Elsevier

Brain Research

Volume 831, Issues 1–2, 12 June 1999, Pages 248-253
Brain Research

Research report
Cardiovascular regulatory actions of the hypocretins in brain

https://doi.org/10.1016/S0006-8993(99)01457-2Get rights and content

Abstract

The hypocretins, also known as the orexins, are alternate translation products of a single gene. The recognition of their production in neurons of the rostral diencephalon, and their axonal localization in brain sites known to be important in the control of appetite, led to the demonstration of their orexogenic actions. However, these peptides are not as potent as other appetite stimulating neuropeptides and they have been localized in areas of brain more related to cardiovascular function. We verified the orexogenic actions of hypocretin-1 (Hcrt-1) and hypocretin-2 (Hcrt-2) in an ad libitum feeding model and identified the threshold dose to be 1 nmol when given into the lateral cerebroventricle (i.c.v.). Even at threshold doses for feeding, both Hcrt-1 and Hcrt-2 given i.c.v. into conscious, unrestrained rats stimulated significant elevations in mean arterial blood pressure, that appeared dose related. These elevations were relatively long lasting, mirroring the time course of a pressor dose of angiotensin II (0.1 nmol i.c.v.); however, the magnitude of blood pressure elevation to hypocretin did not equal that of A II. These data suggest an additional, non-appetitive action of the hypocretins and indicate that the peptide and receptor mapping studies may have predicted important roles for the peptides in the central nervous system control of cardiovascular function.

Introduction

Using directional tag PCR subtraction techniques, Gautvik et al. [6] identified multiple rat mRNAs that were selectively expressed in hypothalamus. Recently, this same group [2] reported that one of the clones encodes a precursor peptide which could be post translationally modified to result in the production of two biologically active peptides. They termed these peptides the hypocretins, because of their hypothalamic localization and their structural homology to the gut hormone secretin. Furthermore, de Lecea et al. [2] also demonstrated the sites of production of the hypocretins in brain, the projection fields of the cells producing the peptides and, importantly, direct neural effects of one of the peptides, hypocretin-2. They suggested that the hypocretins might play important roles in a variety of hypothalamic functions including the control of food intake and blood pressure regulation. These hypotheses were supported by subsequent work which demonstrated projections to cardiovascular centers in brain [10] and direct neural effects [16] of both hypocretin-1 (Hcrt-1) and hypocretin-2 (Hcrt-2).

Another group [12], using cell based reporter strategies to discover novel, orphan receptor ligands, reported the discovery of gene products similar to the hypocretins. This group termed these peptides orexins, because of their observations that when injected in vivo they stimulated food intake. They had correctly anticipated these orexogenic activities on the basis of their orexin peptide and orexin receptor localization studies.

Because nerve fibers containing immunoreactive hypocretin/orexin (henceforth identified as hypocretin) have been reported to project [2] not only to hypothalamic feeding centers in the lateral and medial hypothalamus, but also to other limbic regions of the diencephalon and, importantly, to cardiovascular regulatory centers in the hindbrain, we hypothesized that additional biologic activities other than orexogenesis existed in brain. Specifically, hypocretin-immunopositive neuronal projections predicted effects on the central regulation of cardiovascular function. We studied, therefore, the effects of intracerebroventricular (i.c.v.) administration of Hcrt-1 and Hcrt-2 on mean arterial blood pressure in conscious, unrestrained rats. We report here significant actions of the peptides on mean arterial blood pressure at doses which are minimally orexogenic, suggesting broader physiologic potential than merely stimulation of food intake in the rat.

Section snippets

Materials and methods

Amidated Hypocretin-1 (human, mouse, rat orexin A; EPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-NH2), amidated Hypocretin-2 (mouse, rat orexin B; RPGPPGLQRLQRLLQANGNHAAGILTM-NH2), and angiotensin II (A II) were obtained from Phoenix Pharmaceuticals (Mt. View, CA) and diluted in physiologic saline (0.9% NaCl). Adult male rats (200–250 g, Sprague–Dawley, Harlan, Indianapolis, IN) were housed individually (lights on 0500 h, off 1900 h) following implantation of a chronic indwelling cannula (23 gauge,

Results

Both doses (1 and 5 nmol) of Hcrt-1 significantly stimulated food intake at 60 min (p<0.05) in ad libitum fed rats (Fig. 1). Food intakes did not differ between the three treatment groups at 120 and 180 min and there were no significant differences in food intake between animals at any sampling point in the 1 nmol and the 5 nmol Hcrt-1 treated groups.

Intracerebroventricular administration of 1 nmol Hcrt-1 resulted in significant elevation of arterial blood pressure in conscious rats (Fig. 2,

Discussion

Much attention has been focused recently on the roles played by neuropeptides in the control of food intake and body composition 1, 3, 4, 5, 7, 8, 9, 11, 15. Indeed both stimulatory and inhibitory peptides have been identified and characterized and the importance of genetic models of altered peptide or receptor function established. Neuropeptide Y and galanin remain the most potent orexogenic agents identified; however, recently an additional family of peptides was identified independently by

Acknowledgements

These studies were conducted with funding from the Neuropsychiatric Research Institute of Fargo and the Max Baer Heart Fund (Fraternal Order of Eagles).

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