共查询到20条相似文献,搜索用时 31 毫秒
1.
Lawrence J. Coppey Jill S. Gellett Eric P. Davidson Joyce A. Dunlap Mark A. Yorek 《Experimental diabetes research》2002,3(1):21-36
Previously we have demonstrated that diabetes
causes impairment in vascular function of
epineurial vessels, which precedes the slowing
of motor nerve conduction velocity. Treatment
of diabetic rats with aldose reductase
inhibitors, aminoguanidine or myo-inositol
supplementation have been shown to improve
motor nerve conduction velocity and/or
decreased endoneurial blood flow. However,
the effect these treatments have on vascular
reactivity of epineurial vessels of the sciatic
nerve is unknown. In these studies we examined
the effect of treating streptozotocininduced
rats with sorbinil, aminoguanidine or
myo-inositol on motor nerve conduction velocity,
endoneurial blood flow and endothelium dependent
vascular relaxation of arterioles that
provide circulation to the region of the sciatic
nerve. Treating diabetic rats with sorbinil,
aminoguanidine or myo-inositol improved the
reduction of endoneurial blood flow and motor
nerve conduction velocity. However, only
sorbinil treatment significantly improved the
diabetes-induced impairment of acetylcholinemediated
vasodilation of epineurial vessels of
the sciatic nerve. All three treatments were efficacious
in preventing the appropriate metabolic
derangements associated with either activation
of the polyol pathway or increased nonenzymatic
glycation. In addition, sorbinil was
shown to prevent the diabetes-induced decrease
in lens glutathione level. However, other markers of oxidative stress were not vividly
improved by these treatments. These studies
suggest that sorbinil treatment may be more
effective in preventing neural dysfunction in
diabetes than either aminoguanidine or myoinositol. 相似文献
2.
Yorek MA Coppey LJ Gellett JS Davidson EP Bing X Lund DD Dillon JS 《American journal of physiology. Endocrinology and metabolism》2002,283(5):E1067-E1075
Nutritional supplementation with dehydroepiandrosterone (DHEA) may be a candidate for treating diabetes-induced vascular and neural dysfunction. DHEA is a naturally occurring adrenal androgen that has antioxidant properties and is reportedly reduced in diabetes. Using a prevention protocol, we found that dietary supplementation of streptozotocin-induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused a concentration-dependent prevention in the development of motor nerve conduction velocity and endoneurial blood flow impairment, which are decreased in diabetes. At 0.25%, DHEA significantly prevented the diabetes-induced increase in serum thiobarbituric acid-reactive substances and sciatic nerve conjugated diene levels. This treatment also reduced the production of superoxide by epineurial arterioles of the sciatic nerve. DHEA treatment (0.25%) significantly improved vascular relaxation mediated by acetylcholine in epineurial vessels of diabetic rats. Sciatic nerve Na+-K+-ATPase activity and myoinositol content was also improved by DHEA treatment, whereas sorbitol and fructose content remained elevated. These studies suggest that DHEA, by preventing oxidative stress and perhaps improving sciatic nerve Na+-K+-ATPase activity, may improve vascular and neural dysfunction in diabetes. 相似文献
3.
Obrosova IG Drel VR Oltman CL Mashtalir N Tibrewala J Groves JT Yorek MA 《American journal of physiology. Endocrinology and metabolism》2007,293(6):E1645-E1655
Evidence for important roles of the highly reactive oxidant peroxynitrite in diabetic complications is emerging. We evaluated the role of peroxynitrite in early peripheral neuropathy and vascular dysfunction in STZ-diabetic rats. In the first dose-finding study, control and STZ-diabetic rats were maintained with or without the potent peroxynitrite decomposition catalyst Fe(III)tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) at 3, 5, or 10 mg.kg(-1).day(-1) in the drinking water for 4 wk after an initial 2 wk without treatment for assessment of early neuropathy. In the second study with similar experimental design, control and STZ-diabetic rats were maintained with or without FP15, 5 mg.kg(-1).day(-1), for vascular studies. Rats with 6-wk duration of diabetes developed motor and sensory nerve conduction velocity deficits, mechanical hyperalgesia, and tactile allodynia in the absence of small sensory nerve fiber degeneration. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve and dorsal root ganglia. All these variables were dose-dependently corrected by FP15, with minimal differences between the 5 and 10 mg.kg(-1).day(-1) doses. FP15, 5 mg.kg(-1).day(-1), also corrected endoneurial nutritive blood flow and nitrotyrosine, but not superoxide, fluorescence in aorta and epineurial arterioles. Diabetes-induced decreases in acetylcholine-mediated relaxation by epineurial arterioles and coronary and mesenteric arteries, as well as bradykinin-induced relaxation by coronary and mesenteric arteries, were alleviated by FP15 treatment. The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models. 相似文献
4.
M. A. Yorek L. J. Coppey J. S. Gellett E. P. Davidson 《Experimental diabetes research》2004,5(3):187-193
The authors have determined that epineurial arterioles
of the sciatic nerve are innervated by nonadrenergic,
noncholinergic nerves that contribute to the regulation of
vasodilation. Using immunohistochemistry, the authors
determined that nerves innervating epineurial arterioles
contain the neuropeptide calcitonin gene–related peptide
(CGRP). Using streptozotocin-induced diabetic rats, the authors
demonstrated that CGRP content in sensory nerves
innervating epineurial arterioles and vasodilation in response
to exogenous CGRP was decreased. In summary,
epineurial arterioles of the sciatic nerve are innervated by
sensory nerves containing the neuropeptide CGRP. The
diabetes-like condition induced by streptozotocin reduces
the content of CGRP in these nerves and exogenous CGRPmediated
vasodilation. CGRP is likely an important regulator
of vascular tone and compromising its function could
contribute to nerve ischemia and diabetic neuropathy. 相似文献
5.
Oltman CL Coppey LJ Gellett JS Davidson EP Lund DD Yorek MA 《American journal of physiology. Endocrinology and metabolism》2005,289(1):E113-E122
We have examined the progression of vascular and neural deficits in Zucker rats, Zucker diabetic fatty (ZDF) diabetic rats, and age-matched lean ZDF rats from 8 to 40 wk of age. Both the ZDF diabetic and Zucker rats were glucose intolerant at 8 wk of age. The Zucker rats did not become hyperglycemic but were hyperinsulinemic through 32 wk of age. All ZDF diabetic rats became hyperglycemic by 8 wk of age. Through their life span, serum free fatty acids and triglycerides levels were significantly higher in Zucker and ZDF diabetic rats compared with age-matched lean ZDF rats. After 24 and 28 wk of age, endoneurial blood flow was significantly decreased in ZDF diabetic and Zucker rats. Motor nerve conduction velocity was significantly decreased after 12-14 wk of age in ZDF diabetic rats and at 32 wk of age in Zucker rats. ACh-mediated vascular relaxation of epineurial arterioles of the sciatic nerve was impaired after 8-10 wk of age in ZDF diabetic rats and after approximately 16 wk of age in Zucker rats. In contrast, vascular relaxation mediated by calcitonin gene-related peptide was impaired significantly after 28 wk of age in ZDF diabetic rats but not impaired in Zucker rats up to 40 wk of age. Markers of oxidative stress were differentially elevated in ZDF diabetic rats and Zucker rats. These data indicate that vascular and neural dysfunction develops in both Zucker and ZDF diabetic rats but at different rates, which may be the result of hyperglycemia. 相似文献
6.
Effect of Fidarestat and α-Lipoic Acid on Diabetes-Induced Epineurial Arteriole Vascular Dysfunction
M. A. Yorek L. J. Coppey J. S. Gellett E. P. Davidson D. D. Lund 《Experimental diabetes research》2004,5(2):123-135
In the present study, the authors examined whether treating
streptozotocin-induced diabetic rats with the combination
of α-lipoic acid and fidarestat, an aldose reductase inhibitor,
can promote the formation of dihydrolipoic acid
in diabetic animals and thereby enhance the efficacy of
α-lipoic acid as monotherapy toward preventing diabetic
vascular and neural dysfunction.Treating diabetic rats with
the combination of 0.25% α-lipoic acid (in the diet) and
fidarestat (3 mg/kg body weight) prevented the diabetesinduced
slowing of motor nerve conduction velocity and
endoneurial blood flow. This therapy also significantly improved
acetylcholine-mediated vasodilation in epineurial
arterioles of the sciatic nerve compared to nontreated diabetic
rats. Treating diabetic rats with 0.25% α-lipoic acid
and fidarestat (3 mg/kg body weight) was equally or more
effective in preventing vascular and neural dysfunction than
was monotherapy of diabetic rats with higher doses of
α-lipoic acid or fidarestat. Treating diabetic rats with the
combination of 0.25% α-lipoic acid and fidarestat (3 mg/kg
body weight) significantly improved several markers of oxidative
stress and increased the serum levels of both α-lipoic
acid and dihydrolipoic acid. These studies suggest that combination
therapy consisting of α-lipoic acid and fidarestat
may be more efficacious in preventing diabetes-induced vascular
and neural dysfunction in peripheral tissue compared
to monotherapy, which requires higher doses to be equally effective. The effect of this combination therapy may in part
be due to the increased production and/or level of dihydrolipoic
acid. 相似文献
7.
Oltman CL Davidson EP Coppey LJ Kleinschmidt TL Lund DD Yorek MA 《Obesity (Silver Spring, Md.)》2008,16(1):82-89
Objective: Obese Zucker rats, animal model for the metabolic syndrome, develop a diabetes‐like neuropathy that is independent of hyperglycemia. The purpose of this study was to determine whether drugs used to treat cardiovascular dysfunction in metabolic syndrome also protect nerve function. Methods and Procedures: Obese Zucker rats at 20 weeks of age were treated for 12 weeks with enalapril or rosuvastatin. Lean rats were used as controls. Vasodilation in epineurial arterioles was measured by videomicroscopy. Endoneurial blood flow (EBF) was measured by hydrogen clearance and nerve conduction velocity was measured following electrical stimulation of motor or sensory nerves. Results: Enalapril treatment decreased serum angiotensin‐converting enzyme (ACE) activity and both drugs reduced serum cholesterol levels. In obese Zucker rats at 32 weeks of age superoxide levels were elevated in the aortas and epineurial arterioles, which were reduced by treatment with either drug. Nitrotyrosine levels were increased in epineurial arterioles and reduced with enalapril treatment. EBF was decreased and corrected by treatment with either drug. Motor nerve conduction velocity was decreased and significantly improved with enalapril treatment. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and this was significantly improved with either treatment. Treatment with either enalapril or rosuvastatin significantly reversed the decrease in acetylcholine‐mediated vascular relaxation of epineurial arterioles in obese Zucker rats. Discussion: Even though obese Zucker rats have normal glycemia vascular and neural dysfunctions develop with age and can be improved by treatment with either enalapril or rosuvastatin. 相似文献
8.
Sakai N Mizuno R Ono N Kato H Ohhashi T 《American journal of physiology. Heart and circulatory physiology》2007,293(3):H1498-H1507
Microcirculation of the sheath of the rat sciatic nerve fiber was investigated by using an intravital microscope, and changes in the diameter of the epineurial arterioles in response to highly oxygenated Krebs-bicarbonate solution were evaluated. Superfusion of low-oxygen (0%) Krebs-bicarbonate solution (LKS) onto rat sciatic nerves did not affect changes in the diameter of the arterioles. Nifedipine, a Ca(2+)-channel blocker, caused a dose-dependent dilation of the epineurial arterioles in LKS. In contrast, superfusion of high-oxygen (21%) Krebs-bicarbonate solution (HKS) onto rat sciatic nerves significantly constricted the epineurial arterioles in a time-dependent manner. The HKS-induced constriction of the epineurial arterioles was significantly reduced by treatment with 120 U/ml superoxide dismutase (SOD) alone or 5,000 U/ml catalase alone. In the presence of 120 U/ml SOD plus 5,000 U/ml catalase, 10(-4) M tempol, 10(-6) M diphenyleneiodium, 2 x 10(-4) M apocynin, or 10(-6) M allopurinol, the HKS-induced constriction of the epineurial arterioles completely disappeared. These results suggest that superfusion of highly oxygenated solution onto rat sciatic nerves constricts the epineurial arterioles through reactive oxygen species (ROS), including superoxide and hydrogen peroxide, and that production of superoxide involves a NADPH oxidase- or xanthine oxidase-dependent pathway. In conclusion, ROS play significant roles in the regulation of microcirculation of rat sciatic nerves in vivo. 相似文献
9.
Lawrence J. Coppey Eric P. Davidson Joyce A. Dunlap Donald D. Lund Mark A. Yorek 《Experimental diabetes research》2000,1(2):131-143
Diabetes mellitus produces marked abnormalities in
motor nerve conduction, but the mechanism is not
clear. In the present study we hypothesized that in
the streptozotocin (STZ)-induced diabetic rat impaired
vasodilator function in arterioles that provide
circulation to the region of the sciatic nerve is
associated with reduced endoneural blood flow
(EBF) and that these defects precede slowing of
motor nerve conduction velocity, and thereby may
contribute to nerve dysfunction. As early as three
days after the induction of diabetes endoneural
blood flow was reduced in the STZ-induced diabetic
rat. Furthermore, after 1 week of diabetes acetylcholine-
induced vasodilation was found to be impaired.
This was accompanied by an increase in the superoxide
level in arterioles that provide circulation to
the region of the sciatic nerve as well as changes in
the level of other markers of oxidative stress
including an increase in serum levels of thiobarbituric
acid reactive substances and a decrease in lens
glutathione level. In contrast to the vascular related
changes that occur within 1 week of diabetes, motor
nerve conduction velocity and sciatic nerve Na+/k+
ATPase activity were significantly reduced following
2 and 4 weeks of diabetes, respectively.
These studies demonstrate that changes in vascular function
in the STZ-induced diabetic rat precede the
slowing of motor nerve conduction velocity (MNCV)
and are accompanied by an increase in superoxide
levels in arterioles that provide circulation to the
region of the sciatic nerve. 相似文献
10.
Upregulation of vascular NAD(P)H oxidase has been considered an important source for elevated levels of reactive oxygen species that contribute to several cardiovascular disease states, including the vascular complications of diabetes mellitus. Previous studies have shown that treatment with antioxidants corrects impaired nerve function and blood flow in diabetic rats. The aim was to assess the degree of involvement of NAD(P)H oxidase in experimental diabetic neuropathy. To this end, after 6 weeks of untreated streptozotocin-diabetes, rats were treated for 2 weeks with the NAD(P)H oxidase, apocynin. Two high doses (15 and 100 mg/kg) were used to ensure that maximal effects were registered. Diabetes caused a 20% reduction in sciatic nerve motor conduction velocity, and a 14% deficit for sensory saphenous nerve. Apocynin treatment corrected these defects by 32% and 48%, respectively: there were no significant differences between the effects of the 2 doses. Sciatic nerve nutritive endoneurial perfusion was measured by hydrogen clearance microelectrode polarography. Blood flow and vascular conductance were 47% and 40% reduced by diabetes, respectively. Both doses of apocynin had similar effects, correcting the blood flow deficit by 31% and conductance by 47%. Thus, the data show that NAD(P)H oxidase contributes to the neurovascular deficits in diabetic rats. While only accounting for part of the elevated reactive oxygen species production in diabetes, this mechanism could provide a novel therapeutic candidate for further investigation in diabetic neuropathy and vasculopathy. 相似文献
11.
Arrick DM Sun H Patel KP Mayhan WG 《American journal of physiology. Heart and circulatory physiology》2011,301(3):H696-H703
Decreased dilation of cerebral arterioles via an increase in oxidative stress may be a contributing factor in the pathogenesis of diabetes-induced complications leading to cognitive dysfunction and/or stroke. Our goal was to determine whether resveratrol, a polyphenolic compound present in red wine, has a protective effect on cerebral arterioles during type 1 diabetes (T1D). We measured the responses of cerebral arterioles in untreated and resveratrol-treated (10 mg·kg(-1)·day(-1)) nondiabetic and diabetic rats to endothelial (eNOS) and neuronal (nNOS) nitric oxide synthase (NOS)-dependent agonists and to a NOS-independent agonist. In addition, we harvested brain tissue from nondiabetic and diabetic rats to measure levels of superoxide under basal conditions. Furthermore, we used Western blot analysis to determine the protein expression of eNOS, nNOS, SOD-1, and SOD-2 in cerebral arterioles and/or brain tissue from untreated and resveratrol-treated nondiabetic and diabetic rats. We found that T1D impaired eNOS- and nNOS-dependent reactivity of cerebral arterioles but did not alter NOS-independent vasodilation. While resveratrol did not alter responses in nondiabetic rats, resveratrol prevented T1D-induced impairment in eNOS- and nNOS-dependent vasodilation. In addition, superoxide levels were higher in brain tissue from diabetic rats and resveratrol reversed this increase. Furthermore, eNOS and nNOS protein were increased in diabetic rats and resveratrol produced a further increased eNOS and nNOS proteins. SOD-1 and SOD-2 proteins were not altered by T1D, but resveratrol treatment produced a decrease in SOD-2 protein. Our findings suggest that resveratrol restores vascular function and oxidative stress in T1D. We suggest that our findings may implicate an important therapeutic potential for resveratrol in treating T1D-induced cerebrovascular dysfunction. 相似文献
12.
Sonta T Inoguchi T Tsubouchi H Sekiguchi N Kobayashi K Matsumoto S Utsumi H Nawata H 《Free radical biology & medicine》2004,37(1):115-123
It is well established that oxidative stress is enhanced in diabetes. However, the major in vivo source of oxidative stress is not clear. Here we show that vascular NAD(P)H oxidase may be a major source of oxidative stress in diabetic and obese models. In vivo electron spin resonance (ESR)/spin probe was used to evaluate systemic oxidative stress in vivo. The signal decay rate of the spin probe (spin clearance rate; SpCR) significantly increased in streptozotocin-induced diabetic rats 2 weeks after the onset of diabetes. This increase was completely normalized by treatment with the antioxidants alpha-tocopherol (40 mg/kg) and superoxide dismutase (5000 units/kg), and was significantly inhibited by treatment with a PKC-specific inhibitor, CGP41251 (50 mg/kg), and a NAD(P)H oxidase inhibitor, apocynin (5 mg/kg). Both obese ob/ob mice (10 weeks old) with mild hyperglycemia and Zucker fatty rats (11 weeks old) with normoglycemia exhibited significantly increased SpCR as compared with controls. Again, this increase was inhibited by treatment with both CGP41251 and apocynin. Oral administration of insulin sensitizer, pioglitazone (10 mg/kg), for 7 days also completely normalized SpCR values. These results suggest that vascular NAD(P)H oxidase may be a major source of increased oxidative stress in diabetes and obesity. 相似文献
13.
Wendt MC Daiber A Kleschyov AL Mülsch A Sydow K Schulz E Chen K Keaney JF Lassègue B Walter U Griendling KK Münzel T 《Free radical biology & medicine》2005,39(3):381-391
The nox2-dependent NADPH oxidase was shown to be a major superoxide source in vascular disease, including diabetes. Smooth muscle cells of large arteries lack the phagocytic gp91phox subunit of the enzyme; however, two homologues have been identified in these cells, nox1 and nox4. It remained to be established whether also increases in protein levels of the nonphagocytic NADPH oxidase contribute to increased superoxide formation in diabetic vessels. To investigate changes in the expression of these homologues, we measured their expression in aortic vessels of type I diabetic rats. Eight weeks after streptozotocin treatment, we found a doubling in nox1 protein expression, while the expression of nox4 remained unchanged. This was associated with a significant increase in the NADPH oxidase activity in membrane fractions of diabetic heart and aortic tissue. Furthermore, we observed a decreased sensitivity of diabetic vessels to acetylcholine and nitroglycerin and a decrease in both acetylcholine-stimulated NO production and phosphorylation of VASP, despite an increase in endothelial NO synthase (NOSIII) expression. In addition, xanthine oxidase activity was markedly increased in plasma and 100,000 g supernatant of cardiac tissue of diabetic rats, while myocardial mitochondrial superoxide formation was only weakly enhanced. We conclude that in addition to phagocytic NADPH oxidase, also nonphagocytic, vascular NADPH oxidase subunit nox1, uncoupled NOSIII, and plasma xanthine oxidase contribute to endothelial dysfunction in the setting of diabetes mellitus. 相似文献
14.
The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some of the molecular mechanisms involved. Starting at 8 weeks of diabetes, pioglitazone (10 mg/kg) was administered to STZ-induced diabetic rats for 4 weeks. In untreated STZ rats (vs age-matched control rats): (1) ACh-induced relaxation, cGMP accumulation, phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein at Ser-239 [an established biochemical end-point of nitric oxide (NO)/cGMP signaling], and Cu/Zn-superoxide dismutase (SOD) expression and SOD activity were all reduced; (2) aortic superoxide generation, nitrotyrosine expression, and NAD(P)H oxidase activity were increased; (3) plasma endothelin-1 (ET-1) and aortic c-Jun (AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. Collectively, these results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P)H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway. 相似文献
15.
Our goals were to determine whether acute exposure to nicotine alters neuronal nitric oxide synthase (nNOS)-dependent reactivity of cerebral arterioles and to identify a potential role for oxidative stress in nicotine-induced impairment in nNOS-dependent responses of cerebral arterioles. We measured in vivo diameter of cerebral arterioles to nNOS-dependent (N-methyl-d-aspartate and kainate) and -independent (nitroglycerin) agonists before and during acute treatment with nicotine. We found that nNOS-dependent, but not -independent, vasodilatation was impaired during treatment with nicotine. In addition, treatment of the cerebral microcirculation with tempol (1 h before infusion of nicotine) prevented nicotine-induced impairment in nNOS-dependent vasodilatation. Furthermore, the production of superoxide anion (lucigenin chemiluminescence) was increased in parietal cortex tissue of rats by treatment with nicotine, and this increase in superoxide anion production could be inhibited by tempol. Our findings suggest that acute exposure to nicotine impairs nNOS-dependent dilatation of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide anion. 相似文献
16.
Gao X Zhang H Belmadani S Wu J Xu X Elford H Potter BJ Zhang C 《American journal of physiology. Heart and circulatory physiology》2008,295(6):H2242-H2249
We hypothesized that neutralization of TNF-alpha at the time of reperfusion exerts a salubrious role on endothelial function and reduces the production of reactive oxygen species. We employed a mouse model of myocardial ischemia-reperfusion (I/R, 30 min/90 min) and administered TNF-alpha neutralizing antibodies at the time of reperfusion. I/R elevated TNF-alpha expression (mRNA and protein), whereas administration of anti-TNF-alpha before reperfusion attenuated TNF-alpha expression. We detected TNF-alpha expression in vascular smooth muscle cells, mast cells, and macrophages, but not in the endothelial cells. I/R induced endothelial dysfunction and superoxide production. Administration of anti-TNF-alpha at the onset of reperfusion partially restored nitric oxide-mediated coronary arteriolar dilation and reduced superoxide production. I/R increased the activity of NAD(P)H oxidase and of xanthine oxidase and enhanced the formation of nitrotyrosine residues in untreated mice compared with shams. Administration of anti-TNF-alpha before reperfusion blocked the increase in activity of these enzymes. Inhibition of xanthine oxidase (allopurinol) or NAD(P)H oxidase (apocynin) improved endothelium-dependent dilation and reduced superoxide production in isolated coronary arterioles following I/R. Interestingly, I/R enhanced superoxide generation and reduced endothelial function in neutropenic animals and in mice treated with a neutrophil NAD(P)H oxidase inhibitor, indicating that the effects of TNF-alpha are not through neutrophil activation. We conclude that myocardial ischemia initiates TNF-alpha expression, which induces vascular oxidative stress, independent of neutrophil activation, and leads to coronary endothelial dysfunction. 相似文献
17.
Kryvko IuIa Kozyts'kyĭ ZIa Serhiienko OO Kuchmerovs'ka TM Velykyĭ MM 《Ukrainski? biokhimicheski? zhurnal》2001,73(5):69-74
The increase of sorbitol and fructose levels caused by aldose reductase activation and sorbitol dehydrogenase inhibition were observed in sciatic nerve of streptozotocin-diabetic rats. Elevated polyol pathway activity has been implicated in the development of diabetic complications such as neuropathy. The regulation of polyol pathway enzymes is based on the changes of redox state of free nicotinamide nucleotides. The decrease of the NADP+/NADPH ratio in cytosolic compartment of sciatic nerve cells activated aldose reductase and the decrease of the NAD+/NADH ratio inhibited sorbitol dehydrogenase. Nicotinamide as a precursor of NAD+ biosynthesis increased the free NADP+/NADPH and NAD+/NADH ratios and inhibited the activity of polyol pathway. The sorbitol level decreased in sciatic nerve of nicotinamide-treated streptozotocin-diabetic rats as compared to non-treated ones. Thus, the data provide evidence for important role of nicotinamide, as an antidiabetic drug, in prevention or correction of diabetic neuropathy. 相似文献
18.
Homocysteine stimulates NADPH oxidase-mediated superoxide production leading to endothelial dysfunction in rats 总被引:4,自引:0,他引:4
Edirimanne VE Woo CW Siow YL Pierce GN Xie JY O K 《Canadian journal of physiology and pharmacology》2007,85(12):1236-1247
Elevation of blood homocysteine (Hcy) levels (hyperhomocysteinemia) is a risk factor for cardiovascular disorders. We previously reported that oxidative stress contributed to Hcy-induced inflammatory response in vascular cells. In this study, we investigated whether NADPH oxidase was involved in Hcy-induced superoxide anion accumulation in the aorta, which leads to endothelial dysfunction during hyperhomocysteinemia. Hyperhomocysteinemia was induced in rats fed a high-methionine diet. NADPH oxidase activity and the levels of superoxide and peroxynitrite were markedly increased in aortas isolated from hyperhomocysteinemic rats. Expression of the NADPH oxidase subunit p22 phox increased significantly in these aortas. Administration of an NADPH oxidase inhibitor (apocynin) not only attenuated aortic superoxide and peroxynitrite to control levels but also restored endothelium-dependent relaxation in the aortas of hyperhomocysteinemic rats. Transfection of human endothelial cells or vascular smooth muscle cells with p22 phox siRNA to inhibit NADPH oxidase activation effectively abolished Hcy-induced superoxide anion production, thus indicating the direct involvement of NADPH oxidase in elevated superoxide generation in vascular cells. Taken together, these results suggest that Hcy-stimulated superoxide anion production in the vascular wall is mediated through the activation of NADPH oxidase, which leads to endothelial dysfunction during hyperhomocysteinemia. 相似文献
19.
Qin Fang Hong Sun Denise M Arrick William G Mayhan 《Journal of applied physiology》2006,100(2):631-636
Our goals were to determine whether chronic exposure to nicotine alters nitric oxide synthase (NOS)-dependent reactivity of cerebral (pial) arterioles and to identify a potential role for NADPH oxidase in impaired NOS-dependent responses during chronic exposure to nicotine. We measured in vivo diameter of pial arterioles to NOS-dependent (acetylcholine and ADP) and -independent (nitroglycerin) agonists in saline-treated rats and rats chronically treated with nicotine (2 mg.kg(-1).day(-1) for 2 wk via an osmotic minipump). We found that NOS-dependent, but not -independent, vasodilatation was impaired in nicotine-treated compared with saline-treated rats. In addition, the production of superoxide anion (lucigenin chemiluminescence) was increased in rats treated with nicotine compared with saline-treated rats. Furthermore, using Western blot analysis, we found that chronic exposure to nicotine increased p47phox protein in the parietal cortex. Finally, we found that apocynin (40 mg.kg(-1).day(-1)) in the drinking water to inhibit NADPH oxidase alleviated impaired NOS-dependent cerebral vasodilatation in nicotine treated rats but did not alter NOS-dependent responses in saline treated rats and did not alter NOS-independent reactivity in saline- or nicotine-treated rats. These findings suggest that chronic exposure to nicotine impairs NOS-dependent dilatation of pial arterioles by a mechanism that appears to be related to the formation of superoxide anion via activation of NADPH oxidase. 相似文献
20.
《Biotechnic & histochemistry》2013,88(7):506-515
Endothelial dysfunction develops as a result of oxidative stress and is responsible for diabetic vascular complications. We investigated the effects of selenium on endothelial dysfunction and oxidative stress in type 2 diabetic rats. Male Wistar rats were divided into five groups: controls, untreated diabetics, and diabetics treated with 180, 300, 500 mcg/kg selenium each day. Diabetes was induced by a single intraperitoneal injection of low dose streptozotocin to rats fed a high fat diet. Endothelium-dependent and -independent relaxations were measured in the thoracic aorta. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and endothelial nitric oxide synthase (eNOS) mRNA expressions were analyzed using real-time polymerase chain reaction (RT-PCR). Fasting blood glucose, lipid profile, lipid oxidation, insulin and nitric oxide were measured in blood samples. Malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase levels were measured in liver samples. RT-PCR showed that selenium reversed increased NADPH oxidase expression and decreased eNOS expression to control levels. Selenium also improved the impairment of endothelium-dependent vasorelaxation in the diabetic aorta. Selenium treatment significantly decreased blood glucose, cholesterol and triglyceride levels, and enhanced the antioxidant status in diabetic rats. Our findings suggest that selenium restores a normal metabolic profile and ameliorates vascular responses and endothelial dysfunction in diabetes by regulating antioxidant enzyme and nitric oxide release. 相似文献