Nitroxyl Anion Reverses Endothelin‐1 Mediated Vascular Dysfunction Through a Reduction in Peroxynitrite Generation

Nitroglycerin (GTN) induces tolerance and promotes vascular wall damage when given chronically. A proposed mechanism is that GTN increases superoxide (O −2 ) production which reacts with nitric oxide (NO) to form peroxynitrite (ONOO), which contributes to endothelial dysfunction. A redox variant of NO, nitroxyl anion, was demonstrated to exist as HNO in vivo , giving this molecule superior stability over NO. We have previously demonstrated that the use of the HNO donor, Angeli's Salt (AS), reverses vascular dysfunction by endothelin‐1 (ET‐1) while treatment with GTN does not. We hypothesize that AS mediates its effects through a decrease in reactive oxygen species (ROS) generation. Murine aortic rings were used in functional studies or for primary cell culture. Using DHE to visualize ROS, we observed that vascular smooth muscle cells exhibited an increase in ROS generation with ET‐1 treatment, which was decreased in ET‐1+AS. Co‐treatment with GTN had no effect. Concentration response curves to ACh were performed in the presence of the ONOO scavenger, Fe‐TPPS or vehicle. ET‐1+GTN treated vessels were co‐incubated with Fe‐TPPS, which increased relaxation as compared to vehicle ( R max 62.5±2.7 vs. 72.1±5.0). These data demonstrate that AS may reverse vascular dysfunction through a decrease in ONOO and propose that HNO donors may be an alternative therapeutic approach to treat vascular disease.