Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

Dhaun, Neeraj; Melville, Vanessa; Blackwell, Scott; Talwar, Dinesh; Johnston, Neil R.; Goddard, Jane; Webb, David J.

doi:10.1681/asn.2012040355

Cited by 32 publications

(20 citation statements)

References 35 publications

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“…However, we are aware that the dose selected was relatively higher than previously tested doses in patients. 42 We did not observe any adverse effects (e.g., fluid retention assessed by differences in body weight between groups after treatments) frequently observed in patients, which may have reflected species differences.…”

Section: Discussionmentioning

confidence: 49%

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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Section: Discussionmentioning

confidence: 49%

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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“…7 A few studies have examined the 24-hour variation of BP in CKD. [8][9][10] They suggest that not only is nondipping a feature of CKD but also as glomerular filtration rate declines, reverse dipping (nighttime BP readings that are higher than those during the Recently, we showed that chronic selective ET A receptor antagonism-using the orally active drug sitaxentan-reduces BP, proteinuria, and more novel cardiovascular disease (CVD) risk factors including arterial stiffness, uric acid, and asymmetrical dimethylarginine in patients with proteinuric CKD, 18,19 effects that are potentially renoprotective. Here, we present data from 3 studies: in the first, we examined the nocturnal dip in both ambulatory BP and arterial stiffness in patients with CKD and controls.…”

mentioning

confidence: 99%

“…Recently, we showed that chronic selective ET A receptor antagonism-using the orally active drug sitaxentan-reduces BP, proteinuria, and more novel cardiovascular disease (CVD) risk factors including arterial stiffness, uric acid, and asymmetrical dimethylarginine in patients with proteinuric CKD, 18,19 effects that are potentially renoprotective. Here, we present data from 3 studies: in the first, we examined the nocturnal dip in both ambulatory BP and arterial stiffness in patients with CKD and controls.…”

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confidence: 99%

Diurnal Variation in Blood Pressure and Arterial Stiffness in Chronic Kidney Disease

et al. 2014

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day) becomes more apparent. Importantly, loss of nocturnal dipping is associated with CKD progression.11 However, these studies did not explore interventions to restore BP dipping.Arterial stiffness also contributes significantly to the CVD risk in CKD. 12 Although some studies have examined daytime variations in arterial stiffness, none has included patients with CKD. 13,14 Furthermore, no study has as yet addressed ambulatory arterial stiffness and its 24-hour variation. Thus, there is a need for newer treatments in CKD that will not only lower BP beyond the levels achieved with standard therapies but also favorably affect the 24-hour profile of BP and arterial stiffness, leading to additional cardiovascular and renal protection.Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor produced within the vasculature. 15 ET-1 also promotes cardiovascular proliferation, inflammation, and fibrosis, all of which may contribute to poor outcomes. ET-1 is produced Abstract-Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, −3.2±4.8%, P<0.05; diastolic BP, −6.4±6.2%, P=0.001; pulse wave velocity, −5.8±5.2%, P<0.01) but not in 15 patients with CKD. In CKD, plasma ET-1 increased by 1.2±1.4 pg/mL from midday to midnight compared with healthy volunteers (P<0.05). Urinary ET-1 did not change. In a randomized, double-blind, 3-way crossover study in 27 patients with CKD, 6-week treatment with placebo and nifedipine did not affect nocturnal dips in systolic BP or diastolic BP between baseline and week 6, whereas dipping was increased after 6-week sitaxentan treatment (baseline versus week 6, systolic BP: −7.0±6.2 versus −11.0±7.8 mm Hg, P<0.05; diastolic BP: −6.0±3.6 versus −8.3±5.1 mm Hg, P<0.05). There was no nocturnal dip in pulse pressure at baseline in the 3 phases of the study, whereas sitaxentan was linked to the development of a nocturnal dip in pulse pressure. In CKD, activation of the ET system seems to contribute not only to raised BP but also the loss of BP dipping. The clinical significance of these findings should be explored in future clinical trials. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01770847 and NCT00810732. within the kidney and is implicated in both the development and progression of CKD. 16 The effects of ET-1 are mediated via 2 receptors, the ET A and ET B receptors, with the major pathological effects in CKD being ET A receptor mediated. 17Recen...

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“…These additional effects may, in theory, confer improved cardiovascular and renal protection. 90,116 With regard to the safety data from this study, in contrast to the effects of other ERAs in diabetic nephropathy, it is worth noting that there was no evidence of fluid retention within this cohort. Sitaxentan has been shown to have no functional effect on ET B in vivo in human beings 117 and these observations would be consistent with a role for ET B in fluid accumulation.…”

Section: Clinical Studiesmentioning

confidence: 80%

“…In patients with CKD, however, ET A activity appears increased, with a preferential effect on the efferent arteriole, raising the possibility that ET-1 promotes hyperfiltration in CKD. The vasoconstrictor effect of BQ788 in both health and disease suggests that ET B plays an important role in maintaining basal systemic 90,115,116 Sitaxentan therapy also improved markers of arterial stiffness, improved nocturnal BP dip, and reduced plasma asymmetric dimethylarginine (ADMA) and uric acid and renal vascular tone, and indicates that its blockade in CKD may have negative consequences on both systemic BP and renal blood flow. 111 A further acute study, using BQ123, in 22 patients with nondiabetic proteinuric CKD found that BQ123 caused significant reductions in BP and arterial stiffness and increased renal blood flow while causing a decrease in proteinuria of approximately 30%.…”

Section: Clinical Studiesmentioning

confidence: 99%

Endothelin in Nondiabetic Chronic Kidney Disease: Preclinical and Clinical Studies

Culshaw

MacIntyre

Dhaun

et al. 2015

Seminars in Nephrology

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Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

Cited by 32 publications

References 35 publications

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

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

Diurnal Variation in Blood Pressure and Arterial Stiffness in Chronic Kidney Disease

Endothelin in Nondiabetic Chronic Kidney Disease: Preclinical and Clinical Studies

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