Activation of cold-sensing transient receptor potential melastatin subtype 8 antagonizes vasoconstriction and hypertension through attenuating RhoA/Rho kinase pathway

Hypertension. 2014 Jun;63(6):1354-63. doi: 10.1161/HYPERTENSIONAHA.113.02573. Epub 2014 Mar 17.


Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8(-/-) mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flow-mediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had favorable effects on hypertension treatment.

Keywords: TRPM8 protein, human; hypertension; menthol; muscle; rho-associated kinases; smooth, vascular; vasoconstriction.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Blotting, Western
  • Calcium / metabolism
  • Calcium / pharmacology
  • Capsules
  • Cells, Cultured
  • Cold Temperature
  • Female
  • Humans
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Hypertension / prevention & control*
  • In Vitro Techniques
  • Male
  • Menthol / pharmacology*
  • Menthol / therapeutic use
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / metabolism
  • Mesenteric Arteries / physiology
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth / cytology
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • TRPM Cation Channels / agonists*
  • TRPM Cation Channels / deficiency
  • TRPM Cation Channels / genetics
  • Vasoconstriction / drug effects*
  • Vasoconstriction / genetics
  • Vasoconstriction / physiology
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism*


  • Capsules
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Menthol
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein
  • Calcium