Endothelin B receptor-deficient mice develop endothelial dysfunction independently of salt loading

Quaschning, Thomas; Rebhan, Benjamin; Wunderlich, Christoph H.; Wanner, Christoph; Richter, Claus M; Pfab, Thiemo; Bauer, Christian; Kraemer-Guth, Annette; Galle, Jan; Yanagisawa, Masashi; Hocher, Berthold

doi:10.1097/01.hjh.0000166838.55688.7e

Cited by 25 publications

(26 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that the likely target(s) for CD-derived ET-1 in the kidney that determine the salt-sensitive phenotype are ET B located on non-EC, most likely those on inner medullary CD cells. 27 Consistent with previous reports, 26 the salt-sensitive phenotype seems to be independent of endothelial dysfunction resulting from ET B deficiency.…”

Section: Discussionsupporting

confidence: 81%

“…EC-specific inactivation of ET B results in increased plasma ET-1 concentration and impaired endothelium-dependent vasodilatation but not hypertension. In contrast to models of rescued complete ET B KO 8,26 and CD-specific ET-1 KO, 3 EC-specific KO mice do not demonstrate increased sensitivity to high-salt diets. This suggests that the likely target(s) for CD-derived ET-1 in the kidney that determine the salt-sensitive phenotype are ET B located on non-EC, most likely those on inner medullary CD cells.…”

Section: Discussionmentioning

confidence: 91%

“…After a high-salt diet, rescued ET B -deficient rats 8 and mice 26 and ET B antagonisttreated rats 9 develop grossly elevated BP compared with controls. We observed a clear relationship between salt intake and BP in our mice, with significant increases in BP observed when dietary NaCl intake exceeded Ϸ2.5%.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2006

Self Cite

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

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

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

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…Potassium influences the Ca 2ϩ handling by depolarization of the cell membrane of smooth muscle cells in the arterial wall, resulting in vasoconstriction. This simulation of arterial tone is commonly used in other studies on arterial vasoregulation (35)(36)(37). It is unlikely that the induced state of tone will bear impact on the results of insulin-mediated vasoreactivity and PKC activation because we found that insulin-mediated vasodilation is NO dependent and insulin-mediated vasoconstriction is ET-1 dependent.…”

Section: Discussionmentioning

confidence: 60%

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE—Protein kinase C (PKC) θ activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKCθ is involved. In this study, we investigated whether PKCθ activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries. RESEARCH DESIGN AND METHODS—Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02–20 nmol/l) was studied in a pressure myograph with or without PKCθ activation by palmitic acid (PA) (100 μmol/l). RESULTS—In the absence of PKCθ activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide–dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKCθ is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at Thr538 in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 ± 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKCθ. Analysis of intracellular signaling in muscle resistance arteries showed that PKCθ activation reduced insulin-mediated Akt phosphorylation (Ser473) and increased extracellular signal–related kinase (ERK) 1/2 phosphorylation. Inhibition of PKCθ restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA. CONCLUSIONS—PKCθ activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKCθ activation to insulin resistance.

show abstract

“…1 The influence of ET B receptor (ET B R) on arterial pressure (AP) regulation has been more controversial, but the bulk of evidence supports an antihypertensive function. Knockout of the ET B R gene causes salt-sensitive hypertension in rats 2 and mice, 3,4 as does chronic pharmacological blockade of ET B R in a variety of species. [5][6][7][8] One important antihypertensive mechanism associated with ET B R activation may be enhanced renal sodium and water excretion, because renal-collecting, duct-specific knockout of ET B R causes hypertension.…”

mentioning

confidence: 99%

Chronic Activation of Endothelin B Receptors

Fink

Lau

et al. 2007

Hypertension

View full text Add to dashboard Cite

Abstract-Endothelin (ET) exerts powerful pressor actions primarily through activation of the ET A receptor subtype. The ET B receptor (ET B R) subtype, on the other hand, is generally thought to initiate physiological actions that decrease arterial pressure. Such actions include clearing ET from the bloodstream, initiating endothelium-mediated vasodilation, and facilitating renal sodium and water excretion. The effect of long-term activation of the ET B R on arterial pressure, however, never has been directly tested. In this study we evaluated cardiovascular responses to chronic (5-day) activation of ET B R in male rats using continuous intravenous infusion of the selective agonist sarafotoxin 6c. Surprisingly, we found that sarafotoxin 6c caused a sustained increase in arterial pressure that rapidly reversed on termination of infusion. The hypertension was associated with increased renal excretion of sodium and water and decreased plasma volume. Alterations in daily sodium intake did not affect the magnitude of the hypertension. Hemodynamic studies revealed a decreased cardiac output and increased total peripheral resistance during sarafotoxin 6c infusion. Infusion of sarafotoxin 6c caused a small increase in plasma ET levels. Nevertheless, the hypertension was not affected by coadministration of a selective ET A receptor antagonist (atrasentan) but was completely prevented by treatment with a combined ET A receptor and ET B R antagonist (A186280). These experiments reveal for the first time that chronic activation of ET B R in rats causes sustained hypertension. (Hypertension. 2007;50:512-518.)Key Words: endothelin Ⅲ ET B receptor Ⅲ salt Ⅲ hemodynamics E ndothelins (ETs) have powerful effects on arterial blood pressure regulation and contribute to the genesis of human and experimental hypertension. 1 Most ET-mediated pressor actions result from stimulation of the ET A receptor (ET A R) found in vascular smooth muscle, kidney, heart, adrenal gland, and other tissues. 1 The influence of ET B receptor (ET B R) on arterial pressure (AP) regulation has been more controversial, but the bulk of evidence supports an antihypertensive function. Knockout of the ET B R gene causes salt-sensitive hypertension in rats 2 and mice, 3,4 as does chronic pharmacological blockade of ET B R in a variety of species. 5-8 One important antihypertensive mechanism associated with ET B R activation may be enhanced renal sodium and water excretion, because renal-collecting, duct-specific knockout of ET B R causes hypertension. 9 Other studies, however, do not support a critical role for renal ET B R in controlling AP. 2 ET B Rs on endothelial cells act as plasma ET clearance receptors, 10 and their absence or blockade produces increased plasma ET levels that can activate ET A R to cause hypertension. 6 In addition, ET B Rs located on endothelial cells promote vasodilation by releasing NO and prostanoids. Nevertheless, endothelial cell ET B Rs do not seem necessary for chronic AP regulation, because their selective deletion does not cause...

show abstract

Endothelin B receptor-deficient mice develop endothelial dysfunction independently of salt loading

Cited by 25 publications

References 36 publications

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

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

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Chronic Activation of Endothelin B Receptors

Contact Info

Product

Resources

About