Regular physical exercise improves endothelial function in heart transplant recipients

BACKGROUND: Impaired endothelial function is detectable in heart transplant (HTX) recipients and regarded as risk factor for coronary artery disease. We have studied whether endothelial function can be improved in HTX patients participating in a regular physical training program as demonstrated in patients with chronic heart failure, hypertension and coronary artery disease. METHODS: Male HTX patients and healthy, age-matched controls were studied. Seven HTX patients (age: 60 +/- 6 yr; 6 +/- 2 yr of HTX) participated in an outpatient training program, six HTX patients (age: 63 +/- 8 yr; 7 +/- 1 yr of HTX) maintained a sedentary lifestyle without regular physical exercise since transplantation. A healthy control group comprised six subjects (age: 62 +/- 6 yr). Vascular function was assessed by flow-mediated dilation of the brachial artery (FMD). Systemic haemodynamic responses to intravenous infusion of the endothelium independent vasodilator sodium nitroprusside (SNP) and to NG-monomethyl-L-arginine (L-NMMA), an inhibitor of constitutive nitric oxide synthase, were also measured. RESULTS: Resting heart rate was significantly lower (p < 0.05) in healthy controls (66 +/- 13) than in the HTX training group (83 +/- 11) and in non-training HTX patients (91 +/- 9), baseline blood pressure also tended to be lower in healthy subjects and in the training HTX patients. FMD was significantly higher (p < 0.05) in the control group (8.4 +/- 2.2%) and in the training group (7.1 +/- 2.4%), compared with non-training HTX patients (1.4 +/- 0.8%). The response of systolic blood pressure (p = 0.08) and heart rate (p < 0.05) to L-NMMA was reduced in sedentary HTX patients compared with healthy controls and heart rate response to SNP was also impaired in sedentary HTX patients. DISCUSSION: Regular aerobic physical training restores vascular function in HTX patients, who are at considerable risk for developing vascular complications. This effect is demonstrable in conduit and systemic resistance arteries.     

Dialysis improves endothelial function in humans.

BACKGROUND: Circulating inhibitors of endothelial function have been implicated in the pathogenesis of vascular disease in chronic renal failure. The aim of this study was to determine if lowering the plasma concentration of these and other dialysable toxins improves endothelial function. To do this we compared the acute effects on endothelial function of single episodes of haemodialysis with automated peritoneal dialysis. We hypothesized that endothelial function would improve after dialysis, with a greater effect seen after haemodialysis due to more substantial clearance of endothelial toxins per-treatment. METHODS: Subjects with end-stage renal failure undergoing haemodialysis (n=16) or automated peritoneal dialysis (n=14) were investigated. Endothelial function was determined using vascular ultrasound to measure flow-mediated dilatation of the brachial artery and was compared with the dilatation caused by sublingual glyceryl trinitrate. Endothelial function was assessed before and after a single dialysis treatment. Plasma concentrations of the inhibitors of endothelial function, asymmetric dimethyl-l-arginine and homocysteine were measured. Flow-mediated dilatation was expressed as percentage change from basal diameter and analysed using Student's t test. RESULTS: The plasma concentration of circulating inhibitors of endothelial function was reduced after haemodialysis but not peritoneal dialysis. Haemodialysis increased flow-mediated dilatation from 4.0+/-1.0% to 5.8+/-1.2% (P<0.002). These changes persisted for 5 h but returned to baseline by 24 h. Automated peritoneal dialysis had no acute effect on flow-mediated dilatation (5.9+/-1.1% vs 5.4+/-0.8% after, P>0.5). There were no effects of either dialysis modality on dilatation to glyceryl trinitrate. CONCLUSIONS: Short-term reduction of circulating inhibitors of endothelial function by haemodialysis is associated with increased flow-mediated dilatation. These data suggest that dialysable endothelial toxins have deleterious effects on endothelial function that are rapidly reversible.     

Cardiac diastolic dysfunction in renal-transplant recipients is associated with increased circulating Adrenomedullin

BACKGROUND: Renal transplantation is an excellent therapeutic alternative for end-stage renal diseases. Nevertheless, the cardiac function is often impaired in renal-transplant patients (RTR) and importantly determines their prognosis. Adrenomedullin (ADM), a peptide involved in cardiovascular homeostasis, is believed to protect both cardiac and renal functions - by increasing local blood flows, attenuating the progression of vascular damage and remodelling and by reducing glomerular injury - and might be involved in renal-transplantation physiopathology. This work was performed to investigate whether an increase in circulating ADM might be related to RTR cardiac function. METHODS: Twenty-nine subjects, 19 RTR and 10 healthy subjects, participated in the study. After 15 min rest in supine position, heart rate and systemic blood pressure were measured together with cyclosporine through levels, creatinine and ADM. Systolic and diastolic cardiac functions were assessed, using Doppler echocardiography. RESULTS: Subjects were similar concerning age, weight, heart rate and blood pressure. Creatinine and ADM (53.8 +/- 6.9 vs. 27.2 +/- 4.1 pmol/L, p = 0.02) were significantly increased in RTR (73 +/- 10 months after transplantation). Cardiac systolic function was normal, but a reduced mitral E:A ratio was observed in RTR (0.90 +/- 0.06 vs. 1.38 +/- 0.10, p < 0.001), reflecting their impaired left ventricular relaxation. Such a ratio was negatively correlated with ADM (r = -0.55, p = 0.002). CONCLUSIONS: RTR present with an increased ADM is likely related to cardiac diastolic dysfunction. In view of its protective effect on the cardiovascular system, these data support further studies to better define the role and the therapeutic potential of ADM after renal transplantation.     

The effect of calcineurin inhibitors on endothelial function in renal transplant recipients

Endothelial dysfunction is of vital importance, as it may cause ischemia and dysfunction in various organs. Despite, this problem has been well documented in patients with end-stage renal disease (ESRD), there is not enough data considering this issue following renal transplantation. One of the potential causes of endothelial dysfunction in renal transplant recipients may be administration of calcineurin inhibitors. The aim of this study is to evaluate the effects of two different calcineurin inhibitors [cyclosporin A (CsA) and tacrolimus (FK506)] on endothelial function in renal transplant patients. Forty-four renal transplant recipients [22 on FK506 (group I) and 22 on CsA (group II)] were studied. Endothelial functions of the brachial artery were evaluated by using high resolution vascular ultrasound. Endothelium-dependent and -independent vasodilations were assessed by establishing reactive hyperemia and using sublingual nitroglycerine (NTG), respectively. Results are presented as percentage change from baseline values. Significant endothelial dysfunction was noted in renal transplant patients treated with CsA. While endothelium-dependent vasodilation was 12.1 +/- 5.1% in group I and it was 6.5 +/- 3.7% in group II (p < 0.001). The increase in brachial artery diameter after sublingual NTG was 20.1 +/- 6.3 and 12.7 +/- 5.6% in groups I and II, respectively. This indicates that the endothelium-dependent and -independent vasodilation of the patients on FK506 is better preserved than the patients on CsA therapy. Besides, blood flow volume (BFV) increase was 51.2 +/- 39.4 and 43.9 +/- 24.3%, in groups I and II, respectively, in reactive hyperemia period (p > 0.05). Post-transplant course of renal transplant recipients is complicated by endothelial dysfunction. This problem is more prominent in patients on CsA therapy, which can predispose these patients to more frequent cardiac complications.     

Serum neutrophil gelatinase-associated lipocalin correlates with kidney function in renal allograft recipients

Abstract:  The value of neutrophil gelatinase-associated lipocalin (NGAL) as a novel marker for early detection of acute renal failure has been highlighted recently. The aim of this study was to assess whether serum NGAL correlates with kidney function in kidney allograft recipients. Serum NGAL, creatinine, and estimated glomerular filtration rate (GFR) were evaluated in 100 kidney allograft recipients on triple therapy: calcineurin inhibitor, mycophenolate mofetil or azathioprine, prednisone and healthy volunteers. Kidney transplant recipients had significantly higher NGAL than the control group. Serum NGAL in univariate analysis was strongly correlated with serum creatinine ( r  = 0.78). Estimated GFR ( r  = −0.69), on the other hand, was moderately correlated with white blood cell count ( r  = 0.43) and only weakly with other parameters. In multiple regression analysis, the best predictor of serum NGAL was eGFR (beta −0.69), with other predictors being white blood cell count (beta 0.25) and high sensitivity C-reactive protein (hsCRP) (beta 0.23) explaining 82% of NGAL concentration. Even a successful kidney transplantation is associated with kidney injury as reflected by elevated serum NGAL and lowered eGFR. Therefore, NGAL needs to be investigated as a potential early marker for impaired kidney function/kidney injury, especially in patients with other risk factor for kidney damage, i.e., hypertension or diabetes.     

Association between insulin resistance and endothelial dysfunction in renal transplant recipients

BACKGROUND: Endothelial dysfunction is a common finding in renal transplant recipients (RTR) and is related to impaired local regulation of vasodilative and vasoconstrictive substances, such as nitric monoxide (NO) and endothelin-1 (ET-1). In non-transplanted patients, an association between impaired endothelial function and insulin resistance has been shown. Whether such an association also exists in RTR is unknown. OBJECTIVE: The aim of the present study was to examine whether insulin resistance is associated with endothelial dysfunction in RTR. MATERIAL AND METHODS: A total of 47 RTR in a stable phase six yr post-transplant were included in the statistical analysis. The immunosuppressive therapy was based on cyclosporine and prednisolone. Non-invasive assessment of endothelial function was performed with laser Doppler flowmetry of the forearm skin vasculature after local acetylcholine stimulation. Oral glucose tolerance tests comprising both glucose and insulin measurements were used to calculate insulin sensitivity (IS) indices. NO, ET-1 and von Willebrand factor were measured in fasting plasma samples. RESULTS: Normal glucose tolerance was found in 31 RTR. In these subjects, both IS (r(2) = 0.164, p = 0.044) and plasma NO (r(2) = 0.326, p = 0.002) were significantly correlated with endothelial function. Patients with glucose intolerance (n = 16) had higher plasma ET-1 and lower NO levels, but the association between IS and endothelial function was not significant in these subjects. In the total patient cohort, IS and endothelial function tended to be correlated (p = 0.127). CONCLUSIONS: Endothelial dysfunction is significantly associated with insulin resistance in normoglycemic RTR but explains a rather small part of the variation. In glucose-intolerant recipients, IS appears to be more critically dependent on other factors not revealed in the present study.     

Changes in endothelial function before and after renal transplantation*

Endothelial dysfunction is an early key event in the development of atherosclerotic cardiovascular disease observed in chronic renal failure patients. The role of renal transplantation (RTx) on endothelial dysfunction is still unclear. The aim of this study was to evaluate the endothelial function of chronic renal failure patients before RTx (while they were on hemodialysis, HD), and after RTx (at the 6th and 12th months) by a noninvasive method, brachial arterial ultrasound. A total of 22 (17 male, mean age: 33.9 +/- 11.6 years) RTx recipients were enrolled in the study. Endothelium-dependent vasodilation (EDD) was assessed by establishing reactive hyperemia. EDD prior to transplantation was significantly lower when compared with EDD measured at the 6th and 12th months after RTx (EDD pretransplantation: 6 +/- 3.7%, EDD at the 6th month of RTx: 8.3 +/- 2.3% and EDD at the 12th month of RTx: 12.1 +/- 3.6%, P < 0.001). When the EDD values measured at the 6th and 12th months of RTx were compared, measurements of the 12th month were found significantly higher than those of the 6th month (P < 0.001). Our results also showed that RTx has provided improvement in endothelial function by eliminating the uremic environment although not in the early post-RTx period.     

Increase in nitric oxide bioavailability improves endothelial function in endothelin-1 transgenic mice.

BACKGROUND: Endothelin-1 (ET-1) has been described as a very potent vasoconstrictor. Nevertheless, transgenic mice overexpressing ET-1 have been shown to exhibit normal blood pressure. We thus hypothesized that vascular ET-1 effects may be antagonized by increased activity of other regulatory systems, such as the increase in bioavailability of the endothelial counterpart of ET-1, nitric oxide (NO). METHODS: Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine (10(-10)-10(-4) mol/l), sodium nitroprusside (10(-10)-10(-4) mol/l), ET-1 (10(-10)-10(-7) mol/l) and big ET-1 (10(-10)-10(-7) mol/l), respectively, in ET-1 transgenic mice and corresponding controls. To unmask the impact of the NO system, we furthermore analysed vessel rings incubated in vitro with the NO-synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) mol/l). RESULTS: Maximum endothelium-dependent relaxation was enhanced in ET-1 transgenic mice (93+/-3% vs 84+/-4% for wild-type littermates; P<0.05) and was inhibited by preincubation with L-NAME in both ET-transgenic mice and wild-type littermates (11+/-5% vs 9+/-4% maximum relaxation, respectively). Endothelium-independent relaxation was similar among all groups. Maximum vascular contraction to ET-1 and big ET-1 was reduced in ET-1 transgenic mice (P<0.05 vs wild-type littermates). Preincubation with L-NAME reduced this difference, indicating the involvement of augmented NO availability. Correspondingly, urinary nitrate/nitrite excretion was significantly elevated in ET-1 transgenic mice. CONCLUSIONS: These data suggest that in transgenic mice overexpressing ET-1, increased NO bioavailability counteracts the contractile potency of elevated ET-1 levels and leads to an improvement of endothelium-dependent relaxation. Thus, in the presence of an activated ET system, up-regulation of NO production may be capable of maintaining vascular tone in a normal range and therefore may prevent the development of hypertension.     

B族维生素在肾移植受者高同型半胱氨酸血症及内皮功能异常治疗中的应用

目的探讨B族维生素治疗肾移植受者高同型半胱氨酸血症效果,对内皮功能的影响。方法将36例接受首次肾移植后的高同型半胱氨酸患者,随机分为两组,观察组18例,口服叶酸5mg/d,维生素B650mg/d及维生素B121000μg/d,连续6个月;对照组18例。分别于治疗前和治疗6个月时观察血肌酐水平和肌酐清除率,平均血压值,血胆固醇、甘油三酯和同型半胱氨酸水平变化,应用彩色多普勒超声测定内皮功能。结果观察组患者治疗后同型半胱氨酸与治疗前相比显著降低[(13±4)μmol/L与(20±5)μmol/L,t=5.3,P<0.01];肱动脉反应性充血时内径变化百分率[(12±5)%与(9±5)%,t=2.9,P<0.01]和含服硝酸甘油后肱动脉内径变化百分率[(18±4)%与(12±5)%,t=3.4,P<0.01]均显著增加。其他指标无显著改变。对照组6个月后各项指标与治疗前相比差异无统计学意义;肱动脉反应性充血时内径变化百分率为(9±6)%,含服硝酸甘油后肱动脉内径变化百分率为(12±5)%,均显著低于观察组(t=2.8,P<0.01;t=3.5,P<0.01)。结论应用叶酸、维生素B6及维生素B12能够有效治疗肾移植受者的高同型半胱氨酸血症,并使内皮功能获得明显改善。     

内毒素对脐静脉内皮细胞分泌功能的影响

目的　探讨内毒素对脐静脉内皮细胞分泌功能的影响。方法　选择体外培养的人脐静脉血管内皮细胞 (HUVEC)为研究对象 ,分别用内毒素、L -左旋精氨酸和硝基左旋精氨酸进行处理 ,并检测上清液中内皮素 - 1(ET - 1)和一氧化氮 (NO)含量。结果　内毒素使ET - 1和NO含量增加 ;NO则使ET - 1的含量降低。结论　内毒素能导致人脐静脉内皮细胞损伤 ,使ET - 1和NO的合成和释放增加 ;NO则抑制ET - 1的合成和释放     

Vitamin C improves endothelial dysfunction in renal allograft recipients.

BACKGROUND: Endothelial function is impaired in renal allograft recipients but the effects of antioxidant vitamin therapy on endothelial function in such patients is unknown. METHODS: Thirteen renal allograft recipients were randomized to vitamin C or placebo in a double blind cross-over study design. Flow-mediated endothelium-dependent dilation and glyceryltrinitrate-induced endothelium-independent dilation of the brachial artery were assessed before and 2 h after oral administration of 2 g vitamin C or placebo. RESULTS: Plasma vitamin C levels increased from 33.5+/-17.0 micromol/l to 98.8+/-60.2 micromol/l after treatment (P=0.0001). Endothelium-dependent dilation improved (from 1.6+/-2.6 to 4.5+/-2.5%) after vitamin C administration but was unchanged after placebo (1.9+/-1.5 to 1.8+/-2.5%; P=0.003 for vitamin C vs placebo). There was no significant change in endothelium-independent dilation in response to vitamin C. Vitamin C was also associated with a significant increase in the lag time in dilute serum oxidation (P=0.001). CONCLUSIONS: Vitamin C acutely improves flow-mediated, endothelium-dependent dilation and increases the resistance of lipoproteins in dilute serum to oxidation in renal transplant recipients.     

Pyridoxine improves endothelial function in cardiac transplant recipients.

BACKGROUND: Endothelial dysfunction is common in cardiac transplant recipients and predicts the development of transplant coronary artery disease. Hyperhomocysteinemia is associated with endothelial dysfunction in the general population, is common in transplant recipients, and has been associated with transplant coronary artery disease. Thus therapy that decreases homocysteine concentrations might also improve endothelial function and decrease the risk of transplant coronary artery disease. Folate and pyridoxine are important cofactors in distinct aspects of homocysteine metabolism. The purpose of this study was to determine whether folate or pyridoxine supplementation improves endothelial function in cardiac transplant recipients. METHODS AND RESULTS: This was a double-blind, randomized, placebo-controlled trial. We assigned 31 transplant recipients to either pyridoxine (n = 11:100 mg/day), folate (n = 12:5 mg/day), or placebo (n = 8) for 10 weeks. Fasting and post-methionine-load (methionine 100 mg/kg orally) homocysteine concentrations were determined. Brachial artery flow-mediated dilatation was used as a measure of endothelial function. At follow-up, we noted no significant changes in homocysteine concentrations in any of the groups. However, pyridoxine supplementation was associated with a significant improvement in endothelial function (2.8 +/- 6.7 to 6.9 +/- 6.3, p = 0.05). No significant changes were seen in patients treated with folate or placebo. CONCLUSIONS: Pyridoxine, but not folate supplementation, significantly improves endothelial function in cardiac transplant recipients.     

Calcineurin inhibitor effects on glucose metabolism and endothelial function following renal transplantation

Abstract: Background:  Calcineurin inhibitors (CNI) are involved in the development of post-transplant diabetes mellitus (PTDM). Changes in insulin secretion and sensitivity contribute to the development of PTDM and are associated with endothelial function.
Methods:  In a pre-defined substudy of a previously published randomized trial in renal transplant recipients we compared the effect of CNI treatment (n = 23) with complete CNI-avoidance (n = 21) on insulin secretion and sensitivity (oral glucose tolerance test) as well as endothelial function (laser Doppler flowmetry), 10 wk and 12 months following transplantation.
Results:  Insulin sensitivity differed 10 wk post-transplant and was significantly better after 12 months in patients never treated with CNI drugs [0.091 (0.050) vs. 0.083 (0.036) μmol/kg/min/pmol/L, p = 0.043]. Insulin secretion tended to be higher in CNI treated patients at both time points (p = 0.068). Endothelial function was not significantly different at week 10 [540 (205) vs. 227 (565) arbitary units × minutes, p = 0.35] or month 12 [510 (620) vs. 243 (242), p = 0.33].
Conclusions:  Findings in the present study indicate that long-term CNI treatment negatively affects glucose metabolism and this may contribute to the increased risk for premature cardiovascular disease in CNI treated renal transplant recipients. Further studies to elucidate this hypothesis are, however, needed.     

去乙酰化酶SIRT1与血管内皮功能关系研究进展

沉默信息调节因子2相关酶1(silent information regulator 2-related enzymes 1,Sirtuin 1,SIRT1)是一种烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucletide,NAD)依赖性的去乙酰化酶,通过对组蛋白、非组蛋白及其他转录因子的调节参与了体内许多生理功能的调节,包括众多基因转录、能量代谢、氧化应激以及细胞衰老过程等。最近研究证实,SIRT1在多种病理过程中,通过调节内皮源型一氧化氮合酶(endothelial nitric oxide syntheses,eNOS)、p53、叉头转录因子(forkhead box class O,FOXO)、核转录因子-κB(nuclear factor kappa B,NF-κB)等的活性表现出血管内皮及神经功能保护作用。因此,对于以内皮功能障碍为主要病因的疾病特别是勃起功能障碍(erec-tile dysfunction,ED),SIRT1可能是其潜在的治疗靶点之一。     

Fluvastatin reduces atherogenic lipids without any effect on native endothelial function early after kidney transplantation

BACKGROUND: Cardiovascular risk is greatly increased in renal transplant recipients. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy may reduce cardiovascular risk by improving both dyslipidemia and endothelial function. We therefore performed this study to assess the effect of fluvastatin on endothelial function in renal transplant recipients. METHODS: This randomized, placebo-controlled, double-blind designed study investigated the effect of fluvastatin on endothelial function. Thirty-seven recipients received fluvastatin 40 mg/d and 35 received placebo during the first 12 wk following transplantation. All patients initially received cyclosporin A, prednisolone and azathioprine. At the end of treatment, endothelial function was assessed in the forearm skin microvasculature by laser Doppler flowmetry following acetylcholine stimulation. Samples were taken for measurements of serum lipids and vasoactive markers. RESULTS: There were no differences in endothelial function between fluvastatin recipients and controls, AUCACh was 656 +/- 479 and 627 +/- 518 AU min, respectively (fluv vs. control, p > 0.65). In the placebo limb, total cholesterol and LDL cholesterol increased 22 +/- 12% and 22 +/- 18%, respectively in the first 12 wk following transplantation. The respective values were 18 +/- 13% (p = 0.010) and 34 +/- 19% (p = 0.0013) lower at 12 wk in the fluvastatin treated patients. Plasma ET-1, BigET-1 and urinary excretion of cGMP were not significantly different between treatment groups (p > 0.55). CONCLUSION: Although fluvastatin 40 mg/d significantly lowers cholesterol it does not affect endothelial function the first 3 months after renal transplantation. The lack of effect on endothelial function is consistent with a lack of effect on vasoactive substances.     

Vascular resistance and endothelial function in cyclosporine-treated lung transplant recipients

The majority of patients undergoing solid organ transplantation develop hypertension, to which vasoconstriction and impaired endothelial function have been suggested to contribute. We compared basal vascular resistance and nitric oxide-mediated endothelial-dependent and independent vasoreactivity between cyclosporine-treated lung transplant recipients and healthy subjects. Forearm blood flow was measured by venous occlusion plethysmography at rest and during acetylcholine, glyceryltrinitrate and N(G)-monomethyl-L-arginine acetate (L-NMMA) infusion in 11 lung transplant recipients 3-5 years after transplantation and in eight healthy subjects. Forearm vascular resistance (FVR) was calculated. Plasma levels of endothelin-1 (ET-1) and von Willebrand factor (vWf) were analysed. Basal vascular resistance was 40% lower in transplant recipients than in healthy subjects (P = 0.021). Endothelial-dependent and independent vasodilation did not differ. Plasma levels of ET-1 and vWf were higher in transplant recipients (P = 0.009 and P < 0.001 respectively). There was a significant correlation between ET-1 levels and FVR in healthy subjects (r = 0.83, P = 0.042), but not in transplant recipients (r = -0.14, P = 0.70). The findings oppose the theory of generalized vasoconstriction and impaired endothelial function in the pathogenesis of hypertension after transplantation. Increased plasma levels of ET-1 do not cause increased FVR in lung transplant recipients.     

Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation

Abstract: Background: Endothelial dysfunction is a significant cause of vascular and end‐organ damage after solid organ transplantation. The aim of this study was to compare endothelial function in healthy controls and in patients who received tacrolimus for immunosuppression after orthotopic liver transplantation (OLT). Methods: Eight OLT patients and eight age‐ and BMI‐matched healthy subjects were included in the study. Apart from hemodynamic parameters, enzymatic liver function, fasting plasma glucose levels, creatinine, cholesterol, nitric oxide and endothelin‐1 levels were measured. Flow‐mediated dilatation (FMD) in the brachial artery was determined by bi‐mode ultrasound. Results: Systolic and diastolic blood pressure and heart rate were higher in OLT recipients compared with the control group, but remained within normal limits. Blood results did not differ significantly between the groups. Circulating nitric oxide (152.2 ± 29.7 vs. 180.6 ± 40.1 μmol/L) and endothelin‐1 (20.5 ± 1.0 vs. 18.9 ± 1.3 pmol/L) values were similar, and the FMD was normal in both groups (10.29 ± 0.89 vs. 9.86 ± 2.43% in controls and OLT recipients, respectively). There was a significant positive correlation between plasma tacrolimus levels after OLT and FMD (r = 0.72, p < 0.05). Conclusion: As assessed by both laboratory and functional approaches, endothelial function was unaltered in patients taking tacrolimus after OLT. The positive correlation between tacrolimus plasma levels and FMD suggest that tacrolimus might have beneficial effects on endothelial function after OLT.     

Short-term effect of atorvastatin in hypercholesterolaemic renal-transplant patients unresponsive to other statins.

BACKGROUND: Atherosclerosis associated with hyperlipidaemia is a major cause of morbidity and mortality after renal transplantation. Atorvastatin is a new HMG-CoA reductase inhibitor that has shown a favourable profile of lipid reduction when compared with other statins. The aim of the study was to assess the efficacy and safety of atorvastatin in hypercholesterolaemic renal transplant patients who had previously been on statins with little or no effect. METHODS: Atorvastatin, 10 mg/day, was administered to 10 renal transplant recipients with persistent hypercholesterolaemia (total cholesterol >240 mg/dl) for a period of 3 months. All of them had already been on statins for at least 3 months. RESULTS: Atorvastatin exerted a satisfactory lipid-lowering effect in seven of 10 patients. On average, serum total cholesterol (311+/-36.2 vs 253+/-48.8 mg/dl; P:<0.05) and serum LDL cholesterol (184+/-30.9 vs 136+/-22.9 mg/dl; P:<0.05) significantly decreased after atorvastatin therapy, whereas serum HDL cholesterol (86+/-14.6 vs 84+/-22.1 mg/dl) remained unchanged. In five subjects with a baseline serum triglyceride level above 150 mg/dl, a marked reduction in triglycerides was also observed (261+/-80.3 vs 193+/-53.3 mg/dl; P:<0.05). Lp(a) did not significantly change (13+/-16.3 vs 15+/-23.9 mg/dl, P:=NS). Serum creatinine, transaminases, creatinine phosphokinase (55+/-21.3 vs 56+/-29.4 IU/l) and fasting cyclosporin A levels were unaffected. The drug was generally well tolerated and neither myositis nor rhabdomyolysis was reported. CONCLUSION: Short-term therapy with the new HMG-CoA reductase inhibitor, atorvastatin, appears to be effective in lowering atherogenic lipids in renal transplant patients who had had little or no response to other statins.     

Pulmonary endothelial dysfunction after cardiopulmonary bypass in neonatal pigs

BACKGROUND: In neonatal pigs cardiopulmonary bypass (CPB) is associated with endothelial dysfunction in isolated large pulmonary arteries. It is, however, of great importance if this functional change extends to the small pulmonary resistance arteries, which are the key regulators of pulmonary flow and pressure. The aim of this study was to assess changes in pulmonary microvascular function after CPB using a clinically relevant pediatric procedure. METHODS: From three groups of neonatal pigs (CPB-, sham- and control group) pulmonary resistance arteries and systemic resistance arteries (from skeletal muscle) were isolated and mounted as ring preparations in wire myographs. Vessel diameters were less than 500 microm. Concentration-response curves were constructed for norepinephrine (NA), vasopressin (Vp), and the thromboxane A2-analog U46619, while the endothelium-dependent and -independent vasodilator functions were assessed as responses to acetylcholine and nitric oxide (NO). RESULTS: Maximum pulmonary vasodilator response to acetylcholine was attenuated after CPB compared with sham-operated and control animals (P=0.04). NO-induced relaxation, and contractile responses to NA, Vp, and U46619 were not influenced by CPB. In systemic arteries no changes in contractile or relaxant responses were seen after CPB. CONCLUSION: CPB seems to induce pulmonary endothelial dysfunction in pulmonary but not peripheral resistance arteries in neonatal piglets.