Potent hERG channel inhibition by sarizotan, an investigative treatment for Rett Syndrome.
J Mol Cell Cardiol
; 135: 22-30, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31362019
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 183â¯nM) and of native ventricular IKr from guinea-pig ventricular myocytes. 100â¯nM and 1⯵M sarizotan prolonged ventricular action potential (AP) duration (APD90) by 14.1⯱â¯3.3% (nâ¯=â¯6) and 29.8⯱â¯3.1% (nâ¯=â¯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.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Síndrome de Rett
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Miócitos Cardíacos
Tipo de estudo:
Etiology_studies
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Risk_factors_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido