Inhibition of cardiac sodium currents by toluene exposure.
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 microm (confidence limits: 141-407 microm). 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 microm 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.
Cruz
Silvia L
SL
Departamento de Farmacobiología, Cinvestav, I.P.N. Calzada de los Tenorios, # 235, Col Granjas Coapa, DF 14330, México.
Orta-Salazar
Gerardo
G
Gauthereau
Marcia Y
MY
Millan-Perez Peña
Lourdes
L
Salinas-Stefanón
Eduardo M
EM
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010063:Ovum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014050:Toluene / Q000009:adverse effects / Q000493:pharmacokinetics*; D014162:Transfection; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism
D015222:Sodium Channels; D014050:Toluene; D012964:Sodium