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VASCULAR NA+ PUMP ACTIVITY AND HYPERTENSION

血管 NA 泵活动和高血压

基本信息

批准号：
2668649
负责人：
Emel Songu-Mize
金额：
$ 11.57万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-02-21 至 2001-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2668649
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

项目摘要

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）是细胞膜电位的一个决定因素，可以促进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/或维持中起作用。的酶由α-和β-亚基组成，并且酶的几种同种型酶存在。同种型以种属特异性和组织特异性表达。在健康和疾病方面似乎受到不同的调节 states. 然而，关于同工酶的功能意义的信息而这些蛋白质的调控还远未完成。特别是高血压个体亚型及其调节方式的作用是未知的。研究人员和其他人先前已经表明，NKA催化剂 α-2亚基基因和蛋白质表达下调，心脏和脉管系统中的一些高血压动物模型。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降压治疗。他们希望确定NKA α-亚基的这种下调是否会导致细胞凋亡，血管是高血压的代偿反应或病因。拟议的研究将通过以下方式区分这些可能性：测试关于改变背后的机制的特定假设以及这种调节的功能性后果 (ion运输和血管张力和反应性）。的具体目的是：（1）检验假设的准确性，血管内压力是α-2亚型下调的信号血管平滑肌中的NKA。这一假设预测，在以下情况下，α-2亚基的mRNA将减少条件：（a）体外培养的主动脉平滑肌细胞暴露于持续的脉动拉伸，（B）暴露的分离的灌注的大鼠尾动脉持续升高的灌注压，和（c）在大鼠的脉管系统中高血压，这应该与降压治疗逆转。 (2)为了检验压力刺激导致（a）血管平滑肌Na泵活性的改变，和 (b)血管系统的收缩反应我们将：（a）测量细胞中Na-泵活性和[3 H]哇巴因结合位点暴露在拉伸中。这一假说预测，钠泵活性并且哇巴因结合将随着拉伸而降低。 (b)确定血管对血管活性药物的反应性，并测量钠泵尾动脉高压灌注后的活动期这一假设预测钠泵活性降低，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，另一种假设，下调是高血压的一个致病因素，增加血管反应性。我们将通过以下方式获取间接证据：下调α-2亚单位并确定血管响应能力。这一假设预测，动脉将由于α-2下调而增加。