Systemic arterial pressure response to two weeks of Tempol therapy in SHR: involvement of NO, the RAS, and oxidative stress

Yanes, Licy L.; Romero, Damián G.; Iliescu, Radu; Cucchiarelli, Valeria E.; Fortepiani, Lourdes A.; Santacruz, Francisco Ramírez; Bell, William C.; Zhang, Huimin; Reckelhoff, Jane F.

doi:10.1152/ajpregu.00530.2004

Cited by 55 publications

(57 citation statements)

References 31 publications

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“…Acute administration of tempol decreased MAP, which is consistent with previous reports and likely caused by tempol-induced O 2 2 inactivation increasing NO availability. [34][35][36] The finding that tempol reduces RVR is also consistent with previous findings, 34,35 which can be attributed to the direct BP-lowering effect as previously reported. 37 However, we did not detect any effect of tempol on RVR in CoCl 2 -treated rats, despite similar MAP reduction, which may indicate altered vascular regulation after chronic HIF activation.…”

Section: Discussionsupporting

confidence: 91%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

173

145

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Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetesinduced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

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Section: Discussionsupporting

confidence: 91%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

173

145

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“…These data are in accord with some previous studies using the hypertensive rat strain, the SHR, where tempol has not altered blood pressure (25). In contrast, however, some other investigators have reported a hypotensive effect of tempol administration in the SHR (47). Disparities in reports on the effect of tempol on blood pressure in the SHR may be attributable to the specific doses used, administration route, time course, and device used for blood pressure measurement.…”

Section: Ajp-renal Physiolsupporting

confidence: 89%

Simvastatin and tempol protect against endothelial dysfunction and renal injury in a model of obesity and hypertension

Knight

Yuan

Roy

et al. 2010

American Journal of Physiology-Renal Physiology

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Knight SF, Yuan J, Roy S, Imig JD. Simvastatin and tempol protect against endothelial dysfunction and renal injury in a model of obesity and hypertension. Am J Physiol Renal Physiol 298: F86 -F94, 2010. First published November 11, 2009 doi:10.1152/ajprenal.00351.2009.-Obesity and hypertension are risk factors for the development of chronic kidney disease. The mechanisms by which elevated blood pressure and fatty acids lead to the development of renal injury are incompletely understood. Here, we investigated the contributions of cholesterol and oxidative stress to renal endothelial dysfunction and glomerular injury in a model of obesity and hypertension. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were fed a normal diet, a high-fat diet, a high-fat diet with tempol, or a high-fat diet with simvastatin for up to 10 wk. Blood pressure was not altered by a high-fat diet or treatments. After 3 wk, renal afferent dilatory responses to acetylcholine were impaired in WKY rats and SHR fed a high-fat diet. Tempol treatment prevented this vascular dysfunction in both strains; however, simvastatin treatment demonstrated greater beneficial effects in the SHR. Albuminuria was observed in the SHR and was exacerbated by a high-fat diet. Tempol and simvastatin treatment significantly ameliorated albuminuria in the SHR fed a high-fat diet. Ten weeks on a high-fat resulted in an increase in urinary 8-isoprostane in WKY rats and SHR, and tempol and simvastatin treatment prevented this increase, indicating a reduction in renal oxidative stress. Monocyte chemoattractant protein-1 (MCP-1) excretion was significantly elevated by a high-fat diet in both strains, and tempol prevented this increase. Interestingly, simvastatin treatment had no effect on MCP-1 levels. These data indicate that tempol and simvastatin treatment via a reduction in oxidative stress improve renal endothelial function and decrease glomerular injury in a model of obesity and hypertension. kidney; oxidative stress; metabolic syndrome; inflammation OBESITY HAS REACHED EPIDEMIC proportions in the developed world, with 50% of the US population now classified as overweight or obese, and the numbers are rising (National Health and Nutrition Examination Survey, available at http:// www.cdc.gov/nchs/nhanes.htm). Obesity is associated with increased risk of developing diabetes, hypercholesterolemia, and hypertension, which together are described as the metabolic syndrome (18, 29). Independently, obesity and hypertension increase the risk of renal dysfunction; obese patients are four times more likely to develop renal disease than nonobese patients, and hypertension accounts for 25% of renal dysfunction cases (27). Obese patients are at a higher risk of developing hypertension, therefore combining risk factors and compounding the negative effect on cardiovascular health. In particular, renal injury associated with obesity and hypertension has been shown to be more severe than renal disease observed as a result of each risk factor alone. This addi...

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“…There is another consideration for why antioxidants may have little effect in lowering blood pressure in humans. In young male SHR, we found that, if the nitric oxide system is blocked with nitro-Larginine methyl ester, tempol can no longer reduce their blood pressure, despite the fact that oxidative stress, as measured by F 2 -isoprostane levels in the kidney, was significantly reduced (72). These data suggest that, in aging individuals who suffer endothelial dysfunction, as is common with individuals with longstanding essential hypertension, antioxidants are not able to reduce blood pressure because of the deficiency of nitric oxide, a common finding associated with endothelial dysfunction.…”

Section: Other Considerations In Human Studiesmentioning

confidence: 88%

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

Lopez‐Ruiz¹,

Sartori‐Valinotti²,

Yanes³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Lopez-Ruiz A, Sartori-Valinotti J, Yanes LL, Iliescu R, Reckelhoff JF. Sex differences in control of blood pressure: role of oxidative stress in hypertension in females. Am J Physiol Heart Circ Physiol 295: H466 -H474, 2008. First published June 20, 2007 doi:10.1152/ajpheart.01232.2007.-In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women.F 2-isoprostanes WITH THE USE OF AMBULATORY blood pressure monitoring, it is now well accepted that blood pressure is higher in men than age-matched premenopausal women, and that, following menopause, this trend reverses, such that the incidence of hypertension in postmenopausal women is similar to or higher than in men (5, 69). A comparison of the data from the National Health and Nutrition Examination Survey (NHANES) III (1988III ( -1994 with data from NHANES IV (1999 -2002) revealed that the prevalence of hypertension is currently stable in men, and their blood pressures are well controlled with medication. In contrast, in women, the incidence of hypertension is progressively increasing, and blood pressure is often higher in women than in age-matched men (35). Furthermore, blood pressure in women is not well controlled with medication, despite typically higher levels of compliance compared with men (35). These disturbing statistics suggest that mechanisms responsible for hypertension in men and women may be different, and it is imperative that physicians and scientists begin to determine what these differences are to better treat hypertension in both men and women. Oxidative Stress and Hypertension in Humans: Clinical TrialsThe role that oxidative stress plays in mediating hypertension has been the focus of a significant amount of research in recent years. Several clinical trials have be...

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Systemic arterial pressure response to two weeks of Tempol therapy in SHR: involvement of NO, the RAS, and oxidative stress

Cited by 55 publications

References 31 publications

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Simvastatin and tempol protect against endothelial dysfunction and renal injury in a model of obesity and hypertension

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

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