EICOSANOID MEDIATED PRESSOR MECHANIMS IN HYPERTENSION

这是一个研究机制和对血压的影响的建议 调节类花生酸介导的升压和 正常血压和高血压大鼠的血管降压功能。研究是 在两个相关领域提出。 区域1：血管对花生四烯酸代谢的影响 脂氧合酶在前列腺素介导的血压机制中的作用 监管-要测试的假设是，过度形成的 脂氧合酶产物，可能是花生四烯酸氢过氧化物， 血管紧张素依赖性高血压大鼠的动脉血管 有助于通过促进表达的血压升高 PGH 2介导的血管收缩机制，并通过限制 PGI 2介导的血管舒张机制的活性。实验将 在血管紧张素依赖性高血压（主动脉）大鼠中进行 血管紧张素II输注诱导的高血压 高血压），在大鼠血管紧张素非依赖性高血压（DOCA- 盐诱导的高血压）和相应的血压正常对照。 在这些实验模型中，我们提出实验（a）以识别 并定量血压正常和正常人血管组织中的脂氧合酶活性， （B）检查脂氧合酶与高血压大鼠的关系， 正常血压血管组织的产物形成和PGI_2产生 和高血压大鼠;（c）研究 脂氧合酶产物与高血压机制的关系 脂氧合酶抑制对血压的影响及相关 高血压和正常血压大鼠的肾功能;（d）探索 抑制脂氧合酶的血流动力学反应与 和PGI 2介导的血管降压系统的活性;（e）检查 脂氧合酶产物形成与表达的关系 PGH 2介导的小动脉血管收缩机制 血压正常和高血压大鼠的血压。 区域2：细胞色素P450对花生四烯酸代谢的影响 加氧酶对正常血压和高血压大鼠血压的影响 待检验的假设是2 O-HETE有助于增加血液 压力和血管反应性在年轻的SHR和其他模型， 20-HETE合成过度表达的高血压。实验 将在SHR中进行，在通过用 DOCA-盐或地塞米松，以及相应的血压正常 对照在这些模型中，我们提出实验（a）来研究 用20-HETE合成抑制剂治疗对全身性 正常血压大鼠、自发性高血压大鼠和高血压大鼠的血流动力学和相关肾功能 其他形式的实验性高血压;（B）探索20- HETE在调节血管对收缩激素反应性中的作用 正常血压和高血压大鼠。

This is a proposal to study the mechanisms and impact on blood pressure regulation of relationships between eicosanoid-mediated pressor and vasodepressor functions in normotensive and hypertensive rats. Research is proposed in two related areas. AREA l: The Influence of Arachidonic Acid Metabolism by Vascular Lipoxygenase(s) on Prostanoid-Mediated Mechanisms of Blood Pressure Regulation - The hypothesis to be tested is that excessive formation of lipoxygenase products, presumably arachidonic acid hydroperoxides, by the arterial vessels of rats with angiotensin-dependent hypertension contributes to the elevation of blood pressure by fostering the expression of a vasoconstrictor mechanism mediated by PGH2 and by limiting the activity of a vasodilatory mechanism mediated by PGI2. Experiments will be conducted in rats with angiotensin-dependent hypertension (aortic coarctation-induced hypertension; angiotensin II-infusion-induced hypertension), in rats with angiotensin-independent hypertension (DOCA- salt-induced hypertension) and in the corresponding normotensive controls. In these experimental models we propose experimentation (a) to identify and quantify lipoxygenase activity in vascular tissues of normotensive and hypertensive rats; (b)to examine the relationship between lipoxygenase(s) product formation and PGI2 production by vascular tissues of normotensive and hypertensive rats; (c) to investigate the contribution of lipoxygenase(s) products to mechanisms of hypertension by determining the consequences of lipoxygenase(s) inhibition on blood pressure and relevant renal functions of hypertensive and normotensive rats; (d) to explore relationships between the hemodynamic response to lipoxygenase inhibition and the activity of vasodepressor systems mediated by PGI2; (e) to examine the relationship between lipoxygenase product formation and the expression of PGH2-mediated mechanism of vasoconstriction in small arterial vessels of normotensive and hypertensive rats. AREA 2: The Influence of Arachidonic Acid Metabolism by Cytochrome P450 Oxygenases on the Blood Pressure of Normotensive and Hypertensive Rats - The hypothesis to be tested is that 2O-HETE contributes to increase blood pressure and vascular reactivity in young SHR and in other models of hypertension in which 20-HETE synthesis is hyperexpressed. Experiments will be conducted in SHR, in rats made hypertensive by treatment with DOCA-salt or with dexamethasone, and in the corresponding normotensive controls. In these models we propose experimentation (a) to investigate the effect of treatment with an inhibitor of 20-HETE synthesis on systemic hemodynamics and relevant renal functions in normotensive rats, SHR and other forms of experimental hypertension; (b)to explore the role of 20- HETE in regulation of vascular responsiveness to constrictor hormones in normotensive and hypertensive rats.