Tetraethylammonium, glibenclamide, and 4-aminopyridine modulate post-occlusive reactive hyperemia in non-glabrous human skin with no roles of NOS and COX

Microcirculation. 2020 Jan;27(1):e12586. doi: 10.1111/micc.12586. Epub 2019 Sep 12.

Abstract

Objectives: Post-occlusive reactive hyperemia (PORH) following arterial occlusion is widely used to assess cutaneous microvascular function, though the underlying mechanisms remain to be fully elucidated. We evaluated the hypothesis that Ca2+ -activated, ATP-sensitive, and voltage-gated K+ channels (KC a , KATP , and KV channels, respectively) contribute to PORH while nitric oxide synthase (NOS) and cyclooxygenase (COX) do not.

Methods: On separate occasions, cutaneous blood flow (laser Doppler flowmetry) was monitored before and following 5-min arterial occlusion at forearm skin sites treated via microdialysis with the following: Experiment 1 (n = 11): (a) lactated Ringer solution (Control), (b) 10 mM Nω -nitro-L -arginine (NOS inhibitor), (c) 10 mM ketorolac (COX inhibitor), and (d) combined NOS+COX inhibition; Experiment 2 (n = 14): (a) lactated Ringer solution (Control), (b) 50 mM tetraethylammonium (non-selective KC a channel blocker), (c) 5 mM glibenclamide (non-specific KATP channel blocker), and (d) 10 mM 4-aminopyridine (non-selective KV channel blocker).

Results: Separate and combined NOS and COX inhibition did not influence PORH. Conversely, tetraethylammonium and glibenclamide attenuated, whereas 4-aminopyridine augmented PORH.

Conclusions: We showed that tetraethylammonium, glibenclamide, and 4-aminopyridine modulate PORH with no roles of NOS and COX in human non-glabrous forearm skin in vivo. Thus, cutaneous PORH changes could reflect altered K+ channel function.

Keywords: dermatology; endothelium; heat loss responses; hyperpolarization; ligand-gated ion channels.

Publication types

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

MeSH terms

  • 4-Aminopyridine / administration & dosage*
  • Adult
  • Glyburide / administration & dosage*
  • Humans
  • Hyperemia / metabolism*
  • Male
  • Nitric Oxide Synthase / metabolism*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Skin / blood supply*
  • Skin / metabolism*
  • Skin / physiopathology
  • Tetraethylammonium / administration & dosage*

Substances

  • Tetraethylammonium
  • 4-Aminopyridine
  • Nitric Oxide Synthase
  • Prostaglandin-Endoperoxide Synthases
  • Glyburide