Department of Physiology, Medical College of Georgia, Augusta, GA 30912, United States.
Pharmacol Res. 2012 Jan;65(1):41-7. doi: 10.1016/j.phrs.2011.07.002. Epub 2011 Jul 8.
Hypertension is a disorder affecting millions worldwide, and is a leading cause of death and debilitation in the United States. It is widely accepted that during hypertension and other cardiovascular diseases the vasculature exhibits endothelial dysfunction; a deficit in the relaxatory ability of the vessel, attributed to a lack of nitric oxide (NO) bioavailability. Recently, the one electron redox variant of NO, nitroxyl anion (NO(-)) has emerged as an endothelium-derived relaxing factor (EDRF) and a candidate for endothelium-derived hyperpolarizing factor (EDRF). NO(-) is thought to exist protonated (HNO) in vivo, which would make this species more resistant to scavenging. However, no studies have investigated the role of this redox species during hypertension, and whether the vasculature loses the ability to relax to HNO. Thus, we hypothesize that aorta from angiotensin II (AngII)-hypertensive mice will exhibit a preserved relaxation response to Angeli's Salt, an HNO donor. Male C57Bl6 mice, aged 12-14 weeks were implanted with mini-osmotic pumps containing AngII (90ng/min, 14 days plus high salt chow) or sham surgery. Aorta were excised, cleaned and used to perform functional studies in a myograph. We found that aorta from AngII-hypertensive mice exhibited a significant endothelial dysfunction as demonstrated by a decrease in acetylcholine (ACh)-mediated relaxation. However, vessels from hypertensive mice exhibited a preserved response to Angeli's Salt (AS), the HNO donor. To confirm that relaxation responses to HNO were maintained, concentration response curves (CRCs) to ACh were performed in the presence of scavengers to both NO and HNO (carboxy-PTIO and L-cys, resp.). We found that ACh-mediated relaxation responses were significantly decreased in aorta from sham and almost completely abolished in aorta from AngII-treated mice. Vessels incubated with l-cys exhibited a modest decrease in ACh-mediated relaxations responses. These data demonstrate that aorta from AngII-treated hypertensive mice exhibit a preserved relaxation response to AS, an HNO donor, regardless of a significant endothelial dysfunction.
高血压是一种影响全球数百万人的疾病，也是美国死亡和衰弱的主要原因。人们普遍认为，在高血压和其他心血管疾病中，血管表现出内皮功能障碍；血管的舒张能力不足，归因于一氧化氮（NO）生物利用度的缺乏。最近，NO 的单电子氧化还原变体、硝酰阴离子（NO(-)）已成为内皮衍生的舒张因子（EDRF）和内皮衍生的超极化因子（EDRF）的候选物。NO(-) 被认为在体内以质子化（HNO）的形式存在，这将使这种物质更能抵抗清除。然而，目前还没有研究探讨这种氧化还原物质在高血压期间的作用，以及血管是否失去对 HNO 的舒张能力。因此，我们假设血管紧张素 II（AngII）-高血压小鼠的主动脉将对 Angeli's Salt（一种 HNO 供体）表现出保留的舒张反应。雄性 C57Bl6 小鼠，年龄 12-14 周，植入含有 AngII（90ng/min，14 天加高盐饲料）或假手术的微型渗透泵。取出主动脉，清洗后用于在肌动描记器中进行功能研究。我们发现，AngII-高血压小鼠的主动脉表现出明显的内皮功能障碍，表现为乙酰胆碱（ACh）介导的舒张减少。然而，高血压小鼠的血管对 HNO 供体 Angeli's Salt（AS）表现出保留的反应。为了确认对 HNO 的舒张反应得到维持，在存在清除 NO 和 HNO 的清除剂（分别为 carboxy-PTIO 和 L-cys）的情况下进行了 ACh 的浓度反应曲线（CRC）。我们发现，ACh 介导的舒张反应在 sham 组的主动脉中显著降低，而在 AngII 处理的小鼠的主动脉中几乎完全消除。用 l-cys 孵育的血管表现出 ACh 介导的舒张反应的适度降低。这些数据表明，无论内皮功能障碍是否显著，AngII 处理的高血压小鼠的主动脉对 HNO 供体 AS 表现出保留的舒张反应。
