Involvement of the Brain Orexin System in Hypertension - SUMMARY Hypertension (HTN) is a major risk factor for cardiovascular disease, with salt sensitive hypertension (SSH) accounting for 51% of all cases. As augmented sympathetic nerve activity (SNA) and increased plasma vasopressin (AVP) are known to play key roles in the development of SSH, we propose a study to investigate the mechanism underlying central orexin system influence on both SNA dysregulation and stimulation of AVP production, in the hopes of elucidating a primary component to the development of SSH. The brain paraventricular nucleus (PVN) plays a crucial role in controlling SNA outflow and AVP release, as well as plasma sodium concentration sensing. Orexin A is a neuropeptide produced by hypothalamic neurons with numerous functions, but emerging evidence suggests that the orexin system is also involved in the regulation of blood pressure (BP) and SNA. Orexin A elicits its action by binding to orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R), with a higher affinity for the former. Upregulation of orexin receptors in brain cardiovascular relevant regions including the PVN have been observed in several animal models of HTN, and orexin receptor antagonism lowers BP in those rats, suggesting overactive brain orexin receptors contribute to high BP. However, the impact of orexin receptor in the development and progression of SSH has not been determined. Our preliminary data in this application shows that expression of OX1R and AVP is dramatically increased in the PVN of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, an animal model of SSH mimicking human aldosteronism, a symptom observed in salt sensitive patients and even more so in resistant hypertensive individuals. In normal Sprague Dawley (SD) rats, central administration of orexin A increases PVN AVP expression, and microinjection of orexin A into the PVN increases SNA outflow. This increase in SNA outflow is blocked by pre-administration of an OX1R antagonist. In addition, our preliminary data shows that decreasing PVN OX1R expression using a genetic method markedly decreases PVN AVP expression and prevents HTN development in DOCA-salt rats. These observations have led us to hypothesize that DOCA- salt treatment upregulates PVN orexin signaling, which, in turn, increases SNA outflow and stimulates AVP production and release, ultimately resulting in HTN. We will use normal SD and DOCA-salt models to perform various state-of-the-art molecular and physiological studies to answer the following questions: (1) Does long-term overexpression of OX1R in the PVN of normal rats result in HTN? (2) Does chronic knockdown of the PVN OX1R prevent the development of SSH? (3) Does orexin signaling modulate the actions of central mineralocorticoid receptors (MR) or the brain renin-angiotensin system (RAS), two established players in the development of SSH development? The outcome of this study may provide a new target for both SSH and resistant HTN treatment. Most importantly, we will offer an opportunity for graduate and undergraduate students to participate in this research project.
