Examination of the cardiovascular effects produced by peripheral administration of peptide sequences derived from adrenocorticotropic hormone (ACTH) led to the discovery of the pressor, cardioaccelerator, and natriuretic actions of intravenous (iv) ACTH-(4-10). Based on pharmacological studies in rats with alpha- and beta-adrenergic receptor antagonists, the cardiovascular effects of this peptide appeared to be mediated by the release of catecholamines. A peptide sequence analogous to ACTH-(4-10), gamma-melanocyte-stimulating hormone (gamma-MSH), possesses greater than 100-fold more cardiovascular activity and 1,000-fold more natriuretic activity than ACTH-(4-10). The pressor effect of iv gamma-MSH peptides appears to be dependent on the maintenance of preganglionic sympathetic drive, with no significant contribution of circulating vasopressin or angiotensin II. However, the presence of central vasopressinergic, and perhaps angiotensinergic, pathways appears to be crucial for expression of the full pressor effect of circulating gamma-MSH. Further evidence for the potential importance of the central nervous system (CNS) in these cardiovascular effects was obtained from central lesion experiments and a comparison of intracarotid vs. intrajugular infusions. Structure-activity studies suggested that the cardiovascular effects of ACTH-(4-10) or gamma-MSH are dependent on an Arg-hydrophobic amino acid sequence, located at or near their COOH-terminal. A similar requirement for biological activity is found in molluscan cardioexcitatory peptides, and the molluscan peptides have cardiovascular effects in rats, which resemble ACTH-(4-10) or gamma-MSH. This suggests that peptides of the gamma-MSH family are the pharmacological analogues, and perhaps the physiological homologues, of a cardioexcitatory family of peptides found in molluscs and birds. Elevated circulating levels of peptides derived from the NH2-terminal of pro-opiomelanocortin (POMC) have been found in psychological stress, cardiovascular distress, and hemorrhage. Increases in central sympathetic drive are common to all of these states. gamma-MSH peptides have been localized to POMC neurons in the arcuate nucleus and nucleus commissuralis of the rat. Projections from the latter nucleus innervate hindbrain vasomotor centers. Intraventricular administration of gamma-MSH produces prolonged elevation of mean arterial pressure. gamma-MSH peptides may provide a link between humoral and neurogenic mechanisms in cardiovascular regulation and could potentially be important neurotransmitters for central control of the cardiovascular system.