Endothelin vasoconstriction in a rat model of sleep apnea-induced hypertension.

睡眠呼吸暂停诱发高血压大鼠模型中的内皮素血管收缩。

• 批准号: 7667765
• 负责人: Nancy L Kanagy
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667765
• 关键词: 1,2-diacylglycerol; Acute; Adult; Affect; Agonist; Animals; Apoptosis; Area; Arteries; Arts; Blood Vessels; Caliber; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Data; Development; Diglycerides; Disease; Endothelin; Endothelin-1; Enzymes; Exposure to; Face; Filament; Functional disorder; Hypercapnia; Hypertension; Hypoxia; Incidence; Laboratories; Lead; Mediating; Mesenteric Arteries; Mesentery; Modeling; Molecular; Muscle Contraction; Myosin Light Chains; New Mexico; Pathway interactions; Patients; Peptides; Peripheral Vascular Diseases; Phenylephrine; Phospholipase C; Phosphoric Monoester Hydrolases; Physiology; Plasma; Play; Population; Process; Production; Protein Isoforms; Protocols documentation; ROK kinase; Rattus; Regulation; Relative (related person); Research Design; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Smooth Muscle; Testing; Tissues; Universities; Up-Regulation; Vascular Smooth Muscle; Vasoconstrictor Agents; Work; constriction; experience; in vivo; migration; myosin phosphatase; pressure; prevent; programs; response; treatment strategy; vasoconstriction

DESCRIPTION (provided by applicant): Sleep apnea affects up to 20% of the adult population, exposing sufferers to periods of hypoxia/hypercapnia during sleep. Consequences of this condition include significant vascular changes with concomitant hypertension and cardiovascular disease. Sleep apnea patients have elevated circulating endothelin-1 (ET-1) which may contribute to the hypertension and we have previously demonstrated that exposing rats to intermittent hypoxia/hypercapnia (IH/HC) during sleep to mimic sleep apnea causes sustained, ET-1-dependent systemic hypertension. New preliminary data demonstrate that mesenteric resistance arteries from these hypertensive IH rats have augmented vasoconstrictor responses to ET-1 but not to phenylephrine or KCI. Intriguingly, augmented ET-1 constriction in IH/HC arteries appears to be mediated entirely by increases Ca2+ sensitivity while ET constriction in Sham arteries is mediated by increases in both [Ca2+]i and Ca2+ sensitivity. Furthermore, ET-1 appears to activate PKC in IH/HC but not Sham arteries, a pathway shown to increase arterial Ca2+ sensitivity. Therefore, we hypothesize that augmented ET-1-mediated vasoconstriction in arteries from rats made hypertensive with IH/HC is caused by increased activation of PKC signaling. Three aims will test this hypothesis: Aim 1) Determine PKC isoform expression, activity and agonist-dependent activation in small mesenteric arteries from Sham and IH/HC treated rats. Aim 2) Determine the relative contributions of PKC and ROK to ET-1 and PE activation of Ca2+- sensitization in mesenteric arteries from IH/HC and Sham-treated rats. Aim 3) Determine the effect of IH/HC on basal and agonist stimulated synthesis and degradation of PKC activator, diacylglycerol (DAG) in arteries from Sham and IH/HC rats. Planned studies will determine the role of PKC-dependent Ca-sensitization in augmented ET-1 dependent vasoconstriction in this rat model of sleep apnea. These studies should fundamentally advance our understanding of ET-1 and PKC signaling in vascular smooth muscle and the cardiovascular consequences of chronic exposure to sleep apnea. The anticipated findings are expected to provide a mechanistic explanation for in vivo observations that ET-1 contributes to vascular dysfunction in sleep apnea and other disease states, sometimes when circulating levels of the peptide are not elevated.

描述（由申请人提供）：睡眠呼吸暂停影响多达20%的成年人，使患者在睡眠期间出现缺氧/高碳酸血症。这种情况的后果包括伴随高血压和心血管疾病的明显血管改变。睡眠呼吸暂停患者循环内皮素-1 （ET-1）升高，这可能导致高血压，我们之前已经证明，在睡眠期间将大鼠暴露于间歇性缺氧/高碳酸血症（IH/HC）以模拟睡眠呼吸暂停会导致持续的ET-1依赖性全身性高血压。新的初步数据表明，这些高血压IH大鼠的肠系膜抵抗动脉对ET-1的血管收缩反应增强，但对苯肾上腺素或KCI没有增强。有趣的是，IH/HC动脉中ET-1收缩的增强似乎完全由Ca2+敏感性的增加介导，而Sham动脉中的ET收缩是由[Ca2+]i和Ca2+敏感性的增加介导的。此外，ET-1似乎激活了IH/HC中的PKC，但没有激活Sham动脉，这是一种增加动脉Ca2+敏感性的途径。因此，我们假设高血压IH/HC大鼠的et -1介导的动脉血管收缩增强是由PKC信号激活增加引起的。目的1)确定假手术和IH/HC治疗大鼠肠系膜小动脉中PKC异构体的表达、活性和激动剂依赖性激活。目的2)确定PKC和ROK对IH/HC和sham治疗大鼠肠系膜动脉中ET-1和PE激活Ca2+敏化的相对贡献。目的3)确定IH/HC对假手术大鼠和IH/HC大鼠动脉中PKC激活剂二酰基甘油（DAG）合成和降解的影响。计划中的研究将确定pkc依赖性钙致敏在睡眠呼吸暂停大鼠模型中ET-1依赖性血管收缩增强中的作用。这些研究将从根本上促进我们对血管平滑肌ET-1和PKC信号传导以及慢性暴露于睡眠呼吸暂停的心血管后果的理解。预期的研究结果有望为体内观察提供机制解释，即ET-1有助于睡眠呼吸暂停和其他疾病状态下的血管功能障碍，有时当这种肽的循环水平不升高时。