A selective endothelin‐receptor antagonist to reduce blood pressure in patients with treatment‐resistant hypertension: a randomised, double‐blind, placebo‐controlled trial

State University of New York, Downstate College of Medicine, New York, NY 11203, USA.
The Lancet (Impact Factor: 45.22). 09/2009; 374(9699):1423-31. DOI: 10.1016/S0140-6736(09)61500-2
Source: PubMed

ABSTRACT Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension.
This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (>/=130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with, number NCT00330369.
All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0.0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events.
Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed.
Gilead Sciences.

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Available from: George Bakris, Apr 25, 2015
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    • "In recent years, considerable attention has been paid to the possibility of using this class of drugs for the treatment of resistant hypertension and diabetic nephropathy. The ET A -selective antagonist, darusentan, has been studied in a series of phase 2 and phase 3 clinical trials for blood pressure lowering in patients with resistant hypertension (Weber et al., 2009; Bakris et al., 2010). Ambrisentan significantly reduced ambulatory blood pressure in subjects already being treated with an average of five distinct antihypertensive medications. "
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    ABSTRACT: Experiments determined whether the combination of ETA receptor antagonist (ABT-627, atrasentan) and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome (metS) compared to either treatment alone. Male Dahl salt sensitive rats were fed a high fat (36% fat) high salt (4% NaCl) (HF/HS) diet for four weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg/day, in drinking water), chlorthalidone (CLTD; 5 mg/kg/day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, while the combination further reduced MAP compared to ABT alone. All treatments prevented the proteinuria. CLTD and ABT+CLTD significantly reduced nephrin (a podocyte injury marker) and KIM-1 (a tubulointerstitial injury marker) excretion. ABT with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine (8-OHdG), a measure of DNA oxidation, while CLTD alone had no effect. All treatments suppressed the number of ED1+ cells (macrophages) in the kidney. Plasma TNF receptor 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal protective effects in a model of metabolic syndrome that are more effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.
    Journal of Pharmacology and Experimental Therapeutics 09/2014; 351(2). DOI:10.1124/jpet.114.215566 · 3.86 Impact Factor
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    • "These latter patients, some of whom show functional polymorphism for the B2 receptor (Gainer et al., 2000), also have a marked elevation in plasma levels of endothelin-1 (Ergul et al., 1998; Ergul, 2000). Endothelin-1 (ET-1), a potent endothelial derived pressor peptide discovered by Yanagisawa and colleagues in 1988 (Yanagisawa et al., 1988), has been suggested to play a significant contribution in the aetiology of vascular diseases such as primary pulmonary hypertension (Giaid et al., 1993), scleroderma (Dhaun et al., 2007), renal hypertension (Takeda et al., 1997) and ACEI-resistant systemic hypertension (Weber et al., 2009). It is noticeable that antagonists of ETA and ETB receptors for ET-1, such as bosentan and macitentan have, up until now, only been proven clinically useful in primary pulmonary hypertension (Channick et al., 2001; Bolli et al., 2012) as "
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    ABSTRACT: Background and PurposeThe contribution of endothelin‐1 (ET‐1) in a B2KO mouse model of a high salt‐induced arterial hypertension was investigated. Experimental ApproachWild‐type (WT) or B2KO mice receiving a normal diet (ND) or a high‐salt diet (HSD) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ETA antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET‐1 by RIA. In a separate series of experiments, the ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L‐NG‐nitroarginine methyl ester (L‐NAME) in anaesthetized WT and B2KO mice. Key ResultsIn B2KO, but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure (MAP) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B2KO mice under ND. Significant increases in immunoreactive ET‐1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO compared with WT mice under ND. Finally, BQ123 (2 mg·kg−1) reduced by 50% the pressor response to L‐NAME (2 mg·kg−1) in B2KO, but not WT mice under anaesthesia. Conclusions and ImplicationsOur results support the concept that functional B2 receptors oppose high salt‐induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.
    British Journal of Pharmacology 01/2013; 170(2). · 4.99 Impact Factor
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    • "This has been clearly shown by elevated plasma levels of endothelin-1 (ET-1) [8] and plasma renin activity [9] in such subjects. More recently, endothelin receptor blockers have shown to be effective in resistant hypertensives [10]. It is now well established that increased ET-1 activity is one of the contributors for increased incidence of hypertension in diabetics with insulin resistance [11] [12] [13]. "
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    ABSTRACT: In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT(1)/ET(A) receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat.
    12/2011; 2011:751513. DOI:10.4061/2011/751513
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