title: Vasoactive actions of nitroxyl (HNO) are preserved in resistance arteries in diabetes.
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.
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.|Monash Rural Health, Monash University, Churchill, VIC, Australia.
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Rushita S R
authors.initials: RS
authors.lastname: Kalidindi
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.|Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Bubb
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Wee-Ming
authors.initials: WM
authors.lastname: Boon
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.|Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, VIC, 3800, Australia. barbara.kemp@monash.edu.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D005263:Femoral Artery / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009589:Nitrogen Oxides / Q000494:pharmacology*; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D009589:Nitrogen Oxides; D014665:Vasodilator Agents; D013481:Superoxides; C039900:nitroxyl
keywords: Diabetes; Endothelium-dependent relaxation; Nitric oxide; Nitroxyl; Vascular