Studies using an inhibitor of nitric oxide (NO) synthesis have suggested that endogenous NO may have a role in regulating endothelin release. We investigated the effect of endogenous and exogenous nitric oxide (NO) on the release of irET-1. L-NAME stimulated, but L-arginine inhibited irET-1 release. Perfusing sodium nitroprusside (SNP), however, did not inhibit irET-1 secretion. CyclicGMP, the second messenger for NO action, was stimulated by SNP but not by L-arginine. These data demonstrate that endogenous NO inhibits of irET-1, in a manner which is independent of cGMP, and suggest that this action may contribute to the vasodilatory effect of NO.