The effects of the K+ channel blockers, apamin, tetraethylammonium and 4-aminopyridine, upon the relaxations of the isolated rat proximal duodenum induced by nitregic nerve activation, nitric oxide (NO), the NO donor 3-morpholinosydnonimine (SIN-1) and Br-cyclic GMP were determined. The effects of the guanylate cyclase inhibitors, cystamine and N-methylhydroxylamine, on NO-, SIN-1- and nitrergic nerve-induced responses were also investigated. Apamin inhibited nitrergic nerve-, NO-and SIN-1-induced relaxations but did not affect those induced by Br-cGMP. Tetraethylammonium and 4-aminopyridine as well as cystamine and N-methylhydroxylamine failed to affect the relaxations caused by any of the agents tested. These findings indicate that, in the rat proximal duodenum, nitrergic nerve activation as well as exogenous nitric oxide cause relaxation through a cGMP-independent, apamin sensitive mechanism.