Role of Endothelin-1 in Clinical Hypertension

Dhaun, Neeraj; Goddard, Jane; Kohan, Donald E.; Pollock, David M.; Schiffrin, Ernesto L.; Webb, David J.

doi:10.1161/hypertensionaha.108.117366

Cited by 153 publications

(107 citation statements)

References 116 publications

(110 reference statements)

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“…Moreover, our data suggest that the renal medullary ET B receptors may be a potential target for treatment of hypertension. Thus far, clinical studies utilizing ET-1 receptor blockers have shown little effect on blood pressure in hypertensive patients (22); however, the early ET-1 receptor blockers used were either combined ET A / ET B blockers or were ET A blockers, which lacked in vivo specificity (4). Because of the natriuretic and antihypertensive properties of ET B receptors, blockade of ET B receptors in these studies may have counteracted any beneficial effects of ET A receptor blockade.…”

Section: Perspectives and Significancementioning

confidence: 99%

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Speed

LaMarca

Berry

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ETB receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl saltresistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na ϩ intake (17.8 Ϯ 4 pg/day vs. 112 Ϯ 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na ϩ intake (13 Ϯ 2 pg/day vs. 29.8 Ϯ 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na ϩ diet was also significantly lower than DR rats on a high-Na ϩ diet (31 Ϯ 2.8 pg/mg vs. 70.9 Ϯ 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ET B receptor expression compared with DR rats while on a high-Na ϩ diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat.kidney; blood pressure; hypertension ENDOTHELIN-1 (ET-1) WAS FIRST characterized in 1988 as a potent vasoconstrictor released by endothelial cells (26). Two receptor subtypes have been since identified, ET A and ET B (24). Both of these receptors are located in the kidney with the highest concentration of ET B receptors existing within the medulla (11). Although the role of ET A receptors has been well characterized in the pathophysiology of experimental hypertension, the physiological importance of ET B receptors in modulating sodium excretion and blood pressure regulation in salt-sensitive hypertension is unclear. ET B activation inhibits sodium transport (15,18,19), and growing evidence suggests a critical role for the renal medullary endothelin system in the integrated response to a high-salt diet (6, 20 -21). For example, Pollock and others (4)have shown that renal ET-1 production is enhanced in response to 1 wk of a high-sodium diet, and intramedullary blockade of ET B receptors for 7 days leads to salt-sensitive hypertension. In addition, specific knockout of the ET B receptor gene and the ET-1 gene in the medullary collecting duct produces salt-sensitive hypertension (1, 6).Although there is growing evidence from a number of laboratories that the renal endothelin system via ET B receptor activation plays an important role in modulating renal pressure natriuresis and blood pressure regulation, very little is known about potential abnormalities in renal endothelin system in models of salt-sensitive hypertension. Our laboratory and others have reported that there is a rightward shift in the pressure natriuresis relationship in Dahl salt-sensitive r...

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Section: Perspectives and Significancementioning

confidence: 99%

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Speed

LaMarca

Berry

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The actions of endothelin-1 are mediated by two G-protein coupled receptors, the ET A and ET B endothelin receptors, which are expressed in smooth muscle and in the endothelial cells of the vasculature. 63 Three endothelin receptor antagonists are approved and clinically used for the treatment of pulmonary arterial hypertension: bosentan, sitaxentan and ambrisentan. 64 Recent clinical data for another endothelin antagonist, darusentan, which is developed by Gilead Sciences (Foster City, CA, USA), also establishes the use of this class of compounds for the treatment of hypertension.…”

Section: Next Generation Arbs That Block Endothelin Receptorsmentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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Angiotensin receptor blockers (ARBs) are well-tolerated drugs that are known to be useful for inhibiting activity of the reninangiotensin (RAS) system, treating hypertension and reducing the risk for cardiovascular disease. However, inhibition of the RAS does not control all pathophysiological mechanisms of hypertension or cardiovascular risk and many patients continue to suffer from cardiovascular events and metabolic disturbances despite being treated with an ARB, an angiotensin-converting enzyme inhibitor or both, in addition to other standard therapies for cardiovascular disease. Recently, it has become apparent that bifunctional molecules can be designed that do more than just block AT 1 receptors and that can target additional mechanisms of hypertension, cardiovascular disease and diabetes besides just increased activity of the renin-angiotensin system. Specifically, next generation ARBs are becoming available that are intended to not only antagonize AT 1 receptors, but also block endothelin receptors, function as nitric oxide donors, inhibit neprilysin activity and increase natriuretic peptide levels, or stimulate the peroxisome proliferator-activated receptor c (PPARc). In this review, we: (1) discuss the potential importance of multifunctional ARBs that can reduce cardiovascular and metabolic risk through multiple mechanisms that go beyond just inhibition of the renin-angiotensin system and (2) describe specific examples of next generation ARBs in development that are intended to do more than simply block AT 1 receptors.

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“…[5][6][7] Furthermore, circulating and renal ET-1 increases in patients with renal dysfunction and renal ischemia, and activation of ET-A receptors promotes short-and long-term ischemic renal injury. 8,9 Using a well established swine model of chronic RVD, we recently showed that the ET-1/ET-A pathway is upregulated in RVD both systemically and in the stenotic kidney and that chronic ET-A blockade in experimental RVD improves renal function, decreases renal damage, and protects the renal microvasculature of the stenotic kidney. 10,11 These studies showed the role of the ET-1/ET-A pathways in the development and the progression of renal injury in RVD.…”

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confidence: 99%

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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Percutaneous transluminal renal angioplasty/stenting (PTRAS) is frequently used to treat renal artery stenosis and renovascular disease (RVD); however, renal function is restored in less than one half of the cases. This study was designed to test a novel intervention that could refine PTRAS and enhance renal recovery in RVD. Renal function was quantified in pigs after 6 weeks of chronic RVD (induced by unilateral renal artery stenosis), established renal damage, and hypertension. Pigs with RVD then underwent PTRAS and were randomized into three groups: placebo (RVD+PTRAS), chronic endothelin-A receptor (ET-A) blockade (RVD+PTRAS+ET-A), and chronic dual ET-A/B blockade (RVD+PTRAS+ET-A/B) for 4 weeks. Renal function was again evaluated after treatments, and then, ex vivo studies were performed on the stented kidney. PTRAS resolved renal stenosis, attenuated hypertension, and improved renal function but did not resolve renal microvascular rarefaction, remodeling, or renal fibrosis. ET-A blocker therapy after PTRAS significantly improved hypertension, microvascular rarefaction, and renal injury and led to greater recovery of renal function. Conversely, combined ET-A/B blockade therapy blunted the therapeutic effects of PTRAS alone or PTRAS followed by ET-A blockade. These data suggest that ET-A receptor blockade therapy could serve as a coadjuvant intervention to enhance the outcomes of PTRAS in RVD. These results also suggest that ET-B receptors are important for renal function in RVD and may contribute to recovery after PTRAS. Using clinically available compounds and techniques, our results could contribute to both refinement and design of new therapeutic strategies in chronic RVD. Chronic renovascular disease (RVD) increases the risk of cardiovascular morbidity and mortality and may progressively induce renal injury, leading to ESRD. 1 Percutaneous transluminal renal angioplasty/stenting (PTRAS) is a frequently used therapeutic strategy to treat patients with chronic RVD. Targeting the renal stenosis is a logical choice for treating RVD, because the resolution of the vascular obstruction followed by restoration of blood flow to the site of injured tissues should play an important role to initiate successful repairing responses. The use of PTRAS in RVD grew significantly during the past 20 years, 2 with tremendous progress in successfully resolving renal stenosis and restoring blood flow (.95% of the cases). 3 However, despite the high technical success of PTRAS, improvement in renal function is still observed in a relatively small portion of the cases. 4 The reasons for the persistent poor outcomes after PTRAS in RVD are still unclear. Furthermore, the dissociation between the technical success of PTRAS and renal outcomes underscores a pressing need to identify more effective therapeutic strategies in RVD.Endothelin-1 (ET-1) is a powerful renal vasoconstrictor and mitogenic peptide that plays important roles in controlling BP and renal function.

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Role of Endothelin-1 in Clinical Hypertension

Cited by 153 publications

References 116 publications

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Next generation multifunctional angiotensin receptor blockers

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

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