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.

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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There are no published controlled clinical trials of regular phosphodiesterase type 5 inhibitor therapy as a long-term treatment of hypertension. In a randomized, double-blind, 2-way crossover study, 25 otherwise untreated hypertensive subjects were administered 50 mg of sildenafil or matched placebo 3 times daily for 16 days, and the effects on ambulatory blood pressure (BP), clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity, and brachial artery flow-mediated dilatation were assessed. Three subjects were withdrawn because of adverse effects, and the data from the remaining 22 subjects were analyzed. Sildenafil reduced ambulatory BP (mean [SE] change from baseline for average daytime BP: systolic -8 [2] mm Hg versus 2 [2] mm Hg with placebo, P<0.01; diastolic -6 [1] mm Hg versus 0 [1] mm Hg, P<0.01) and clinic BP (change from baseline to 1 hour after drug administration on day 16: systolic -5 [2] mm Hg versus 4 [2] mm Hg, P<0.01; diastolic -5 [1] mm Hg versus 2 [2] mm Hg, P<0.01). Compared with baseline, sildenafil, but not placebo, reduced arterial wave reflection both acutely and after chronic treatment, but the chronic change in arterial wave reflection was not statistically different from the chronic change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The main adverse effects of sildenafil, which were generally transient and rated as mild or moderate in severity, were dyspepsia, headache, and myalgia. In conclusion, regular sildenafil constitutes effective antihypertensive therapy. Further studies are warranted to evaluate the role of longer-acting phosphodiesterase type 5 inhibitors as antihypertensive agents in clinical practice.

Chronic kidney disease (CKD) is a serious and increasingly common condition ( 1 ). Patients with CKD have a greatly increased risk of CVD, which represents the most common cause of mortality and morbidity in these patients, to the extent that CKD is considered an independent risk factor for CVD ( 2, 3 ). In CKD, many conventional risk factors for CVD are prevalent, including hypertension, dyslipidemia, and insulin resistance. Underlying conditions that are typical of CVD also occur, such as heightened infl ammatory status, oxidative stress, endothelial dysfunction, and arterial stiffness ( 3, 4 ). Consequently, understanding the factors in CKD that could contribute to increased CVD risk is very important.In CVD there is a clearly established link between dyslipidemia (specifi cally hypercholesterolemia and hypertriglyceridemia) and atherosclerosis, an underlying pathology of most CVD ( 5, 6 ). In view of the clear cardiorenal relationship, there has been considerable interest in the possible contribution of hyperlipidemia to CKD-associated CVD ( 7,8 )

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...

OBJECTIVEMetabolic syndrome (MS) is common in patients with chronic kidney disease (CKD), but its contribution to arterial stiffness and endothelial dysfunction in CKD is not well defined. We hypothesized that risk factors for MS would independently predict arterial stiffness and endothelial dysfunction in CKD patients.RESEARCH DESIGN AND METHODSRisk factors for MS, carotid-femoral pulse wave velocity (CF-PWV) and flow-mediated dilation (FMD) as measures of arterial stiffness and endothelial dysfunction, respectively, were assessed in 113 minimally comorbid CKD patients and in 23 matched control subjects.RESULTSCF-PWV correlated with systolic blood pressure (SBP), waist circumference, and plasma glucose (r2 = 0.25, 0.09, and 0.09; P < 0.01 for all). FMD correlated with SBP (r2 = 0.09; P < 0.01) and waist circumference (r2 = 0.03; P < 0.05). CF-PWV increased progressively (r2 = 0.07; P < 0.01) with increasing number of risk factors for MS. In multiple linear regression, SBP and waist circumference were independent determinants of CF-PWV, whereas only SBP predicted FMD.CONCLUSIONSThe number of MS risk factors is an important determinant of arterial stiffness in CKD patients irrespective of the degree of renal impairment. Although BP remains the major determinant of arterial stiffness and endothelial dysfunction, waist circumference independently predicts arterial stiffness. MS risk factors, particularly abdominal girth, are potential targets for future interventional studies in patients with CKD.

Background: Acetaminophen is widely used as first-line therapy for chronic pain because of its perceived safety and the assumption that, unlike nonsteroidal anti-inflammatory drugs, it has little or no effect on blood pressure (BP). Although observational studies suggest that acetaminophen may increase BP, clinical trials are lacking. We, therefore, studied the effects of regular acetaminophen dosing on BP in individuals with hypertension. Methods: In this double-blind, placebo-controlled, crossover study, 110 individuals were randomized to receive 1 g acetaminophen 4× daily or matched placebo for 2 weeks followed by a 2-week washout period before crossing over to the alternate treatment. At the beginning and end of each treatment period, 24-hour ambulatory BPs were measured. The primary outcome was a comparison of the change in mean daytime systolic BP from baseline to end of treatment between the placebo and acetaminophen arms. Results: One-hundred three patients completed both arms of the study. Regular acetaminophen, compared with placebo, resulted in a significant increase in mean daytime systolic BP (132.8±10.5 to 136.5±10.1 mm Hg [acetaminophen] vs 133.9±10.3 to 132.5±9.9 mm Hg [placebo]; P <0.0001) with a placebo-corrected increase of 4.7 mm Hg (95% CI, 2.9–6.6) and mean daytime diastolic BP (81.2±8.0 to 82.1±7.8 mm Hg [acetaminophen] vs 81.7±7.9 to 80.9±7.8 mm Hg [placebo]; P =0.005) with a placebo-corrected increase of 1.6 mm Hg (95% CI, 0.5–2.7). Similar findings were seen for 24-hour ambulatory and clinic BPs. Conclusions: Regular daily intake of 4 g acetaminophen increases systolic BP in individuals with hypertension by ≈5 mm Hg when compared with placebo; this increases cardiovascular risk and calls into question the safety of regular acetaminophen use in this situation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01997112. URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2013-003204-40.