Angeli's Salt, a nitroxyl anion donor, reverses endothelin-1 mediated vascular dysfunction in murine aorta

• Type of Material: Article
• Authors: Brandi M. Wynne, Emory University; Hicham Labazi, Augusta University; Zidonia N. Carneiro, Augusta University; Rita C. Tostes, University of Sao Paulo; R. Clinton Webb, Augusta University
• Language: English
• Date: 2017-11-05
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ejphar.2017.08.024
• Title of Journal or Parent Work: European Journal of Pharmacology
• ISSN: 0014-2999
• Volume: 814
• Start Page: 294
• End Page: 301
• Grant/Funding Information: This work was supported by the American Heart Association, Grant-in-Aid [15GRNT25700451] to RCW and the National Heart, Lung and Blood Institute at the National Institutes of Health [5R01HL071138-08] to RCW.
• Keywords: CEREBRAL-ARTERIES; BLOOD-PRESSURE; Life Sciences & Biomedicine; INDUCED RELAXATION; ANGIOTENSIN-II; Nitroglycerin; Endothelin-1; AQUEOUS-SOLUTION; Angeli's Salt; HNO; Science & Technology; NITRATE TOLERANCE; RESISTANCE ARTERIES; OXIDATIVE STRESS; Vascular dysfunction; NITRIC-OXIDE; Pharmacology & Pharmacy; NO-CENTER-DOT
• Research Categories: Biology, Physiology

Abstract

B.V. 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 (O2-)-oxidative stress hypothesis, which suggests that Gtn increases O2- 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 [0.1 μM, 1 μM], ET-1+Gtn [Gtn 1 μM] and ET-1+AS [AS 1 μM]. Concentration response curves (CRCs) to acetylcholine (ACh) and phenylephrine (Phe) were performed. Aorta incubated with ET-1 (for 20–22 h) 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.