Pentamidine reduces hERG expression to prolong the QT interval

Abstract

1 Pentamidine, an antiprotozoal agent, has been traditionally known to cause QT prolongation and arrhythmias; however, its ionic mechanism has not been illustrated. 2 In a stable HEK-293 cell line, we observed a concentration-dependent inhibition of the hERG current with an IC 50 of 252 mM. 3 In freshly isolated guinea-pig ventricular myocytes, pentamidine showed no effect on the L-type calcium current at concentrations up to 300 mM, with a slight prolongation of the action potential duration at this concentration. 4 Since the effective concentrations of pentamidine on the hERG channel and APD were much higher than clinically relevant exposures (B1 mM free or lower), we speculated that this drug might not prolong the QT interval through direct inhibition of I Kr channel. We therefore incubated hERG-HEK cells in 1 and 10 mM pentamidine-containing media (supplemented with 10% serum) for 48 h, and examined the hERG current densities in the vehicle control and pentamidine-treated cells. 5 In all, 36 and 85% reductions of the current densities were caused by 1-and 10-mM pentamidine treatment (Po0.001 vs control), respectively. A similar level of reduction of the hERG polypeptides and a reduced intensity of the hERG protein on the surface membrane in treated cells were observed by Western blot analysis and laser-scanning confocal microscopy, respectively. 6 Taken together, our data imply that chronic administration of pentamidine at clinically relevant exposure reduces the membrane expression of the hERG channel, which may most likely be the major mechanism of QT prolongation and torsade de pointes reported in man.

Protein trafficking abnormalities: a new mechanism in drug‐induced long QT syndrome

“…The mechanism by which this drug alters repolarization has not been previously elucidated. In this issue of British Journal of Pharmacology, Cordes et al (2005) describe the mechanism by which pentamidine reduces I Kr . These authors show that pentamidine, like many drugs, blocks KCNH2 channels stably expressed in a human embryonic kidney cell (HEK293) line, and does so in a concentration-and voltage-dependent manner.…”

“…What is new in the work by Cordes et al (2005) and Kuryshev et al (2005) is the recognition that some drugs causing LQTS can selectively reduce I Kr by disrupting protein trafficking and channel maturation, rather than by direct block of surface membrane channels. This represents a new and novel indirect mechanism for causing drug-induced LQTS, and it raises several interesting questions.…”

Inhibitory Effect of Nicardipine on hERG Channel

“…3, 4). The effect was evaluated by comparison with pentamidine, an antiprotozoal agent, which has been known to prolong the QT interval and inhibit hERG expression (Singh et al, 1985;Cordes et al, 2005;Kuryshev et al, 2005). Incubation with pentamidine for 24 hr produced strong reduction of ma- ture, fully glycosylated hERG in the western blot experiment; nicardipine however, had no effect on hERG expression (Fig.…”

Effects of Acute Intravenous Administration of Pentamidine, a Typical hERG-Trafficking Inhibitor, on the Cardiac Repolarization Process of Halothane-Anesthetized Dogs

“…Meanwhile, pentamidine has been clinically shown to induce QT-interval prolongation, leading to the onset of lethal ventricular arrhythmias, namely, torsades de pointes (5 -9). The mechanism of pentamidine-induced long QT syndrome has been extensively investigated in vitro (10,11). Acute treatment of therapeutically relevant concentrations of pentamidine hardly affected human ether a-go-go related gene (hERG) current, but its continuous exposure for >16 h can decrease hERG channel current together with the reduction of hERG channel protein of cell surface membrane (11).…”

“…Acute treatment of therapeutically relevant concentrations of pentamidine hardly affected human ether a-go-go related gene (hERG) current, but its continuous exposure for >16 h can decrease hERG channel current together with the reduction of hERG channel protein of cell surface membrane (11). Since pentamidine did not affect the other cardiac ion channels either by acute or continuous exposure (11), hERG trafficking inhibition is considered to play a major role for the pentamidine-induced long QT syndrome (10,11). Similar inhibitory action on hERG trafficking has been reported with some other drugs, including arsenic trioxide, an anticancer agent for acute promyelocytic leukemia, and ketoconazole, an antifungal agent (12,13).…”