VASCULAR NA+ PUMP ACTIVITY AND HYPERTENSION

血管 NA 泵活动和高血压

• 批准号: 2378715
• 负责人: Emel Songu-Mize
• 金额: $ 13.11万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-02-21 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2378715
• 关键词: disease /disorder model; enzyme activity; enzyme induction /repression; hypertension; isozymes; laboratory rat; protein structure function; sodium potassium exchanging ATPase; spontaneous hypertensive rat; stretch receptors; tissue /cell culture; vascular smooth muscle; vascular smooth muscle nervous control; vasomotion

DESCRIPTION (Adapted from the applicant's abstract): Na+ K+ ATPase (NKA) is a determinant of the cellular membrane potential and can contribute to the vascular smooth muscle reactivity and tone and myocardial contractility, and thus may play a role in development and/or maintenance of hypertension. The enzyme is composed of alpha- and beta-subunits, and several isoforms of the enzyme exist. The isoforms are expressed in a species- and tissue-specific manner and appear to be differently regulated in both health and disease states. However, information on the functional significance of the isozymes and the regulation of these proteins is far from complete. Especially, the role of individual isoforms and the mode of their regulation in hypertension is not known. The investigators and others have previously shown that NKA catalytic alpha-2 subunit gene and protein expressions are downregulated both in the heart and in the vasculature in several animal models of hypertension. They have also shown that the downregulation in the heart can be reversed by antihypertensive treatment in genetically hypertensive rats. They wish to determine whether this downregulation of the NKA alpha-subunit in the vasculature is a compensatory reaction or a causal factor in hypertension. The proposed studies will differentiate between these possibilities by testing specific hypotheses about the mechanisms underlying the alterations in the alpha-2 subunit and the functional consequences of this regulation (ion transport and the vascular tone and reactivity) in hypertension. The specific aims are: (1) To test the veracity of the hypothesis that intravascular pressure is a signal for downregulation of the alpha-2 isoform of NKA in the vascular smooth muscle. This hypothesis predicts that there will be decreases in mRNA for the alpha-2 subunit under the following conditions: (a) in vitro, cultured aortic smooth muscle cells exposed to sustained pulsating stretch, (b) isolated perfused rat tail artery exposed to sustained elevated perfusion pressure, and (c) in the vasculature of rats with hypertension, which should be reversed with antihypertensive treatment. (2) To test the veracity of the hypothesis that pressure stimulus results in an alteration in (a) the activity of the vascular smooth muscle Na-pump, and (b) the contractile responsiveness of the vasculature. We will: (a) measure the Na-pump activity and the [3H]ouabain binding sites in cells exposed to stretch. This hypothesis predicts that both the Na-pump activity and the ouabain binding will decrease with stretching. (b) determine the vascular responsiveness to vasoactive agents and measure the Na-pump activity in tail arteries after perfusing with high pressure for a prolonged period. This hypothesis predicts a decrease in Na-pump activity and an enhancement of vascular reactivity. (3) If the data from Aims 1 and 2 fail to support the hypothesis that pressure downregulates alpha-2, the alternate hypothesis that alpha-2 downregulation is a causal factor to hypertension by contributing to increased vascular reactivity. We will obtain indirect evidence by downregulating the alpha-2 subunit and determining the vascular responsiveness. This hypothesis predicts that the responsiveness of the arteries will increase as a result of alpha-2 downregulation.

描述（改编自申请人的摘要）：Na+ K+ ATP酶 (NKA) 是 细胞膜电位的决定因素，可以有助于 血管平滑肌反应性和张力以及心肌收缩力，以及 因此可能在高血压的发展和/或维持中发挥作用。 这 酶由 α 和 β 亚基以及几种异构体组成 酶存在。 同工型以物种和组织特异性表达 方式，并且在健康和疾病方面似乎受到不同的监管 州。 然而，有关同工酶功能意义的信息 而且这些蛋白质的调节还远未完成。 特别是， 各个亚型的作用及其在高血压中的调节模式 尚不清楚。 研究人员和其他人之前已经表明NKA催化 α-2 亚基基因和蛋白质表达在 几种高血压动物模型中的心脏和脉管系统。 他们 还表明，心脏的下调可以通过以下方式逆转： 遗传性高血压大鼠的抗高血压治疗。 他们希望 确定 NKA α 亚基的下调是否 血管系统是高血压的代偿反应或致病因素。 拟议的研究将通过以下方式区分这些可能性 测试有关改变背后机制的具体假设 在 alpha-2 亚基中以及该调节的功能后果 （离子传输和血管张力和反应性）高血压。 这 具体目标是： (1) 检验以下假设的正确性： 血管内压力是 α-2 异构体下调的信号 血管平滑肌中的NKA。 这个假说预测有 在以下条件下，α-2 亚基的 mRNA 会减少 条件：（a）体外培养的主动脉平滑肌细胞暴露于 持续搏动拉伸，(b) 暴露分离的灌注大鼠尾动脉 持续升高的灌注压，以及（c）在大鼠的脉管系统中 患有高血压，应通过抗高血压治疗来逆转。 (2) 检验压力刺激导致的假设的正确性 (a) 血管平滑肌钠泵活性的改变，以及 (b)脉管系统的收缩反应性。 我们将：（一） 测量细胞中的钠泵活性和 [3H]哇巴因结合位点 暴露于拉伸。 该假设预测 Na 泵活性 哇巴因结合力会随着拉伸而减少。 (b) 确定 血管对血管活性药物的反应并测量钠泵 长时间高压灌注后尾动脉活动 时期。 该假设预测钠泵活性会降低，并且 血管反应性增强。 (3) 如果目标 1 和 2 的数据不能支持以下假设： 压力下调 alpha-2，替代假设 alpha-2 下调是高血压的一个致病因素 血管反应性增加。 我们将通过以下方式获取间接证据 下调α-2亚基并确定血管 反应能力。 该假设预测， 由于 alpha-2 下调，动脉血管会增加。