ABNORMALITY OF THE ATP-SENSITIVE POTASSIUM CHANNEL IN HYPERTENSION

高血压时 ATP 敏感性钾通道异常

• 批准号: 6241572
• 负责人: PHILIP B FURSPAN
• 金额: $ 15.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6241572
• 关键词: adenylate kinase; adrenal hypertension; antihypertensive agents; cardiovascular pharmacology; disease /disorder model; familial hypertension; gene expression; hypertension; hypertrophy; laboratory rat; posttranslational modifications; potassium channel; tissue /cell culture; vascular smooth muscle; voltage /patch clamp

Evidence that the ATP-sensitive K+(KATP) channel is the specific site of action of the antihypertensive K+ channel activators has focussed a great deal of attention on the role of this channel in vascular smooth muscle function. Investigation and elucidation of these characteristics in a variety of blood vessel types may provide insight into the role of these channels in norm,al smooth muscle function. In hypertension, the ATP sensitivity of this channel appears to be decreased. The studies proposed in this grant are designed to test the following hypotheses: 1) the altered sensitivity to ATP of the KATP channel of vascular smooth muscle cells in hypertension is part of the adaptive response to the vascular hypertrophy associated with high blood pressure; 2) the altered sensitivity to ATP is indicative of the genetic expression of a different from this channel. Specific aims: 1) To characterize the effects of specific agonists and antagonists of the KATP channel on basal and agonist-stimulated contractile responses in vascular smooth muscle from hypertensive and normotensive rats;2) To determine the properties of single KATP channels in membrane patches from isolated vascular smooth muscle cells derived from hypertensive and normotensive rats; 3) To prevent the rise in or lower blood pressure in hypertensive rats by pharmacological means or arterial obstruction and then determine the effect of such treatment on:a) the actions of specific agonists and antagonists of the KATP channel on basal and agonist-stimulated contractile responses in vascular smooth muscle from hypertensive and normotensive rats,b) the properties of single KATP channels in membrane patches from isolated vascular smooth muscle cells derived from hypertensive and normotensive rats; 5) To determine if the properties of single KATP channels are altered when vascular smooth muscle cells from hypertensive and normotensive rats are grown in primary cell culture; 6) To determine whether the sensitivity of the KATP channel to ATP is altered in a non-genetic model of hypertension; 7) To determine whether the change in ATP sensitivity of the KATP channel is associated with a change in the membrane environment (posttranslational effect) or whether the change represents the expression of a different form of this channel (pretranslational effect). The proposed experiments will be performed on isolated blood vessel segments and cells (carotid, tail, mesenteric and coronary arteries) from the stroke-prone strain of the spontaneously hypertensive rat and normotensive Wistar-Kyoto rats using standard muscle bath technique and the patch clamp technique. The expression of vascular smooth muscle cell mRNA in frog oocytes will indicate whether the genetic expression of the KATP channel is altered in hypertension. Elucidation of the relationship between the greater potency of KATP channel agonists and the altered properties of this channel in hypertension may lead a better understanding of the phenomenon of vascular hypertrophy and to the development of more effective and better tolerated pharmacological agents for the treatment of this disease.

ATP敏感性K+（KATP）通道是心肌细胞凋亡的特异性位点， 抗高血压K+通道激活剂的作用集中在很大程度上 对这一通道在血管平滑肌中的作用给予关注 功能 研究和阐明这些特点， 各种血管类型可以提供对这些作用的深入了解。 通道正常，平滑肌功能。 在高血压中，ATP 该通道的灵敏度似乎降低。 建议的研究 在这个补助金的目的是测试以下假设：1） 血管平滑肌KATP通道对ATP的敏感性改变 高血压中的细胞是对血管的适应性反应的一部分， 与高血压相关的肥大; 2）敏感性改变 与ATP的结合表明了一种与此不同的 频道 具体目标：（1）确定具体的 KATP通道的激动剂和拮抗剂， 激动剂刺激的血管平滑肌收缩反应 高血压和正常血压大鼠;2）确定单个 离体血管平滑肌细胞膜斑的KATP通道 细胞来源于高血压和正常血压大鼠; 3）为了防止 通过药理学方法升高或降低高血压大鼠的血压 手段或动脉阻塞，然后确定这种影响 治疗：a）特异性激动剂和拮抗剂的作用， KATP通道对心肌细胞基础和激动剂刺激收缩反应的影响 来自高血压和血压正常大鼠的血管平滑肌，B） 单个KATP通道的特性 血管平滑肌细胞来源于高血压和正常血压 5）确定单个KATP通道的性质是否改变 当高血压和正常血压大鼠的血管平滑肌细胞 在原代细胞培养中生长; 6）确定是否敏感 KATP通道的ATP在非遗传模型中被改变， 高血压; 7）确定是否ATP敏感性的变化， KATP通道与细胞膜环境的改变有关 （翻译后效应）或变化是否代表表达 这种通道的另一种形式（翻译前效应）。 的 所提出的实验将在分离的血管段上进行 和细胞（颈动脉、尾动脉、肠系膜动脉和冠状动脉） 自发性高血压大鼠和正常血压大鼠的易卒中品系 Wistar-Kyoto大鼠采用标准肌浴技术和膜片钳技术 法 青蛙血管平滑肌细胞mRNA的表达 卵母细胞将指示KATP通道的基因表达是否是 在高血压中改变。 阐明了 KATP通道激动剂的更大效力和这种激动剂的改变的性质， 经络在高血压中的作用可能会使人们更好地理解这一现象 对血管肥大和发育更有效，更好 用于治疗这种疾病的耐受的药理学药剂。