Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats

Nassar, Taher; Kadery, Bashir; Lotan, Chaim; Da’as, Nael; Kleinman, Yosef; Haj‐Yehia, Abdullah

doi:10.1016/s0014-2999(01)01566-7

Cited by 85 publications

(55 citation statements)

References 38 publications

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“…The ability of tempol to restore endothelial function during hyperglycemia observed in the current investigation supports the results of a previous study in which a superoxide dismutase mimetic enhanced the vasodilator responsiveness of isolated aortic rings harvested from diabetic rats (30). Thus the current and previous studies strongly implicate a role for ROS in endothelial dysfunction during acute and chronic hyperglycemia.…”

Section: Discussionsupporting

confidence: 91%

“…Dogs were randomly assigned to receive 0.9% saline (vehicle; n ϭ 6) or the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol; 100 mg/kg in 0.9% saline over 15 min; Sigma, St. Louis, MO; n ϭ 6). Hemodynamics were acquired under steady-state conditions after vehicle or tempol pretreatment and during acetylcholine infusions (10,30, and 100 ng/kg) (27). Tissue samples were removed with a biopsy needle (Bard, Billerica, MA) during each intervention from the left circumflex coronary artery perfusion territory for measurement of ROS.…”

Section: Methodsmentioning

confidence: 99%

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Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Gross

LaDisa

Weihrauch³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia. Am J Physiol Heart Circ Physiol 284: H1552-H1559, 2003. First published January 23, 2003 10.1152/ajpheart.01013. 2002-Hyperglycemia is associated with generation of reactive oxygen species (ROS), and this action may contribute to accelerated atherogenesis. We tested the hypothesis that hyperglycemia produces alterations in left anterior descending coronary artery (LAD) wall shear stress concomitant with endothelial dysfunction and ROS production in dogs (n ϭ 12) instrumented for measurement of LAD blood flow, velocity, and diameter. Dogs were randomly assigned to receive vehicle (0.9% saline) or the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) and were administered intravenous infusions of D-glucose to achieve target blood glucose concentrations of 350 and 600 mg/dl (moderate and severe hyperglycemia, respectively). Endothelial function and ROS generation were assessed by coronary blood flow responses to acetylcholine (10, 30, and 100 ng/kg) and dihydroethidium fluorescence of myocardial biopsies, respectively. Indexes of wall shear stress were calculated with conventional fluid dynamics theory. Hyperglycemia produced dose-related endothelial dysfunction, increases in ROS production, and reductions in oscillatory shear stress that were normalized by tempol. The results suggest a direct association between hyperglycemia-induced ROS production, endothelial dysfunction, and decreases in oscillatory shear stress in vivo. coronary artery disease; diabetes; oscillatory shear stress; oxidant stress REACTIVE OXYGEN SPECIES (ROS) have been implicated in the pathogenesis of cardiovascular disease during diabetes mellitus and hyperglycemia. Several potential mechanisms have been identified that may account for increases in ROS generation during hyperglycemia including glucose autooxidation (2), mitochondrial superoxide anion overproduction by the electron transport chain (32), depletion of tetrahydrobiopterin (34), and synthesis of advanced glycation end-products (36). Hyperglycemia inhibits endothelium-dependent coronary vasodilation through oxidant-sensitive mechanisms (20,21,38). A disproportionate increase in superoxide anion compared with nitric oxide (NO) concentrations occurs during hyperglycemia that may account for endothelial dysfunction by altering the balance of oxidant stress (2,5,6), and this effect is attenuated by free radical scavengers that indirectly increase the availability of NO (2,29,35,38).Hyperglycemia has also been shown to adversely alter vascular fluid dynamics. An inverse relation between fasting blood glucose concentrations and wall shear stress has been observed in patients with diabetes compared with age-matched controls (15, 16), and endothelium-derived relaxing factors including NO are modulated by wall shear stress in a frequency-and amplitude-dependent manner (11,12). Regions of the arterial vasculature that are chronically exposed to low-ma...

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Gross

LaDisa

Weihrauch³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…Because the water intake of diabetic rats is markedly increased, they received approximately 120 mg/kg/day tempol, which is higher than that used in most other studies, e.g., Sedeek et al (2003) used tempol at approximately 30 mg/kg/day and showed that it reduced urinary excretion of isoprostanes in both control and endothelin-treated rats. The dose that we used is comparable with that used by Nassar et al (2002) who reported that tempol treatment abolished the increase in vascular superoxide and isoprostane formation in diabetic rats. The second group of diabetic rats and the control group received no treatment.…”

Section: Methodsmentioning

confidence: 69%

Effect of Tempol on Renal Cyclooxygenase Expression and Activity in Experimental Diabetes in the Rat

Chen²,

Quilley³

2005

J Pharmacol Exp Ther

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Renal cyclooxygenase (COX)-2 expression is increased in the streptozotocin (STZ)-diabetic rat and is associated with enhanced renal prostaglandin release in response to arachidonic acid (AA). Endoperoxide-mediated vasoconstrictor responses to AA were also enhanced in the diabetic rat kidney. Because oxidative stress is increased in diabetes and has been shown to induce COX-2, we assessed its contribution to prostaglandin release by treating diabetic rats with tempol (120 mg/kg/day) for 28 days. Release of AA-stimulated prostaglandins PGE 2 and 6-ketoPGF 1␣ from the isolated perfused kidney was used as an index of COX activity, and Western analysis was used to determine COX-2 protein expression. In untreated diabetic rats, the release of prostaglandins in response to AA was markedly enhanced; the increase in release of both 6-ketoPGF 1␣ and PGE 2 after AA was twice that in control rats. Renal cortical COX-2 expression in diabetic rats was 3-fold that of control rats. Tempol treatment reduced the AA-stimulated release of prostaglandins to levels seen in control rats; this was associated with reduced expression of COX-2 protein to levels not different from that in control rats. However, the enhanced vasoconstrictor response to AA in diabetic rats was unaffected by tempol treatment but abolished by inhibition of COX-1 with SC58560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole]. The addition of tempol to the perfusate of kidneys from diabetic and control rats had only a slight effect on prostaglandin release. We conclude that oxidative stress is an integral component of the mechanism involved in the induction of renal COX-2 in diabetes.

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“…[14,15] Furthermore, antioxidant therapy is renoprotective in experimental nephropathy, [16,17] and tempol (a superoxide dismutase mimetic) reduces vascular injury and exhibits renal protection in diabetic rats. [17] Therefore, we also examined the effects of concomitant antioxidant therapy with tempol on renal injury induced by caffeine.…”

Section: Introductionmentioning

confidence: 99%

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

et al. 2007

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Our previous studies indicate that prolonged caffeine consumption exacerbates renal failure in nephropathy associated with the metabolic syndrome. Reduced activity of the antioxidant defense system and beneficial effects of antioxidant therapy have been reported in diabetic rats and humans. The purpose of this study was to examine the early renal effects of caffeine consumption and the effects of concomitant antioxidant therapy in young obese, diabetic ZSF1 rats. Eleven-week-old male ZSF1 rats were randomized to drink tap water, caffeine (0.1%), tempol (1 mmol/ L), or a solution containing caffeine and tempol for nine weeks. Caffeine significantly reduced body weight and glycosuria (weeks 2-9), improved glucose tolerance (week 9), had no effect on elevated plasma triglycerides, plasma cholesterol (week 9) and blood pressure (week 9), and significantly increased plasma cholesterol level (weeks 5 and 9). Yet, as early as after two weeks, caffeine greatly augmented proteinuria and increased renal vascular resistance (RVR) and heart rate (HR: week 9). Tempol had no effects on metabolic status and development of proteinuria, did not alter caffeine-induced metabolic changes and early proteinuria, and attenuated caffeine-induced increase in HR and RVR. Immunohistochemical analysis revealed significant glomerular and interstitial inflammation, proliferation, and fibrosis in control animals. Caffeine augmented the influx of glomerular and interstitial macrophages (ED1+ cells) influx, glomerular and tubular proliferative response, and glomerular collagen IV content. Tempol abolished the exacerbation of renal inflammation, proliferation, and fibrosis induced by caffeine. In conclusion, in nephropathy associated with the metabolic syndrome, caffeine-most likely through the interaction with adenosine receptors and interference with anti-inflammatory and/or glomerular hemodynamic effects of adenosine-augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. Tempol does not prevent early renal injury (i.e., proteinuria) induced by caffeine, yet abolishes late renal inflammatory, proliferative, and fibrotic change induced by chronic caffeine consumption in obese ZSF1 rats.

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Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats

Cited by 85 publications

References 38 publications

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Effect of Tempol on Renal Cyclooxygenase Expression and Activity in Experimental Diabetes in the Rat

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

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Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats

Cited by 85 publications

References 38 publications

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Effect of Tempol on Renal Cyclooxygenase Expression and Activity in Experimental Diabetes in the Rat

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF1Rats

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Product

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Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats