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

描述(申请人提供)：睡眠呼吸暂停影响高达20%的成年人口，使患者在睡眠期间处于低氧/高碳酸血症状态。这种情况的后果包括显著的血管改变，并伴有高血压和心血管疾病。睡眠呼吸暂停患者的循环内皮素-1(ET-1)升高，这可能是高血压的原因之一，我们先前已经证明，在睡眠中暴露于间歇性低氧/高二氧化碳(IH/HC)以模拟睡眠呼吸暂停会导致持续的ET-1依赖的全身性高血压。新的初步数据表明，这些高血压IH大鼠的肠系膜阻力动脉对ET-1有增强的血管收缩反应，但对苯肾上腺素或KCI没有。有趣的是，IH/HC动脉增强的ET-1收缩似乎完全是由增加的钙敏感性介导的，而在Sham动脉的ET收缩似乎完全由[Ca~(2+)]i和Ca~(2+)敏感性的增加所介导。此外，ET-1似乎激活IH/HC动脉的PKC，但不激活Sham动脉的PKC，这是一条增加动脉钙敏感性的途径。因此，我们推测，高血压合并高血压的大鼠动脉中ET-1介导的血管收缩增强是由PKC信号的激活增加引起的。三个目的将验证这一假说：目的1)测定Sham和IH/HC处理的大鼠肠系膜小动脉PKC亚型的表达、活性和激动剂依赖的激活。目的2)测定PKC和ROK在IH/HC和Sham处理大鼠肠系膜动脉钙增敏的ET-1和PE活化中的相对作用。目的3)观察IH/HC对基础和激动剂刺激的Sham和IH/HC大鼠动脉中PKC激活剂二酰甘油(DAG)合成和降解的影响。计划中的研究将确定PKC依赖的钙敏化在这种睡眠呼吸暂停大鼠模型中增强的ET-1依赖的血管收缩中的作用。这些研究将从根本上促进我们对血管平滑肌中的ET-1和PKC信号以及长期暴露于睡眠呼吸暂停的心血管后果的理解。这些预期的发现有望为体内观察到的ET-1导致睡眠呼吸暂停和其他疾病状态下的血管功能障碍提供机制上的解释，有时是当循环中的多肽水平没有升高时。

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.