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Vasoactive actions of nitroxyl (HNO) are preserved in resistance arteries in diabetes

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Abstract

Endothelial dysfunction is a major risk factor for the vascular complications of diabetes. Increased reactive oxygen species (ROS) generation, a hallmark of diabetes, reduces the bioavailability of endothelial vasodilators, including nitric oxide (NO·). The vascular endothelium also produces the one electron reduced and protonated form of NO·, nitroxyl (HNO). Unlike NO·, HNO is resistant to scavenging by superoxide anions (·O2 ─). The fate of HNO in resistance arteries in diabetes is unknown. We tested the hypothesis that the vasodilator actions of endogenous and exogenous HNO are preserved in resistance arteries in diabetes. We investigated the actions of HNO in small arteries from the mesenteric and femoral beds as they exhibit marked differences in endothelial vasodilator function following 8 weeks of streptozotocin (STZ)-induced diabetes mellitus. Vascular reactivity was assessed using wire myography and ·O2 ─ generation using lucigenin-enhanced chemiluminescence. The HNO donor, Angeli’s salt, and the NO· donor, DEA/NO, evoked relaxations in both arteries of control rats, and these responses were unaffected by diabetes. Nox2 oxidase expression and ·O2 ─ generation were upregulated in mesenteric, but unchanged, in femoral arteries of diabetic rats. Acetylcholine-induced endothelium-dependent relaxation was impaired in mesenteric but not femoral arteries in diabetes. The HNO scavenger, l-cysteine, reduced this endothelium-dependent relaxation to a similar extent in femoral and mesenteric arteries from control and diabetic animals. In conclusion, HNO and NO· contribute to the NO synthase (NOS)-sensitive component of endothelium-dependent relaxation in mesenteric and femoral arteries. The role of HNO is sustained in diabetes, serving to maintain endothelium-dependent relaxation.

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Acknowledgements

This work was supported by a Diabetes Australia Research Trust Grant (# Y13G-KEMB to BKH and MT) and a National Health & Medical Research Council (NHMRC) project grant (# 546087; to MT and HCP). C.G. Sobey, G.R. Drummond and R.H. Ritchie are Senior Research Fellows of the NHMRC.

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    Authors and Affiliations

    1. Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia

      Marianne Tare, Kristen J. Bubb, Helena C. Parkington, Wee-Ming Boon & Xiang Li

    2. Monash Rural Health, Monash University, Churchill, VIC, Australia

      Marianne Tare

    3. Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, VIC, 3800, Australia

      Rushita S. R. Kalidindi, Christopher G. Sobey, Grant R. Drummond & Barbara K. Kemp-Harper

    4. Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia

      Kristen J. Bubb

    5. Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia

      Rebecca H. Ritchie

    6. Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia

      Rebecca H. Ritchie

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    1. Marianne Tare
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    2. Rushita S. R. Kalidindi
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    Correspondence to Barbara K. Kemp-Harper.

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    All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies using animals were in accordance with the ethical standards of the Monash Animal Research Platform Animal Ethics Subcommittee.

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    Marianne Tare and Rushita S. R. Kalidindi contributed equally to this work.

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    Tare, M., Kalidindi, R.S.R., Bubb, K.J. et al. Vasoactive actions of nitroxyl (HNO) are preserved in resistance arteries in diabetes. Naunyn-Schmiedeberg's Arch Pharmacol 390, 397–408 (2017). https://doi.org/10.1007/s00210-016-1336-1

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