Cardiovascular regulatory actions of the hypocretins in brain

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.