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A close association between salt-sensitive hypertension and insulin resistance has been recognized for more than two decades, although the mechanism(s) underlying this relationship have not been elucidated. Recent data in mice with genetic disruption of the gamma-melanocyte-stimulating hormone (gamma-MSH) system suggest that this system plays a role in the pathophysiological relationship between hypertension and altered glucose metabolism during ingestion of a high-sodium diet (8% NaCl, HSD). We tested the hypothesis that these two consequences of interrupted gamma-MSH signalling were the result of sympathetic activation by studying rats treated with the dopaminergic agonist bromocriptine (5 mg kg(-1) i.p., daily for 1 week; Bromo) to cause relative gamma-MSH deficiency. Bromo-treated rats fed the HSD developed hypertension and also exhibited fasting hyperglycaemia (P < 0.005) and hyperinsulinaemia (P < 0.025). Furthermore, Bromo-treated rats on the HSD had impaired glucose tolerance and blunted insulin-mediated glucose disposal. Intravenous infusion of gamma(2)-MSH, or of the alpha-adrenergic receptor antagonist phentolamine, to Bromo-HSD rats lowered both mean arterial pressure (MAP) and blood glucose to normal after 15 min (P < 0.001 versus control), but had no effect in rats receiving vehicle and fed the HSD; gamma(2)-MSH infusion also reduced the elevated plasma noradrenaline to control levels in parallel with the reductions in MAP and blood glucose concentration. Infusion of hydralazine to Bromo-HSD rats lowered MAP but had only a trivial effect on blood glucose. We conclude that rats with relative gamma-MSH deficiency develop abnormal glucose metabolism, with features of insulin resistance, in association with hypertension when ingesting the HSD. Elevated plasma noradrenaline concentration in Bromo-HSD rats is normalized by gamma(2)-MSH infusion, suggesting that an adrenergic mechanism may link the salt-sensitive hypertension and the impaired glucose metabolism of relative gamma-MSH deficiency.

Alpha-, beta-, and gamma-melanocyte stimulating hormones (MSHs) are melanotropin peptides that are derived from the ACTH/beta-endorphin prohormone proopiomelanocortin (POMC). They have been highly conserved through evolutionary development, although their functions in mammals have remained obscure. The identification in the last decade of a family of five membrane-spanning melanocortin receptors (MC-Rs), for which the melanotropins are the natural ligands, has permitted the characterization of a number of important actions of these peptides, although the physiological function(s) of gamma-MSH have remained elusive. Much evidence indicates that gamma-MSH stimulates sympathetic outflow and raises blood pressure through a central mechanism. However, this review focuses on newer cardiovascular and renal actions of the peptide, acting in most cases through the MC3-R. In rodents, a high-sodium diet (HSD) increases the pituitary abundance of POMC mRNA and of gamma-MSH content and results in a doubling of plasma gamma-MSH concentration. The peptide is natriuretic and acts through renal MC3-Rs, which are also upregulated by the HSD. Thus the system appears designed to participate in the integrated response to dietary sodium excess. Genetic or pharmacologic induction of gamma-MSH deficiency results in marked salt-sensitive hypertension that is corrected by the administration of the peptide, probably through a central site of action. Deletion of the MC3-R also produces salt-sensitive hypertension, which, however, is not corrected by infusion of the hormone. These observations in aggregate suggest the operation of a hormonal system important in blood pressure control and in the regulation of sodium excretion. The relationship of these two actions to each other and the significance of this system in humans are important questions for future research.

The gamma-melanocyte-stimulating hormone (gamma-MSH) is a natriuretic peptide derived from the N-terminal region of proopiomelanocortin (POMC). Evidence suggests that it may be part of the coordinated response to a low-sodium diet (LSD). We tested the effect of the HSD (8% NaCl) compared with LSD (0.07%) on mean arterial pressure (MAP) in mice with targeted disruption of the PC2 gene (PC2(-/-)), necessary for processing of POMC into gamma-MSH, or the melanocortin receptor 3 gene (Mc3r(-/-); the receptor for MSH). In wild-type mice, HSD for 1 week did not alter MAP versus LSD mice, but plasma gamma-MSH immunoreactivity was more than double the LSD value. In contrast, in PC2(-/-) mice, MAP on the LSD was not greater than in wild-type mice, but plasma gamma-MSH was reduced to one-seventh the wild-type value. On the HSD, MAP rose to a markedly hypertensive level while plasma gamma-MSH concentration remained severely depressed. Intravenous infusion of gamma-MSH (0.2 pmol/min) for 30 min to PC2(-/-) mice after 1 week of HSD lowered MAP from hypertensive levels to normal; infusion of alpha-MSH at the same rate had no effect. Injection of 60 fmol of gamma-MSH into the lateral cerebral ventricle of hypertensive mice also lowered MAP to normal. Administration of a stable analogue of gamma-MSH intra-abdominally by microosmotic pump to PC2(-/-) mice prevented the development of hypertension when ingesting the HSD. In mice with targeted disruption of the Mc3r gene, the HSD also led to marked hypertension accompanied by elevated plasma levels of gamma-MSH; infusion of exogenous gamma-MSH to these mice had no effect on MAP. These results strongly suggest that PC2-dependent processing of POMC into gamma-MSH is necessary for the normal response to the HSD. gamma-MSH deficiency results in marked salt-sensitive hypertension that is rapidly improved with exogenous gamma-MSH through a central site of action. alpha-MSH infused at the same rate had no effect on MAP, indicating that the hypertension is a specific consequence of impaired POMC processing into gamma-MSH. Absence of Mc3r produces gamma-MSH resistance and hypertension on the HSD. These findings demonstrate a novel pathway mediating salt-sensitivity of blood pressure.

The melanocortin (MC) gamma3MSH is a peptide that can be generated from the N-terminal domain of POMC and is believed to signal through the MC3 receptor. We recently showed that it induces a sustained rise in intracellular free calcium levels ([Ca(2+)](i)) in a subpopulation of pituitary cells, particularly in the lactosomatotroph lineage. In the present study we report that gamma3MSH and some analogs increase [Ca(2+)](i) in the GH- and PRL-secreting GH3 cell line and evaluate on the basis of pharmacological experiments and gene expression studies which MC receptor may be involved. A dose as low as 1 pM gamma3MSH induced an oscillating [Ca(2+)](i) increase in a significant percentage of GH3 cells. Increasing the dose recruited an increasing number of responding cells; a maximum was reached at 0.1 nM. gamma2MSH, alphaMSH, and NDP-alphaMSH displayed a similar effect. SHU9119, an MC3 and MC4 receptor antagonist, and an MC5 receptor agonist, did not affect the number of cells showing a [Ca(2+)](i) rise in response to gamma3MSH. SHU9119 had also no effect when added alone. MTII, a potent synthetic agonist of the MC3, MC4, and MC5 receptor as well as an N-terminally extended recombinant analog of gamma3MSH showed low potency in increasing [Ca(2+)](i) in GH3 cells, but high potency in stimulating cAMP accumulation in HEK 293 cells stably transfected with the MC3 receptor. In contrast, a peptide corresponding to the gamma2MSH sequence of POMC-A of Acipenser transmontanus increased [Ca(2+)](i) in GH3 cells, but was about 50 times less potent than gamma2- or gamma3MSH in stimulating cAMP accumulation in the MC3 receptor expressing HEK 293 cells. By means of RT-PCR performed on a RNA extract from GH3 cells, the messenger RNA of the MC2, MC3, and MC4 receptor was undetectable, but messenger RNA of the MC5 receptor was clearly present. These data suggest that the GH3 cell line does not mediate the effect of gamma3MSH through the MC3 receptor. The involvement of the MC5 receptor is unlikely, but cannot definitely be excluded. The findings animate the hypothesis that there exists a second, hitherto unidentified, MC receptor that displays high affinity for gamma3MSH.