Cardiovascular effects of melanocortins

Abstract

Melanocortins (MSH's) are three structurally related peptides derived from proopiomelanocortin. They regulate several physiologic functions including energy metabolism, appetite, and inflammation. Recent work in rodents has also identified important effects of MSH's, particularly γ-MSH, on sodium metabolism and blood pressure regulation. Normal rats and mice respond to a high sodium diet with an increase in the plasma concentration of γ-MSH, and remain normotensive, while those with genetic or pharmacologic γ-MSH deficiency become hypertensive on a high sodium diet. This hypertension is corrected by exogenous administration of the peptide. Mice lacking the γ-MSH receptor (the melanocortin 3 receptor, Mc3r) also become hypertensive on a high sodium diet but remain so when administered γ-MSH, and infusions of physiologic levels of the peptide stimulate urinary sodium excretion in normal rats and mice, but not in mice with deletion of Mc3r. The salt-sensitive hypertension in rodents with impaired γ-MSH signaling appears due to stimulation of noradrenergic activity, since plasma noradrenaline is increased and the hypertension is rapidly corrected with infusion of the α-adrenoceptor antagonist phentolamine. In contrast to the antihypertensive property of physiologic levels of γ-MSH, intravenous or intracerebroventricular injections of high levels of the peptide raise blood pressure. This occurs in mice lacking Mc3r, indicating an interaction with some other central receptor. Finally, the salt-sensitive hypertension in rodents with disruption of γ-MSH signaling is accompanied by insulin resistance, an observation which offers a new window into the study of the association of salt-sensitive hypertension with insulin resistance and type II diabetes.

Figure 1

Schematic view of sequential processing of proopiomelanocortin. ACTH, adrenocorticotrophic hormone; LPH, Lipotropin; PC1, Proconvertase 1; PC2, Proconvertase 2; NT, N-terminal peptide; JP, joining peptide; END, endorphin; CLIP, corticotrophin-like intermediate peptide; MSH, melanocyte stimulating hormone. From (Reudelhuber, 2003).

Figure 2

Blood pressure (MAP, top) and immunoreactive (IR) plasma γ-MSH concentration (bottom) in proconvertase 2 (PC2) wild type (+/+) and knockout (−/−) mice (left) and melanocortin 3 receptor (Mc3r) wild type and knockout mice during ingestion of a low sodium (LSD) vs a high sodium (HSD) diet.. From (Ni et al., 2003).

Figure 3

Mean arterial pressure and heart rate in conscious, unrestrained rats ingesting a high sodium diet (HSD) while receiving daily injections of bromocriptine intraperitoneally, 0.5 mg/kg. The rats were intstrumented with radiotelemetry transmitters for the recording; they were implanted with osmotic miniumps to deliver normal saline vehicle (filled circles) or the stable γ-MSH analog NDP-γ-MSH. Bromocriptine injections were discontinued after 14 days. From (Ni and Humphreys, 2007).

Figure 4

Mean arterial pressure (MAP, mm Hg), heart rate (HR), blood glucose, and plasma insulin concentrations in proconvertase 2 (PC2) wild type (+/+) and knockout (−/−) and Mc3r wild type and knockout mice during ingestion of a normal sodium (NSD) or high sodium diet (HSD). Both knockout strains of mice developed hyperglycemia and hyperinsulinemia as well as hypertension while ingesting the high sodium diet. From (Ni and Humphreys, 2008).

Figure 5

Mean arterial pressure (mm Hg, left) and blood glucose concentration (mg/dL, right) in bromocriptine-(closed circles) or vehicle- (open circles) treated rats fed the high sodium diet. Bromocriptine-treated rats were hypertensive; intravenous infusion of γ₂-MSH (top), phentolamine (middle), or hydralazine (bottom) at the infusion rates indicated rapidly corrected the hypertension. However, only γ-MSH and phentolamine corrected the hyperglycemia; hydralazine had a trivial effect on blood glucose concentration despite its effect on blood pressure. *, bromocriptine value significantly greater than vehicle, P < 0.01 or greater; ^†, value significantly different from corresponding control value, P < 0.01 or greater, repeated-measures ANOVA. From (Ni et al., 2009).

Figure 6

Schematic view of the role of γ-MSH during ingestion of a high sodium diet. See Section 6 for details.