Jane Goddard

Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure A Comparison of Selective and Combined Endothelin Receptor Blockade

Background—Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade. Methods and Results—We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls −4±2%, CRF −13±2%, P <0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8±23.9%, P <0.01 versus placebo) and reduced renal vascular resistance (−44.5±11.3%, P <0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls. Conclusions—ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

The Endothelin System and Its Antagonism in Chronic Kidney Disease

The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease (CVD) is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Treatments that slow the progression of CKD and improve the cardiovascular risk profile of patients with CKD are needed. The endothelins (ET) are a family of related peptides, of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both CVD and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness and more novel cardiovascular risk factors such as oxidative stress and inflammation. Through these, ET also contributes to endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In particular relation to the kidney, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET likely also is involved in progression of renal disease, and data are emerging to suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.

Role of Endothelin-1 in Clinical Hypertension 20 Years On

Hypertension is the most common risk factor worldwide for cardiovascular morbidity and mortality.1,2 Currently it is estimated that a quarter of the world’s adult population is hypertensive, and this number is projected to increase to ≈30% by 2025.1 Although, there exist a number of drug therapies for hypertension, blood pressure (BP) control to target is still only achieved in ≈30% of patients.3 Over the last 20 years, novel licensed therapies have primarily focused on the renin-angiotensin-aldosterone system. Endothelin (ET) receptor antagonism represents an innovative, but as yet only partially explored, alternative approach in the management of hypertension. A review in Hypertension 10 years ago outlined the potential role that ET-1 may play in the development of hypertension,4 as proposed by Yanagisawa et al in their original Nature article in 1988.5 This largely focused on preclinical data because, at that time, there was only 1 published study of ET receptor antagonism in patients with essential hypertension.6 There were also few data that focused on the relative benefits of selective or mixed ET blockade. Finally, the lack of longer-term data on safety and tolerability for these drugs made their place in the antihypertensive armamentarium unclear. In this review we aim to answer many of these questions and outline some of the key findings in this field from the last decade. The ET family consists of three 21-amino acid peptides (ET-1, ET-2, and ET-3) with powerful vasoconstrictor and pressor properties.7 Of the 3 peptides, ET-1 is the major vascular isoform and of most importance in the cardiovascular system.8 The gene product is the 212-amino acid prepro-ET-1. This is cleaved to big ET-1, after which an ET-converting enzyme (ECE) catalyzes the generation of the biologically active ET-1 and a C-terminal fragment. ET-1 acts by binding to …

Blood Pressure–Independent Reduction in Proteinuria and Arterial Stiffness After Acute Endothelin-A Receptor Antagonism in Chronic Kidney Disease

Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: −7±1%; P<0.001 versus placebo) and increased renal blood flow (17±4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (−26±4%; P<0.01 versus placebo) and pulse wave velocity (−5±1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (−38±3% versus 26±11%; P<0.001) and pulse wave velocity (−9±1% versus −3±1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

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

Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four–hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (−0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (−38±15 mg/mmol; P=0.0102), BP (−3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (−0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.

Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men.

The effect on systemic haemodynamics of BQ‐123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min−1 BQ‐123, each for 15 min, in a randomized, placebo‐controlled, double‐blind study. The response of forearm blood flow to brachial artery infusion of endothelin‐1 (ET‐1; 5 pmol min−1 for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre‐treatment, on separate occasions, with one of two doses of BQ‐123 (300 and 1000 nmol min−1 for 15 min) or placebo. Systemic BQ‐123 dose‐dependently decreased systemic vascular resistance (P<0.01 for all doses vs placebo) and mean arterial pressure (P<0.05 for 300 nmol min−1 and P<0.01 for 1000 and 3000 nmol min−1) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ‐123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min−1. Intra‐brachial ET‐1 infusion, after pre‐treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre‐treatment with BQ‐123 at 300 nmol min−1 and abolished by BQ‐123 at 1000 nmol min−1 (P<0.01 vs placebo). These effects occurred at concentrations of BQ‐123 in the plasma (510±64 nmol l−1) that were ETA receptor selective, and were not accompanied by an increase in plasma ET‐1 that would have indicated ETB receptor blockade. We conclude that ETA‐mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.

Blood pressure and not uraemia is the major determinant of arterial stiffness and endothelial dysfunction in patients with chronic kidney disease and minimal co-morbidity

INTRODUCTION Patients with chronic kidney disease (CKD) have increased risk of cardiovascular disease to which co-morbidity and associated conventional risk factors contribute. We hypothesised that arterial stiffness (AS) and endothelial dysfunction (ED), as surrogates of cardiovascular risk, would worsen as renal function declined even in patients without co-morbidity and that this would relate to emerging cardiovascular risk factors. METHODS Carotid-femoral pulse wave velocity (PWV), as a measure of AS, and flow-mediated dilatation (FMD) of the brachial artery, as a measure of ED, were assessed in CKD patients without established cardiovascular disease or diabetes mellitus. RESULTS PWV increased linearly as renal function declined (r(2) = 0.08, p < 0.01) whereas FMD was reduced only in patients with advanced kidney disease. In multivariable analysis, blood pressure was the major determinant of PWV and FMD. High-sensitivity C-reactive protein and asymmetric dimethylarginine, and isoprostanes and endothelin-1, were independent predictors of PWV and FMD, respectively. However, renal function did not independently predict either AS or ED. CONCLUSIONS These findings suggest that declining renal function, in the absence of significant co-morbidity, is associated with progressive arterial stiffness, but only patients close to dialysis exhibit endothelial dysfunction. Whilst blood pressure remains the major determinant of PWV and FMD, inflammation, oxidative stress and endothelin-nitric oxide balance contribute to cardiovascular risk, in this non-comorbid cohort.

Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve +/- SEM; BQ-123, -2.3 +/- 1.8%; BQ-123+E, -5.1 +/- 1.1%; P < 0.05 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, -0.1 +/- 2.4%; BQ-123+E, 10.9 +/- 4.2%; P < 0.01 versus BQ-123), reduced effective renal vascular resistance (BQ-123, -1.2 +/- 3.1%; BQ-123+E, -12.8 +/- 3.0%; P < 0.01 versus placebo and versus BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 +/- 12.8%; BQ-123+E, 25.2 +/- 12.6%; P < 0.05 versus BQ-123, P < 0.01 versus placebo and versus E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptor-mediated, NO-dependent, COX-independent mechanism. The reduction of BP and renal vascular resistance and associated substantial natriuresis make this a potentially attractive therapeutic combination in renal disease.

Plasma endothelin concentrations in hypertension.

The endothelins comprise a family of potent vasoconstricting peptides. Endothelin-1 appears to be the predominant isoform produced by the vascular endothelium, acting mainly in a paracrine fashion on vascular smooth muscle cells to cause vasoconstriction. It also has a range of other local actions--in the kidney, in the nervous system and on other hormone systems--that could, potentially, play a part in the genesis of hypertension. The association of raised plasma endothelin concentrations in human hypertension has caused much interest, but the literature is not consistent. Given the generally low plasma concentration of the endothelins, and their mainly paracrine actions, it remains unclear whether plasma endothelin has a functional role in hypertension. Additionally, problems remain with the measurement of plasma endothelin that raise doubts about the validity of conclusions drawn from these measurements.