Peptides of the ACTH4-10/gamma 2-MSH3-9 class produce pressor and cardioaccelerator effects upon i.v. administration. These actions appear to be mediated by peripheral catecholamines. To ascertain the role of sympathetic nerve terminals in the cardiovascular effects of these peptides, we used bretylium tosylate to prevent nerve terminal release of norepinephrine. Pretreatment with bretylium significantly attenuated the pressor and cardioaccelerator responses of gamma 2-MSH, and shifted the peak of the remaining responses to a later time point. It appears that the acute cardiovascular response to gamma-MSH administration depends primarily on the release of sympathetic terminal norepinephrine, though some contribution from other pressor systems such as adrenal catecholamines is possible.