[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

Abstract

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.

The adrenergic regulation of proximal tubular Na+/H+ exchanger 3 in the rat

“…The α1‐adrenergic receptor agonist, phenylephrine, was infused directly into the cortical/medullary interstitium, which was an approach used previously (Cope et al . , O'Neill et al . ).…”

“…Further studies were undertaken to examine the role of catecholamines in the regulation of fluid reabsorption and NHE3 content of proximal tubular brush border membranes. The a1-adrenergic receptor agonist, phenylephrine, was infused directly into the cortical/medullary interstitium, which was an approach used previously (Cope et al 2013, O'Neill et al 2013. Intrarenal infusion of phenylephrine at the highest rate reduced UV, UNaV and FeNa without significantly altering GFR, suggesting that activation of tubular a 1 -adrenoceptors triggered increased sodium and water absorption.…”

α-MSH Analogue Attenuates Blood Pressure Elevation in DOCA-Salt Hypertensive Mice

“…Although there are conflicting views about the expression of melanocortin receptor subtypes in the kidney [12,15], supportive evidence for the MC3-R based mechanism came from studies showing that protein for MC3-R is present in the rat kidney and that the expression of MC3-R becomes upregulated when rats are fed with a high sodium diet [16,17]. Furthermore, these studies demonstrated that γ-MSH, which is the natural ligand for the MC3-R, stimulates cAMP formation in cultured inner medullary collecting duct cells.…”

“…The present finding that the diuretic and natriuretic actions of NDP-α-MSH were reversible with SHU9119 lends support to this concept. Controversy still remains concerning the role of renal nerves in the natriuretic response, since renal denervation was previously found to prevent the natriuretic response to γ-MSH infusion [19], but Cope et al did not observe such an effect [16]. Although the renal MC3 receptors seem to play a pivotal role, the exact mechanism and site of action of melanocortin-evoked natriuresis are still unknown.…”