains unclear.

Purpose of the Study:

• To elucidate the ionic mechanism of pentamidine-induced QT prolongation.
• To investigate the effect of pentamidine on the hERG channel and cardiac action potential.

Main Methods:

• HEK-293 cells stably expressing hERG channels were used to assess hERG current inhibition.
• Freshly isolated guinea-pig ventricular myocytes were used to evaluate effects on L-type calcium current and action potential duration.
• Chronic incubation studies with pentamidine were performed to examine long-term effects on hERG channel expression.

Main Results:

• Pentamidine showed concentration-dependent inhibition of hERG current (IC50 = 252 microM) but did not affect L-type calcium current.
• At clinically relevant concentrations, acute pentamidine exposure had minimal effects on action potential duration.
• Chronic incubation with clinically relevant pentamidine concentrations (1 and 10 microM) significantly reduced hERG current density (36% and 85%, respectively).
• Western blot and confocal microscopy revealed reduced hERG protein levels and surface membrane expression in treated cells.

Conclusions:

• Pentamidine's direct inhibition of the hERG channel occurs at concentrations higher than typically achieved clinically.
• Chronic administration of pentamidine at clinically relevant exposures reduces the membrane expression of the hERG channel.
• This reduction in hERG channel expression is the likely mechanism for pentamidine-induced QT prolongation and torsade de pointes in patients.