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

描述（由申请人提供）：睡眠呼吸暂停影响多达20%的成年人，使患者在睡眠期间暴露于缺氧/高碳酸血症时期。这种情况的后果包括伴随高血压和心血管疾病的显著血管变化。睡眠呼吸暂停患者的循环内皮素-1（ET-1）升高，这可能导致高血压，我们以前已经证明，暴露大鼠间歇性缺氧/高碳酸血症（IH/HC）在睡眠期间模仿睡眠呼吸暂停引起持续的，ET-1依赖性全身性高血压。新的初步数据表明，肠系膜阻力动脉从这些高血压IH大鼠增强血管收缩反应ET-1，但不苯肾上腺素或氯化钾。有趣的是，IH/HC动脉中增强的ET-1收缩似乎完全由Ca 2+敏感性增加介导，而Sham动脉中的ET收缩由[Ca 2 +]i和Ca 2+敏感性两者的增加介导。此外，ET-1似乎激活PKC在IH/HC，但不假动脉，一个途径，显示增加动脉Ca 2+的敏感性。因此，我们推测，增强ET-1介导的血管收缩大鼠动脉高血压与IH/HC是由增加激活PKC信号。三个目的将检验这一假设：目的1）确定来自Sham和IH/HC处理的大鼠的小肠系膜动脉中的PKC同种型表达、活性和激动剂依赖性活化。目的（2）探讨PKC和ROK在ET-1和PE激活IH/HC和Sham大鼠肠系膜动脉Ca ~（2+）敏感性中的相对作用。目的3）观察IH/HC对Sham和IH/HC大鼠动脉基础和激动剂刺激的PKC激活剂二酰甘油（diacylglycerol，DAG）合成和降解的影响。计划中的研究将确定PKC依赖性Ca-敏化在该睡眠呼吸暂停大鼠模型中增强ET-1依赖性血管收缩中的作用。这些研究将从根本上推进我们对血管平滑肌中ET-1和PKC信号传导的理解，以及慢性睡眠呼吸暂停对心血管的影响。预期的发现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，有时当肽的循环水平未升高时。

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.