Division of Nephrology, San Francisco General Hospital and Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
Eur J Pharmacol. 2011 Jun 11;660(1):43-52. doi: 10.1016/j.ejphar.2010.10.102. Epub 2011 Jan 1.
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.
黑素细胞刺激素（MSH）是从促黑激素原衍生而来的三种结构相关的肽。它们调节多种生理功能，包括能量代谢、食欲和炎症。最近在啮齿动物中的研究还确定了 MSH 的重要作用，特别是γ-MSH，对钠代谢和血压调节的作用。正常大鼠和小鼠对高盐饮食的反应是血浆中γ-MSH 浓度增加，血压正常，而遗传或药物γ-MSH 缺乏的动物在高盐饮食时会发生高血压。这种高血压可以通过外源性给予该肽来纠正。缺乏γ-MSH 受体（黑皮质素 3 受体，Mc3r）的小鼠在高盐饮食时也会发生高血压，但给予γ-MSH 时仍会发生高血压，并且给予生理水平的肽可刺激正常大鼠和小鼠的尿钠排泄，但 Mc3r 缺失的小鼠则不会。由于去甲肾上腺素能活性的刺激，γ-MSH 信号受损的啮齿动物中的盐敏感型高血压似乎是由于 γ-MSH 信号受损所致，因为血浆去甲肾上腺素增加，并且用α-肾上腺素能受体拮抗剂酚妥拉明输注可迅速纠正高血压。与生理水平的γ-MSH 的降压特性相反，静脉内或脑室内给予高浓度的肽会升高血压。在缺乏 Mc3r 的小鼠中会发生这种情况，表明与其他中枢受体相互作用。最后，γ-MSH 信号中断的啮齿动物中的盐敏感型高血压伴随着胰岛素抵抗，这一观察结果为研究盐敏感型高血压与胰岛素抵抗和 2 型糖尿病的相关性提供了新的窗口。
