Comparison between YM099 and captopril in rats with renal mass reduction-induced progressive renal disease

The effects of the ATP-sensitive potassium (KATP) channel opener YM099, and the angiotensin-converting enzyme (ACE) inhibitor captopril, on the progression of renal disease in rats with surgical renal mass reduction (RMR) were evaluated. Rats were subtotal (5/6) nephrectomized by resection of the renal poles. After 2 weeks of RMR, rats were randomized to three groups and treated for 6 weeks: no treatment (n=9); YM099 at a dose of 0.3 mg/kg by daily oral administration (n=9); or captopril at a dose of 50 mg/kg by daily oral administration (n=9). Sham-operated rats were used as normal animals (n=9). In RMR rats with no treatment, proteinuria progressively developed. At 8 weeks after RMR, renal function as assessed by plasma creatinine (Pcr) and blood urea nitrogen (BUN) was impaired. Pharmacological activation of KATP channel opening by YM099 showed no beneficial effect on proteinuria and renal functional parameters. On the other hand, pharmacological ACE inhibition by captopril significantly attenuated proteinuria, and tended to inhibit the increases in Pcr and BUN; however, these effects were not statistically significant. The presents study indicates that YM099 exhibits no renoprotection with antiproteinuric effect in rats with progressive renal disease. These findings suggest that activation of KATP channel opening may play no role in the retardation of progressive renal disease.     

Therapeutic resistance to angiotensin converting enzyme (ACE) inhibition is related to pharmacodynamic and -kinetic factors in 5/6 nephrectomized rats

Proteinuria plays a pathogenic role in the development of end stage renal disease. Angiotensin converting enzyme (ACE) inhibitors lower proteinuria and are renoprotective. However, large inter-individual variation in antiproteinuric response to ACE inhibitors exists. In this study, we explored the mechanism of therapeutic resistance to an ACE inhibitor in the rat 5/6 nephrectomy model. At week 6 after 5/6 nephrectomy, treatment with lisinopril was initiated for 6 weeks. Proteinuria and blood pressure were evaluated weekly. At the end of the experiment, rats were divided into tertiles according to their antiproteinuric response: (1) responders (n=9), (2) intermediate responders (n=8) and (3) non-responders to ACE inhibitor therapy (n=9). At the start of treatment, proteinuria had progressively increased to 154 (95% confidence interval [CI]: 123-185) mg/24 h in the entire cohort, with comparable proteinuria and blood pressure in all groups. Following treatment with ACE inhibitor, proteinuria was significantly lower in the responders (68, CI: 46-89 mg/24 h) compared to the non-responders (251, CI: 83-420) mg/24 h). Similarly, blood pressure was reduced in the responders, but unaffected in the non-responders. At autopsy, renal ACE activity and renal ACE expression were significantly lower in the responders compared to the non-responders. Although lisinopril intake was comparable in all animals, urinary drug excretion was increased in the non-responders, demonstrating increased drug clearance. Average urinary lisinopril excretion was correlated with antiproteinuric response (R(2)=0.32, P=0.003). In conclusion, both pharmacodynamic and -kinetic factors account for the non-response to lisinopril. Whether these can be overcome simply by increasing drug dosage in non-responders should be investigated.     

Acute renal failure during lisinopril and losartan therapy for proteinuria

The use of combined therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) for treatment of proteinuria has been gaining support. Limited data are available regarding this treatment in the pediatric population. This report describes a case of acute compromise of renal function associated with hypotension in a 7-year-old boy treated with the ACE inhibitor lisinopril and the ARB losartan. It emphasizes the need for close surveillance of renal function and blood pressure during such therapy even in patients with relative preservation of renal function. Further investigation into the utility and safety of dual therapy with an ACE inhibitor plus an ARB in pediatric patients is warranted. Key Words: renal failure, proteinuria, angiotensin-converting enzyme inhibitor, ACEI, angiotensin II receptor blocker, ARB.     

单核细胞趋化蛋白-1在肾毒血清肾炎大鼠肾组织中的表达

目的：探讨单核细胞趋化蛋白－（ＭＣＰ－１）在肾毒血清肾炎大鼠肾组织中的表达及其意义。方法肾毒血清肾炎应用兔抗鼠肾小球基底膜肾毒血清制备。采用免疫组化及真彩色计算机图像分析系统观察肾小球及肾小管中ＭＣＰ－１的表达,并分析其与蛋白尿和肾小球细胞数之间的关系。结果肾毒血清肾炎大鼠出现大量蛋白尿,肾小球细胞数明显增多;肾小球及肾小管中ＭＰＣ－１表达显上调,并与肾小球细胞数和蛋白尿密切相关。结论ＭＣＰ－１     

Effects of nonpeptide endothelin receptor antagonists in rats with reduced renal mass

This study was set up to evaluate the long-term effects of nonpeptide endothelin (ET) antagonists in rats with renal mass reduction (RMR). In the first series of experiments, rats were administered bosentan (100 mg/kg/day) or the angiotensin-converting enzyme inhibitor cilazapril (10 mg/kg/day) for 14 weeks beginning 24 h after RMR. As expected, cilazapril completely prevented the development of hypertension, proteinuria, and renal structural damage. In contrast, bosentan had no influence on the development of proteinuria and renal structural damage, although it had a moderate antihypertensive effect and improved creatinine clearance. A second set of experiments was performed to assess whether Ro 48-5695, a very potent ET antagonist optimized from bosentan, could prevent the development of renal damage and reverse established renal damage. Rats received Ro 48-5695 (30 mg/kg/day) beginning either 24 h (prevention) before for 8 weeks, or 4 weeks (reversal) after RMR. Ro 48-5695 attenuated the hypertension and the decline of creatinine clearance when treatment was started at 24 h, but not when started at 4 weeks. Ro 48-5695 had no effect on proteinuria. These observations suggest that ET-receptor activation does not play a major role in the progression of glomerular sclerosis in this model of chronic renal failure.     

Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e. g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n=8; endogenous creatinine clearance [CL_CR]: 18 ml·min^?1·1.73m^?2) and in healthy subjects with normal renal function (n=16; CL_CR: 107 ml·min^?1·1.73m^?2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1–2.2 mg) was adjusted to the individual CL_CR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (C _max) in patients was lower than in volunteers (30.7 vs 40.7 ng·ml^?1, while the mean area under the concentration-time curve (AUC _{0–24 h}) was higher (525 vs 473 ng·h^?1·ml^?1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9–2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose. Despite substantial dose reduction, blood pressure and proteinuria decreases were observed.     

The antiproteinuric effect of ACE inhibition in renal disease

Proteinuria due to non-steroid-responsive renal disease may be harmful. Firstly, because it may cause a nephrotic syndrome, and, secondly, because it is, like hypertension, associated with an increased risk of progressive renal damage and loss of renal function over the years. Until recently, only non-steroidal antiinflammatory drugs (NSAIDs) were available to reduce proteinuria in such patients. Due to their potential side-effects, however, NSAIDs have never been widely used as antiproteinuric agents. In 1985 some studies were published showing that inhibition of angiotensin-converting enzyme (ACE) not only reduced the elevated blood pressure in rats with chronic renal failure (experimentally induced by renal ablation or by induced diabetic nephropathy), but also prevented the development of glomerular damage with proteinuria and loss of renal function in these animals. This beneficial effect of ACE inhibition was attributed to the prevention of glomerular hypertension. At the same time it was reported that ACE inhibition could reduce proteinuria in patients with advanced diabetic nephropathy. ACE inhibitors might thus be an attractive alternative for NSAIDs as antiproteinuric treatment, possibly being renoprotective, and being generally well-tolerated.     

The effect of angiotensin II receptor blockade on an end-stage renal failure model of type 2 diabetes

The effect of olmesartan medoxomil (OLM), an angiotensin II receptor blocker (ARB), on advanced nephropathy and mortality was evaluated in Zucker Diabetic Fatty (ZDF) rats, a type 2 diabetes model. OLM was administered from 36 weeks of age, when the animals developed advanced proteinuria. OLM effectively suppressed the progression of proteinuria. The ZDF rats started to die at 50 weeks of age, which was accompanied by abrupt increase in blood urea nitrogen, suggesting that the cause of death was renal insufficiency. OLM suppressed increases in blood urea nitrogen and increased the survival rate of the ZDF rats. The histological examination revealed that the renal damage was ameliorated by OLM. The macrophage infiltration and monocyte chemoattractant protein-1 (MCP-1) expression was increased in the glomeruli and tubulointerstitium of the ZDF rat kidneys, and the increase was lessened by OLM. In a separate study, albumin increased MCP-1 release from cultured tubular epithelial cells. These results suggest that protein leakage from the glomeruli stimulates MCP-1 production in tubular cells and that MCP-1 released into the interstitial space induces macrophage infiltration and inflammation. It is conceivable that the beneficial actions of ARB on diabetic nephropathy are, at least in part, due to decrease of proteinuria and the subsequent reduction of inflammatory changes in tubular cells.     

High level of proteinuria during treatment with renin-angiotensin inhibitors is a strong predictor of renal outcome in nondiabetic kidney disease

This study investigated whether proteinuria not only could serve as a marker of renal outcome but also could monitor the renoprotection of renin-angiotensin system (RAS) inhibitor treatment in patients with nondiabetic chronic kidney disease (CKD). Data from the Renoprotection of Optimal Antiproteinuric Doses (ROAD) trial were used to examine the contribution of the antiproteinuric effect of benazepril and losartan on renal outcome (the primary composite end point of doubling of serum creatinine and end-stage renal disease or death) in 339 Chinese nondiabetic CKD patients with overt proteinuria and renal insufficiency. The degree of proteinuria at month 6 of treatment (residual proteinuria) and during follow-up (time-average proteinuria) showed a close relationship with renal end points. Lowering of proteinuria reduced the risk of renal progression in patients with high, as well as low, proteinuria at baseline. After adjustment for baseline risk markers, therapy-induced change in these variables at month 6 and during follow-up--high residual proteinuria and time-average proteinuria (≥ 1.0 g/d)--remained the independent predictors for renal end points. Therefore, minimization of proteinuria at least to less than 1.0 g/d should be a therapeutic goal in the management of nondiabetic patients with heavy proteinuria and renal insufficiency.     

Angiotensin converting enzyme (ACE) inhibitors and renal function. A review of the current status

Angiotensin converting enzyme (ACE) inhibitors are well established in the treatment of hypertension and cardiac failure. Experimental studies in rats have suggested that these agents may protect renal function in chronic nephropathy by a mechanism other than simply lowering the systemic blood pressure. In human studies of incipient diabetic nephropathy, worsening of microalbuminuria was prevented during 3 years of ACE inhibition. ACE inhibitors reduce arterial blood pressure in chronic nephropathy, and may cause a fall in glomerular filtration rate. In diabetic nephropathy, proteinuria was reduced by 2 months' treatment with enalapril to less than half of the values obtained in a control group treated with metoprolol. Nonrandomised trials have suggested that ACE inhibitors may slow the deterioration of renal function, but no comparisons with other antihypertensive agents in prospective studies have been published to date. In chronic renal failure, ACE inhibitors may worsen anaemia and hyperkalaemia. Renovascular hypertension can be treated with ACE inhibitors, but the treatment may lead to a compromised renal function. The dosage of these drugs should be reduced in renal failure and therapy should be started cautiously in this setting, with close monitoring of blood pressure, renal function and plasma potassium.     

Retinoids as a potential treatment for experimental puromycin-induced nephrosis

1 Puromycin aminonucleoside (PAN)-induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic-range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types. 2 Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all-trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte. 3 Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti-inflammatory effect of tRA was evidenced by the inhibition of PAN-induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein-1. TUNEL assays showed that tRA inhibited the PAN-induced apoptosis of cultured differentiated mouse podocytes. 4 We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.     

福辛普利对慢性肾功能衰竭幼鼠凝血纤溶变化的干预影响

目的探讨血管紧张素转换酶抑制剂(ACEI)——福辛普利干预治疗对幼年大鼠慢性进展性肾脏病变过程中肾组织组织型纤溶酶原激活物(tPA)、组织型纤溶酶原激活物特异性抑制剂(PAI)-1蛋白表达的影响。方法以5/6肾切除SD大鼠为实验动物模型,予ACEI治疗12周后分别检测大鼠体重、血压、血尿生化及残肾组织常规病理和用免疫组织化学染色定性定量评价残肾tPA、PAI-1蛋白表达。结果于5/6肾切除后,大鼠肾功能进行性丧失,表现为尿蛋白、血压、血尿素氮(BUN)、肌酐(Scr)及血脂增高,残肾组织出现肾小球硬化和间质纤维化。免疫组织化学染色提示肾组织PAI-1表达增高,而tPA表达下降。经ACEI治疗后,大鼠肾功能改善、血压下降、尿蛋白下降、残肾组织tPA蛋白表达增加、PAI-1表达下降。结论ACEI具有改善5/6肾切除大鼠凝血纤溶系统紊乱的作用。     

RAS blockade in experimental renal transplantation. Benefits and limitations

In renal transplantation, chronic renal transplant failure (CRTF) is the principal cause of late graft loss. Both immunological and non-immunological factors play a role in the pathogenesis of CRTF. However, CRTF is unresponsive to immunosuppressive therapy. In several kidney diseases, inhibition of the renin-angiotensin system (RAS) has shown to reduce the rate of progression of renal disease more effectively than conventional antihypertensive drugs. Therefore, RAS blockade may be of benefit in the treatment of CRTF. Several short-term studies in human renal transplant recipients showed that RAS blockade had a beneficial effect on renal transplant function, blood pressure and proteinuria. Despite these benefits physicians remain reluctant to use ACE inhibition in these recipients, because of fear of functional decrease in renal perfusion, especially in the setting of renal transplant artery stenosis. To study the long-term effects of RAS blockade we used the established Fisher to Lewis (F-L) model for CRTF, which mirrors the progressive changes seen in humans. Studies in our lab and by others showed that RAS blockade in the F-L model prevents proteinuria, glomerulosclerosis and hypertension. However, when treated for 34 weeks with RAS blockade, renal arteries developed severe intimal hyperplasia. This effect was specific for Fisher rats. Syngrafted Fisher rats treated with ACE inhibition developed intimal hyperplasia, but allografting significantly aggravated it. Fisher rats have a four times higher renal ACE activity, compared with the Lewis rat. This is comparable to the human DD/II genotype differences in ACE activity. Renal transplant patients with the DD genotype may be more vulnerable for vascular changes when treated with RAS blockade.     

Pharmacokinetics and antihypertensive effects of lisinopril in hypertensive patients with normal and impaired renal function.

The antihypertensive effects and pharmacokinetic properties of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, were investigated in hypertensive patients with normal renal function (NRF, mean serum creatinine 1.0 mg/dl, n = 9) and those with impaired renal function (IRF, mean serum creatinine 1.7 mg/dl, n = 8). Lisinopril was administered orally (10-mg dose once daily for 5 or 8 days). Measurement of blood pressure (BP) and sampling of blood specimens were made on the first and last days of treatment. During consecutive dosing of lisinopril, its antihypertensive effects were sustained for greater than or equal to 12 h with less diurnal variation of BP. Serum ACE activity was markedly suppressed for 24 h. Plasma levels of lisinopril in the IRF group were higher than those in NRF with significant differences in the peak levels and areas under the plasma concentration time curve (AUC). A significant inverse correlation was found between the creatinine clearance and the AUC for lisinopril. These results suggest that lisinopril has a long-lasting action and that it is a useful antihypertensive agent for controlling BP in patients with either NRF or mild IRF. When administered for an extended period, however, more careful consideration should be given to the dose in patients with IRF than in patients with NRF to minimize the possibility of untoward side effects.     

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance 相似文献   

黄芪丹参茯苓龟板合剂对大鼠肾间质纤维化的抑制作用

目的 探讨黄芪丹参茯苓龟板合剂对肾间质纤维化进展过程的干预作用及其机制.方法 通过单侧输尿管梗阻法建立肾间质纤维化的大鼠模型,实验分为假手术(Sham) 组、单侧输尿管梗阻 (UUO) 组、血管紧张素转换酶抑制剂(ACEI) 组及黄芪丹参茯苓龟板合剂(中药)组,术后第14天取大鼠肾组织进行常规HE、Masson染色及C...     

Protection of Renal Function with ACE Inhibitors: Experience with Benazepril

Research into progressive renal scarring has been closely linked over the last two decades with angiotensin II (AII). This has led to a better understanding of the mechanisms underlying the development of glomerulosclerosis and tubulointerstitial scarring. AII appears to play an important role in the pathogenesis of both; this may be because of either a direct proliferative and fibrogenic effect of AII or an indirect effect mediated by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF(beta1)). These findings have led to significant therapeutic advances as ACE inhibition prevents the progression of experimental renal scarring and attenuates the progression of chronic renal failure in humans. Benazepril, through its metabolite benazeprilat, is a non-sulfhydryl orally active ACE inhibitor. The kinetics of benazeprilat are substantially affected by severe renal impairment; for patients with a creatinine clearance of <30 ml/min the initial recommended daily dose is 5mg. The angiotensin converting enzyme inhibition in a progressive renal insufficiency (AIPRI) study confirmed that benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases and that this treatment is well tolerated.     

Slowing the progression of adult chronic kidney disease: therapeutic advances

When kidney disease of any aetiology results in substantial loss of nephrons, a common clinical syndrome, characterised by hypertension, proteinuria and a progressive decline in renal function, ensues. This observation suggests that common mechanisms may contribute to progressive renal injury and that therapeutic interventions that inhibit these common pathways may afford renal protection. Research to date has identified several mechanisms that may contribute to progressive renal injury including glomerular haemodynamic changes, multiple effects of angiotensin II and detrimental effects of excessive filtration of plasma proteins by injured glomeruli. Clinical trials over the past decade have identified several interventions that are effective in slowing the rate of progression of chronic kidney disease (CKD). The use of ACE inhibitors, angiotensin receptor antagonists or a combination of the two should be regarded as fundamental to any therapy for slowing the rate of CKD progression. Hypertension should be treated aggressively to achieve a blood pressure target of < 130/80 mm Hg. Reduction of proteinuria to < 0.5 g/day should be regarded as an independent therapeutic goal. Although inconclusive, there is some evidence to support moderate dietary protein restriction to 0.6 g/kg/day in appropriate patients. Hyperlipidaemia may contribute to CKD progression and should be treated to reduce cardiovascular risk and potentially improve renal protection. Smoking cessation should be encouraged and, where necessary, assisted. Among diabetic patients tight glycaemic control should be achieved (glycosylated haemoglobin < 7%). These interventions are simple and relatively inexpensive. If applied to all patients with CKD they will result in substantial slowing of renal function decline in many patients and thereby reduce the number who progress to end-stage renal disease and require renal replacement therapy.     

Anaemia due to ACE inhibitors and losartan in patients with renal failure

(1) Angiotensin-converting-enzyme inhibitors (ACE inhibitors) can cause or aggravate anaemia in patients with chronic renal failure (especially those on dialysis) and in renal graft recipients. (2) In these settings, ACE inhibitor therapy can increase epoetin consumption. (3) Similar reports have been made with losartan, an angiotensin II receptor antagonist. (4) The risk-benefit ratio of ACE inhibitors and angiotensin II receptor antagonists in patients with chronic renal failure should be regularly reassessed.