Investigation of the inhibitory effects of homocysteine and copper on nitric oxide‐mediated relaxation of rat isolated aorta

Emsley, Alison M; Jeremy, Jamie Y.; Gomes, Guiomar Nascimento; Angelini, Gianni D; Plane, Frances

doi:10.1038/sj.bjp.0702374

Cited by 86 publications

(50 citation statements)

References 31 publications

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“…This marked potentiating effect was also reversed by SOD, indicating that Hcy augments an already established increase in O 2 -formation by vascular tissue from diabetic animals, possibly by acting at a common denominator site. In previous studies in which the effect of Hcy on endothelium-dependent relaxation was investigated, exposure to 1 mmol/l Hcy for 3 h was required to elicit an inhibitory effect in isolated rat aortic rings [18]. Since Hcy autoxidises to form O 2 - [3] it is reasonable to suggest that arterial tissue from diabetic animals could accelerate the auto-oxidation of Hcy.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

et al. 2002

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Aims/hypothesis. Both diabetes mellitus and hyperhomocysteinaemia are risk factors for cardiovascular disease and are associated with impaired endothelial nitric oxide and with excess superoxide formation. To explore potential vasculopathic interactions between these risk factors, the effect of homocysteine on endothelium-dependent relaxation and cyclic GMP formation was investigated in aortae from diabetic rabbits. Methods. Rabbits were rendered diabetic by intravenous injection of alloxan. Six months later, the aortae were excised, cut into rings and mounted in an organ bath for isometric measurement of acetylcholineevoked relaxation in rings pre-contracted with phenylephrine. Cyclic GMP formation by aortic rings after stimulation with acetylcholine, calcium ionophore A23187 and sodium nitroprusside was assessed using radioimmunoassay. The effect of homocysteine on these parameters was then studied.Results. Ach-evoked relaxation and cyclic GMP formation induced with acetylcholine and calcium ionophore A23187 were impaired in aortae from diabetic rabbits compared with the control rabbits, effects that were reversed with superoxide dimutase (SOD) and augmented by 10-100 µmol/l homocysteine, an effect again reversed by SOD. Conclusion/interpretation. These data show that the bioavailability of nitric oxide is reduced in aortae from diabetic rabbits due to excess production of superoxide, an effect augmented by homocysteine. These results indicate that patients with diabetes mellitus could be susceptible to homocysteine-mediated angiopathy at lower concentrations than those that promote vasculopathy in non-diabetic patients. [Diabetologia (2002[Diabetologia ( ) 45:1325[Diabetologia ( -1331

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Section: Discussionmentioning

confidence: 99%

Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

et al. 2002

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“…To examine the effects of free radical scavenging on flow-induced dilation in coronary arterioles, responses were also assessed in the presence of the cell-permeable superoxide dismutase (SOD) mimetic Tempol [100 M (32)], the H2O2 scavenger catalase [100 U/ml (12)], or the Cu/Zn SOD inhibitor diethyldithiocarbamate [DETC, 1 mM (11)]. Each pharmacological agent was applied for 20 min before evaluation of the flow response.…”

Section: Methodsmentioning

confidence: 99%

Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles

Kang

Chen

Reyes

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Kang LS, Chen B, Reyes RA, LeBlanc AJ, Teng B, Mustafa SJ, Muller-Delp JM. Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles. Am J Physiol Heart Circ Physiol 300: H2105-H2115, 2011. First published March 25, 2011 doi:10.1152/ajpheart.00349.2010.-Endothelium-dependent, nitric oxide (NO)-mediated vasodilation can be impaired by reactive oxygen species (ROS), and this deleterious effect of ROS on NO availability may increase with aging. Endothelial function declines rapidly after menopause, possibly because of loss of circulating estrogen and its antioxidant effects. The purpose of the current study was to determine the role of O 2 Ϫ and H2O2 in regulating flow-induced dilation in coronary arterioles of young (6-mo) and aged (24-mo) intact, ovariectomized (OVX), or OVX ϩ estrogen-treated (OVE) female Fischer 344 rats. Both aging and OVX reduced flowinduced NO production, whereas flow-induced H 2O2 production was not altered by age or estrogen status. Flow-induced vasodilation was evaluated before and after treatment with the superoxide dismutase (SOD) mimetic Tempol (100 M) or the H2O2 scavenger catalase (100 U/ml). Removal of H 2O2 with catalase reduced flow-induced dilation in all groups, whereas Tempol diminished vasodilation in intact and OVE, but not OVX, rats. Immunoblot analysis revealed elevated nitrotyrosine with aging and OVX. In young rats, OVX reduced SOD protein while OVE increased SOD in aged rats; catalase protein did not differ in any group. Collectively, these studies suggest that O 2 Ϫ and H2O2 are critical components of flow-induced vasodilation in coronary arterioles from female rats; however, a chronic deficiency of O 2 Ϫ buffering by SOD contributes to impaired flowinduced dilation with aging and loss of estrogen. Furthermore, these data indicate that estrogen replacement restores O 2 Ϫ homeostasis and flow-induced dilation of coronary arterioles, even at an advanced age. superoxide dismutase; hydrogen peroxide; ovariectomy; estrogen replacement

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“…However, endothelium-dependent dilatations are impaired in young children with severe hyperhomocysteinemia and homocystinuria [2], indicating that the concentration of Hcy is another major determinant for endothelial dysfunction. In acute studies, rat aortas incubated with high concentrations of Hcy (1,000 µ M ) for 3 h exhibited a marked reduction in endothelium-dependent relaxation [39]. Coexistence of hyperhomocysteinemia with other environmental stimuli may have a synergetic effect on endothelial function.…”

Section: Discussionmentioning

confidence: 99%

Chronic Mild Hyperhomocysteinemia Induces Aortic Endothelial Dysfunction but Does Not Elevate Arterial Pressure in Rats

Villeneuve¹,

Brunel-Jacquemin²,

Petit³

et al. 2005

J Vasc Res

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Mild hyperhomocysteinemia is prevalent in the general population and has been linked to endothelial dysfunction and high arterial pressure (AP) in clinical studies. The present study was designed to determine whether a rise in AP was induced by mild hyperhomocysteinemia and whether the potential rise in AP is secondary or prior to endothelial dysfunction. Experiments were performed in a rat model of mild hyperhomocysteinemia induced by oral administration of homocysteine for 1–4 months. Aortic endothelial dysfunction was observed 2 months after homocysteine treatment while endothelium-independent vasodilation was normal. In parallel, homocysteine treatment increased phenylephrine-induced contraction in aortas with endothelium, but did not modify the contraction in aortas without endothelium, suggesting a decrease of basal NO production. In conscious unrestrained rats, AP was not significantly different 1, 2, 3 and 4 months after homocysteine treatment. In correlation, endothelial function of a resistance vessel (mesenteric artery), mainly non-NO nonprostanoid factor mediated, was preserved, indicating that homocysteine treatment only affected the NO pathway. In conclusion, mild hyperhomocysteinemia alone is not sufficient to elevate arterial blood pressure, at least in the rat model. Aortic endothelial dysfunction produced by mild hyperhomocysteinemia is independent of hemodynamic factors.

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Investigation of the inhibitory effects of homocysteine and copper on nitric oxide‐mediated relaxation of rat isolated aorta

Cited by 86 publications

References 31 publications

Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles

Chronic Mild Hyperhomocysteinemia Induces Aortic Endothelial Dysfunction but Does Not Elevate Arterial Pressure in Rats

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