Topical application of neuronal nitric oxide synthase inhibitor accelerates cutaneous barrier recovery and prevents epidermal hyperplasia induced by barrier disruption

J Invest Dermatol. 2007 Jul;127(7):1713-9. doi: 10.1038/sj.jid.5700742. Epub 2007 Mar 15.

Abstract

The effect of nitric oxide (NO) on skin barrier recovery rate was evaluated in hairless mouse. Topical application of an NO synthase (NOS) inhibitor and a neuronal nitric oxide synthase (nNOS) inhibitor accelerated the barrier recovery after tape stripping, whereas application of an inducible NOS (iNOS) inhibitor had no effect. After tape stripping, the barrier recovery in nNOS-/- mice was significantly faster than in wild type. Topical application of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) delayed the barrier recovery in hairless mice. Immediately after barrier disruption on skin organ culture, NO release from the skin was significantly increased. The increase was blocked by nNOS inhibitor, but not by iNOS inhibitor. Topical application of the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) accelerated the barrier recovery, whereas SIN-1 chloride, a guanylyl cyclase activator, delayed the barrier recovery. In cultured human keratinocytes, SNAP increased the intracellular calcium concentration. The increase was blocked by ODQ, but not by the calcium channel-blocker nifedipine. In calcium-free medium, SNAP increased the intracellular calcium concentration. Topical application of both nNOS inhibitor and ODQ also reduced the epidermal hyperplasia induced by barrier disruption under low environmental humidity. These results suggest that NO plays an important signaling role in cutaneous barrier homeostasis and in epidermal hyperplasia induced by barrier disruption.

MeSH terms

  • Administration, Topical
  • Animals
  • Calcium / metabolism
  • Cell Membrane Permeability / drug effects*
  • Cell Membrane Permeability / physiology
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Humans
  • Hyperplasia / pathology
  • Hyperplasia / prevention & control
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Male
  • Mice
  • Mice, Hairless
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / physiology*
  • Nitric Oxide Donors / administration & dosage
  • Nitric Oxide Donors / pharmacology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / physiology
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Nitric Oxide Synthase Type I / genetics
  • Nitric Oxide Synthase Type I / physiology
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / physiology
  • Oxadiazoles / pharmacology
  • Penicillamine / administration & dosage
  • Penicillamine / analogs & derivatives*
  • Penicillamine / pharmacology
  • Quinoxalines / pharmacology
  • Skin / drug effects
  • Skin / pathology*

Substances

  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Enzyme Inhibitors
  • Nitric Oxide Donors
  • Oxadiazoles
  • Quinoxalines
  • S-nitro-N-acetylpenicillamine
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Penicillamine
  • Calcium