Journal
PHARMACOLOGICAL RESEARCH
Volume 66, Issue 5, Pages 383-391Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2012.07.010
Keywords
Diabetes; Endothelium-dependent relaxation; Nitroxyl; Nitric oxide; Superoxide anion
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Funding
- RMIT University International Research Scholarship
- Melbourne University International Fee Remission Scholarship
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The aim of the study was to investigate whether diabetes-induced oxidant stress affects the contribution of nitroxyl (HNO) to endothelium-dependent relaxation in the rat aorta. Organ bath techniques were employed to determine vascular function of rat aorta. Pharmacological tools (3 mM L-cysteine, 5 mM 4-aminopyridine (4-AP), 200 mu M carboxy-PTIO and 100 mu M hydroxocobalamin, HXC) were used to distinguish between NO and HNO-mediated relaxation. Superoxide anion levels were determined by lucigenin-enhanced chemiluminescence. In the diabetic aorta, where there is increased superoxide anion production, responses to the endothelium-dependent relaxant ACh were not affected when the contribution of NO to relaxation was abolished by either HXC or carboxy-PTIO, indicating a preserved HNO-mediated relaxation. Conversely, when the contribution of HNO was inhibited with L-cysteine or 4-AP, the sensitivity and maximum relaxation to ACh was significantly decreased, suggesting that the contribution of NO was impaired by diabetes. Furthermore, whereas HNO appears to be derived from eNOS in normal aorta, in the diabetic aorta it may also arise from an eNOS-independent source, perhaps derived from nitrosothiol stores. Similarly, exposure to the superoxide anion generator, pyrogallol (100 mu M) significantly reduced the sensitivity to the NO donor, DEANONOate and ACh-induced NO-mediated relaxation but had no effect on responses to the HNO donor, Angeli's salt and ACh-induced HNO-mediated relaxation in the rat aorta. These findings demonstrate that NO-mediated relaxation is impaired during oxidative stress but the HNO component of relaxation is preserved under those conditions. (C) 2012 Elsevier Ltd. All rights reserved.
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