Topically applied S-nitrosothiol-containing hydrogels as experimental and pharmacological nitric oxide donors in human skin.
BACKGROUND
Nitric oxide (NO) has a wide range of functions in the skin, and topical NO donors have several potential clinical applications. However, currently available donors are either unstable on the skin surface, release low concentrations of NO, or have a short duration of action. Endogenous S-nitrosothiols (RSNOs) store and transport NO within the body and can be used as exogenous sources of NO.


OBJECTIVE
To study in vitro and in vivo the chemical and biological behaviour of two RSNO species, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC), in an easily applied hydrogel, and to correlate dermal nitrite concentration with erythema following application of the RSNOs. To assess the suitability of GSNO and SNAC as biologically effective NO donors for clinical research and as potential therapeutic agents.


METHODS
GSNO (0.3 mol g(-1)) and SNAC (0.6 mol g(-1)) were incorporated in Synperonic F-127 hydrogels (Uniquema, Belgium). The in vitro kinetics of decomposition were measured by spectrophotometry at 37 degrees C. The RSNO-containing hydrogels were applied to the forearm skin of eight subjects. Blood flow was measured by laser Doppler for 3 h following application of NO donors and dermal nitrite simultaneously measured in microdialysate in four subjects.


RESULTS
The mean peak blood flow achieved was 250. At blood flow values of < 250, dermal nitrite correlated closely with blood flow and could be defined by the equation: blood flow = (nitrite concentration x 0.66) + 120, (P = 0.013). At higher blood flows there was a paradoxical fall in dermal nitrite concentration.


CONCLUSIONS
Topical RSNOs produce a consistent, sustained and biologically effective release of NO on human skin in vivo, which offers advantages over currently available topical NO donors. Dermal nitrite concentration--the oxidation product of NO--is directly correlated with blood flow at low and moderate levels of blood flow. At high levels of blood flow, there is a reduction in dermal nitrite, which is presumed to be due to increased blood scavenging.
Seabra
A B
AB
Instituto de Química, Universidade Estadual de Campinas, CP 6154, CEP 13084-971, Campinas, SP, Brazil.
Fitzpatrick
A
A
Paul
J
J
De Oliveira
M G
MG
Weller
R
R
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000279:Administration, Cutaneous; D000328:Adult; D005260:Female; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D026403:S-Nitrosothiols / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism
D020100:Hydrogels; D020030:Nitric Oxide Donors; D009573:Nitrites; D026403:S-Nitrosothiols; D009569:Nitric Oxide; C024940:S-nitroso-N-acetylcysteine; D026422:S-Nitrosoglutathione; D000111:Acetylcysteine