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 Ca(2+) channel currents (I(Ca,L)), the actions of the TRPM8 agonists on rabbit ventricular myocyte I(Ca,L) were examined at near-physiological temperature (≈35°C) using whole-cell recording. Icilin (3-100 μM) did not significantly inhibit I(Ca,L). (3) in contrast, (-)-menthol concentration-dependently inhibited peak I(Ca,L) (IC(50)=74.6 μM; log(10)IC(50)(M)=-4.13±0.14). (-)-Menthol blocked the late I(Ca,L) remaining at the end of depolarising pulses with greater efficacy (96.1±2.4% block at 1 mM) than peak I(Ca,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 voltage-dependence. 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 (IC(50)=0.74 μM; log(10)IC(50)(M)=-6.13±0.08, P<0.0001) blocker of peak I(Ca,L) than (-)-menthol. In contrast to (-)-menthol, nimodipine showed greater potency (IC(50)=0.056 μM; log(10)IC(50)(M)=-7.25±0.17, P<0.0001), but not greater efficacy, in block of late compared with peak I(Ca,L). In summary, these data demonstrate that, at near-physiological temperature, (-) -menthol blocks cardiac I(Ca,L) at concentrations similar to those reportedly effective in TRPM8-agonism. The data suggest that the mechanism of L-type Ca(2+) channel block by (-)-menthol differs from that of nimodipine.