Roles of Central OX2R Activities in the Pathophysiology of Hypertension in SHR

Hypertension and related cardiovascular diseases have been the leading causes of death worldwide, including Taiwan. Primary hypertension is the most common type of hypertension. Our previous studies show that an elevated orexin 2 receptor (OX2R) activity in the CNS contributes to the pathogenesis of hypertension in spontaneously hypertensive rats (SHR), an animal model of primary hypertension. The OX2R activity in the paraventricular hypothalamic nucleus (PVN) and rostral ventrolateral medulla (RVLM) had been implicated in the regulation of blood pressure. Our preliminary studies demonstrated that microinjection of an OX2R antagonist into the PVN or RVLM caused a larger reduction of arterial pressure in SHR than in its counterpart, the Wistar Kyoto rats (WKY). Our previous and preliminary studies also revealed that OX2R agonists could activate the bulbospinal vasomotor neurons in the RVLM and the preautonomic neurons in the PVN, i.e. the key neurons responsible for the sympathoexcitatory outflow from these two nuclei to cardiovascular system. Therefore, we hypothesizes that elevated OX2R activities within the RVLM and PVN contribute to the pathogenesis of hypertension in SHR and the bulbospinal vasomotor neurons in the RVLM and preautonomic neurons in the PVN are the major neuron types involved. Two specific aims are proposed to examine the hypothesis and also to explore the underlying mechanisms: aim 1. to evaluate the contribution of RVLM OX2R activity in the pathogenesis of hypertension in SHR and to probe the underlying mechanisms, including the neuron types and cellular mechanisms involved; and aim 2. to evaluate the contribution of PVN OX2R activities in the pathogenesis of hypertension in SHR and to probe the underlying mechanisms, including neuron types and cellular mechanisms involved. Three issues will be clarified for both aims: (1) to confirm the contribution of RVLM or PVN OX2R activity in the pathogenesis of hypertension in SHR, by comparing the cardiovascular effects of intra-nucleus OX2R blockade, (2) to elucidate the mechanisms underlying elevated OX2R activities in the RVLM and PVN, by comparing the levels of orexinergic inputs and of functional responses induced by OX2R agonists, and (3) to evaluate the roles of RVLM bulbospinal vasomotor neurons and PVN preautonomic neurons in OX2R-related pathogenesis of hypertension in SHR and to probe the underlying cellular mechanisms, by investigating the effects and underlying cellular mechanisms of OX2R activation on phenotype-identified neurons with electrophysiological approaches. These mechanisms will then be confirmed in in vivo cardiovascular experiments. Several preliminary findings support our hypothesis. 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.