The orexins: linking circulatory control with behavior.

NORMAL CARDIOVASCULAR CONTROL is accomplished by a close interplay of homeostatic feedback mechanisms, such as the baroreceptor and chemoreceptor reflexes, and adaptive feedforward mechanisms that allow the organism to adapt to environmental changes and behavioral responses, such as exercise, hunting, fighting, or escape from predators. A hallmark of the adaptive mechanisms is an involvement of hypothalamic neural circuits, which integrate somatomotor, hormonal, and autonomic pathways. Such mechanisms include the defense response, “central command,” vasovagal response, and circadian rhythmicity. A common feature of all of these responses is the unidirectional change of heart rate and arterial pressure, which implicates a concomitant modification of the homeostatic mechanisms. For example, during the defense response arterial pressure and heart rate increase, which is associated with a vasodilatation in skeletal muscle and a vasoconstriction in other areas, these reactions are typically evoked by threatening emotional stimuli (9, 15). The perifornical region of the hypothalamus plays a crucial role in the defense response (8) and is part of a vasodilator pathway from the motor cortex through the hypothalamus and brain stem to vasodilator projections to skeletal muscle vasculature (21). Very similar responses can also be elicited by much more subtle stimuli than those leading to a full-grown fight-orflight reaction (1, 3, 11). Although the concept of cardiovascular control by cortico-hypothalamic mechanisms was introduced nearly 100 years ago, its molecular mediators have remained obscure. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Kayaba and colleagues (11a) provide experimental evidence suggesting that orexins may play such a role. Orexins (also called hypocretins) were first described in 1998 as the result of a search for unknown regulatory peptides in the hypothalamus (6, 16). The orexin system consists of two closely related neuropeptides, orexin A and orexin B, which are produced from a common precursor, and two receptors, the orexin receptor type-1 (or Hcrtr1) and orexin receptor type-2 (or Hcrtr2) (12). The orexin receptor type-1 has a 10-fold higher affinity for orexin A than orexin B, whereas the orexin receptor type-2 binds the two peptides with equal affinity (16). Both receptors couple to Gq proteins, resulting in elevated intracellular Ca2 concentrations, protein phosphorylation, and depolarization, ultimately leading to an enhanced neuronal excitability (12, 16). Furthermore, orexins can stimulate the release of the excitatory neurotransmitters glutamate and GABA (22). The formation of orexins is limited to a very small subset of specific neurons in the lateral perifornical area of the hypothalamus (6). The input to these neurons includes projections from the hypothalamic orexinergic neurons themselves from the suprachiasmatic nucleus, which is believed to generate the circadian rhythm, as well as those from the arcuate nucleus, a major integration site for metabolic and reproductive hormone regulation (12). Projections of the orexinergic cells and the expression sites of orexin receptors are widespread, including the hypothalamus, thalamus, brain stem, and spinal cord (12). Noteworthy among these sites with respect to cardiovascular regulation are the paraventricular nucleus (PVN) in the hypothalamus, the nucleus of the solitary tract (NTS), and the rostral ventrolateral area (RVLM) in the medulla oblongata, as well as the intermediolateral (IML) column in the spinal cord. The PVN harbors the cells, releasing vasopressin in the hypophysis; the NTS and RVLM provide important relay stations for the baroreceptor and chemoreceptor reflexes and are major determinants of efferent sympathetic tone; and the IML column gives rise to the peripheral preganglionic sympathetic neurons (5). Finally, the perifornical region is also part of the sympathetic cholinergic dilator pathway of the defense response (21). Taken together, the orexinergic neurons are in a perfect strategic position for a central role in hypothalamic cardiovascular control, both with respect to the defense response as well as regarding resting arterial pressure. Early functional studies using intracerebroventricular infusions of orexins suggested the primary physiological function of the orexin system to be the regulation of food intake by increasing appetite (16). However, changes in the feeding behavior do not constitute the major phenotype of orexin-deficient animals. Although mice carrying a targeted disruption of the orexin-preprohormone eat less than their wild-type littermates, they are not anorexic and show a normal postnatal body growth (4). When orexin-producing neurons are gradually destroyed postnatally by introducing an ataxin-3 transgene under the control of the Address for reprint requests and other correspondence: H. Ehmke, Institut für Physiologie und Pathophysiologie, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany (E-mail: ehmke @uke.uni-hamburg.de), or A. Just, Dept. of Cell and Molecular Physiology, UNC at Chapel Hill, Medical Biomolecular Res. Bldg., 103 Mason Farm Rd. CB 7545, Chapel Hill, NC 27599 (E-mail: just @med.unc.edu). Am J Physiol Regul Integr Comp Physiol 285: R519–R521, 2003; 10.1152/ajpregu.00311.2003.