Key result
Droperidol is a high-affinity blocker of HERG channels (half-maximal inhibition 0.6-0.9 microM) and prolongs action potentials at antiemetic concentrations without inducing early afterdepolarizations.
Why the study?
Does droperidol inhibit HERG channels and induce action potential prolongation or early afterdepolarizations in cardiac myocytes?
Does droperidol inhibit HERG channels and induce action potential prolongation or early afterdepolarizations in cardiac myocytes?
Droperidol is a high-affinity blocker of HERG channels that prolongs action potentials at antiemetic concentrations without inducing early afterdepolarizations, likely due to concurrent interaction with calcium currents.
May explain QT prolongation without torsadogenicity in animals; leaves open human arrhythmia risk assessment.
BACKGROUND: The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes. METHODS: Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique. RESULTS: Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 microM. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nM prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed. CONCLUSIONS: Droperidol is a high-affinity blocker of HERG channels. Amino acid residues typically involved in high-affinity block mediate droperidol effects. Patch clamp results and computational modeling allow the hypothesis that interaction with calcium currents may explain why droperidol at antiemetic concentrations prolongs the action potential without inducing early afterdepolarizations.
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Schwoerer et al. (2007) studied this question. Droperidol was evaluated on HERG current inhibition and action potential duration. Droperidol is a high-affinity blocker of HERG channels (half-maximal inhibition 0.6-0.9 microM) and prolongs action potentials at antiemetic concentrations without inducing early afterdepolarizations.
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