Bristol Heart Institute Cardiovascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, UK.
J Physiol Pharmacol. 2010 Oct;61(5):543-50.
(-)-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.
（-）-薄荷醇和伊西利定是热敏受体非选择性阳离子通道 TRPM8 的激动剂，常用于研究 TRPM8 功能，而没有充分认识到它们的非特异性作用。为了验证（-）-薄荷醇和伊西利定抑制心血管型 L 型 Ca(2+)通道电流（I(Ca,L)）的假说，本研究在接近生理温度（≈35°C）下，采用全细胞膜片钳记录技术，研究了 TRPM8 激动剂对兔心室肌细胞 I(Ca,L)的作用。伊西利定（3-100 μM）对 I(Ca,L)无明显抑制作用。（3）相比之下，（-）-薄荷醇浓度依赖性地抑制峰值 I(Ca,L)（IC(50)=74.6 μM；log(10)IC(50)(M)=-4.13±0.14）。（-）-薄荷醇对去极化脉冲末期残留的晚期 I(Ca,L)的阻断作用更有效（1 mM 时 96.1±2.4%阻断，P<0.01），而对峰值 I(Ca,L)的阻断作用较弱（1 mM 时 68.9±5.7%阻断，P<0.01），尽管峰值和晚期电流的阻断强度没有差异。（-）-薄荷醇的作用无电压依赖性。（-）-薄荷醇的作用与尼莫地平进行了比较。尼莫地平是一种更有效的（30 μM 时 97.3±1.5%阻断，P<0.01）和有效的（IC(50)=0.74 μM；log(10)IC(50)(M)=-6.13±0.08，P<0.0001）峰值 I(Ca,L)阻断剂，而（-）-薄荷醇则不是。与（-）-薄荷醇不同，尼莫地平在晚期与峰值 I(Ca,L)的阻断作用相比，具有更高的阻断作用（IC(50)=0.056 μM；log(10)IC(50)(M)=-7.25±0.17，P<0.0001），但阻断作用较弱。综上所述，这些数据表明，在接近生理温度下，（-）-薄荷醇以类似于报道的 TRPM8 激动剂中有效的浓度阻断心脏 I(Ca,L)。这些数据表明，（-）-薄荷醇对 L 型 Ca(2+)通道的阻断作用机制与尼莫地平不同。
