Nitric oxide, which is produced from L-ar-ginine by a nitric oxide-synthase enzyme, has been shown to be a ubiquitous messenger molecule. Recently, it has been suggested that nitric oxide might influence insulin secretion by activating the soluble guanylate cyclase and generating cyclic guanosine monophosphate (cGMP). We have investigated the role of the nitric oxide pathway in insulin secretion by evaluating the insulin response to several secretagogues in rats in which nitric oxide-synthase was chronically inhibited by oral administration of the L-arginine analogue, NG-nitro-L-arginine methyl ester (L-NAME). Blood pressure and aortic wall cGMP content were used as indices of nitric oxide-synthase blockade. Insulin secretion was evaluated after an intravenous bolus of D-glucose, L-arginine or D-arginine. Chronic L-NAME administration induced a 30% increase in blood pressure and a seven-fold drop in arterial cGMP content. Body weight, fasting plasma glucose and insulin were not influenced by L-NAME administration. First-phase insulin secretion (1 + 3 min) in response to glucose was not significantly different in L-NAME and control rats. The areas under the insulin curve were similar in both groups. Insulin secretion in response to D-arginine or L-arginine in L-NAME-treated and control rats were also similar. In conclusion, chronic nitric oxide-synthase blockade increases blood pressure and decreases aortic cGMP content, but does not alter insulin secretion in response to several secretagogues. Chronic oral administration of L-NAME in the rat provides an adequate animal model for studying the L-arginine nitric oxide-pathway.