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[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 (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. 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 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‐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.