FUNCTIONAL SIGNIFICANCE OF CYTOCHROME P450 CYCLOOXYGENASE

20-羟基二十碳四烯酸(20-HETE)是重要肾脏结构的主要二十烷类化合物，在调节肾血管和肾小管功能中起重要作用。鉴于20-HETE对肾功能的重要性，对那些控制20-HETE的产生和活性的因素的鉴定和表征具有高度的优先地位，因为它们决定了二十烷类化合物的肾脏作用的深度和广度。环氧合酶(COX-1和COX-2)和一氧化氮合酶(NOS)分别被认为是20-HETE代谢和产生的中心调节因子。三个目标将解决假定的重要性，COX和NO到20-HETE水平和肾脏的活动。目的1建立高血压AII灌流模型，探讨影响20-HETE产生和生物学活性的细胞因子、NO和COX(-1和-2)之间的关系和可能的相互作用。目的利用高盐摄入量对NO产生的相对选择性和低盐摄入量对皮层COX-2表达的相对选择性，研究它们对20-HETE组织水平和20-HETE代谢物在皮层的生物活性的影响。目的研究糖皮质激素对TAL中COX-2表达的影响，以明确肿瘤坏死因子和COX-2(可能还有诱导型一氧化氮合酶)在肾上腺后的相互作用，以及其中一个或多个因素可能与细胞色素P450氨基酸代谢的抑制和肾功能的改变有关。

20-hydroxyeicosatetraenoic acid (20-HETE) is the principal eicosanoid of key renal structures where it serves an essential component in the regulation of renal vascular and tubular function. In view of the importance of 20-HETE to renal function, the identification and characterization of those factors that govern production and activity of 20-HETE assume a high priority as they determine the depth and breadth of the renal actions of the eicosanoid. Cyclooxygenases (COX-1 and COX 2) and nitric oxide synthases (NOS) have been identified as being central to the regulation of 20-HETE metabolism and production, respectively. Three Aims will address the postulated importance of COX and NO to 20-HETE levels and activities in the kidney. AIM 1 makes of the AII infusion model of hypertension to determine relationship and possible interactions of cytokines, NO and COX (both-1 and -2) that affect production and biological activities of 20-HETE. Aim 2 draws upon the relatively selective effect of high salt intake on NO production and low salt intake on cortical COX-2 expression in order to study their separate effects on 20-HETE tissue levels and spectrum of biological activities of 20-HETE metabolites in the cortex. AIM 3 addresses the powerful negative effect of glucocorticoids on COX- 2 expression in the TAL in order to define interactions involving TNF and COX-2 (and possibly iNOS) post-adrenal and to relate one or more of these factors to a postulated depression of CYP450 AA metabolism and to changes in renal function.