[Nle 3 , d ‐Phe 6 ]‐γ 2 ‐melanocyte‐stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ 2 ‐melanocyte‐stimulating hormone in anaesthetized rats

• Published in: Clinical and experimental pharmacology & physiology Vol. 40; no. 1; pp. 5 - 12
• Main Authors: Cope, Georgina, Flanagan, Evelyn T, Houghton, Belinda L, Walsh, Sarah A, Johns, Edward J, Healy, Vincent
• Format: Journal Article
• Language: English
• Published: 01.01.2013
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/1440-1681.12025

Summary The present study compared the cardiovascular and renal actions of γ 2 ‐melanocyte‐stimulating hormone (γ 2 MSH ) with those of the synthetic analogue [Nle 3 , d ‐Phe 6 ]‐γ 2 MSH ( NDP ‐γ 2 MSH ) and explored the effects of high dietary salt intake on the renal actions of NDP ‐γ 2 MSH . 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 N a V), urinary output ( UV ) and fractional sodium excretion were determined, as was expression of the melanocortin MC 3 receptor in inner medullary collecting duct ( IMCD ) epithelial cells. Both renal and systemic infusion of γ 2 MSH increased MAP by 23 ± 2% and 54 ± 4%, respectively, but equivalent doses of NDP ‐γ 2 MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP ‐γ 2 MSH increased U N a V 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 ‐γ 2 MSH induced a 3.5‐fold increase in GFR only in rats fed the HS diet. These renal effects of NDP ‐γ 2 MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5‐fold increase in MC 3 receptor expression in IMCD epithelial cells. Intrarenal infusion of NDP ‐γ 2 MSH induced the natriuretic but not the cardiovascular effects exhibited by γ 2 MSH . The renal activities may be attributed to a direct binding of NDP ‐γ 2 MSH to MC 3 receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation.