Abstract 14743: α-Melanocyte Stimulating Hormone Improves NO-dependent Endothelial Function and Protects against DOCA-salt-induced Hypertension
Alpha-Melanocyte stimulating hormone (MSH), a peptide derivative of prohormone pro-opiomelanocortin (POMC), is implicated in the central regulation of cardiovascular functions. Melanocortin receptors have been identified in the endothelial cells, but no peripheral effect has been described for alpha-MSH in circulatory regulation. We hypothesized that alpha-MSH regulates endothelial function. The hypothesis was tested by studying the effects of MSH analogues in isolated mouse arteries, in human endothelial cells and in DOCA-salt-induced hypertension in mice. First, addition of alpha-MSH (1 nM - 1 microM) to preconstricted mouse aorta or small resistance arteries did not cause vessel relaxation or constriction. However, pretreatment with alpha-MSH (1 microM for 1 h) significantly improved endothelium-dependent relaxation responses to acetylcholine (ACh) in the aorta but not in the resistance arteries. Next, we subjected mice to in vivo treatment with potent analogues of alpha-MSH and found that both acute (NDP-alpha-MSH 0.3 mg/kg ip 24h before) and subchronic (melanotan-II 0.3 mg/kg/day ip for 3 weeks) treatment improved endothelium-dependent relaxation responses of the aorta. Pretreatment with NOS inhibitor L-NNA abolished the initial difference in relaxation responses suggesting that the improved endothelial function is dependent on augmented NO bioavailability. This was supported by enhanced ACh-stimulated production of cGMP in alpha-MSH- compared with saline-treated vessels. To investigate the underlying mechanism, we stimulated cultured endothelial cells with alpha-MSH and observed upregulation of eNOS expression. Finally, we tested whether alpha-MSH-treatment could hold promise as an antihypertensive therapy and employed DOCA-salt-model of hypertension. Treatment with NDP-alpha-MSH (0.6 mg/kg/day ip for 2 weeks) restrained the progression of hypertension in DOCA-salt mice without affecting blood pressure levels of normotensive control animals. In conclusion, we found that alpha-MSH by acting directly on the vasculature improves endothelial function through its ability to enhance NO bioavailability.
- © 2011 by American Heart Association, Inc.