FUNCTIONAL SIGNIFICANCE: CYTOCHROME P450/HEME OXYGENASE

这一建议旨在研究血管中的血红素-血红素加氧酶-一氧化碳系统与细胞色素P450衍生的二十烷类化合物之间相互作用的机制和功能意义，涉及调节血管张力和血压的机制。四个主要的假设将被检验。首先，小动脉血管产生的20-HETE受到起源于血管的一氧化碳的抑制调节。第二，血红素加氧酶来源的一氧化碳对血管张力和反应性的抑制涉及下调血管20-HETE的合成，并激活血管平滑肌上的钙激活的K+通道。第三，慢性钾摄入量的改变导致血管血红素加氧酶表达和20-HETE产生的交互变化，进而影响血管反应性，例如，钾摄入量的增加促进了血管血红素加氧酶的表达，减少了20-HETE的产生，降低了血管反应性。第四，实验诱导的高血压大鼠血红素加氧酶过度表达的降压作用与一氧化碳生成增加，导致20-HETE合成下调和血管反应性降低有关。在测试这些假说的过程中，将在大鼠身上实现以下具体目标。目的1：探讨增加或降低血管血红素-血红素加氧酶-一氧化碳系统活性的干预对20-HETE血管合成的影响。目的：明确血管20-HETE合成在实现血管对一氧化碳的反应中的意义以及改变血管血红素-血红素加氧酶-一氧化碳系统活性的干预措施。目的：探讨一氧化碳20-HETE相互作用在慢性钾摄入量改变引起的血管反应性改变中的作用。目的4：确定一氧化碳-20-HETE相互作用对因增加血红素-血红素加氧酶-一氧化碳系统表达而引起的血压变化的影响。

This proposal aims at studying the mechanisms and functional significance of the interaction among the vascular heme-heme oxygenase- carbon monoxide system and cytochrome P450-derived eicosanoids in relation to mechanisms regulating vascular tone and blood pressure. Four major hypotheses will be examined. First, the production of 20-HETE by small arterial vessels is subject to inhibitory regulation by carbon monoxide of vascular of origin. Second, the inhibitory of heme oxygenase-derived carbon monoxide on vascular tone and reactivity involves down-regulation of vascular 20-HETE synthesis coupled to activation of Ca2+-activated K+ channels in vascular smooth muscle. Third, chronic alterations in potassium intake brings about reciprocal changes in vascular heme oxygenase expression and 20-HETE production which, in turn, impact on vascular reactivity, e.g., augmentation of potassium intake promotes vascular heme oxygenase expression, decrease 20-HETE production and diminishes vascular reactivity. Fourth, the anti- hypertensive effect accompanying experimentally induced over- expression of heme oxygenase in hypertensive rats is linked to augmentation of carbon monoxide production, leading to down-regulation of 20-HETE synthesis and reduction of vascular reactivity. In testing these hypotheses, the following specific aims will be addressed in rats. AIM 1: To Elucidate the Effect of Interventions That Increase or Decrease the Activity of the Vascular Heme-Heme Oxygenase-Carbon Monoxide System on Vascular Synthesis of 20-HETE. AIM 2: To define the Significance of Vascular 20-HETE Synthesis in the Implementation of Vascular Responses to Carbon Monoxide and Interventions That Alter the Activity of the Vascular Heme-Heme Oxygenase-Carbon Monoxide System. AIM 3: To Determine the Contribution of Carbon Monoxide 20-HETE Interactions to the Changes in Vascular Reactivity Caused by Chronic Alterations of Potassium Intake in Rats. AIM 4: Determine the Impact of Carbon Monoxide-20-HETE Interactions on the Changes in Blood Pressure Caused by Interventions That Increased Expression of the Heme-Heme Oxygenase-Carbon Monoxide System.