Selective Endothelin-A Receptor Antagonism Reduces Proteinuria, Blood Pressure, and Arterial Stiffness in Chronic Proteinuric Kidney Disease

Dhaun, Neeraj; MacIntyre, I.; Kerr, D.; Melville, Vanessa; Johnston, Neil R.; Haughie, Scott; Goddard, Jane; Webb, David J.

doi:10.1161/hypertensionaha.110.167486

Cited by 145 publications

(118 citation statements)

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“…21 In brief, in a randomized, double-blind, three-way crossover study, 27 patients receiving recommended renoprotective treatment underwent 6 weeks of placebo; sitaxentan, 100 mg once daily; and nifedipine long-acting, 30 mg once daily. Twenty-four-hour proteinuria, urine protein-to-creatinine ratio, 24-hour ambulatory BP, and PWV (as an index of arterial stiffness) were measured at baseline, week 3, and week 6 of each treatment period.…”

Section: Concise Methodsmentioning

confidence: 99%

“…20 Its effects are mediated via two receptors, the ET A and ET B receptors; the major pathologic effects are ET A receptor mediated. 20 We have recently shown that long-term selective ET A receptor antagonist therapy using the orally active drug sitaxentan reduces proteinuria, BP, and arterial stiffness in patients with proteinuric CKD, 21 effects that are potentially renoprotective. We hypothesized that in this same cohort of patients with CKD, sitaxentan would also reduce levels of serum uric acid, ADMA, and urine ET-1 (as a measure of renal ET-1 production) and so provide broader cardiovascular and renal protection.…”

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confidence: 99%

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Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

Dhaun

Melville

Blackwell

et al. 2013

Journal of the American Society of Nephrology

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Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET A receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulsewave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET A receptor antagonism may modify risk factors for cardiovascular disease in CKD.

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Section: Concise Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

Dhaun

Melville

Blackwell

et al. 2013

Journal of the American Society of Nephrology

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“…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. More recently, sitaxsentan, a very specific ET A blocker, was shown to reduce blood pressure and proteinuria in patients with chronic kidney disease (5). Therefore, determining the importance of ET-1 in human essential hypertension deserves further investigation.…”

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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“…8 Its effects are mediated via 2 receptors, the ET-A (ET A ) and ET-B (ET B ) receptors, with the major pathological effects being ET A receptor mediated. 8 We have shown recently that chronic selective ET A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in patients with nondiabetic, hypertensive, proteinuric CKD, 9 effects that are potentially renoprotective. The current data show the effects of sitaxsentan and placebo on sUA in this same cohort of CKD patients.…”

Section: Chronic Selective Endothelin a Receptor Antagonism Reduces Smentioning

confidence: 99%

“…9 In brief, in a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, sitaxsentan 100 mg once daily and nifedipine LA 30 mg once daily. Twenty-four-hour proteinuria, urine protein:creatinine ratio, 24-hour ambulatory blood pressure, and pulse wave velocity, as an index of arterial stiffness, were measured at baseline, week 3, and week 6 of each treatment period.…”

Section: Chronic Selective Endothelin a Receptor Antagonism Reduces Smentioning

confidence: 99%