Selective inhibition by riluzole of voltage-dependent sodium channels and catecholamine secretion in adrenal chromaffin cells

Abstract

We examined the effects of riluzole, a neuroprotective drug, on voltage-dependent Na channels, nicotinic receptors, and voltage-dependent Ca channels, as well as catecholamine secretion, in comparison with those of verapamil and nicardipine, in primary cultures of bovine adrenal chromaffin cells. Riluzole inhibited veratridine-induced 22Na influx via voltage-dependent Na channels even in the presence of ouabain, an inhibitor of Na,K-ATPase. Blockade of Na channels by riluzole was concentration-dependent with an IC50 of 5.3 microM. It was associated with a similar concentration-related reduction of veratridine-induced 45Ca influx via voltage-dependent Ca channels, and of catecholamine secretion. Riluzole had no effect on 45Ca influx caused by high K, which directly activates voltage-dependent Ca channels, and on nicotine-induced 22Na influx, which passes through the nicotinic receptors. Verapamil and nicardipine attenuated 22Na influx caused by veratridine or nicotine at the same concentrations as they suppressed high K-induced 45Ca influx. The inhibitory effect of riluzole on veratridine-induced 22Na influx disappeared at high concentrations of veratridine. A potentiation of veratridine (site 2 toxin)-induced 22Na influx caused by alpha-scorpion venom (site 3 toxin), beta-scorpion venom (site 4 toxin), or brevetoxin PbTx-3 (site 5 toxin), occurred in the presence of riluzole in the same manner as in control cells. These results suggest that riluzole binds to the veratridine site in voltage-dependent Na channels. It does not impair the cooperative interaction between the functional peptide segments of Na channels, but selectively inhibits gating of Na channels, thereby reducing Ca influx via Ca channels and catecholamine secretion. In contrast, verapamil and nicardipine suppress Na influx both Na channels and nicotinic receptors.

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

“…First, the known I L blockers diltiazem and Cd 2ϩ showed no effect on the ACh-induced hyperpolarization. Verapamil caused 20% inhibition on the ACh-induced hyperpolarization; this could be related to its side action on other channels, rather than to its Ca 2ϩ antagonism, since its inhibition on voltage-gated K ϩ channels and Na ϩ channels has been well documented (Lin et al, 1995;Yokoo et al, 1998). It is noteworthy that these data are consistent with a previous report that diltiazem and verapamil showed little inhibition on human IK channels expressed in HEK-293 cells (Jensen et al, 1998).…”

Riluzole-induced block of voltage-gated Na+ current and activation of BKCa channels in cultured differentiated human skeletal muscle cells

“…It was demonstrated to reduce glutamate excitotoxicity by inhibiting glutamate release and/or modifying the postsynaptic glutamate receptor cascade (Martin et al, 1993;Mantz et al, 1994;Rothstein and Kuncl, 1995;De Sarro et al, 2000). In addition, emerging evidence has unraveled that riluzole can inhibit voltage-gated Na + channels (Hebert et al, 1994;Siniscalchi et al, 1997;Song et al, 1997;Yokoo et al, 1998;Zona et al, 1998;Mohammadi et al, 2002). This effect has been proposed to be mainly responsible for the prevention of epilepsy and cellular death caused by this drug (Hebert et al, 1994).…”

Neuroprotective Effect of the Novel Compound ITH33/IQM9.21 Against Oxidative Stress and Na+ and Ca2+ Overload in Motor Neuron-like NSC-34 Cells

“…and Ca 2? ion channels by riluzole (Chen et al 2006;Lamanauskas and Nistri 2008;Wang et al 2008;Yokoo et al 1998) might explain the drug's neuroprotective effect on the VTD model in NSC-34 cells. Thus, decreased entry of Ca 2?…”