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Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action
- Source :
- International Journal of Molecular Sciences, Volume 20, Issue 23
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- Roxadustat (FG-4592), an analog of 2-oxoglutarate, is an orally-administered, heterocyclic small molecule known to be an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase. However, none of the studies have thus far thoroughly investigated its possible perturbations on membrane ion currents in endocrine or heart cells. In our studies, the whole-cell current recordings of the patch-clamp technique showed that the presence of roxadustat effectively and differentially suppressed the peak and late components of IK(DR) amplitude in response to membrane depolarization in pituitary tumor (GH3) cells with an IC50 value of 5.71 and 1.32 &mu<br />M, respectively. The current inactivation of IK(DR) elicited by 10-sec membrane depolarization became raised in the presence of roxadustatt. When cells were exposed to either CoCl2 or deferoxamine (DFO), the IK(DR) elicited by membrane depolarization was not modified<br />however, nonactin, a K+-selective ionophore, in continued presence of roxadustat, attenuated roxadustat-mediated inhibition of the amplitude. The steady-state inactivation of IK(DR) could be constructed in the presence of roxadustat. Recovery of IK(DR) block by roxadustat (3 and 10 &mu<br />M) could be fitted by a single exponential with 382 and 523 msec, respectively. The roxadustat addition slightly suppressed erg-mediated K+ or hyperpolarization-activated cation currents. This drug also decreased the peak amplitude of voltage-gated Na+ current with a slowing in inactivation rate of the current. Likewise, in H9c2 heart-derived cells, the addition of roxadustat suppressed IK(DR) amplitude in combination with the shortening in inactivation time course of the current. In high glucose-treated H9c2 cells, roxadustat-mediated inhibition of IK(DR) remained unchanged. Collectively, despite its suppression of HIF prolyl hydroxylase, inhibitory actions of roxadustat on different types of ionic currents possibly in a non-genomic fashion might provide another yet unidentified mechanism through which cellular functions are seriously perturbed, if similar findings occur in vivo.
- Subjects :
- Patch-Clamp Techniques
pituitary cell and heart cell
Glycine
Ionophore
Nonactin
Inhibitory postsynaptic potential
Article
Catalysis
Hypoxia-Inducible Factor-Proline Dioxygenases
Membrane Potentials
delayed-rectifier K+ current
current kinetics
Inorganic Chemistry
chemistry.chemical_compound
In vivo
Cell Line, Tumor
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
IC50
Spectroscopy
Ion Transport
voltage-gated Na+ current
roxadustat
Chemistry
Sodium
Organic Chemistry
Prolyl-Hydroxylase Inhibitors
Depolarization
General Medicine
HIF prolyl-hydroxylase inhibitor
Isoquinolines
Rats
Computer Science Applications
Hypoxia-inducible factors
Potassium
Biophysics
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....596266be5607cd6e725adb7c504a09ef