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Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time. [ABSTRACT FROM AUTHOR]

Background and Objectives: Elderly patients with end-stage kidney disease (ESKD) are at high risk for fractures. However, the prevalence of vertebral fractures and hyperkyphosis is not studied well. This is relevant, because in the general population, both vertebral fractures and hyperkyphosis are associated with poor outcome. Therefore, the primary aim of our study was to assess the prevalence of vertebral fractures and hyperkyphosis in the ESKD population. The secondary aim was to assess if patients with vertebral fractures and/or hyperkyphosis more often have poor outcome after starting dialysis, such as accidental falling, functional decline and mortality compared to the patients without vertebral fractures and/or hyperkyphosis., Design, Setting, Participants & Measurements: This study included patients ≥65 years with ESKD who were enrolled in the Geriatric assessment in Older patients starting Dialysis (GOLD) study of whom a lateral chest radiograph was available. Chest radiographs were scored independently by two observers for vertebral fractures (Genant ≥1) and hyperkyphosis (≥50 degrees). The relation between vertebral fractures and hyperkyphosis with clinical outcomes (falls, decline in ADL and IADL, mortality) was studied using the Chi-square test., Results: Of the 196 enrolled patients, chest radiographs were available for 160 patients. Mean age was 75.3 (SD ±6.9), and 35% were female. The prevalence of vertebral fractures was 43% and of hyperkyphosis 22%. Patients with hyperkyphosis had a higher one-year mortality compared to patients without hyperkyphosis (20% vs. 8%, p = 0.04). No differences were observed between patients with and without hyperkyphosis, vertebral fractures and the remaining outcomes after six months of follow-up., Conclusions: In patients ≥65 years old with ESKD starting dialysis, vertebral fractures are highly prevalent. In contrast to the general population, patients with vertebral fractures did experience poor outcome as often as patients without vertebral fractures. Remarkably, patients with hyperkyphosis did have a higher one-year mortality. However, these patients did not experience more functional decline or accidental falls., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Essentials Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown. We compared death causes of 201 918 dialysis patients with the general population. Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis. Clinicians should be aware of the increased bleeding and thrombosis risks., Summary: Background Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death. Objectives To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population. Methods We included 201 918 patients from 11 countries providing data to the ERA-EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age-standardized and sex-standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional-hazards regression. Results As compared with the general population, the age-standardized and sex-standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9-13.7) for bleeding as a cause of death (6.2 per 1000 person-years among dialysis patients versus 0.3 per 1000 person-years in the general population), 13.4 (95% CI 13.0-13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person-years), and 12.4 (95% CI 11.9-12.9) for stroke (14.3 versus 0.7 per 1000 person-years). Conclusion Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions., (© 2018 International Society on Thrombosis and Haemostasis.)

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence., (© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: Quality of life (QoL) is an important outcome in evaluating treatment effect in severe limb ischemia. The randomized, double blind, placebo controlled JUVENTAS trial, investigating the effect of bone marrow derived mononuclear cell (BMMNC) administration in no option severe limb ischemia, showed an improved QoL at 6 months compared with baseline in both the treatment and placebo groups. The aim of the present study was to evaluate whether the improved QoL persisted beyond 6 months' follow up, whether this differed in both trial arms, and if major amputation influenced QoL., Methods: Short form 36 (SF-36) and EuroQol 5D (EQ5D), including the EQ Visual Analogue Scale (EQ-VAS), questionnaires were sent to JUVENTAS trial participants. In the JUVENTAS trial, a norm based scoring method was applied to report the results of the SF-36. The results of the long-term follow up were compared with baseline and 6 month follow up and the results of both trial arms were compared, as were the results of patients with and without amputation., Results: One hundred and nine patients (86.5% of surviving patients) responded to the questionnaires. Median follow up after inclusion was 33 months (interquartile range [IQR] 21.2-50.6) for the BMMNC and 36 months (IQR 21.4-50.9) for the placebo group. The improvement in QoL at 6 months persisted in both arms at a median follow up of 35 months. The long-term QoL did not differ between the BMMNC and placebo group in any of the SF-36 or EQ5D domains. Patients with and without a major amputation had similar QoL scores., Conclusions: The increased QoL in patients with no option severe limb ischemia persisted until 3 years after inclusion, but did not differ between the BMMNC and placebo arms or between patients with and without a major amputation., (Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective/background: Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease (PAD), and many patients with CLI are not eligible for conventional revascularization. In the last decade, cell based therapies have been explored as an alternative treatment option for CLI. A meta-analysis was conducted of randomized placebo controlled trials investigating bone marrow (BM) derived cell therapy in patients with CLI., Methods: The MEDLINE, Embase, and the Cochrane Controlled Trials Register databases were systematically searched, and all included studies were critically appraised by two independent reviewers. The meta-analysis was performed using a random effects model., Results: Ten studies, totaling 499 patients, were included in this meta-analysis. No significant differences were observed in major amputation rates (relative risk [RR] 0.91; 95% confidence interval [CI] 0.65-1.27), survival (RR 1.00; 95% CI 0.95-1.06), and amputation free survival (RR 1.03; 95% CI 0.86-1.23) between the cell treated and placebo treated patients. The ankle brachial index (mean difference 0.11; 95% CI 0.07-0.16), transcutaneous oxygen measurements (mean difference 11.88; 95% CI 2.73-21.02), and pain score (mean difference -0.72; 95% CI -1.37 to -0.07) were significantly better in the treatment group than in the placebo group., Conclusions: This meta-analysis of placebo controlled trials showed no advantage of stem cell therapy on the primary outcome measures of amputation, survival, and amputation free survival in patients with CLI. The potential benefit of more sophisticated cell based strategies should be explored in future randomized placebo controlled trials., (Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: The decision-making process of dialysis initiation in the elderly involves different considerations compared with younger patients. Cognitive, functional and psychosocial issues are likely to be more important than standard prognostic factors. To assess the role of these issues in the decision-making process regarding dialysis initiation in the elderly, a survey was conducted among nephrologists in the Netherlands., Methods: An internet-based survey was sent to all members of the Netherlands Federation of Nephrology., Results: Out of 298 invited, 94 Dutch nephrologists responded to the questionnaire. Reaching consensus with the patient and relatives and early withdrawal are difficult issues in the decision-making process in elderly end-stage renal disease patients. Geriatric impairments were considered (very) relevant issues (varying from 7- 0 on a scale from 1-10) in the context of dialysis initiation, with cognitive dysfunction being most relevant (median 10, range 6-10). The majority of nephrologists (56%) underlined the need for screening for geriatric problems when considering dialysis in the elderly. A total of 26% reported using some form of screening measurement for the determination of the presence of one or more geriatric impairments., Conclusions: Although cognitive, functional and psychosocial issues are considered relevant items in the context of dialysis initiation in the elderly, systematic assessment of these items is not standard of care in nephrology practice. Future research is needed to determine whether a more systematic screening for the presence of geriatric impairments can improve the decision-making process.

Aims: Atherosclerotic plaque development is accelerated in patients with diabetes. Bone marrow-derived smooth muscle-like cells have been detected in neointima and diabetes has a numerical and functional effect on circulating vascular progenitor cells. We hypothesized that an increased number of bone marrow-derived smooth muscle-like cells correlates with accelerated atherosclerosis in diabetic apoE-deficient mice., Methods: ApoE(-/-) mice were subjected to total body irradiation and transplanted with bone marrow cells from GFP-transgenic mice. Mice were rendered diabetic by streptozotocin injection and examined after 4, 8, 11 and 15 weeks of diabetes., Results: Diabetic mice showed a larger plaque area and a higher number of smooth muscle-like cells compared to non-diabetic mice at 11 and 15 weeks after diabetes induction. Bone marrow-derived smooth muscle-like cells were detected in atherosclerotic plaques of both diabetic and control mice, but numbers were higher in plaques of diabetic mice 11 weeks after induction of diabetes. The higher number of bone marrow-derived smooth muscle-like cells in plaque was associated with an increase in in vitro differentiation of smooth muscle-like cells from spleen mononuclear cells in diabetic mice., Conclusions: Diabetes increases the number of bone marrow-derived smooth muscle-like cells in atherosclerotic plaques and the differentiation of mononuclear cells towards smooth muscle-like cells, which may contribute to accelerated atherosclerotic plaque development in diabetic apoE(-/-) mice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA; 20 mg/l water; SNX+L-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, L-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX+L-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose L-NNA (L-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX+L-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In L-NNA-High, LVSD was not as severe as in SNX+L-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in L-NNA-High after L-NNA was stopped, but both were persistently low in SNX+L-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX+L-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.

Critical limb ischemia (CLI) continues to form a substantial burden on Western health care. Despite recent advances in surgical and radiological vascular techniques, a large number of patients is not eligible for these revascularisation procedures and faces amputation as their ultimate treatment option. Growth factor therapy and stem cell therapy - both therapies focussing on augmenting postnatal neovascularisation - have raised much interest in the past decade. Based on initial pre-clinical and clinical results, both therapies appear to be promising strategies to augment neovascularisation and to reduce symptoms and possibly prevent amputation in CLI patients. However, the underlying mechanisms of postnatal neovascularisation are still incompletely understood. Both fundamental research as well as large randomised trials are needed for further optimisation of these treatment options, and will hopefully lead to needed advances in the treatment of no-option CLI patients in the near future.

A total of 3 patients, a female aged 66 years, a male aged 67 years and a female aged 82 years, presented with rest pain or gangrene of their lower extremities as a result of critical limb ischemia (CLI). Radiographic studies showed non-reconstructable arterial obstructive disease in the 66-year-old female patient, who underwent an uncomplicated primary amputation and subsequent rehabilitation. Bypass surgery was initially performed in the male patient. However, failed reconstruction and progression of ischaemia necessitated transfemoral amputations to be performed, which was followed by impaired rehabilitation. In the 82-year-old female patient gangrene was the indication for primary amputation. She died due to progressive sepsis following surgery. In about 40% of patients with CLI, major lower extremity amputation is the ultimate solution. The morbidity, mortality and rehabilitation potential in CLI and the factors that influence these outcomes are discussed. The most clinically relevant determinants of morbidity, mortality and rehabilitation following major lower extremity amputation are comorbidity, age, preoperative mobility and amputation level.

More women die of cardiovascular disease than men; in women, cardiovascular mortality is 1.5 times greater than cancer mortality. The pathophysiology of cardiovascular disease has female-specific aspects such as fragile coronary arteries and microvascular ischaemia. Women with acute coronary syndromes are more likely to present with atypical symptoms such as dyspnoea, nausea or fatigue. With regard to diagnostic tests in women, exercise ECG can be difficult to interpret and a normal coronary angiogram does not exclude coronary heart disease. Myocardial perfusion scintigraphy may be considered for high-risk women who are clinically suspected of having coronary heart disease and have a normal or inconclusive exercise ECG and angiogram. Women are less likely to be treated according to guidelines than men, and their prognosis after a myocardial infarction or a coronary intervention is worse. Female-specific aspects such as gestational hypertension and diabetes allow for early detection and treatment of women at risk for cardiovascular disease.

The implementation of the intriguing concept of the polypill to prevent cardiovascular events remains doubtful due to a lack of evidence, expected adherence problems, the inevitable overtreatment and undertreatment of individuals, and potential side effects. Lifestyle changes and individual interventions are more preferable strategies.

Statins safely and effectively reduce the morbidity and mortality due to cardiovascular disease. In the trials conducted so far, which have been carried out predominantly on high-risk patients, the observed risk reduction is probably completely attributable to the reduction of the cholesterol level. However, statins also influence the atherosclerotic disease process in a lipid-independent way. This includes beneficial effects on the early pathogenetic components of atherosclerosis, such as endothelial dysfunction and inflammation. These effects are probably not visible in the large clinical trials that usually follow up cohorts of patients with late stages of atherosclerosis during a relatively short period of time. These cholesterol-independent effects do affect intermediate factors in the atherosclerotic process, such as endothelial dysfunction. In clinical practice, where not only short-term effects in patients with manifest vascular disease but also the prevention of the long-term complications of atherosclerosis in high-risk patients is an important goal, these so-called pleiotropic effects may contribute to risk reduction.

It is increasingly recognized that folates may play a role in the prevention of cardiovascular disease. Over the last few years, several studies have reported beneficial effects of folates on endothelial function, a surrogate end point for cardiovascular risk. Consistently, observational studies have demonstrated an association between folate levels and cardiovascular morbidity and mortality. The exact mechanisms underlying the ameliorative effects of folates on the endothelium remain to be elucidated. Thus far, most studies have focused on the homocysteine-lowering effects of folates. However, recently, benefits of folates independent of homocysteine lowering have also been reported. Potential mechanisms include antioxidant actions, effects on cofactor availability, or direct interactions with the enzyme endothelial NO synthase. Obviously, beneficial effects of folates on cardiovascular risk would have important clinical and dietary consequences. However, for definite conclusions, the completion of ongoing randomized controlled trials will have to be awaited.

The endothelium, long considered merely an inert, semipermeable membrane between blood and the vessel wall, is now viewed as an important, large and highly active endocrine organ which is responsible for a number of vital physiological functions. In this editorial we will discuss the important role of the endothelium and endothelial (dys)function in health and disease, with particular focus on postmenopausal cardiovascular disease and preeclampsia.

Aims: Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT-627 in healthy humans., Methods: Healthy volunteers were included in two studies with cross-over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT-627 or matched placebo, in a dose range of 0.2-40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET-1 were assessed., Results: ABT-627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62% vs 4% during placebo, P < 0.05, for Study 1 and in 42% vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at approximately 1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET-1. ABT-627 caused a significant reduction in peripheral resistance as compared with placebo (16 +/- 1 vs 19 +/- 1, 18 +/- 2 vs 23 +/- 3, 15 +/- 1 vs 17 +/- 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 +/- 2 vs 84 +/- 3, 80 +/- 4 vs 90 +/- 5, 75 +/- 3 vs 79 +/- 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate dose-dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level)., Conclusions: The oral ETA receptor blocker ABT-627 is well tolerated, rapidly absorbed, effectively blocks ET-1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease.

Background: Folates have been suggested to be of benefit in reducing cardiovascular risk. The present study was designed to examine whether oral folic acid supplementation could improve endothelial function as an intermediate end point for cardiovascular risk in patients with increased risk of atherosclerosis due to familial hypercholesterolemia (FH)., Methods and Results: In a prospective, randomized, double-blind, placebo-controlled study with crossover design, we evaluated the effects of 4 weeks of treatment with oral folic acid (5 mg PO) on endothelial function in FH. In 20 FH patients, forearm vascular function was assessed at baseline, after 4 weeks of folic acid treatment, and after 4 weeks of placebo treatment by venous occlusion plethysmography, with serotonin and sodium nitroprusside used as endothelium-dependent and -independent vasodilators. In addition, we examined the vasoconstrictor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine to assess basal NO activity. In FH patients, folic acid supplementation restored the impaired endothelium-dependent vasodilation, whereas it did not significantly influence endothelium-independent vasodilation or basal forearm vasomotion. There was a trend toward improvement in basal NO activity., Conclusions: These data demonstrate that oral supplementation of folic acid can improve endothelial function in patients with increased risk of atherosclerotic disease due to hypercholesterolemia, without changes in plasma lipids.

Objective: Dihydropyridine calcium antagonists have been shown to retard atherogenesis in animal models and to prevent the development of early angiographic lesions in human coronary arteries. Endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. We investigated whether nifedipine could improve endothelial function in hypercholesterolemia, independently of changes in blood pressure or plasma lipids., Methods: First, we compared in vivo forearm vascular responses to the endothelium-dependent and independent vasodilators serotonin (5-HT) and sodium nitroprusside (SNP) in 11 patients with familial hypercholesterolemia before and after 6-weeks treatment with nifedipine GITS (60 mg, OD) and in 12 matched controls. In a subgroup of six control subjects forearm vascular function was also assessed before and after 6-weeks nifedipine GITS treatment. In vitro, we subsequently explored possible mechanisms underlying the effect of nifedipine on endothelial function. We investigated the effects of nifedipine on both NO production by recombinant endothelial NO synthase (eNOS) and endothelial cells, using 3H-arginine conversion, as well as on superoxide generation by endothelial cell lysates, using lucigenin enhanced chemiluminescence., Results: In hypercholesterolemia 5-HT-induced vasodilation was impaired (47 +/- 9% increase in forearm bloodflow vs. 99 +/- 8% in controls). Treatment with nifedipine completely restored 5-HT-induced vasodilation (113 +/- 13%), whereas it did not influence basal forearm vasomotion or SNP-induced vasodilation. Nifedipine did not alter forearm vascular responses in control subjects and did not alter blood pressure or plasma lipids. In vitro, we found no direct effect of nifedipine on NO production by recombinant eNOS or endothelial cells. However, we did observe a reduction in endothelial superoxide generation., Conclusions: Our data show that nifedipine improves endothelial function in hypercholesterolemia. It is suggested from our in vitro experiments that this effect is due to reduced NO degradation.

Assessment of endothelial function appears to be a valuable additional tool for diagnosing and therapeutic monitoring of coronary artery disease. The first part of this review discusses the biosynthesis, degradation, and antiatherosclerotic properties of nitric oxide, a major determinant of endothelial function. In the second part methods for assessing endothelial function and strategies for reversal of endothelial dysfunction are reviewed. Improvement of endothelial function may be obtained by lifestyle modifications, such as cessation of smoking, better blood glucose regulation, exercise, dietary measures, and pharmacological interventions, such as lipid lowering, antioxidant therapy, angiotensin-converting enzyme inhibition, and calcium channel blockers.

Background: The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET(A) receptors are clear, the contribution from endothelial and vascular smooth muscle ET(B) receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET(A) and ET(B) receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET(A)-selective receptor antagonist BQ-123., Methods and Results: Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% (P=.006) with inhibition of the endogenous generation of nitric oxide and by 38% (P<.001) with coinfusion of the ET(B) receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow (P<.001)., Conclusions: Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET(B) receptor antagonism either alone or on a background of ET(A) antagonism causes local vasoconstriction, indicating that ET(B) receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.

Background: Impaired nitric oxide (NO) activity is an early event in the pathogenesis of cardiovascular disease, resulting from either reduced NO formation or increased NO degradation. Administration of tetrahydrobiopterin (BH4), an essential cofactor for NO production, could restore NO activity in familial hypercholesterolemia (FH). Because folates have been suggested to stimulate endogenous BH4 regeneration, we hypothesized that administration of 5-methyltetrahydrofolate (5-MTHF, the active circulating form of folate) might improve NO formation in FH., Methods and Results: We studied the effects of 5-MTHF on NO bioavailability in vivo in 10 patients with FH and 10 matched control subjects by venous occlusion plethysmography, using serotonin and nitroprusside as endothelium-dependent and -independent vasodilators. In vitro, we investigated the effect of 5-MTHF on NO production by recombinant endothelial NO synthase (eNOS) by use of [3H]arginine to [3H]citrulline conversion. We also studied the effects of 5-MTHF on superoxide generation by eNOS and xanthine oxidase (XO) by use of lucigenin chemiluminescence. The impaired endothelium-dependent vasodilation in FH (63% versus 90% in control subjects) could be reversed by coinfusion of 5-MTHF (117% vasodilation), whereas 5-MTHF had no significant effect on endothelium-dependent vasodilation in control subjects. 5-MTHF did not influence basal forearm vasomotion or endothelium-independent vasodilation. 5-MTHF had no direct effect on in vitro NO production by eNOS. However, we did observe a dose-dependent reduction in both eNOS- and XO-induced superoxide generation., Conclusions: These results show that the active form of folic acid restores in vivo endothelial function in FH. It is suggested from our in vitro experiments that this effect is due to reduced catabolism of NO.