1. The present study compared the cardiovascular and renal actions of gamma(2)-melanocyte-stimulating hormone (gamma 2MSH) with those of the synthetic analogue [Nle(3),D-Phe(6)]-gamma 2MSH (NDP-gamma 2MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-gamma 2MSH.2. Both peptides were infused systemically (3-1000 nmol/kg) and intrarenally (500 fmol/min) into innervated and renally denervated rats fed either a normal (0.4% NaCl) or high-salt (4% NaCl; HS) diet. Mean arterial pressure (MAP), glomerular filtration rate (GFR), urinary sodium excretion (UNaV), urinary output (UV) and fractional sodium excretion were determined, as was expression of the melanocortin MC3 receptor in inner medullary collecting duct (IMCD) epithelial cells.3. Both renal and systemic infusion of gamma 2MSH increased MAP by 23 +/- 2% and 54 +/- 4%, respectively, but equivalent doses of NDP-gamma 2MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-gamma 2MSH increased UNaV and UV by two- to threefold in rats fed the normal salt diet and by six- to sevenfold in rats fed the HS diet. Furthermore, NDP-gamma 2MSH induced a 3.5-fold increase in GFR only in rats fed the HS diet. These renal effects of NDP-gamma 2MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5-fold increase in MC3 receptor expression in IMCD epithelial cells.4. Intrarenal infusion of NDP-gamma 2MSH induced the natriuretic but not the cardiovascular effects exhibited by gamma 2MSH. The renal activities may be attributed to a direct binding of NDP-gamma 2MSH to MC3 receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation.