Instillation of the nitric oxide (NO) generator isosorbide dinitrate (0.1-1 mM) into the rat gastric lumen in vivo produced a dose-related increase in mucus gel thickness that was prevented by coadministration of oxyhaemoglobin (10 microM). Isosorbide dinitrate did not induce epithelial cell damage. S-Nitroso-N-acetyl-penicillamine (0.3 mM) and dibutyryl cyclic GMP (1 mM) also increased mucus thickness. These findings, along with the presence of NO synthase in the gastric mucosa, imply a role for NO in vivo in mediation of gastric mucus release.