Neuroendocrine dysfunction and hypertension

点击翻译按钮获取中文摘要

Project Summary Hypertension is a high-risk factor for stroke, cardiovascular diseases, and renal failure and it is one of the leading causes of death in the US and afflicts 75 million people. Primary hypertension, the most common form of hypertension, is associated with elevated sympathetic vasomotor tone and hyperactivity of the hypothalamic pituitary adrenal (HPA) axis. However, the role of hyperactivity of the HPA axis in elevated sympathetic outflow in primary hypertension remains largely unknown. The paraventricular nucleus (PVN) of the hypothalamus is a critical brain region that integrates neuroendocrine and cardiovascular functions. In primary hypertension, PVN presympathetic neuron activity is increased and provides excitatory drive to maintain heightened sympathetic vasomotor tone. Glutamatergic synaptic inputs to the PVN presympathetic neurons are enhanced in spontaneously hypertensive rats (SHRs). However, the cellular mechanisms underlying hyperactivity of PVN presympathetic neurons and enhanced excitatory synaptic inputs in SHRs remain unknown. The corticotrophin-releasing hormone (CRH)-containing neurons in the PVN (PVN-CRH neurons) are an essential component of the HPA axis. PVN-CRH neurons are activated in hypertension as indicated by increased expression levels of CRH protein and mRNA levels in the PVN in patients with primary hypertension. The objective of this project is to determine the role of PVN-CRH neurons in regulating blood pressure and sympathetic outflow in primary hypertension. Our pilot study found that PVN-CRH neuron activity was increased in SHRs, and selective inhibition or ablation of PVN-CRH neurons decreased arterial blood pressure in SHRs. In addition, selective inhibition of PVN-CRH neurons suppressed the activity of PVN presympathetic neurons in SHRs; the effect was eliminated by blocking CRH receptor 1. Thus, we will test our central hypothesis that increased activity of PVN-CRH neurons leads to hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension. We will first determine if hyperactivity of PVN-CRH neurons is required for high blood pressure and elevated sympathetic outflow in primary hypertension (Aim 1). We will also identify the synaptic mechanism underlying hyperactivity of PVN-CRH neurons in hypertension (Aim 2). Finally, we will determine the role of PVN-CRH neurons in the elevated activity of PVN presympathetic neurons and enhanced glutamatergic synaptic inputs in hypertension (Aim 3). Our proposed studies will greatly improve the understanding of the cellular and molecular mechanisms underlying primary hypertension. We expect our studies to provide novel information about the neuronal mechanisms responsible for primary hypertension and an important rationale for developing novel treatment strategies to reduce sympathetic vasomotor tone in primary hypertension.