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

Abstract

Abstract. Although acute treatment of pentamidine does not directly modify any ionic channel function in the heart at clinically relevant concentrations, its continuous exposure can prolong QT interval. Recent in vitro studies have indicated that hERG trafficking inhibition may play an important role in the onset of pentamidine-induced long QT syndrome. In this study, we examined acute in vivo electropharmacological effects of pentamidine using the halothaneanesthetized canine model (n = 5). The clinically relevant total dose of 4 mg/kg of pentamidine (namely, 1 mg/kg, i.v. over 10 min followed by 3 mg/ kg, i.v. over 10 min with a pause of 20 min) decreased the mean blood pressure, ventricular contraction, preload to the left ventricle, and peripheral vascular resistance. Pentamidine also enhanced the atrioventricular conduction in parallel with its cardiohemodynamic actions, but it gradually prolonged both the ventricular repolarization period and effective refractory period, whereas no significant change was detected in the intraventricular conduction. Thus, acute administration of a clinically relevant dose of pentamidine can suppress cardiac function and vascular tone with reflex-mediated increase of sympathetic activity, whereas it may delay the repolarization process, suggesting that inhibition of potassium-channel trafficking might be induced more acutely in vivo than those previously expected in vitro.

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

“…Intravenous administration in some patients delays ventricular repolarization and induces ventricular tachycardia, consistent with hERG block. Although pentamidine does indeed inhibit hERG function, this requires prolonged drug treatment and is mediated through inhibition of channel trafficking [23], a mechanism that is too slow to explain the more rapid cardiac effects of the drug [24]. Van der Hayden and colleagues [25] reasoned that some of the effects could be due to inhibition of I K1 current carried by members of the Kir2.x subfamily.…”

Effect of Terfenadine and Pentamidine on the hERG Channel and Its Intracellular Trafficking: Combined Analysis with Automated Voltage Clamp and Confocal Microscopy

“…7) Nevertheless, assessment of hERG-blocking activity has been proven to be valid for the risk evaluation of a majority of drugs. [8][9][10] However, there are some drugs which have no acute effect on the hERG channel current, but induce QT prolongation and ventricular arrhythmia such as pentamidine, [11][12][13] probucol 14,15) and cardiac glycosides. 16) These drugs have been reported to inhibit the intracellular trafficking of the hERG channel to the cell membrane.…”

Cardiac and Haemodynamic Effects of Tacrolimus in the Halothane‐Anaesthetized Dog

“…In experiment 2, we examined this hypothesis; however, only supratherapeutic tacrolimus concentrations inhibited hERG K + current which defines the rapid component of delayed rectifier K + current in the human heart. Recently, we reported a similar extent of discrepancy in drug concentrations between repolarization delay in the halothane‐anaesthetized canine model and in vitro hERG K + current inhibition for a typical hERG‐trafficking inhibitor pentamidine, leading a conclusion that hERG‐trafficking inhibition by pentamidine can be induced more acutely in vivo than those previously expected in vitro [35]. It remains to be elucidated that tacrolimus may induce such trafficking defects using specific screening system, as approximately 40% of acute hERG blockers also affect trafficking at lower concentrations, leading to reduced density of ionic channel [36].…”