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.