- Title
- Phenytoin Reduces Activity of Cardiac Ryanodine Receptor 2; A Potential Mechanism for Its Cardioprotective Action
- Creator
- Ashna, A.; van Helden, D. F.; dos Remedios, C.; Molenaar, P.; Laver, D. R.
- Relation
- NHMRC.APP1082204 http://purl.org/au-research/grants/nhmrc/1082204
- Relation
- Molecular Pharmacology Vol. 97, Issue 4, p. 250-258
- Publisher Link
- http://dx.doi.org/10.1124/mol.119.117721
- Publisher
- American Society for Pharmacology and Experimental Therapeutics
- Resource Type
- journal article
- Date
- 2020
- Description
- Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca2+ leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca2+ release during systole or affecting Ca2+ release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC50 ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca2+] but not at Ca2+ levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca2+ in a manner paralleling that of dantrolene. Moreover, the IC50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias.
- Subject
- phenytoin; cardiac; calcium; ryanodine receptor
- Identifier
- http://hdl.handle.net/1959.13/1463579
- Identifier
- uon:46774
- Identifier
- ISSN:1521-0111
- Language
- eng
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