Cardiovascular and renal actions of melanocyte-stimulating hormone peptides

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Abstract
Melanocyte stimulating hormones (MSHs, melanocortins) have important roles in feeding and energy metabolism and in inflammation. Recent observations have uncovered major functions for these peptides, particularly gamma-MSH, in cardiovascular regulation and sodium metabolism. Both alpha- and gamma-MSH acutely elevate blood pressure and heart rate through central stimulation of sympathetic nervous outflow. This action of alpha-MSH is mediated by the melanocortin 4 receptor (MC4R), whereas sympathetic nervous stimulation by gamma-MSH does not involve its receptor MC3R but rather is likely due to activation of a sodium channel in the central nervous system. In contrast, gamma-MSH deficiency in rodents, or disruption of MC3R, leads to marked salt-sensitive hypertension, again through a central mechanism: a small dose of exogenous peptide delivered into the cerebroventricular system of mice with gamma-MSH deficiency restores blood pressure to normal. This salt-sensitive hypertension is accompanied by the development of insulin resistance; the mechanism linking these two consequences of a high-salt diet is not yet known but may involve activation of the sympathetic nervous system. The study of MSH peptides in blood pressure regulation offers a new opportunity to gain insight into the mechanisms underlying salt sensitivity and its link to insulin resistance, and to new therapies.