Abstract
Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder associated with respiratory abnormalities and, in up to ~40% of patients, with prolongation of the cardiac QTc interval. QTc prolongation calls for cautious use of drugs with a propensity to inhibit hERG channels. The STARS trial has been undertaken to investigate the efficacy of sarizotan, a 5-HT1A receptor agonist, at correcting RTT respiratory abnormalities. The present study investigated whether sarizotan inhibits hERG potassium channels and prolongs ventricular repolarization. Whole-cell patch-clamp measurements were made at 37 °C from hERG-expressing HEK293 cells. Docking analysis was conducted using a recent cryo-EM structure of hERG. Sarizotan was a potent inhibitor of hERG current (IhERG; IC50 of 183 nM) and of native ventricular IKr from guinea-pig ventricular myocytes. 100 nM and 1 μM sarizotan prolonged ventricular action potential (AP) duration (APD90) by 14.1 ± 3.3% (n = 6) and 29.8 ± 3.1% (n = 5) respectively and promoted AP triangulation. High affinity IhERG inhibition by sarizotan was contingent upon channel gating and intact inactivation. Mutagenesis experiments and docking analysis implicated F557, S624 and Y652 residues in sarizotan binding, with weaker contribution from F656. In conclusion, sarizotan inhibits IKr/IhERG, accessing key binding residues on channel gating. This action and consequent ventricular AP prolongation occur at concentrations relevant to those proposed to treat breathing dysrhythmia in RTT. Sarizotan should only be used in RTT patients with careful evaluation of risk factors for QTc prolongation.
Highlights
Rett Syndrome (RTT) is a severe X-chromosome-linked developmental disorder characterized by cognitive and motor skill deficits, together with autistic spectrum features, seizures and microencephaly [1,2,3]
This study demonstrates that sarizotan inhibits both inhibitor of hERG current (IhERG) and native IKr at sub-micromolar concentrations (IC50 for IhERG block of 183 nM), prolongs ventricular APD90 and increases ventricular action potential (AP) triangulation, which is a marker of proarrhythmic risk [38]
Both dofetilide and quinidine are well established to be linked to QTc interval prolongation [19] and it is notable that sarizotan is a more potent inhibitor of IhERG than is quinidine under similar experimental conditions
Summary
Rett Syndrome (RTT) is a severe X-chromosome-linked developmental disorder characterized by cognitive and motor skill deficits, together with autistic spectrum features, seizures and microencephaly [1,2,3]. Patients with RTT are almost exclusively female; males exhibit more severe respiratory and heart rate abnormalities and most die within a year of birth [2]. MECP2 gene mutations were identified in > 95% of individuals with RTT [8]. A proportion of RTT patients exhibit prolongation of the rate-corrected QT (QTc) interval and T wave abnormalities [10,11,12,13,14]., which appear to be independent of electrolyte abnormalities [11]. In 1994 Sekul and colleagues reported lengthened QTc intervals and T wave abnormalities in 41% of girls with RTT compared to age-matched healthy controls [10]. Examination of 74 females with RTT syndrome and 10 with an atypical RTT variant with preserved speech found QTc prolongation in 55% of girls with classic RTT compared to 20% with the atypical variant [12]
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