Role of Reactive Oxygen Species in Endothelin-Induced Hypertension

Sedeek, Mona; Llinás, María T.; Drummond, Heather A.; Fortepiani, Lourdes A.; Abram, Sean R.; Alexander, Barbara T.; Reckelhoff, Jane F.; Granger, Joey P.

doi:10.1161/01.hyp.0000084372.91932.ba

Cited by 110 publications

(98 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In support of this hypothesis, Sedeek et al recently showed that the increase in arterial pressure in response to ET-1 infusion for 9 days was attenuated by tempol. 13 Obviously, these results conflict with findings in the current study, although the reason for the difference is not clear. Sedeek et al used the same dose of ET-1; however, tempol was administered intravenously in the same minipump as with ET-1.…”

Section: Discussioncontrasting

confidence: 94%

“…9,12 In conscious rats, Sedeek et al observed that 9 days of ET-1 infusion significantly increased blood pressure that was completely abolished when rats were treated with the superoxide dismutase (SOD) mimetic, tempol. 13 In isolated carotid arteries from DOCA-salt hypertensive rats, blockade of ET A receptors and NADPH oxidase will inhibit superoxide production. 14 Furthermore, our laboratory has also shown that ET A receptor blockade can prevent the increase in blood pressure and oxidative stress in salt-sensitive ET B -deficient hypertensive rats, an example of a high-endothelin model of hypertension.…”

mentioning

confidence: 99%

See 1 more Smart Citation

NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1

et al. 2005

View full text Add to dashboard Cite

Abstract-Experiments were conducted to test the hypothesis that hypertension produced by chronic ET-1 infusion is mediated by NADPH oxidase-dependent superoxide production. Mean arterial pressure (MAP) was continuously monitored in male Sprague Dawley rats by telemetry. After baseline measurements, rats were placed on a high-salt diet (8% NaCl) and osmotic minipumps were implanted to infuse ET-1 (5 pmol/kg per minute intravenous) for 12 days. Control rats were maintained on the high-salt diet only. Separate groups of rats were also infused with ET-1 and given the superoxide dismutase mimetic, tempol (1 mmol/L), or the NADPH oxidase inhibitor, apocynin (1.5 mmol/L), in the drinking water. Infusion of ET-1 significantly increased MAP when compared with baseline values (132Ϯ3 versus 114Ϯ2 mm Hg, PϽ0.05). Neither tempol nor apocynin treatment had any effect on the increase in MAP produced by ET-1 when compared with baseline values (127Ϯ5 versus 113Ϯ2 and 130Ϯ3 versus 115Ϯ2 mm Hg, respectively). Plasma 8-isoprostane, an indicator of oxidative stress, was significantly increased in ET-1-infused rats compared with rats on a high-salt diet alone (128Ϯ33 versus 51Ϯ5 pg/mL; PϽ0.05). Both tempol and apocynin treatment significantly attenuated the ET-1-induced increase in plasma 8-isoprostane (72Ϯ10 and 61Ϯ6 pg/mL, respectively). Similarly, ET-1 infusion also significantly increased aortic superoxide production (chemiluminescence and dihydroethidium staining techniques), which was prevented by both tempol and apocynin. These data provide evidence that chronic ET-1 infusion increases vascular NADPH oxidase-dependent superoxide production but does not account for chronic ET-1-induced hypertension. Key Words: endothelin Ⅲ oxidative stress Ⅲ sodium E ndothelin-1 (ET-1) is a potent vasoconstrictor peptide that can produce vasoconstriction primarily through ET A receptor activation. 1 Salt-dependent models of hypertension such as DOCA-salt rats 2,3 and chronic angiotensin II-infused rats 4 display a high level of ET-1 mRNA and peptide expression. Furthermore, ET A receptor antagonists attenuated the increase in blood pressure in these models, suggesting an important role of ET-1 in the pathogenesis of salt-dependent hypertension. 2,5,6 Additionally, ET-1 is believed to contribute to hypertension in the black population that is known to be predominantly salt-sensitive. 7,8 Considerable recent attention has been paid to the possibility that ET-induced vasoconstriction may be dependent, at least in part, on the production of superoxide anion. 9 -11 In cultured pulmonary artery smooth muscle cells, Wedgwood et al have shown that exposure to ET-1 significantly increases superoxide production, and this effect can be blocked by pre-incubation with the ET A receptor antagonist PD-156707. 11 Additionally, exogenously applied ET-1 can stimulate superoxide anion formation in rat aortic rings. 9,12 In conscious rats, Sedeek et al observed that 9 days of ET-1 infusion significantly increased blood pressure that was completely abolished when ...

show abstract

Section: Discussioncontrasting

confidence: 94%

mentioning

confidence: 99%

NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1

et al. 2005

View full text Add to dashboard Cite

show abstract

“…32 In vitro studies 33 suggest that the increase in reduced nicotinamide-adenine dinucleotide phosphate oxidase activity is ET A mediated and, hence, may be increased when plasma ET-1 levels are raised. However, whether superoxide contributes significantly to BP in models of exogenous 34,35 or endogenous 32,36 elevation of ET-1 remains controversial. Our experiments confirm the results of previous transgenic studies demonstrating that an isolated increase in plasma ET-1 does not result in hypertension in young mice.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Endothelial Cell Endothelin B Receptors Does Not Affect Blood Pressure or Sensitivity to Salt

et al. 2006

View full text Add to dashboard Cite

Abstract-Endothelin B receptors in different tissues regulate diverse physiological responses including vasoconstriction, vasodilatation, clearance of endothelin-1, and renal tubular sodium reabsorption. To examine the role of endothelial cell endothelin B receptors in these processes, we generated endothelial cell-specific endothelin B receptor knockout mice using a Cre-loxP approach. We have demonstrated loss of endothelial cell endothelin B receptor expression and function and preservation of nonendothelial endothelin B receptor-mediated responses through binding and functional assays. Ablation of endothelin B receptors exclusively from endothelial cells produces endothelial dysfunction in the absence of hypertension, with evidence of decreased endogenous release of NO and increased plasma endothelin-1. In contrast to models of total endothelin B receptor ablation, the blood pressure response to a high-salt diet is unchanged in endothelial cell-specific endothelin B receptor knockouts compared with control floxed mice. These findings suggest that the endothelial cell endothelin B receptor mediates a tonic vasodilator effect and that nonendothelial cell endothelin B receptors are important for the regulation of blood pressure. Key Words: endothelin Ⅲ mice Ⅲ endothelium Ⅲ receptors, endothelin Ⅲ vasodilation E ndothelin-1 (ET-1) was initially described as a potent vasoconstrictor and potential mediator of hypertension. 1,2 More recently, attention has focused on how ET-1 generated within the kidney may promote natriuresis and diuresis 3 and thus contribute to a lowering of blood pressure (BP). ET-1 acts through 2 types of receptors, endothelin receptor type A (ET A ) and endothelin receptor type B (ET B ). 4,5 Activation of ET A and ET B on vascular smooth muscle cells results in vasoconstriction. 6 In contrast, vascular endothelial cells (ECs) exclusively express the ET B subtype and mediate vasodilatation. 7 ET B has been proposed as the target receptor through which collecting duct (CD)-derived ET-1 regulates natriuresis and diuresis. 3,8,9 However, ET B may also influence BP through regulation of peripheral vascular tone, 6,7 renal hemodynamics, 10,11 and clearance of circulating ET-1. 12 The autocrine/paracrine nature of ET-1 signaling, the close interdependence between renal tubular function and intrarenal blood flow, and the modulation of peripheral vascular tone by ET-1 have made the precise mechanisms by which ET B on different cell types contribute to the regulation of BP and natriuresis difficult to define, although EC ET B may be central to each of these pathways. 13 We hypothesized that CD-derived ET-1 acted in a paracrine manner on medullary vasa recta EC ET B to regulate natriuresis 11,13 and that deletion of these receptors would result in salt-sensitive hypertension. We, thus, adopted a Cre-loxP approach that permitted specific ablation of EC ET B while preserving CD ET B expression to test this hypothesis. MethodsThe general approach to producing cell type-specific knockout (KO) of ET B throug...

show abstract

“…33,35 Sedeek et al reported that the superoxide dismutase mimetic, tempol, inhibited the development of hypertension produced by infusion of ET-1 for 9 days. 36 It is important to note that Wang and Wang were unable to observe ET-1-induced hypertension in an identical preparation, ie, the same dose of ET-1 in rats on a normal salt diet. 37 The reasons for the disparate findings are not clear.…”

Section: Et-1 and Oxidative Stressmentioning

confidence: 98%

“…51 Similarly, chronic ET-1 infusion is associated with elevations in reactive oxygen species, although reports disagree as to the extent to which oxidative stress contributes to the associated hypertension. 36,52 Whereas hypertension associated with chronic ET B receptor blockade can be inhibited by ET A receptor antagonists, evidence for a role of oxidative stress, or specifically superoxide, is not straightforward. Williams et al recently observed that the superoxide dismutase mimetic, tempol, attenuated the hypertension associated with ET B receptor blockade in rats on a high-salt diet, but only during the initial days of treatment.…”

Section: Et B Receptors In Hypertensionmentioning

confidence: 99%

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

View full text Add to dashboard Cite

E ndothelin (ET)-1 is a potent vasoconstrictor and mitogen, and because of these properties, it is thought to play a role in the development of hypertension. 1,2 The vascular endothelium is a major source of ET-1 production, although a variety of other cell types also have been shown to synthesize and release ET-1. ET-1 is believed to act in a paracrine manner on ET A and ET B receptors on smooth muscle, which mediate contraction, cell proliferation, and hypertrophy. Activation of ET B receptors on endothelial cells stimulates the production of prostacyclin and nitric oxide to induce vasorelaxation and inhibition of sodium transport in renal tubules. Given these properties, considerable attention has been paid to the mechanisms of ET-1 action as it relates to the renal control of blood pressure and the pathogenesis of salt-dependent hypertension. Renal ET synthesis is increased in experimental animals maintained on a high-salt diet and ET A receptor antagonists lower arterial pressure primarily in salt-dependent models of hypertension. 1,2 For the past 30 to 40 years, the actions of angiotensin (Ang) II has been arguably the most widely investigated factor in hypertension research. Although physiology textbooks agree on the major actions of Ang II, eg, vasoconstriction and release of aldosterone, recent attention has focused on its ability to stimulate the synthesis of ET-1, 3-5 as well as reactive oxygen species. 6 There are many reactive oxygen species such as superoxide, hydroxyl radical, and hydrogen peroxide that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Most recent attention has been paid to the role of superoxide. There are many enzymatic sources of superoxide including NADPH oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. The focus of the current review, however, is be on the interaction between the 2 peptide systems, ET-1 and Ang II, as they relate to oxidative stress. ET-1 in Ang II Hypertension ET-1 and Oxidative StressThe clinical significance of oxidative stress and its role in hypertension was recently reviewed by Touyz, 18 and so the current discussion is limited to the interaction between ET-1, Ang II, and superoxide.Studies from Ortiz et al have shown that the slow pressor response to Ang II is associated with increases in ET, as well as isoprostanes, a marker of lipid oxidation and an index of oxidative stress. 9 These effects could be prevented with bosentan, suggesting a role for ET in mediating the increase in oxidative stress in this model. They went on to demonstrate that antioxidant treatment with the superoxide dismutase mimetic, tempol, or the combination of vitamins C and E reduced Ang II-induced changes in ET expression. 14 Acute administration of tempol also has antihypertensive effects in rats chronically infused with Ang II. 15 Long-term treatment with tempol will lower arterial pressure in several models of hypertension associated with increases in ET production, including chroni...

show abstract

Role of Reactive Oxygen Species in Endothelin-Induced Hypertension

Cited by 110 publications

References 27 publications

NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1

NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1

Deletion of Endothelial Cell Endothelin B Receptors Does Not Affect Blood Pressure or Sensitivity to Salt

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Contact Info

Product

Resources

About