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

Elmarakby, Ahmed A.; Loomis, E. Dabbs; Pollock, Jennifer S.; Pollock, David M.

doi:10.1161/01.hyp.0000153051.56460.6a

Cited by 116 publications

(101 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, deletion of ecSOD results in oxidative stress and hypertension, whereas gene transfer to SHRs ameliorates hypertension. We and others also observed that tempol fails to "treat hypertension" (61,358), although it has multiple beneficial effects, including reduction of oxidative stress, improvement in insulin sensitivity, reduction of myocardial remodeling, etc. This illustrates the complex relation between oxidative stress and hypertension and requires further clarification through studies.…”

Section: Pathologic Role Of Ros In Hypertensionmentioning

confidence: 83%

Redox Control of Renal Function and Hypertension

Nistala

Whaley‐Connell

Sowers

2008

Antioxidants & Redox Signaling

139

123

View full text Add to dashboard Cite

Section: Pathologic Role Of Ros In Hypertensionmentioning

confidence: 83%

Redox Control of Renal Function and Hypertension

Nistala

Whaley‐Connell

Sowers

2008

Antioxidants & Redox Signaling

139

123

View full text Add to dashboard Cite

“…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

“…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%

“…Elmarakby et al have recently demonstrated that apocynin inhibits the increase in oxidative stress associated with chronic ET-1 infusion, yet the resulting hypertension was unaffected. 52 …”

Section: Et B Receptors In Hypertensionmentioning

confidence: 99%

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

Self Cite

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

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

Cited by 116 publications

References 31 publications

Redox Control of Renal Function and Hypertension

Redox Control of Renal Function and Hypertension

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