Elevated systemic levels of endothelin-1 and blood pressure correlate with blunted constrictor responses and downregulation of endothelinA, but not endothelinB, receptors in an animal model of hypertension

Télémaque-Potts, Sabine; Kuc, Rhoda E.; Maguire, Janet J.; Ohlstein, Eliot H.; Yanagisawa, Masashi; Davenport, Anthony P.

doi:10.1042/cs103s357s

Cited by 17 publications

(11 citation statements)

References 6 publications

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“…41 We have found that deletion of EC ET B from peripheral resistance vessels and from the renal vasculature does not alter BP, despite endothelial dysfunction and an increase in plasma ET-1 concentration. However, prolonged exposure to increased ET-1 may have caused downregulation or desensitization of ET A , 42 decreasing both vascular tone and BP in EC ET B KO mice. We analyzed ET A expression by quantitative autoradiography 43 and assessed functional responses to infusion of big ET-1 (1 to 10 nmol/kg) during anesthesia.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…For example, chronic elevation of ET-1 suppresses ET A , with little effect on ET B , expression (405, 766). Surface flow and NO enhance vascular smooth muscle ET A expression and affinity (614, 615).…”

Section: Endothelin and The Kidneymentioning

confidence: 99%

Regulation of Blood Pressure and Salt Homeostasis by Endothelin

Kohan

Rossi

Inscho

et al. 2011

Physiological Reviews

368

459

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Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

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“…ET A , but not ET B , receptor mRNA and protein density are downregulated in association with high levels of ET 1 in the systemic vasculature [799,800] . ET A , but not ET B , receptor mRNA and protein density are downregulated in association with high levels of ET 1 in the systemic vasculature [799,800] .…”

Section: Endothelin and Et Receptorsmentioning

confidence: 99%