Abstract
Melanocyte-stimulating hormones, α-, β- and γ-MSH, regulate important physiological functions including energy homeostasis, inflammation and sodium metabolism. Previous studies have shown that α-MSH increases sodium excretion and promotes vascular function in rodents, but it is unexplored whether these characteristics of α-MSH could translate into therapeutic benefits in the treatment of hypertension. Therefore, we first assessed the diuretic and natriuretic properties of the stable α-MSH analogue [Nle4, D-Phe7]-α-MSH (NDP-α-MSH) and investigated whether it has protective effects in deoxycorticosterone acetate (DOCA)-salt hypertensive mice. Adult male C57Bl/6N mice were subjected to DOCA-salt treatment and randomized to receive intraperitoneal injections of either saline as vehicle or NDP-α-MSH (0.3 mg/kg/day for 14 days) starting 7 days after the DOCA-salt treatment. Systemic hemodynamics, serum and urine electrolytes, and oxidative stress markers were assessed in control sham-operated and DOCA-salt mice. NDP-α-MSH elicited marked diuretic and natriuretic responses that were reversible with the MC3/4 receptor antagonist SHU9119. Chronic NDP-α-MSH treatment attenuated blood pressure elevation in DOCA-salt mice without affecting the blood pressure of normotensive control animals. Owing to the enhanced sodium excretion, NDP-α-MSH-treated mice were protected from DOCA-salt-induced hypernatremia. DOCA-salt treatment mildly increased oxidative stress at the tissue level, but NDP-α-MSH had no significant effects on the oxidative stress markers. In conclusion, treatment with NDP-α-MSH increases urinary sodium excretion and protects against DOCA-salt-induced hypertension. These findings point to the potential future use of α-MSH analogues in the treatment of hypertension.
Highlights
Melanocyte-stimulating hormones (α, β- and γ-MSH) and adrenocorticotropic hormone or melanocortins are a family of peptides that are proteolytically cleaved from a common precursor molecule known as pro-opiomelanocortin
Since oxidative stress is known to contribute to the development of hypertension [9], combined with the concept that α-MSH can suppress oxidative damage in cardiovascular disease models [6,10,11,12], we aimed to evaluate the effects of NDP-α-MSH treatment on oxidative stress markers in deoxycorticosterone acetate (DOCA)-salt mice
It is noteworthy that NDP-α-MSH administration did not cause kaliuresis despite the profound diuresis and natriuresis (Figure 1F)
Summary
Melanocyte-stimulating hormones (α-, β- and γ-MSH) and adrenocorticotropic hormone or melanocortins are a family of peptides that are proteolytically cleaved from a common precursor molecule known as pro-opiomelanocortin. They regulate a multitude of physiological functions including energy homeostasis, electrolyte balance and inflammatory responses. The natriuretic action of melanocortins is thought to be mediated, at least in part, by the melanocortin 3 receptor (MC3-R) expressed in the kidney [4] It is an open question whether pharmacological targeting of the MC3-R could have therapeutic efficacy in experimental models of hypertension
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