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Title: Modulation of endothelium-dependent arterial relaxation by inorganic arsenic and glucose
Author: Ellinsworth, David Carl
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2010
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Inorganic arsenic and elevated glucose concentrations increase endothelial production of superoxide, which impairs endothelium-derived nitric oxide bioavailability and associated nitric oxide-dependent arterial relaxations. However, there is now evidence in animal models of diabetes mellitus that relaxations attributed to endothelium-dependent smooth muscle hyperpolarization or endothelium-derived hyperpolarizing factor (EDHF) may be augmented and serve to compensate for the loss of nitric oxide, thereby maintaining arterial responsiveness. The effects of arsenite and elevated glucose concentrations on "EDHF-type" relaxations were thus investigated in isolated rabbit iliac artery rings using the G-protein-coupled agonist acetylcholine and the sarcoendoplasmic reticulum Ca2+ ATPase inhibitor cyclopiazonic acid. Arsenite and elevated glucose both potentiated EDHF-type relaxations evoked by cyclopiazonic acid. Differential effects of arsenite and glucose against EDHF-type responses to acetylcholine were identified in that arsenite attenuated relaxation, whereas glucose potentiated relaxation. Further experiments showed that the arsenite- and glucose-augmented components of relaxation were reversed to control levels by the hydrogen peroxide scavenger catalase and the NADPH oxidase inhibitor apocynin. Arsenite-augmented responses were also reversed by the cell-permeable superoxide dismutase/catalase mimetic manganese porphyrin. It follows that hydrogen peroxide derived from NADPH oxidase may augment EDHF-type relaxations in diabetes mellitus and arsenic toxicity, thus maintaining endothelial control of arterial tone when nitric oxide bioavailability is impaired by oxidative stress. These results are consistent with the demonstrations that hydrogen peroxide augments EDHF-type relaxations in the rabbit iliac artery by promoting endothelial Ca2+ mobilization and enhancing the opening of endothelial Ca2+-activated K + channels, and that the increased activity of these channels underpins augmented EDHF-type arterial relaxations in animal models of diabetes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available