Inhibition of the cardiac l-type calcium channel current by the trpm8 agonist,(-)-menthol

(-)-menthol and icilin are agonists of the thermoreceptor non-selective cation channel,trpm8,and are commonly used to investigate trpm8 function without a full appreciation of their non-specific effects. to investigate the hypothesis that (-)-menthol and icilin inhibit cardiovascular-type l-type ca2+ channel currents (ica,l),the actions of the trpm8 agonists on rabbit ventricular myocyte ica,l were examined at near-physiological temperature (~35°c) using whole-cell recording. icilin (3-100 μm) did not significantly inhibit ica,l. (3) in contrast,(-)-menthol concentration-dependently inhibited peak ica,l (ic50=74.6 μm; log10ic50(m)=-4.13±0.14). (-)-menthol blocked the late ica,l remaining at the end of depolarising pulses with greater efficacy (96.1±2.4% block at 1 mm) than peak ica,l (68.9±5.7% block at 1 mm,p<0.01),although there was no difference in potency of block of peak and late currents. block by (-)-menthol showed no voltagedependence. the actions of (-)-menthol were compared with those of nimodipine. nimodipine was a more efficacious (97.3±1.5 % block at 30 μm,p<0.01) and potent (ic50=0.74 μm; log10ic50(m)=-6.13±0.08,p<0.0001) blocker of peak ica,l than (-)-menthol. in contrast to (-)-menthol,nimodipine showed greater potency (ic50=0.056 μm; log10ic50(m)=- 7.25±0.17,p<0.0001),but not greater efficacy,in block of late compared with peak ica,l. in summary,these data demonstrate that,at near-physiological temperature,(-) -menthol blocks cardiac ica,l at concentrations similar to those reportedly effective in trpm8-agonism. the data suggest that the mechanism of l-type ca2+ channel block by (-)- menthol differs from that of nimodipine.