Inhibition of cardiac sodium currents by toluene exposure
Source:
Abstract
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 Nav1.5 cDNA and in isolated rat ventricular myocytes.
In oocytes, toluene inhibited sodium currents (INa+) in a concentration‐dependent manner, with an IC50 of 274 μM (confidence limits: 141–407μM). The inhibition was complete, voltage‐independent, and slowly reversible.
Toluene had no effect on: (i) the shape of the I–V curves; (ii) the reversal potential of Na+; and (iii) the steady‐state inactivation.
The slow recovery time constant from inactivation of INa+ decreased with toluene exposure, while the fast recovery time constant remained unchanged.
Block of INa+ by toluene was use‐ and frequency‐dependent.
In rat cardiac myocytes, 300 μM toluene inhibited the sodium current (INa+) by 62%; this inhibition was voltage independent.
These results suggest that toluene binds to cardiac Na+ channels in the open state and unbinds either when channels move between inactivated states or from an inactivated to a closed state.
The use‐ and frequency‐dependent block of INa+ by toluene might be responsible, at least in part, for its arrhythmogenic effect.
British Journal of Pharmacology (2003) 140, 653–660. doi:10.1038/sj.bjp.0705481
Abbreviations:
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CL: confidence limits
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gNa+: sodium conductance
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gNa+max: maximum sodium conductance
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INa+: whole‐cell sodium current
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IC50: inhibitory concentration at 50%
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k: slope factor
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Nav1.5: human cardiac sodium channels
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τf: fast recovery time constant
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τon: time constant for block
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τs: slow recovery time constant
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Vm: membrane potential
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Vm1/2: half‐activation or inactivation potential
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Vt: test potential
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