In vitro ion channel profile and ex vivo cardiac electrophysiology properties of the R(-) and S(+) enantiomers of hydroxychloroquine
| Autor: | Céline Prévost, Eric Brohan, Odile Angouillant-Boniface, G.Andrees Böhme, Sylvie Houtmann, Céline Chantoiseau, Thierry Carriot, Veronique Ballet, Sophie Fouconnier, Laurent Schio, Michel Partiseti, Rachid Boukaiba, Jean-Marie Chambard, Brigitte Schombert |
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| Rok vydání: | 2022 |
| Předmět: |
Patch-Clamp Techniques
Purkinje fibers hERG Action Potentials Pharmacology Ion Channels Membrane Potentials Afterdepolarization Purkinje Fibers Antimalarials Electrocardiography medicine Animals Humans Ion channel biology Chemistry Arrhythmias Cardiac Heart Stereoisomerism Cardiac action potential Resting potential Ether-A-Go-Go Potassium Channels Potassium channel Electrophysiology medicine.anatomical_structure biology.protein Rabbits Electrophysiologic Techniques Cardiac Hydroxychloroquine |
| Zdroj: | European Journal of Pharmacology. 915:174670 |
| ISSN: | 0014-2999 |
| Popis: | Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 μM–100 μM range with a 2–4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 μM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 μM and 30 μM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro. |
| Databáze: | OpenAIRE |
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