Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Abstract

Chlorpheniramine is a potent first-generation histamine H1 receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. W e examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the H1 antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

“…An antihistamine overdose can cause cardiac arrhythmia by directly inhibiting cardiac K + currents. Among the various cardiac K + currents, I Kr is important for the termination of the cardiac action potential [4] . The inhibition of hERG channels has been implicated in drug-induced prolongation of the QT interval and torsades de pointes [24] .…”

“…However, the most common mechanism of delayed repolarization-which results in a prolonged QT interval-is by blocking one or more outward K + currents [3] . Among the various cardiac K + currents, I Kr is the most critical current for terminating the cardiac action potential, and this current determines the shape of the repolarization phase [4] . The pore-forming α subunit of the I Kr channel is the human ether-a-go-go-related gene (hERG) protein.…”

Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription

“…Previous literature suggests that chlorpheniramine, an H1 antihistamine, is a blocker of the hERG channels, providing a molecular mechanism for the drug‐induced arrhythmogenic side effects (Hong & Jo, ). Indeed, the hERG potassium ion channel plays a key role in cardiotoxicity and is therefore a key target as a part of preclinical drug discovery toxicity screening (Shen, Su, Esposito, Hopfinger, & Tseng, ; Sun, Xia, Austin, & Huang, ).…”

Effect of Lead Ion on the Function of the Human Ether-À-Go-Go-Related Gene K+ Channel

“…This loop makes up the pore domain (P-domain) of the channel. The functional channel works as a tetramer, with the P-domains of each subunit interacting to form a narrow construction that contains the K + binding and recognition site It has been reported that some small molecules, such as sophocarpine [31], sophoridine [31], chloroquine [32], promethazine [33], chlorpheniramine [34], isoquinoline alkaloid neferine [35], bupivacaine [36], desipramine [37], capsaicin [38], etc., can weakly interact with the K + channel protein. The weak interaction makes these small molecules enter the cavity of the K + channel protein [39].…”