Renal Vascular Reactivity in Genetic Hypertension

描述（由申请人提供）：本研究的长期目标是 更好地了解控制血管反应性的机制， 激素、旁分泌和自分泌药物对健康肾脏微循环的影响 和疾病我们将继续把研究重点放在血管调节上， 反应性和受体信号通路的肾小球前血管。一 体内与体外方法协调的独特组合， 重叠的主题旨在深入了解监管机制 在年轻自发性高血压大鼠中负责肾血管收缩 （SHR）。我们以前的研究表明，过度的肾血管收缩是 与高血压的发展相关，并由异常的 血管收缩剂血管紧张素II（Ang II）、加压素 (AVP)血栓素（TxA 2）和血管扩张系统（前列腺素，硝酸 氧化物）。在拟议的研究中，我们将描述其他血管收缩剂 系统，如α-肾上腺素能神经系统和内皮素（ET），以及 机制，他们产生增强的肾脏血管紧张素在年轻的SHR。我们 将检验过度的血管收缩是由 通过收缩剂对血管平滑肌细胞的直接作用， 单独，由于增强的受体密度或受体后信号传导，或 与血管扩张剂缓冲能力不足的组合 前列腺素类具体目的是：I）评价体内肾血管反应性 确定去甲肾上腺素、ET、前列腺素和反应性 氧在年轻SHR肾血管收缩中的作用; II）评估 体内和体外细胞信号传导，以确定信号传导途径 血管收缩剂的介导作用和负责 增强年轻SHR的肾血管张力; III）研究体内调节 血管紧张素II、AVP、TxA 2、α 1-肾上腺素能和ET受体的作用;和IV）定义 酪氨酸激酶和MAP/ERK激酶途径对肾血管扩张的影响 对收缩剂的反应性。我们将评估关键信号 来自受体mRNA表达和蛋白质结合的转导步骤，以及 与细胞内途径偶联以刺激细胞溶质钙， 动员和招募进入渠道。我们对重要的 血管活动的异常应该提供重要的新信息， 促进对正常调节机制的更全面理解， 控制器中可能导致或有助于以下发展的缺陷 遗传性高血压

DESCRIPTION (provided by applicant): The long-range goal of this research is to gain a better understanding of mechanisms that control vascular reactivity in the renal microcirculation by hormonal, paracrine and autacoid agents in health and disease. We will continue to focus our studies on regulation of vascular reactivity and receptor signaling pathways in the preglomerular vasculature. A unique combination of coordinated in vivo with in vitro approaches of overlapping themes is designed to gain insight into regulatory mechanisms responsible for renal vasoconstriction in young spontaneously hypertensive rats (SHR). Our previous studies indicate that excessive renal vasoconstriction is associated with the development of hypertension and is mediated by an abnormal balance of actions of vasoconstrictor angiotensin II (Ang II), vasopressin (AVP), and thromboxane (TxA2) and vasodilator systems (prostanoids, nitric oxide). In the proposed studies, we will characterize other vasoconstrictor systems, such as a-adrenergic nervous system and endothelin (ET), and the mechanisms by which they produce enhanced renal vasomotor tone in young SHR. We will test the central hypothesis that exaggerated vasoconstriction is mediated by direct actions of the constrictor agents on vascular smooth muscle cells, either alone, due to enhanced receptor density or postreceptor signaling, or in combination with a deficiency in the buffering capacity of vasodilator prostanoids. Specific aims are: I) Evaluate renal vascular reactivity in vivo to define the contribution of norepinephrine, ET, prostanoids and reactive oxygen species in exaggerated renal vasoconstriction in young SHR; II) Assess cellular signaling in vivo and in vitro to determine signaling pathways mediating actions of vasoconstrictor agents and mechanisms responsible for enhanced renal vasomotor tone in young SHR; III) Investigate in vivo regulation of Ang II, AVP, TxA2, a1-adrenergic, and ET receptors; and IV) Define the roles of tyrosine kinase and MAP/ERK kinase pathways to exaggerated renal vascular reactivity to constrictor agents in young SHR. We will evaluate key signal transduction steps from receptor mRNA expression and protein binding, and coupling with intracellular pathways to stimulate cytosolic calcium via mobilization and recruitment of entry channels. Our search for significant abnormalities in vascular actions should provide important new information that advances a more complete understanding of normal regulatory mechanisms and defects in controllers that may cause or contribute to the development of genetic hypertension.