Roles of Central Orexin Activities in the Pathophysiology of Hypertension in Shr

Hypertension and related cardiovascular diseases have been the leading causes of death worldwide, including Taiwan. It is of importance to understand the regulating mechanisms of blood pressure in both physiological and pathological aspects. Essential hypertension is the most common type of hypertension. Increased sympathetic activity, leading to blood pressure elevation and increased cardiovascular responses to stress, has been implicated in the genesis of essential hypertension. Our previous studies show that two hypothalamic neuropeptides, orexin A and B, can elevate arterial pressure by activating sympathetic pathway in the CNS. The dorsomedial hypothalamic area (DMH), where orexin-expressing neurons are located, has been shown to be a key structure responsible for greater sympathetic vasomotor response to stressors in spontaneously hypertensive rats (SHR), a well-established animal model for essential hypertension. Therefore, the PI hypothesizes that elevated central orexin activity contributes to the pathophysiology of hypertension in SHR, through specific orexinergic receptor(s) in cardiovascular relevant nuclei in the hypothalamus and brain stem. Our preliminary data show that multiple sites of action for orexins to regulate blood pressure may exist in both forebrain and hindbrain. However, only a few nuclei in the hindbrain, such as the rostral ventrolateral medulla (RVLM) and caudal nucleus tractus solitarius (cNTS), have been well studied for orexin’s cardiovascular effect. The paraventricular hypothalamic nucleus (PVN) and DMH are two potential sites mediating orexin’s cardiovascular regulation. Besides, the receptor subtypes mediating orexin’s cardiovascular effects have been fully understood. Two specific aims are proposed to examine the hypothesis and also to explore the involved neural structure(s) and receptor(s): Aim 1. to evaluate the roles of central orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) activities in the maintenance of basal arterial pressure in Wistar-Kyoto rats (WKY) and elevated arterial pressure in SHR; and Aim 2. to evaluate possible involvement of the PVN, DMH, RVLM, and/or cNTS in OX1R- and/or OX2R-associated elevation of arterial pressure in SHR. In vivo measurement of arterial pressure combined with central blockade of specific orexin receptor will be performed in anesthetized and conscious SHR and WKY for Aim 1. By comparing the protein levels of OX1R, OX2R, orexin A, and orexin B, as well as central OX1R or OX2R blockade-induced changes of Fos expression in the PVN, DMH, RVLM and NTS between SHR and WKY, potential neural structure(s) involving in central orexin-associated pathophysiology of hypertension in SHR will be selected for further confirmation in the studies of Aim 2. Intra-nucleus application of OX1R or OX2R antagonism and whole-cell patch clamp recordings from neurons in the nuclei of interest will be performed to evaluate the involvement of the neural structure(s) and receptor(s) in orexin-associated pathophysiology of hypertension in SHR. The completion of this study will lead to a better understanding toward the orexinergic neural pathways involving in the pathophysiology of hypertension in SHR and may help the development of novel treatments against hypertension.