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

Abstract

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.

Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107

“…Treatment with GPR107 siRNA did not interfere with the pressor response (Fig. 3D) to a dose of ANG II (50 pmol) (20).…”

“…Baseline mean arterial pressure (MAP) and heart rate (HR) were recorded at 1-min intervals for at least 30 min. Rats were injected then intracerebroventricularly with three subsequent substances, each injection spaced at a minimum of 1 h apart: saline vehicle, 300 pmol of neuronostatin in sterile saline (15,20), and 50 pmol of ANG II in sterile saline (22). MAP and HR were recorded In Vitro, In Vivo at 1-min intervals.…”

“…In rats treated with siRNA directed against eGFP, we observed that central administration of neuronostatin induced a significant increase in MAP when the data were analyzed as area under the curve for the total observation time of 45 min (Fig. 3, A and B) (15,20), compared with eGFP siRNA-treated, saline-injected controls (Fig. 3B).…”

“…NEURONOSTATIN, A PRODUCT OF the somatostatin preprohormone, is a recently described 13-amino acid peptide hormone that exerts multiple cardiovascular and metabolic actions in a variety of tissues (10,15,20). When injected into the lateral cerebroventricle (intracerebroventricularly) of adult, male rats, neuronostatin induced a significant, dose-related, and biphasic increase in mean arterial pressure (MAP) (15,20).…”

“…When injected into the lateral cerebroventricle (intracerebroventricularly) of adult, male rats, neuronostatin induced a significant, dose-related, and biphasic increase in mean arterial pressure (MAP) (15,20). This elevation in MAP was found to be dependent upon two separate mechanisms: activation of the sympathetic nervous system and stimulation of vasopressin secretion from the posterior pituitary gland, since the first phase was blocked by pretreatment with phentolamine, while the second phase was reversed by pretreatment with a vasopressin receptor antagonist (20). In addition, neuronostatin directly altered the contractility of isolated cardiomyocytes and whole heart preparations via PKA and/or JNK-dependent mechanisms (10,19).…”