Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, United States; Department of Medicine, Renal Division, Emory University, 615 Michael St. Ste 605C, Atlanta, GA 30322, United States.
Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, United States; Center for Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, United States.
Eur J Pharmacol. 2017 Nov 5;814:294-301. doi: 10.1016/j.ejphar.2017.08.024. Epub 2017 Aug 20.
Nitroglycerin (Gtn) is a treatment for cardiovascular patients due to its vasodilatory actions, but induces tolerance when given chronically. A proposed mechanism is the superoxide (O)-oxidative stress hypothesis, which suggests that Gtn increases O production. Nitric oxide (NO) exists in three different redox states; the protonated, reduced state, nitroxyl anion (HNO) is an emerging candidate in vascular regulation. HNO is resistant to scavenging and of particular interest in conditions where high levels of reactive oxygen species (ROS) exist. We hypothesize that treatment with Gtn will exacerbate endothelin 1 (ET-1) induced vascular dysfunction via an increase in ROS, while treatment with Angeli's Salt (AS), an HNO donor, will not. Aorta from mice were isolated and divided into four groups: vehicle, ET-1 [0.1μM, 1μM], ET-1+Gtn [Gtn 1μM] and ET-1+AS [AS 1μM]. Concentration response curves (CRCs) to acetylcholine (ACh) and phenylephrine (Phe) were performed. Aorta incubated with ET-1 (for 20-22h) exhibited a decreased relaxation response to ACh and an increase in Phe-mediated contraction. Aorta incubated with AS exhibited a reversal in ET-1 induced vascular and endothelial dysfunction. ET-1 increased ROS in aortic vascular smooth muscle cells (VSMCs), visualized by dihydroethidium (DHE) staining. AS incubated reduced this ROS generation, yet maintained with Gtn treatment. These data suggest that aorta incubated with the HNO donor, AS, can reverse ET-1 mediated vascular dysfunction, which may be through a decrease or prevention of ROS generation. We propose that HNO may be vasoprotective and that HNO donors studied as a therapeutic option where other organic nitrates are contraindicative.
硝化甘油（Gtn）因其血管扩张作用而成为心血管患者的治疗药物，但长期使用会产生耐受性。一种提出的机制是超氧化物（O）-氧化应激假说，该假说表明 Gtn 会增加 O 的产生。一氧化氮（NO）存在于三种不同的氧化还原态；质子化、还原态，硝基亚硝酰阴离子（HNO）是血管调节中的一个新兴候选物。HNO 不易被清除，在存在大量活性氧物种（ROS）的情况下尤其有趣。我们假设 Gtn 治疗会通过增加 ROS 来加剧内皮素 1（ET-1）诱导的血管功能障碍，而 HNO 供体 Angeli's Salt（AS）的治疗则不会。从小鼠中分离出主动脉并分为四组：载体、ET-1[0.1μM、1μM]、ET-1+Gtn[Gtn 1μM]和 ET-1+AS[AS 1μM]。对乙酰胆碱（ACh）和苯肾上腺素（Phe）进行浓度反应曲线（CRC）。用 ET-1（孵育 20-22h）孵育的主动脉对 ACh 的舒张反应减弱，对 Phe 介导的收缩反应增加。用 AS 孵育的主动脉表现出对 ET-1 诱导的血管和内皮功能障碍的逆转。二氢乙啶（DHE）染色显示 ET-1 增加了主动脉血管平滑肌细胞（VSMCs）中的 ROS。用 AS 孵育可减少这种 ROS 的产生，但与 Gtn 处理一起维持。这些数据表明，用 HNO 供体 AS 孵育的主动脉可以逆转 ET-1 介导的血管功能障碍，这可能是通过减少或预防 ROS 的产生。我们提出 HNO 可能具有血管保护作用，并且 HNO 供体作为其他有机硝酸盐禁忌的治疗选择进行研究。
