Modulation of endothelium-dependent arterial relaxation by inorganic arsenic and glucose

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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Modulation of endothelium-dependent arterial relaxation by inorganic arsenic and glucose

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

Peroxynitrate formed during a transient episode of brain ischemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor stimulated rat cerebral arteries

Aim Increased thromboxane A2 and peroxynitrite are hallmarks of cerebral ischemia/reperfusion (I/R). Stimulation of thromboxane/prostaglandin receptors (TP) attenuates endothelium-derived hyperpolarization (EDH). We investigated whether EDH-type middle cerebral artery (MCA) relaxations following TP stimulation are altered after I/R and the influence of peroxynitrite. Methods Vascular function was determined by wire myography after TP stimulation with the thromboxane A2 mimetic 9,11-Dideoxy-9α,11α-methano-epoxy prostaglandin F2α (U46619) in MCA of Sprague-Dawley rats subjected to MCA occlusion (90 min)/reperfusion (24 h) or sham operation, and in non-operated (control) rats. Some rats were treated with saline or the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) (20 mg kg-1). Protein expression was evaluated in MCA and in human microvascular endothelial cells submitted to hypoxia (overnight)/reoxygenation (24 h) (H/R) using immunofluorescence and immunoblotting. Results In U46619-preconstricted MCA, EDH-type relaxation by the proteinase-activated receptor 2 agonist serine–leucine–isoleucine–glycine–arginine–leucine–NH2 (SLIGRL) was greater in I/R than sham rats due to an increased contribution of small-conductance calcium-activated potassium channels (SKCa), which was confirmed by the enlarged relaxation to the SKCa activator N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine. I/R and H/R induced endothelial protein tyrosine nitration and filamentous-actin disruption. In control MCA, either cytochalasin D or peroxynitrite disrupted endothelial filamentous-actin and augmented EDH-type relaxation. Furthermore, peroxynitrite decomposition during I/R prevented the increase in EDH-type responses. Conclusion Following TP stimulation in MCA, EDH-type relaxation to SLIGRL is greater after I/R due to endothelial filamentous-actin disruption by peroxynitrite, which prevents TP-induced block of SKCa input to EDH. These results reveal a novel mechanism whereby peroxynitrite could promote postischemic brain injury

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

Endothelial cells are routinely exposed to elevated glucose concentrations post-prandially in healthy individuals and permanently in patients with metabolic syndrome and diabetes, and so we assessed their sugar transport capabilities in response to high glucose. In human umbilical vein (HUVEC), saphenous vein, microdermal vessels and aorta, GLUT1 (SLC2A1), GLUT3 (SLC2A3), GLUT6 (SLC2A6), and in microdermal vessels also GLUT12 (SLC2A12), were the main glucose transporters as assessed by mRNA, with no fructose transporters nor SGLT1 (SLC5A1). Uptake of 14C-fructose was negligible. GLUT1 and GLUT3 proteins were detected in all cell types and were responsible for ~ 60% glucose uptake in HUVEC, where both GLUT1 and GLUT3, but not GLUT6 siRNA knock-down, reduced the transport. Under shear conditions, GLUT1 protein decreased, GLUT3 increased, and 14C-deoxy-glucose uptake was attenuated. In high glucose, lipid storage was increased, cell numbers were lower, 14C-deoxy-glucose uptake decreased owing to attenuated GLUT3 protein and less surface GLUT1, and trans-endothelial transport of glucose increased due to cell layer permeability changes. We conclude that glucose transport by endothelial cells is relatively resistant to effects of elevated glucose. Cells would continue to supply it to the underlying tissues at a rate proportional to the blood glucose concentration, independent of insulin or fructose

Effects of Aspirin on Endothelial Function and Hypertension

PURPOSE OF REVIEW: Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. RECENT FINDINGS: Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. SUMMARY: Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations

Regulation of Coronary Blood Flow

The heart is uniquely responsible for providing its own blood supply through the coronary circulation. Regulation of coronary blood flow is quite complex and, after over 100 years of dedicated research, is understood to be dictated through multiple mechanisms that include extravascular compressive forces (tissue pressure), coronary perfusion pressure, myogenic, local metabolic, endothelial as well as neural and hormonal influences. While each of these determinants can have profound influence over myocardial perfusion, largely through effects on end-effector ion channels, these mechanisms collectively modulate coronary vascular resistance and act to ensure that the myocardial requirements for oxygen and substrates are adequately provided by the coronary circulation. The purpose of this series of Comprehensive Physiology is to highlight current knowledge regarding the physiologic regulation of coronary blood flow, with emphasis on functional anatomy and the interplay between the physical and biological determinants of myocardial oxygen delivery. © 2017 American Physiological Society. Compr Physiol 7:321-382, 2017

Title Page Arsenic, reactive oxygen, and endothelial dysfunction 2 Running Title Page Running title: arsenic and endothelial dysfunction

, +44 Number of text pages: 24 Number Abstract Human exposure to drinking water contaminated with arsenic is a serious global health concern, and predisposes to cardiovascular disease states such as hypertension, atherosclerosis and microvascular disease. The most sensitive target of arsenic toxicity in the vasculature is the endothelium, and incubation of these cells with low concentrations of arsenite, a naturally occurring and highly toxic inorganic form of arsenic, rapidly induces reactive oxygen species (ROS) formation via activation of a specific NADPH oxidase (Nox2). Arsenite also induces ROS accumulation in vascular smooth muscle cells, but this is relatively delayed because depending on the vessel from which they originate these cells often lack Nox2 and/or its essential regulatory cytosolic subunits. The net effect of such activity is attenuation of endothelium-dependent conduit artery dilation via superoxide anion-mediated scavenging of nitric oxide (NO) and inhibition and downregulation of endothelial NO synthase; events that are temporally matched to the accumulation of oxidants across the vessel wall. By contrast, ROS induced by the more toxic organic trivalent arsenic metabolites (monomethylarsonous and dimethylarsinous acids) may originate from sources other than Nox2. As such, the mechanisms through which vascular oxidative stress develops in vivo under continuous exposure to all three of these potent arsenicals is unknown. This review is a comprehensive analysis of the mechanisms that mediate arsenic effects associated with Nox2 activation, ROS activity and endothelial dysfunction, and also considers future avenues of research into what is a relatively poorly understood topic with major implications for human health