Expression and function of nesfatin-1 are altered by stage of the estrous cycle.

Nesfatin-1 is a peptide derived from the nucleobindin 2 (Nucb2) precursor protein that has been shown to exert potent effects on appetite and cardiovascular function in male animals. Sex hormones modulate the expression of Nucb2 in several species, including goldfish, mouse, and rat, and human studies have revealed differential expression based on male or female sex. We therefore hypothesized that the ability of nesfatin-1 to increase mean arterial pressure (MAP) would be influenced by stage of the estrous cycle. Indeed, we found that in cycling female Sprague-Dawley rats, nesfatin-1 induced an increase in MAP on diestrus, when both estrogen and progesterone levels are low but not on proestrus or estrus. The effect of nesfatin-1 on MAP was dependent on functional central melanocortin receptors, because the nesfatin-1-induced increase in MAP was abolished by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119. We previously reported that nesfatin-1 inhibited angiotensin II-induced water drinking in male rats but found no effect of nesfatin-1 in females in diestrus. However, nesfatin-1 enhanced angiotensin II-induced elevations in MAP in females in diestrus but had no effect on males. Finally, in agreement with previous reports, the expression of Nucb2 mRNA in hypothalamus was significantly reduced in female rats in proestrus compared with rats in diestrus. From these data we conclude that the function and expression of nesfatin-1 are modulated by sex hormone status. Further studies are required to determine the contributions of chromosomal sex and individual sex hormones to the cardiovascular effects of nesfatin-1.

Neuropeptide W increases mean arterial pressure as a result of behavioral arousal.

Neuropeptide W (NPW), an endogenous ligand for G protein-coupled receptors NPBWR1 (GPR7) and NPBWR2 (GPR8), has been detected in neurons in limbic and reticular activating system areas known to be important in arousal, as well as hypothalamic nuclei known to be important in food and water intake and the neuroendocrine response to stress. In rat, central administration of NPW increased mean arterial pressure (MAP) and behaviors associated with locomotion and grooming. We hypothesized that the NPW-induced increase in MAP was secondary to those increases in physical activity. Since peptides that stimulate arousal have been shown to increase sympathetic activity (e.g., orexin), we tested the ability of the mixed α1- and α2-adrenergic antagonist, phentolamine, to block the NPW-23-induced rise in MAP. Phentolamine pretreatment abrogated the NPW-induced MAP increase. However, we noticed the animals no longer exhibited NPW-associated behavioral arousal when pretreated with phentolamine. Anesthesia also blocked the NPW-induced increase in MAP, although the animals still were able to respond with an increase in MAP to centrally administered ANG II. Additionally, pretreatment with an orexin type 1 receptor antagonist significantly reduced the behavioral action of NPW-23 and completely blocked the peptide's action to increase MAP, suggesting that orexin neurons are downstream targets of NPW. Our results suggest that NPW increased MAP secondary to increased behavioral arousal.

Neuronostatin acts in brain to biphasically increase mean arterial pressure through sympatho-activation followed by vasopressin secretion: the role of melanocortin receptors.

Neuronostatin is a recently described neuropeptide that is derived from the somatostatin preprohormone. We have shown previously that neuronostatin led to a biphasic, dose-related increase in mean arterial pressure when injected into the lateral cerebroventricle of adult, male rats. Because neuronostatin depolarized both magnocellular and parvocellular, paraventricular nucleus neurons in hypothalamic slice preparations, we hypothesized that neuronostatin elevated mean arterial pressure first by stimulating sympathetic nervous system activity followed by the release of a pressor hormone, specifically vasopressin. We found that the first phase of neuronostatin-induced increase in mean arterial pressure was reversed by pretreatment with phentolamine, indicating that phase 1 was, indeed, due to an increase in sympathetic activity. We also found that centrally injected neuronostatin led to a dose-related increase in vasopressin secretion in a time course consistent with the peak of the second phase. Furthermore, the second phase of arterial pressure elevation was reversed by pretreatment with a vasopressin 1 receptor antagonist, indicating that phase 2 was likely due to an increase in vasopressin secretion. We previously have shown that the anorexigenic and antidipsogenic effects of neuronostatin were reversed by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119, so we evaluated the ability of SHU9119 to reverse the effects of neuronostatin on MAP and vasopressin secretion. We found that SHU9119 abrogated the second phase of neuronostatin-induced increase in MAP and neuronostatin-induced vasopressin secretion, indicating that neuronostatin acts through the central melanocortin system to increase vasopressin release, ultimately leading to an elevation in MAP.