Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine

Ülker, Sibel; Çınar, Mustafa; Can, Cenk; Evinç, Akgün; Koşay, Sezen

doi:10.1006/phrs.2001.0814

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…Results obtained in the present research, according to Gunnet et al, (2005), allow us to speculate that selective expression of iNOS in endothelium may be considered the main cause of impairment in endothelial function. Several mechanisms have been proposed by which iNOS may impair endothelial function (Shelkovnikov and Gonick, 2004;Ulker et al, 2001): for example, iNOS may compete with eNOS by limiting availability of BH 4 , an essential cofactor for NO production by eNOS. Furthermore we showed that nitrosative stress induced by iNOS overexpression causes a decrease in DDAH activity.…”

Section: Discussionmentioning

confidence: 99%

High Glucose-Mediated Imbalance of Nitric Oxide Synthase and Dimethylarginine Dimethylaminohydrolase Expression in Endothelial Cells

Sorrenti

Mazza²,

Campisi³

et al. 2006

CNR

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The mechanisms involved in endothelial dysfunction are multifactorial. A correlation between oxidative stress and derangements of nitric oxide synthase (NOS) pathways in altered endothelial homeostasis has been most studied and demonstrated in different pathophysiological conditions. NOS activities are regulated by endogenous inhibitors such as asymmetric dimethyl-L-arginine (ADMA) that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). Since recent data demonstrated that some endothelial dysfunction may be related to reduced expression and/or activity of DDAH, the aim of the present research was to investigate the expression of DDAH-2 and NOS isoforms in high glucose-mediated oxidative stress. Endothelial cells were incubated with normal (7 mM) and high concentrations (33 mM) of D-glucose for 5 days; mannose (26 mM) plus D-glucose (7 mM) was used as osmotic control. Data obtained in the present study show that the exposure for 5 days to high glucose increases oxidative stress, reduces DDAH-2 and eNOS expression and increases iNOS expression. These results indicate that DDAH-2 and iNOS/eNOS dysregulation may play a key role in high glucose-mediated oxidative stress, suggesting that selective modulation of DDAH isoforms may result in selective inhibition/activation of NOS isoforms, thereby providing a novel strategy of approach in vascular complications of several pathologies.

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Section: Discussionmentioning

confidence: 99%

High Glucose-Mediated Imbalance of Nitric Oxide Synthase and Dimethylarginine Dimethylaminohydrolase Expression in Endothelial Cells

Sorrenti

Mazza²,

Campisi³

et al. 2006

CNR

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“…The finding that ECSOD did not improve impaired constrictor responses to phenylephrine suggests that extracellular superoxide may not be functionally important in impairment. LPS induces inducible nitric oxide (NO) synthase (iNOS) in arteries, and iNOS mediates impaired constrictor responses produced by LPS (3,14,27). A likely mechanism by which iNOS impairs vasoconstrictor responses is by a direct effect of high levels of NO.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Lund¹

2004

American Journal of Physiology-Heart and Circulatory Physiology

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transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin. Am J Physiol Heart Circ Physiol 287: H805-H811, 2004; 10.1152/ajpheart.00907.2003 impairs vascular function, in part by generation of reactive oxygen species. One goal of this study was to determine whether gene transfer of extracellular SOD (ECSOD) improves vascular responsiveness in LPS-treated rats. A second goal was to determine whether effects of ECSOD are dependent on the heparin-binding domain of the enzyme, which facilitates binding of ECSOD to the outside of cells. Adenoviruses containing ECSOD (AdECSOD), ECSOD with deletion of its heparin-binding domain (AdECSOD-HBD), or a control virus (AdLacZ) were injected intravenously into rats. Three days later, vehicle or LPS (10 mg/kg ip) was injected. After 24 h, vascular reactivity was examined in aortic rings in vitro. Maximum relaxation to acetylcholine was 95 Ϯ 1% (means Ϯ SE) after AdlacZ plus vehicle and 77 Ϯ 3% after AdlacZ plus LPS (P Ͻ 0.05). Responses to calcium ionophore A-23187 and submaximal concentrations of nitroprusside also were impaired by LPS. Gene transfer of ECSOD, but not AdECSOD-HBD, improved (P Ͻ 0.05) relaxation to acetylcholine and A-23187 after LPS. Maximum relaxation to acetylcholine was 88 Ϯ 3% after LPS plus AdECSOD. Superoxide was increased in aorta after LPS, and the levels were reduced after AdECSOD but not AdECSOD-HBD. LPS-induced adhesion of leukocytes to aortic endothelium was reduced by AdECSOD but not by AdECSOD-HBD. We conclude that after gene transfer in vivo, binding of ECSOD to arteries effectively decreases the numbers of adherent leukocytes and levels of superoxide and improves impaired endothelium-dependent relaxation produced by LPS. acetylcholine; adenovirus; rats; hydroethidine LPS PRODUCES IMPAIRMENT OF endothelium-dependent vascular relaxation (3,4,15). Several studies suggest that endothelial dysfunction in LPS-treated vessels may be produced, in part, by increased levels of reactive oxygen species (ROS), especially superoxide, in blood vessels (15,21). SOD, which reduces superoxide to hydrogen peroxide, improves endothelium-dependent relaxation in several pathological conditions in which superoxide is elevated in blood vessels (6, 10, 11, 18 -20, 28).Extracellular SOD (ECSOD), in contrast to other isoforms of SOD, is a secreted protein found predominantly outside of cells (12). A COOH-terminal binding domain has affinity for heparin [thus heparin-binding domain (HBD)] or sulfated proteoglycans, which facilitate binding of ECSOD to the external surfaces of many cells, including endothelial cells (12). Truncated forms of ECSOD, without HBDs or with decreased heparin-binding affinity, normally constitute a small percentage of endogenous ECSOD (12) and may, or may not, be important for vascular function. Decreases in ECSOD with high affinity for heparin, and increases in forms of ECSOD with low affinity for heparin, have been observed in atherosclerosis (12). Thus decreased function of the HBD on ECSOD may...

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“…For selective transfection of either endothelium or adventitia, viruses were diluted in MEM to a concentration of 3ϫ10 10 pfu/mL and arteries were incubated with virus for 3 to 4 hours at 37°C in an incubator. Ligated vessels were then trimmed, rinsed, and cut into 4 equal segments (Ϸ3 mm in length).…”

Section: Gene Transfermentioning

confidence: 99%

Mechanisms of Inducible Nitric Oxide Synthase–Mediated Vascular Dysfunction

Gunnett

Lund

McDowell

et al. 2005

ATVB

122

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Objective-Inducible nitric oxide synthase (iNOS) is expressed in arteries during inflammation and may contribute to vascular dysfunction. Effects of gene transfer of iNOS to carotid arteries were examined in vitro in the absence of systemic inflammation to allow examination of mechanisms by which iNOS impairs contraction and relaxation. Methods and Results-After gene transfer of iNOS with an adenovirus (AdiNOS), constrictor responses to phenylephrine (PE) and U46619 were impaired. After AdiNOS, inhibition of soluble guanylate cyclase (sGC) with 1H-[1,2,4]oxadiazolo-[4,3,2]quinoxalin-1-one (ODQ) reduced the EC 50 for PE from 4.33Ϯ0.78 mol/L to 1.15Ϯ0.43 mol/L (meanϮSEM). These results imply that iNOS impairs contraction by activation of the NO/cGMP pathway. Relaxation to acetylcholine (ACh) also was impaired after AdiNOS. Sepiapterin (300 mol/L), the precursor for tetrahydrobiopterin (BH 4 ), improved relaxation to Ach. Because BH 4 is an essential cofactor for production of NO by both iNOS and endothelial nitric oxide synthase (eNOS), these results suggest that iNOS may reduce production of NO by eNOS by limiting availability of BH 4 . Next, we examined effects of expression of iNOS in endothelium and adventitia. Selective expression of iNOS in endothelium, but not adventitia, impaired contraction to phenylephrine and relaxation to acetylcholine. Conclusions-We conclude that: (1) iNOS may impair contraction in part by activation of sGC; (2)

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Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine

Cited by 9 publications

References 22 publications

High Glucose-Mediated Imbalance of Nitric Oxide Synthase and Dimethylarginine Dimethylaminohydrolase Expression in Endothelial Cells

High Glucose-Mediated Imbalance of Nitric Oxide Synthase and Dimethylarginine Dimethylaminohydrolase Expression in Endothelial Cells

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Mechanisms of Inducible Nitric Oxide Synthase–Mediated Vascular Dysfunction

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