NITRIC-OXIDE PRODUCTION DURING VIBRIO-CHOLERAE INFECTION

Vibrio cholerae induces massive intestinal fluid secretion that contin ues for the life of the stimulated epithelial cells. Enhanced regional blood flow and peristalsis are required to adapt to this obligatory i ntestinal secretory challenge. Nitric oxide (NO) is a multifunctional molecule that modulates blood flow and peristalsis and possesses both cytotoxic and antibacterial activity. We demonstrate that, compared wi th those in asymptomatic control subjects, levels of stable NO metabol ites (NO2-/NO3-) are significantly increased in sera from acutely iu P eruvian patients with natural cholera infection as well as from sympto matic volunteers from the United States infected experimentally with V . cholerae. In a rabbit ileal loop model in vivo, cholera toxin (CT) e licited fluid secretion and dose-dependent increases in levels of NO2- /NO3- in the fluid (P < 0.01). In contrast, lipopolysaccharide (LPS) e licited no such effects when applied to the intact mucosa. NO synthase (NOS) catalytic activity also increased in toxin-exposed tissues (P < 0.05), predominantly in epithelial cells. The CT-induced NOS activity was Ca2+ dependent and was not suppressed by dexamethasone. In conclu sion, symptomatic V. cholerae infection induces NO production in human s. In the related animal model, CT, but not LPS, stimulated significan t production of NO in association with increases in local Ca2+-depende nt NOS activity in the tissues.