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.