Cytochrome P450 overexpression and hypertension in SHR

描述(申请人提供)：高血压是心血管疾病和中风的主要原因之一，占美国所有死亡人数的近一半。此外，高血压的存在放大了肾功能衰竭和糖尿病的不良影响。然而，高血压的确切病因尚不清楚。为了研究与高血压发病相关的机制，越来越多的研究纳入了高血压的啮齿动物模型，如自发性高血压大鼠(SHR)。细胞色素P450 4A(CYP)在自发性高血压病中过度表达，导致20-HETE水平升高，20-HETE是一种有效的血管收缩和利钠因子。然而，20-HETE在SHR高血压的发生和维持中的作用尚不清楚。此外，目前尚不清楚神经系统是否影响SHR中CYP的表达水平。这项拟议的研究将探索在SHR和高血压伴随门脉高压和肺功能障碍的实验模型中，CYP过度表达是否与高血压有关。这些研究将检验清醒动物体内CYP过度表达对局部血管血流动力学和肾功能的独立贡献，并将进一步探索CYP表达水平与神经系统之间的潜在关系。具体地说，拟议的研究将检验以下假设：特定目的1.CYP过表达改变SHR的肾脏血流动力学(包括血管张力、血流和GFR)以及非肾脏外周阻力。具体目的2.自发性高血压的发生是由交感神经系统活动增强引起的细胞色素P450表达改变所致。具体目的3.肝失神经大鼠门脉高压和肺功能障碍与CYP的过度表达有关。

DESCRIPTION (provided by applicant): Hypertension is one of the leading causes of cardiovascular disease and stroke, accounting for nearly one-half of all deaths in the United States. Additionally, the presence of hypertension magnifies the adverse effects of renal failure and diabetes. However, the exact etiology of hypertension is unknown. To investigate mechanisms associated with the development of high blood pressure, research has increasingly incorporated rodent models of hypertension such as the Spontaneously Hypertensive Rat (SHR). Cytochrome P450 4A (CYP) is overexpressed in SHR, resulting in elevated levels of 20-HETE, a potent vasoconstrictor and natriuretic factor. However, the role of 20-HETE in the development and maintenance of hypertension in SHR is unclear. Further, it is not known whether the nervous system influences CYP expression levels in SHR. The proposed studies will explore whether CYP overexpression contributes to hypertension in both SHR and an experimental model in which hypertension is concomitantly expressed with portal hypertension and pulmonary dysfunction. The studies will examine the independent contribution of CYP overexpression on regional vascular hemodynamics and renal function in conscious animals, and will further explore a potential relationship between CYP expression levels and the nervous system. Specifically, the proposed studies will test the hypotheses that: Specific Aim 1. CYP overexpression alters both renal hemodynamics, including vascular tone, blood flow and GFR, and non-renal peripheral resistance in SHR. Specific Aim 2. The development of hypertension in SHR is driven by alterations in CYP expression secondary to increased sympathetic nervous system activity. Specific Aim 3. CYP overexpression contributes to portal hypertension and pulmonary dysfunction in hepatic denervated rats.