[Nle³,d-Phe⁶]-γ₂-melanocyte-stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ₂-melanocyte-stimulating hormone in anaesthetized rats

The present study compared the cardiovascular and renal actions of γ₂-melanocyte-stimulating hormone (γ₂MSH) with those of the synthetic analogue [Nle³,d-Phe⁶]-γ₂MSH (NDP-γ₂MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-γ₂MSH. 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 (U_NaV), 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. Both renal and systemic infusion of γ₂MSH increased MAP by 23 ± 2% and 54 ± 4%, respectively, but equivalent doses of NDP-γ₂MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-γ₂MSH increased U_NaV 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-γ₂MSH induced a 3.5-fold increase in GFR only in rats fed the HS diet. These renal effects of NDP-γ₂MSH 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. Intrarenal infusion of NDP-γ₂MSH induced the natriuretic but not the cardiovascular effects exhibited by γ₂MSH. The renal activities may be attributed to a direct binding of NDP-γ₂MSH to MC₃ receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation.