PMID- 27899298
OWN - NLM
STAT- MEDLINE
DCOM- 20171002
LR  - 20220318
IS  - 1095-9319 (Electronic)
IS  - 0026-2862 (Print)
IS  - 0026-2862 (Linking)
VI  - 110
DP  - 2017 Mar
TI  - Mechanisms and time course of menthol-induced cutaneous vasodilation.
PG  - 43-47
LID - S0026-2862(16)30175-3 [pii]
LID - 10.1016/j.mvr.2016.11.008 [doi]
AB  - Menthol is a vasoactive compound that is widely used in topical analgesic agents. 
      Menthol induces cutaneous vasodilation, however the underlying mechanisms are 
      unknown. Determining the rates of appearance and clearance of menthol in the skin 
      is important for optimizing topical treatment formulation and dosing. The purpose 
      of this study was to determine the mechanisms contributing to menthol-mediated 
      cutaneous vasodilation and to establish a time course for menthol 
      appearance/clearance in the skin. Ten young (23+/-1years, 5 males 5 females) 
      subjects participated in two protocols. In study 1, four intradermal 
      microdialysis fibers were perfused with increasing doses of menthol (0.1-500mM) 
      and inhibitors for nitric oxide (NO), endothelium derived hyperpolarizing factors 
      (EDHFs), and sensory nerves. Skin blood flow was measured with laser Doppler 
      flowmetry and normalized to %CVC(max). In study 2, two intradermal microdialysis 
      fibers were perfused with lactated Ringer's solution. 0.017mL.cm(-2) of a 4% 
      menthol gel was placed over each fiber. 5muL samples of dialysate from the 
      microdialysis fibers were collected every 30min and analyzed for the presence of 
      menthol with high performance gas chromatography/mass spectrometry. Skin blood 
      flow (laser speckle contrast imaging) and subjective ratings of menthol sensation 
      were simultaneously obtained with dialysate samples. In study 1, menthol induced 
      cutaneous vasodilation at all doses >/=100mM (all p<0.05). However, inhibition of 
      either NO, EDHFs, or sensory nerves fully inhibited menthol-mediated vasodilation 
      (all p>0.05). In study 2, significant menthol was detected in dialysate 30min 
      post menthol application (0.89ng, p=0.0002). Relative to baseline, cutaneous 
      vasodilation was elevated from minutes 15-45 and ratings of menthol sensation 
      were elevated from minute 5-60 post menthol application (all p<0.05). Menthol 
      induces cutaneous vasodilation in the skin through multiple vasodilator pathways, 
      including NO, EDHF, and sensory nerves. Topical menthol is detectable in the skin 
      within 30min and is cleared by 60min. Skin blood flow and perceptual measures 
      follow a similar time course as menthol appearance/clearance.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Craighead, Daniel H
AU  - Craighead DH
AD  - The Pennsylvania State University, University Park, PA 16802, United States. 
      Electronic address: dhc139@psu.edu.
FAU - McCartney, Nathaniel B
AU  - McCartney NB
AD  - The Pennsylvania State University, University Park, PA 16802, United States.
FAU - Tumlinson, James H
AU  - Tumlinson JH
AD  - The Pennsylvania State University, University Park, PA 16802, United States.
FAU - Alexander, Lacy M
AU  - Alexander LM
AD  - The Pennsylvania State University, University Park, PA 16802, United States.
LA  - eng
GR  - R01 HL093238/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20161127
PL  - United States
TA  - Microvasc Res
JT  - Microvascular research
JID - 0165035
RN  - 0 (Biological Factors)
RN  - 0 (Vasodilator Agents)
RN  - 0 (endothelium-dependent hyperpolarization factor)
RN  - 1490-04-6 (Menthol)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Administration, Cutaneous
MH  - Biological Factors/metabolism
MH  - Blood Flow Velocity
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gas Chromatography-Mass Spectrometry
MH  - Humans
MH  - Laser-Doppler Flowmetry
MH  - Male
MH  - Menthol/*administration & dosage
MH  - Microcirculation/*drug effects
MH  - Microdialysis
MH  - Microvessels/*drug effects/innervation/metabolism
MH  - Nitric Oxide/metabolism
MH  - Regional Blood Flow
MH  - Sensory Receptor Cells/drug effects/metabolism
MH  - Skin/*blood supply
MH  - Skin Temperature
MH  - Time Factors
MH  - Vasodilation/*drug effects
MH  - Vasodilator Agents/*administration & dosage
MH  - Young Adult
PMC - PMC5396183
MID - NIHMS856341
OTO - NOTNLM
OT  - Cutaneous
OT  - Gas chromatography
OT  - Menthol
OT  - Microdialysis
OT  - Microvasculature
OT  - TRPM8
EDAT- 2016/12/03 06:00
MHDA- 2017/10/03 06:00
PMCR- 2017/04/19
CRDT- 2016/12/01 06:00
PHST- 2016/10/13 00:00 [received]
PHST- 2016/11/20 00:00 [revised]
PHST- 2016/11/22 00:00 [accepted]
PHST- 2016/12/03 06:00 [pubmed]
PHST- 2017/10/03 06:00 [medline]
PHST- 2016/12/01 06:00 [entrez]
PHST- 2017/04/19 00:00 [pmc-release]
AID - S0026-2862(16)30175-3 [pii]
AID - 10.1016/j.mvr.2016.11.008 [doi]
PST - ppublish
SO  - Microvasc Res. 2017 Mar;110:43-47. doi: 10.1016/j.mvr.2016.11.008. Epub 2016 Nov 
      27.