Nitric oxide is generated on the skin surface by reduction of sweat nitrate

Nitric oxide (NO) is known to be synthesized by mammalian cells from L-arginine by a group of NO synthase enzymes. We now show that NO is generated from human skin and propose a different mechanism of production. Whereas enzymatic NO synthesis is inhibited by monomethyl L-arginine, this arginine analog, when infused into the brachial artery at concentrations sufficient to inhibit endothelial NO synthase activity, has little effect on hand skin NO production. Hand skin NO production is increased by topical acidification of the skin surface and greatly increased by the addition of nitrite solutions. We propose that NO generation from skin derives from sweat nitrite (the concentration of which was found to average 3.4 microM in six subjects) due to chemical reduction consequent to the acidic nature of sweat. Sweat contains nitrate in appreciable amounts, and skin commensal bacteria can synthesize nitrate reductase enzyme. Patients on long-term tetracycline antibiotics showed significantly reduced skin NO synthesis, although topical antiseptic and antibiotics had little effect on NO generation in the short-term. We propose that NO generation from skin is dependent on bacterial nitrate reduction to nitrite and subsequent reduction by acidification. We speculate that this has a physiologic role in the inhibition of infection by pathogenic fungi and other susceptible microorganisms and may affect cutaneous T-cell function, keratinocyte differentiation, and skin blood flow.