title: α-MSH analogue attenuates blood pressure elevation in DOCA-salt hypertensive mice.
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 [Nle(4), D-Phe(7)]-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.
authors: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland. pperin@utu.fi
authors: Petteri
authors: P
authors: Rinne
authors: Anna-Maija
authors: AM
authors: Penttinen
authors: Wendy
authors: W
authors: Nordlund
authors: Markku
authors: M
authors: Ahotupa
authors: Eriika
authors: E
authors: Savontaus
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000652:urine; D064791:Desoxycorticosterone Acetate; D004231:Diuresis / Q000187:drug effects; D006955:Hypernatremia / Q000188:drug therapy / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009318:Natriuresis / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D044104:Receptor, Melanocortin, Type 3 / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013686:Telemetry; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C103272:SHU 9119; D009569:Nitric Oxide; D000521:alpha-MSH; D064791:Desoxycorticosterone Acetate; C027756:MSH, 4-Nle-7-Phe-alpha-; D009074:Melanocyte-Stimulating Hormones; D006152:Cyclic GMP
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