Block of tetrodotoxin-sensitive, Na(V)1.7 and tetrodotoxin-resistant, Na(V)1.8, Na+ channels by ranolazine.

Evidence supports a role for the tetrodotoxin-sensitive Na(V)1.7 and the tetrodotoxin-resistant Na(V)1.8 in the pathogenesis of pain. Ranolazine, an anti-ischemic drug, has been shown to block cardiac (Na(V)1.5) late sodium current (I(Na)). In this study, whole-cell patch-clamp techniques were used to determine the effects of ranolazine on human Na(V)1.7 (hNa(V)1.7 + beta(1) subunits) and rat Na(V)1.8 (rNa(V)1.8) channels expressed in HEK293 and ND7-23 cells, respectively. Ranolazine reduced hNa(V)1.7 and rNa(V)1.8 I(Na) with IC50 values of 10.3 and 21.5 microM (holding potential = -120 or -100 mV, respectively). The potency of I(Na) block by ranolazine increased to 3.2 and 4.3 microM when 5-sec depolarizing prepulses to -70 (hNa(V)1.7) and -40 (rNa(V)1.8) mV were applied. Ranolazine caused a preferential hyperpolarizing shift of the steady-state fast, intermediate and slow inactivation of hNa(V)1.7 and intermediate and slow inactivation of rNa(V)1.8, suggesting preferential interaction of the drug with the inactivated states of both channels. Ranolazine (30 microM) caused a use-dependent block (10-msec pulses at 1, 2 and 5 Hz) of hNa(V)1.7 and rNa(V)1.8 I(Na) and significantly accelerated the onset of, and slowed the recovery from inactivation, of both channels. An increase of depolarizing pulse duration from 3 to 200 msec did not affect the use-dependent block of I(Na) by 100 microM ranolazine. Taken together, the data suggest that ranolazine blocks the open state and may interact with the inactivated states of Na(V)1.7 and Na(V)1.8 channels. The state-and use-dependent modulation of hNa(V)1.7 and rNa(V)1.8 Na+ channels by ranolazine could lead to an increased effect of the drug at high firing frequencies, as in injured neurons.