We have studied the modulatory actions of two members of the tachykinin family (neurokinin A and B) on endogenous catecholamine (CA) secretion from cultured adrenal chromaffin cells. Their ability to modulate the nicotinic response was compared to that of substance P (SP). Both neurokinin A and neurokinin B were found to have two distinct actions similar to SP, on nicotine-induced CA release: (1) an inhibitory action at low nicotine concentrations; and (2) a protective action against desensitization by high nicotine concentrations. However, on a molar basis, the efficacy of neurokinin A or B to modulate the nicotinic response (both inhibition or protection) was 30 times less than SP. We have also tested the ability of a SP antagonist (D-Arg1-D-Pro2-D-Trp7,9-Leu11-SP) to antagonize the modulatory actions of SP on the nicotinic response. The results suggest the possibility that SP's actions on the bovine adrenal chromaffin cells might be mediated through two receptor subtypes of two different affinities.