Effects of the antianginal drug, ranolazine, on the brain sodium channel Na(V)1.2 and its modulation by extracellular protons.

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Citation

Peters CH, Sokolov S, Rajamani S, Ruben PC

Effects of the antianginal drug, ranolazine, on the brain sodium channel Na(V)1.2 and its modulation by extracellular protons.

Br J Pharmacol. 2013 Jun;169(3):704-16. doi: 10.1111/bph.12150.

PubMed ID
23472826 [ View in PubMed
]
Abstract

BACKGROUND AND PURPOSE: Ranolazine is an antianginal drug currently approved for treatment of angina pectoris in the United States. Recent studies have focused on its effects on neuronal channels and its possible therapeutic uses in the nervous system. We characterized how ranolazine affects the brain sodium channel, Na(V)1.2, and how its actions are modulated by low pH. In this way, we further explore ranolazine's potential as an anticonvulsant and its efficacy in conditions like those during an ischaemic stroke. EXPERIMENTAL APPROACH: We performed whole-cell patch-clamp experiments on the voltage-gated sodium channel, Na(V)1.2. Experiments were performed with extracellular solution titrated to either pH 7.4 or pH 6.0 before and after ranolazine perfusion. KEY RESULTS: Ranolazine accelerates onset and slows recovery of fast and slow inactivation. Ranolazine increases the maximum probability of use-dependent inactivation and reduces macroscopic and ramp sodium currents at pH 7.4. pH 6.0 reduced the slowing of fast inactivation recovery and inhibited use-dependent block by ranolazine. In the presence of ranolazine, the time constants of slow inactivation recovery and onset were significantly increased at pH 6.0 relative to pH 7.4 with 100 muM ranolazine. CONCLUSIONS AND IMPLICATIONS: Our work provides novel insights into the modulation of brain sodium channel, Na(V)1.2, by ranolazine. We demonstrate that ranolazine binds Na(V)1.2 in a state-dependent manner, and that the effects of ranolazine are slowed but not abolished by protons. Our results suggest that further research performed on channels with epilepsy-causing mutations may prove ranolazine to be an efficacious therapy.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
RanolazineVoltage gated L-type calcium channel (Protein Group)Protein groupHumans
Unknown
Inhibitor
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