Background and aims: Ranolazine, a clinically approved anti-anginal drug, has been shown to block the late sodium current. Previous studies have found the drug to be effective in animal models of inflammatory and neuropathic pain. Here, we investigated whether ranolazine has a demonstrable effect on action potential propagation in peripheral sensory nerves. 

Methods: Compound action potentials (CAP) were recorded in vitro from rat saphenous nerves in response to supramaximal electrical stimulation. The tonic block was assessed using 0.25Hz stimulus frequency whereas a frequency-dependent block was measured by trains of 100 impulses at 100Hz. Ranolazine was applied to a ring placed on the nerve between the recording and stimulation site.

Results: Ranolazine at high concentrations (100µM) failed to show CAP inhibition of intact nerves. However, in mechanically desheathed nerves, ranolazine exhibited a dose-dependent tonic block of A-fibre CAP. 1, 10 and 100µM reduced the CAP by (mean±SEM) 10±4%, 21±8% and 35±10%, respectively. Completeness of desheathing was determined at the end of each experiment by applying 1µM TTX which abolished responses in desheathed, but not in intact nerves. High-frequency trains of stimulation showed an additional reduction of CAP amplitude. In the absence of drug, it was 16% on average and was only slightly increased with ranolazine of 18%, 21% and 42% at 1, 10 and 100µM respectively.

Conclusions: Our results suggest that ranolazine is effective at clinically relevant concentrations (1-10µM) and raises the exciting possibility of repurposing the drug to treat conditions that involve neuronal hyperexcitability such as pain.

EFFECTS OF RANOLAZINE, A LATE SODIUM CURRENT BLOCKER, ON ACTION POTENTIAL PROPAGATION IN PERIPHERAL NERVES