The objective of this study was to compare the cardiovascular and renal effects of the two gamma-melanocyte-stimulating hormone (MSH) peptide sequences in the pro-opiomelanocortin prohormone structure in conscious, anesthetized, and pithed spontaneous hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) controls. In the conscious but not in the pithed rats, intravenous injection of gamma 2- and gamma 1-MSH induced a rapid and dose-dependent increase in mean arterial pressure (MAP), and gamma 2-MSH was more potent than gamma 1-MSH. The pressor response was more pronounced and more sustained in the SHR compared with the WKY. There were dose-dependent and significant increases in heart rate (HR) after gamma 2- and gamma 1-MSH in the SHR. At intravenous infusions of low doses of gamma 2-MSH, which did not significantly influence MAP or HR, urinary sodium excretion was significantly increased in both SHR and WKY. In conscious, but not in anesthetized rats, intracerebroventricular administration of the gamma 2-MSH peptide induced sustained increases in MAP in both SHR and WKY. After intrathecal administration, there were transient pressor effects of gamma 2-MSH. We conclude that the pro-opiomelanocortin-derived gamma 2- and gamma 1-MSH peptide sequences possess potent rapid pressor actions. The pressor effects, which require an intact sympathetic nervous system, are more pronounced in the SHR strain. Moreover, gamma 2-MSH induces natriuresis when administered in nonpressor doses in WKY and SHR.