Nitric Oxide Synthases: Roles, Tolls, and Controls

Carl Nathan and Qiao-wen Xie Beatrice and Samuel Seaver Laboratory Department of Medicine Cornell University Medical College New York, New York 10021 Imagine it’s 1985. You’ve joined an environmentally con- scious friend at a sidewalk cafe. Your companion is irked that traffic has fouled the air with nitric oxide (NO). Be- cause your imagination was piqued by a paper in the Pro- ceedings of the National Academy of Sciences reporting inorganic nitrite production by activated macrophages (StuehrandMarietta, 1985),youcounteryourfriend’scom- plaint with a prediction that the next ten years will bring forth evidence that NO is produced in slime molds, locusts, beetles, horseshoe crabs, mollusks, chickens, mice, rats, cows, and humans (Eiphick et al., 1993; Geiperin, 1994; Lee et al., 1994; Nathan and Xie, 1994; Werner-Feimayer et al., 1994). if so, your friend retorts, this would be no more than eukaryotic smog, a waste product of L-arginine metabolism. You concede that L-arginine-derived NO and its oxidation products will be excreted in people’s saliva, breath, and urine, but you insist NO is an autacoid, not a byproduct. Its physiologic roles will be at least as protean as those discovered for corticosteroids in the 194Os- 1980s and eicosanoids in the 196Os-198Os- ail three the products of hemecontaining oxygenases. You speculate that NO will regulate the following: tran- scription factor activation; translation of mRNAs controi- ling Fe metabolism; mutagenesis; apoptosis; giycolysis and mitochondriai electron transport; protein acyiation; deoxynucieotide synthesis; fusion of myObiaSt8; adhesion of platelets and neutrophiis; proliferation of myeloid pro- genitors T cells, keratinocytes, and tumor ceils; release of pituitary hormones; the tone of bronchi and sphincters; the contractions of