Blockade of the human cardiac K+ channel Kv1.5 by the antibiotic erythromycin

Abstract

Erythromycin administration has been associated with a prolongation of cardiac repolarization in certain clinical settings. This could be due to blockade of voltage-dependent K+ channels in the human heart. For this reason we examined the effects of erythromycin on a rapidly activating delayed rectifier K+ channel (Kv1.5) cloned from human heart and stably expressed in human embryonic kidney cells. When examined using the whole-cell patch clamp technique, erythromycin (100 microM) blocked Kv1.5 current in a time-dependent manner but required prolonged exposure to do so. However, when we examined Kv1.5 current using inside-out macro-patches, erythromycin applied to the cytoplasmic surface rapidly (within 1-2 min) inhibited Kv1.5 current with an IC50 value of 2.6 x 10(-5)M (1.7 - 3.9 x 10(-5)M, 95% C.L.). The main effect of erythromycin was to accelerate the rate of Kv1.5 current decay thereby reducing the current at the end of a prolonged voltage-clamp pulse. Erythromycin also blocked Kv1.5 current in both a voltage- and frequency-dependent manner but had little effect on the activation kinetics, deactivation kinetics, or the steady-state inactivation properties of Kv1.5. These data suggest that erythromycin acts as a blocker of an activated state of the Kv1.5 channel and that it may access its binding site from the intracellular face of the channel. This study is the first to examine the effects of erythromycin on a cloned human cardiac K+ channel. It is concluded that erythromycin blocks Kv1.5 at clinically relevant concentrations. Blockade of voltage-dependent K+ channels in the heart could contribute to the alterations in cardiac repolarization that have been observed with erythromycin.

Understanding hERG inhibition with QSAR models based on a one-dimensional molecular representation

“…Since these differences were small compared to the estimated error in the data itself, we believe the procedure is essentially independent of the initial alignment. All subsequent models were built based on a subset alignment of ziprasidone [18,41], verapamil [61,62], thioridazine [18,41], sertindole [18,41,42], risperidone [18,41], pimozide [18,41], loratadine [65,72], haloperidol [18,21,75], E-4031 [11,18], and cisapride [21,[49][50][51]. Next, to thoroughly determine the optimal value of the ridge coefficient (c of Eq.…”

Combined Effect of Disopyramide and Erythromycin on Ventricular Repolarization in Dogs With Complete Atrioventricular Block

“…[8][9][10][11][12] Erythromycin has been shown to block the rapid component of the delayed rectifier potassium current in guinea pig ventricular myocytes and human cardiac K + channel Kv1.5 at clinically relevant concentrations. 15,16) However, Rubart, et al reported that erythromycin at doses exceeding 20 mg/L prolonged APD both in vitro and in vivo, but the relative rare occurrence of EAD and ventricular arrhythmias suggested that other predisposing factors contribute to the acquired LQTS associated with erythromycin. 17) Eckardt, et al reported that ventricular tachyarrhythmias occurred in erythromycin-treated atrioventricular-blocked isolated rabbit hearts only in the presence of hypokalemia.…”

Molecular Predictors of Drug-induced Prolongation of the QT Interval

“…These mutations are predicted to cause a wide spectrum of diminished I Kr and delayed ventricular repolarization, consistent with the prolonged QT observed in individuals with LQTS. Several drugs that bind with high affinity to HERG channels (nanomolar range) expressed in Xenopus oocytes prolong the QT interval and cause TdP [14,[31][32][33][34][35]. Missence mutations of KCNE1 are also associated with prolongation of the QT interval, and have been found both in patients with LQTS or drug-induced arrhythmia [28].…”