Vinpocetine is a potent blocker of rat Nav1.8 tetrodotoxin-resistant sodium channels

Vinpocetine is a clinically used synthetic vincamine derivative with a diverse pharmacological profile that includes action at several ion channels, principally "generic" populations of sodium channels that give rise to tetrodotoxin-sensitive conductances. A number of cell types are known to express tetrodotoxin-resistant (TTXr) sodium conductances, the molecular bases of which have remained elusive until recently. One such TTXr channel, termed Na(V)1.8, is of particular interest because of its prominent and selective expression in peripheral afferent nerves. The effects of vinpocetine on TTXr channels specifically, are unknown. We have assessed the effects of the drug on cloned rat Na(V)1.8 channels expressed in a dorsal root ganglion-derived cell line, ND7/23. Vinpocetine produced a concentration- and state-dependent inhibition of Na(V)1.8 sodium channel activity. Voltage-clamp experiments revealed an similar to3-fold increase in vinpocetine potency when whole-cell NaV1.8 conductances were elicited from relatively depolarized potentials (-35 mV; IC50 = 3.5 muM) compared with hyperpolarized holding potentials (-90 mV; IC50 = 10.4 muM). Vinpocetine also produced an similar to22 mV leftward shift in the voltage dependence of Na(V)1.8 channel inactivation but did not affect the voltage range of channel activation. These properties are reminiscent of several other known sodium channel blockers and suggested that vinpocetine may exhibit frequency-dependent block. Accordingly, tonic block of Na(V)1.8 channels by vinpocetine (3 muM) increased proportionally with increasing depolarizing commands over the frequency range 0.1 to 1Hz. In summary, the present data demonstrate that vinpocetine is capable of blocking Na(V)1.8 sodium channel activity and suggest a potential additional utility in various sensory abnormalities arising from abnormal peripheral nerve activity.