Evidence for TRPV4 channel induced skin vasodilatation through NOS, COX, and KCa channel mechanisms with no effect on sweat rate in humans

Eur J Pharmacol. 2019 Sep 5;858:172462. doi: 10.1016/j.ejphar.2019.172462. Epub 2019 Jun 16.


Transient receptor potential vanilloid 4 (TRPV4) channels exist in the endothelial cells of cutaneous blood vessels and the secretory cells of eccrine sweat glands. We assessed if exogenous TRPV4 channel activation elicits cutaneous vasodilatation and sweating in humans in vivo, and if so, whether this response is mediated by nitric oxide synthase (NOS)- cyclooxygenase (COX)- and/or Ca2+-sensitive K+ (KCa) channel-related mechanisms. In ten healthy young adults (24±2 years, 5 women), cutaneous vascular conductance and sweat rate were assessed at four dorsal forearm skin sites continuously treated with either: 1) lactated Ringer's solution (Control), 2) 20 mM L-NAME, a non-selective NOS inhibitor, 3) 10 mM ketorolac, a non-selective COX inhibitor, or 4) 50 mM TEA, a non-selective KCa channel blocker. A potent and selective TRPV4 channel agonist, GSK1016790 A (GSK101), was administered to each skin site in a dose-dependent manner (1, 10, 100, 1000 μM each for ≥30min) via intradermal microdialysis. Administration of 100 and 1000 μM GSK101 increased cutaneous vascular conductance from pre-infusion level at the Control site (48±12 and 57±9%max, respectively, P≤0.004). This response was markedly (53-83%) attenuated by NOS inhibition, COX inhibition, or KCa channel blockade (all P≤0.037), except KCa channel blockade had no effect during 1000 μM GSK101 administration. GSK101 did not influence sweat rate regardless of skin site. We showed that in human skin in vivo, exogenous activation of TRPV4 channels mediates cutaneous vasodilatation, but not sweating through NOS, COX, and KCa channel mechanisms.

Keywords: Microcirculation; Perspiration; Temperature-dependent gating; Temperature-sensitive ion channels; Thermoregulation; Warm temperature.

Publication types

  • Clinical Trial

MeSH terms

  • Female
  • Humans
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Male
  • Nitric Oxide Synthase / metabolism*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Regional Blood Flow / drug effects
  • Skin / blood supply*
  • Skin / drug effects
  • Sweating* / drug effects
  • TRPV Cation Channels / metabolism*
  • Vasodilation* / drug effects


  • Large-Conductance Calcium-Activated Potassium Channels
  • TRPV Cation Channels
  • Nitric Oxide Synthase
  • Prostaglandin-Endoperoxide Synthases