1 Toluene is an industrial solvent widely used as a drug of abuse, which can produce sudden sniffing death due to cardiac arrhythmias. In this paper, we tested the hypothesis that toluene inhibits cardiac sodium channels in Xenopus laevis oocytes transfected with Na v 1.5 cDNA and in isolated rat ventricular myocytes. 2 In oocytes, toluene inhibited sodium currents (I Na þ ) in a concentration-dependent manner, with an IC 50 of 274 mM (confidence limits: 141 -407mM). The inhibition was complete, voltage-independent, and slowly reversible. 3 Toluene had no effect on: (i) the shape of the I -V curves; (ii) the reversal potential of Na þ ; and (iii) the steady-state inactivation. 4 The slow recovery time constant from inactivation of I Na þ decreased with toluene exposure, while the fast recovery time constant remained unchanged. 5 Block of I Na þ by toluene was use-and frequency-dependent. 6 In rat cardiac myocytes, 300 mM toluene inhibited the sodium current (I Na þ ) by 62%; this inhibition was voltage independent. 7 These results suggest that toluene binds to cardiac Na þ channels in the open state and unbinds either when channels move between inactivated states or from an inactivated to a closed state. 8 The use-and frequency-dependent block of I Na þ by toluene might be responsible, at least in part, for its arrhythmogenic effect.

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