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

<div><p>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.</p> </div

NDP-α-MSH treatment prevents the elevation of blood pressure in DOCA-salt mice.

<p>Systolic blood pressure (<b>A</b>) and heart rate (<b>B</b>) in control and DOCA-salt treated mice measured by a tail cuff method. After 7 days on the control and DOCA-salt treatments mice were randomized to daily i.p. injections of either saline or NDP-α-MSH (0.3 mg/kg). Data are mean ± SEM of six mice per group. * <i>P</i> < 0.05 versus saline-treated DOCA-salt mice, # # <i>P</i> < 0.01 versus control mice.</p

NDP-α-MSH induces diuretic and natriuretic responses that are blocked with the MC3/4 receptor antagonist SHU9119.

<p>(<b>A</b>) Time course of weight change after an intraperitoneal (i.p.) injection of saline and NDP-α-MSH (0.3 mg/kg). The values are based on a change from pretreatment weight. n = 7 per group. (<b>B</b>) Dose-dependent effects of NDP-α-MSH on body weight. Mice were weighed 2 hours after the injection. (<b>C</b>) Effect of a selective MC3/4-R antagonist (SHU9119) on NDP-α-MSH-induced diuresis. SHU9119 (1 mg/kg i.p) was given 30 min prior to administration of NDP-α-MSH (0.3 mg/kg i.p.). (<b>D</b>–<b>F</b>) 24-hour urine volume and urinary excretion of sodium (U N_aV) and potassium (U _KV) in control, NDP-α-MSH-treated and SHU9119-pretreated mice. The number of mice analyzed is shown in the graphs. Data are mean ± SEM. ** <i>P</i> < 0.01 versus saline, # # <i>P</i> < 0.01 versus NDP-α-MSH.</p

NDP-α-MSH treatment increases urinary excretion of cGMP.

<p>Urinary excretion of NO metabolites (<b>A</b>), cGMP (<b>B</b>) and 8-isoprostane (<b>C</b>) in control and DOCA-salt mice. Number of mice analyzed is given in Table 1. * <i>P</i> < 0.05 versus saline group, # # <i>P</i> < 0.01 versus control mice.</p

NDP-α-MSH treatment protects against DOCA-salt-induced hypernatremia.

<p>Serum sodium (<b>A</b>) and potassium (<b>B</b>) concentrations in control and DOCA-salt mice. Data are mean ± SEM. Number of mice analyzed is given in Table 1. * <i>P</i> < 0.05 versus saline-treated DOCA-salt mice, # <i>P</i> < 0.05 and # # <i>P</i> < 0.01 versus control mice.</p

Telemetric measurements of blood pressure in saline- and NDP-α-MSH-treated DOCA-salt mice.

<p>Systolic blood pressure (<b>A</b>) and heart rate (<b>B</b>) in control and DOCA-salt treated mice measured by radiotelemetry. Data represent 24 h mean values of SBP and HR. (<b>C</b>) Circadian amplitude, the difference between night- and day-time SBP, at baseline and at day 21 after the beginning of DOCA-salt treatment. * <i>P</i> < 0.05 versus saline-treated mice. Data are mean ± SEM of five mice per group.</p

Cohort Profile : Pregnancy And Childhood Epigenetics (PACE) Consortium

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