VASCULAR NA+-PUMP ACTIVITY AND HYPERTENSION

血管 NA 泵活动和高血压

• 批准号: 3343616
• 负责人: Emel Songu-Mize
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1992-02-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3343616
• 关键词: adenosinetriphosphatase; adrenal hypertension; desoxycorticosterone; digitalis; disease /disorder model; enzyme inhibitors; familial hypertension; laboratory rat; molecular pathology; monoclonal antibody; neurogenic hypertension; vascular smooth muscle

The long term objective of this project is to define the mechanisms underlying changes in Na. K-ATPase (NKA), or the Na-Pump (NaP), activity in vascular smooth muscle in development and maintenance of hypertension. Tail artery NaP activity, measured as ouabain-sensitive Rb uptake, shows tri- phasic changes in DOCA-salt hypertension. An endogenous inhibitor of the pump contributes to these changes. To determine whether the alterations in NaP are associated with changes in the kinetic properties of the vascular NaP, we will measure the km and V max of the vascular NaP during early, established, and late stages of DOCA-salt hypertension. We will also quantitate the NaP sites using a monoclonal antibody against NKA. An endogenous digitalis-like inhibitor(s) of the vascular NaP may be important in development and maintenance of hypertension. To further define the relationships between chronic exposure to a circulating NaP inhibitor, alterations in vascular NaP activity and development of hypertension, ASI- 222 (a polar analog of digitalis, 10 times more potent an inhibitor of NKA than digoxin) will be administered to inhibit chronically the vascular NaP. Preliminary experiments show that chronic iv administration of ASI-222 produces hypertension. Studies will be conducted to determine whether chronic exposure to a circulating NaP inhibitor produces hypertension and alterations in vascular NaP activity and NaP site density comparable to those seen in the DOCA-salt model, which is characterized by a circulating endogenous NaP inhibitor. There are two major limitations of the DOCA-salt hypertensive model in the study of NaP activity determinants; I) it is difficult to study the NKA enzyme activity in vascular tissue because the arteries contain small amounts of this enzyme, and 2) there are other confounding variables inherent to an in vivo system which complicate a focuses and in-depth study of vascular NaP function/NKA activity regulation by endogenous and/or exogenous inhibitors. To overcome these limitations, cultured vascular smooth muscle cells will be used to define the direct effects of chronic NaP inhibition on regulation of NaP/NKA. Effects of plasma or plasma extracts treated with DOCA-salt and ASI-222 will be compared. Additionally, effects or certain long-chain unsaturated fatty acids known to inhibit NKA, and which are possible candidate(s) for an endogenous inhibitor of the NaP, will be studied.

本项目的长期目标是确定 钠的潜在变化。K-ATP酶（NKA）或Na泵（NaP）活性， 血管平滑肌在高血压的发展和维持中的作用。尾巴 动脉NaP活性，以哇巴因敏感的Rb摄取来测量，显示三- DOCA盐性高血压的阶段性变化。一种内源性抑制剂， 泵有助于这些变化。以确定是否在改变 NaP与血管动力学特性的变化有关， NaP，我们将在早期测量血管NaP的km和Vmax， 和DOCA盐高血压的晚期。我们还将 使用抗NKA的单克隆抗体定量NaP位点。 血管NaP的内源性洋地黄样抑制剂可以是 对高血压的发展和维持很重要。以进一步限定 慢性暴露于循环NaP抑制剂， 血管NaP活性的改变和高血压的发展， 222（洋地黄的极性类似物，是NKA抑制剂的10倍 比地高辛）将被施用以长期抑制血管NaP。 初步实验表明，长期静脉注射ASI-222 产生高血压。将进行研究，以确定是否 慢性暴露于循环NaP抑制剂会产生高血压， 血管NaP活性和NaP位点密度的改变与 在DOCA-盐模型中看到的那些，其特征在于循环 内源性NaP抑制剂。 DOCA-盐高血压模型的两个主要局限性是： NaP活性决定因素的研究; I）NKA的研究是困难的 血管组织中的酶活性，因为动脉含有小的 这种酶的量，2）还有其他混杂变量 这使得焦点和深入研究复杂化 血管NaP功能/NKA活性调节的内源性和/或 外源性抑制剂为了克服这些局限性， 平滑肌细胞将被用来定义慢性炎症的直接影响。 NaP抑制对NaP/NKA的调节。等离子体或等离子体的影响 将比较用DOCA-盐和ASI-222处理的提取物。此外，本发明还 作用或已知抑制NKA的某些长链不饱和脂肪酸， 并且是NaP的内源性抑制剂的可能候选物， 将被研究。