title: Inhibition of the cardiac L-type calcium channel current by the TRPM8 agonist, (-)-menthol.
abstract: (-)-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.
authors.affiliation: Bristol Heart Institute Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, UK.
authors.forename: R L
authors.initials: RL
authors.lastname: Baylie
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: P D
authors.initials: PD
authors.lastname: Langton
authors.forename: A F
authors.initials: AF
authors.lastname: James
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002460:Cell Line; D003080:Cold Temperature; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008610:Menthol / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000502:physiology; D009553:Nimodipine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D050053:TRPM Cation Channels / Q000819:agonists*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011744:Pyrimidinones; D050053:TRPM Cation Channels; D008610:Menthol; D009553:Nimodipine; C490483:icilin