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.

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 Ϫ4Ϯ2%, CRF Ϫ13Ϯ2%, PϽ0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8Ϯ23.9%, PϽ0.01 versus placebo) and reduced renal vascular resistance (Ϫ44.5Ϯ11.3%, PϽ0.01 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.

Abstract-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.

H ypertension 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 Ϸ30% by 2025. 1 Although, there exist a number of drug therapies for hypertension, blood pressure (BP) control to target is still only achieved in Ϸ30% 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. Biology of the ET SystemThe 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 ETconverting enzyme (ECE) catalyzes the generation of the biologically active ET-1 and a C-terminal fragment.ET-1 acts by binding to 2 distinct receptors, the ET A and the ET B receptors (ET A R and ET B R). 9,10 ET receptors are expressed by a wide variety of cells and tissues. Within the vasculature, ET A R and ET B R, located on vascular smooth muscle cells, mediate the vasoconstrictor effects of ET B Rs are also found on vascular endothelial cells, where their activation results in vasodilation mediated mainly by NO. 12,13 In addition, ET B Rs have a major role in the clearance of circulating ET-1. The plasma half-life of ET-1 in health is Ϸ1 minute, 14 with removal through receptor-and nonreceptormediated mechanisms. ET-1 binds to ET B R, with subsequent ligand-receptor complex internalization and intracellular degradation accounting for the majority of clearance, particularly in the pulmonary circulation, 15 although the splanchnic and renal circulations also contribute. 16 Therefore, a reduction in ET B R number, or ET B R blockade, may reduce ET-1 clearance, increasing plasma concentrations without altering production. For this reason and, importantly, because most ET-1 is released albuminally, plasma concentrations of ET-1 do not accurately reflect ET-1 productio...

1 The eect 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 71 BQ-123, each for 15 min, in a randomized, placebocontrolled, double-blind study. The response of forearm blood¯ow to brachial artery infusion of endothelin-1 (ET-1; 5 pmol min 71 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 71 for 15 min) or placebo. 2 Systemic BQ-123 dose-dependently decreased systemic vascular resistance (P50.01 for all doses vs placebo) and mean arterial pressure (P50.05 for 300 nmol min 71 and P50.01 for 1000 and 3000 nmol min 71) 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 eect at 1000 nmol min 71.3 Intra-brachial ET-1 infusion, after pre-treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic eects. This vasoconstriction was attenuated by pretreatment with BQ-123 at 300 nmol min 71 and abolished by BQ-123 at 1000 nmol min 71 (P50.01 vs placebo). 4 These eects occurred at concentrations of BQ-123 in the plasma (510+64 nmol l 71) that were ETA receptor selective, and were not accompanied by an increase in plasma ET-1 that would have indicated ETB receptor blockade. 5 We conclude that ETA-mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.

Abstract-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. Key Words: endothelin Ⅲ blood pressure Ⅲ arterial stiffness Ⅲ proteinuria Ⅲ chronic kidney disease C hronic kidney disease (CKD) is common, affecting 6% to 11% of the population in the developed world. 1 Hypertension is a frequent finding in patients with CKD, 2 and its prevalence increases as CKD progresses. 3 Despite treatment with multiple antihypertensive agents, the majority of CKD patients fail to reach target blood pressure (BP). 4 Proteinuria is a common feature of CKD and is independently associated with an adverse renal outcome. 5 Current treatments for proteinuria focus on BP reduction, 5 ideally using angiotensin-converting enzyme (ACE) inhibitors 6 and angiotensin receptor blockers, 7 both of which are thought to reduce proteinuria to a greater extent than accounted for by BPlowering alone. 5 Nevertheless, many CKD patients have significant residual proteinuria despite optimal treatment. 8 CKD is also strongly associated with incident cardiovascular disease (CVD). 9 Hypertension 10 and proteinuria 11 make an important contribution to CVD risk in CKD, as do arterial stiffness 12 and endothelial dysfunction. 13 Thus, there remains an unmet need for newer treatments in CKD that will not only lower BP and proteinuria beyond the levels achieved with standard therapies but will also have favorable effects on arterial stiffness and endothelial dysfunction and so offer longer term cardiovascular and renal protection.Endothelin (ET) 1 is the most potent endogenous vasoconstrictor produced within the vasculature. It is implicated in both the development and progression of CKD. 14 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. 14 However, there are currently few human studies. 15,16 ET-1 also contributes to arterial stiffness 17 and endothelial dysfunction 18 in patients with CVD; however, there are no similar studies in CKD patients.Our group has shown previously that selective ET A receptor antagonism, but not mixed ET A/B antagonism, reduces BP, increases renal blood flow, and reduces the effective filtration fraction in patients with CKD. 15 However, this was a s...

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Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations.