Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD

Didion, Sean P.; Hathaway, Christopher A.; Faraci, Frank M.

doi:10.1152/ajpheart.2001.281.4.h1697

Cited by 75 publications

(78 citation statements)

References 60 publications

(104 reference statements)

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“…Superoxide levels were measured by lucigenin-enhanced chemiluminescence as previously described (13,14,45). In separate groups of sedentary (n ϭ 11) and exercised (n ϭ 29) nondiabetic rats and sedentary (n ϭ 34) and exercised (n ϭ 25) diabetic rats, the brain was removed and placed in a Krebs-HEPES buffer (pH 7.4) with the following composition: (in mmol/l) 118 NaCl, 4.7 KCl, 1.2 KH2PO4, 1.2 MgCl2, 1.3 CaCl2, 10 HEPES, 25 NaHCO3, and 5 (nondiabetic) or 20 (diabetic) glucose.…”

Section: Induction Of Diabetesmentioning

confidence: 99%

Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats

Mayhan

Arrick

Patel

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Mayhan WG, Arrick DM, Patel KP, Sun H. Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats. Am J Physiol Heart Circ Physiol 300: H1013-H1020, 2011. First published December 17, 2010; doi:10.1152/ajpheart.00873.2010.-Our goal was to examine whether exercise training (ExT) could normalize impaired nitric oxide synthase (NOS)-dependent dilation of cerebral (pial) arterioles during type 1 diabetes (T1D). We measured the in vivo diameter of pial arterioles in sedentary and exercised nondiabetic and diabetic rats in response to an endothelial NOS (eNOS)-dependent (ADP), an neuronal NOS (nNOS)-dependent [N-methyl-D-aspartate (NMDA)], and a NOS-independent (nitroglycerin) agonist. In addition, we measured superoxide anion levels in brain tissue under basal conditions in sedentary and exercised nondiabetic and diabetic rats. Furthermore, we used Western blot analysis to determine eNOS and nNOS protein levels in cerebral vessels/brain tissue in sedentary and exercised nondiabetic and diabetic rats. We found that ADP and NMDA produced a dilation of pial arterioles that was similar in sedentary and exercised nondiabetic rats. In contrast, ADP and NMDA produced only minimal vasodilation in sedentary diabetic rats. ExT restored impaired ADP-and NMDA-induced vasodilation observed in diabetic rats to that observed in nondiabetics. Nitroglycerin produced a dilation of pial arterioles that was similar in sedentary and exercised nondiabetic and diabetic rats. Superoxide levels in cortex tissue were similar in sedentary and exercised nondiabetic rats, were increased in sedentary diabetic rats, and were normalized by ExT in diabetic rats. Finally, we found that eNOS protein was increased in diabetic rats and further increased by ExT and that nNOS protein was not influenced by T1D but was increased by ExT. We conclude that ExT can alleviate impaired eNOS-and nNOS-dependent responses of pial arterioles during T1D. adenosine 5=-diphosphate; N-methyl-D-aspartate; nitroglycerin; pial arterioles; Western blot; superoxide; endothelial nitric oxide synthase; neuronal nitric oxide synthase EXERCISE TRAINING (ExT) has been shown to play a significant role in the prevention of cardiovascular-related diseases. Although the precise cellular/molecular mechanisms accounting for the favorable effects of ExT on the cardiovascular system remain uncertain, many investigators have suggested that ExT may dramatically influence vascular endothelial function. Support for this concept can be found in studies that have examined the effects of ExT on endothelial nitric oxide synthase (eNOS)-dependent vasoreactivity in animals and human subjects (22,23,27,28,60,69). These studies have reported that ExT can enhance eNOS-dependent responses of large and small blood vessels in skeletal muscle, heart, and skin. Mechanisms by which ExT potentiates nitric oxide synthase (NOS)-dependent relaxation/dilation of blood vessels are not entirely clear but are likely to be related to an increase in shear forces actin...

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Section: Induction Of Diabetesmentioning

confidence: 99%

Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats

Mayhan

Arrick

Patel

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…First, basal superoxide levels were measured in aorta using lucigenin (5 mol/ L)-enhanced chemiluminescence as described previously. 3,4,25 In some experiments, vessel segments were preincubated for 30 minutes with either 4,5-dihydroxy-1,3-benzne disulfonic acid (Tiron; 10 mmol/L) or polyethylene-glycol-SOD (PEG-SOD) to quench the superoxide signal. Second, superoxide levels were also evaluated in carotid artery using hydroethidine (2 mol/L)-based confocal microscopy as described previously.…”

Section: Measurement Of Superoxidementioning

confidence: 99%

“…The present findings are consistent with previous reports, in which pharmacological inhibition of SOD activity with diethyldithiocarbamate (DDC), an inhibitor of coppercontaining SODs (CuZnSOD and EC-SOD) results in increased superoxide in vessels. 4,43,44 …”

Section: Selective Deficiency In Cuznsod Decreases Total Sod Activitymentioning

confidence: 99%

“…Because the initial finding of Kontos and Wei that superoxide inactivates nitric oxide in vivo, 2 many studies have suggested that inactivation of nitric oxide by superoxide contributes to impaired vascular function. [3][4][5][6][7] Indeed, nitric oxide reacts with superoxide at a rate 3 times faster than dismutation of superoxide by superoxide dismutases (SODs). 1 Substances that generate superoxide (such as pyrogallol, tetrahydrobiopterin, amyloid ␤ peptide, and xanthine/xanthine oxidase) impair endothelium-dependent relaxation of blood vessels.…”

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Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice

Didion

Ryan

Didion

et al. 2002

Circulation Research

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211

189

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Abstract-Increased superoxide is thought to play a major role in vascular dysfunction in a variety of disease states.Superoxide dismutase (SOD) limits increases in superoxide; however, the functional significance of selected isoforms of SOD within the vessel wall are unknown. We tested the hypothesis that selective loss of CuZnSOD results in increased superoxide and altered vascular responsiveness in CuZnSOD-deficient (CuZnSOD Ϫ/Ϫ ) mice compared with wild-type (CuZnSOD ϩ/ϩ ) littermates. Total SOD activity was reduced (PϽ0.05) by approximately 60% and CuZnSOD protein was absent in aorta from CuZnSOD Ϫ/Ϫ as compared with wild-type mice. Vascular superoxide levels, measured using lucigenin (5 mol/L)-enhanced chemiluminescence and hydroethidine (2 mol/L)-based confocal microscopy, were increased (approximately 2-fold; PϽ0.05) in CuZnSOD Ϫ/Ϫ mice as compared with wild-type mice. Relaxation of the carotid artery in response to acetylcholine and authentic nitric oxide was impaired (PϽ0.05) in CuZnSOD Ϫ/Ϫ mice. For example, maximal relaxation to acetylcholine (100 mol/L) was 50Ϯ6% and 69Ϯ5% in CuZnSOD Ϫ/Ϫ and wild-type mice, respectively. Contractile responses of the carotid artery were enhanced (PϽ0.05) in CuZnSOD Ϫ/Ϫ mice in response to phenylephrine and serotonin, but not to potassium chloride or U46619. In vivo, dilatation of cerebral arterioles (baseline diameterϭ31Ϯ1 m) to acetylcholine was reduced by approximately 50% in CuZnSOD Ϫ/Ϫ mice as compared with wild-type mice (PϽ0.05). These findings provide the first direct insight into the functional importance of CuZnSOD in blood vessels and indicate that this specific isoform of SOD limits increases in superoxide under basal conditions. CuZnSOD-deficiency results in altered responsiveness in both large arteries and microvessels.

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“…Studies suggest that inactivation of nitric oxide by superoxide contributes to impaired vascular function. [57][58][59][60] NO reacts with superoxide radical (O 2 -) to form peroxynitrite (ONOO -), which can further induce protein modification and DNA damage in the microvascular system. 61 Thus, decrease in NO bioavailability as a result of excess O 2 -formation is a major cause of endothelial dysfunction in aging.…”

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confidence: 99%

Aged Lymphatic Contractility: Recent Answers and New Questions

Gashev

Chatterjee

2013

Lymphatic Research and Biology

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An overview is presented of recent findings related to biology of aging of the lymph transport system. The authors discuss recently obtained data on the aging-associated alterations of lymphatic contractility in thoracic duct and mesenteric lymphatic vessels; on comparisons of function of aged mesenteric lymphatic vessels in situ versus isolated specimens and important conclusions which arose from these studies; on aging-associated changes in functional status of mast cells located close to aged mesenteric lymphatic vessels; on evidence of presence of oxidative stress in aged lymphatic vessels and changes in arrangement of muscle cells in their walls. The authors conclude that future continuation of the research efforts in this area is necessary and will be able to provide not only novel fundamental knowledge on the biology of lymphatic aging, but also will create solid foundation for the subsequent developments of lymphatic-oriented therapeutic interventions in many diseases of the elderly.T he major task of the lymphatic system is lymph transport. This system of initial capillaries, transporting vessels, and nodes is designed to transport fluid, soluble molecules, and immune cells from the interstitium through the lymph nodes to the central veins. This system also provides the transportation route for inflammatory mediators, the products of tissue injury/destruction, foreign substances, and tumor cells. Dysfunctional lymph transport can result in a wide range of disturbances, including edema, altered immune cell trafficking, depressed immune function, and impaired lipid metabolism. The lack of knowledge on how aging affects lymphatic vessels certainly contributes to the situation when researchers and clinicians ignore lymph transport-related components of various diseases. Thus, investigation of the mechanisms affecting lymphatic contractile function during aging are extremely important for ongoing attempts to better understand the lymphatic system and to discover the pathogenesis and effective treatment of various aging-associated disorders.Until recently, there were no published reports on systematic studies on aging-associated changes in the active lymph pumps. Due to the profound difficulty of measuring lymph flow in vivo, there are only a few reports demonstrating the measurements of reduced lymph flow in aged animals. [1][2][3] In particular, it was reported 3 that aging significantly decreases lymph flow from the main mesenteric lymph duct by *60% between ages of 3 and 22 mo in rats.During the last years, we obtained important functional and molecular evidence of the aging-associated alterations of contractility in lymphatic vessels, which already widened our knowledge on the biology of aged lymph flow. On the other hand, our recent studies raise new important questions that may link several diseases to impaired coordination between lymphatic function and function of other systems in the aged body. While this review provides some recent answers on current questions in biology of lymphatic aging,...

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Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD

Cited by 75 publications

References 60 publications

Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats

Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats

Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice

Aged Lymphatic Contractility: Recent Answers and New Questions

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