enalapril and Proteinuria

Amyloidosis secondary to juvenile idiopathic arthritis is a known complication of poorly controlled systemic juvenile idiopathic arthritis (SJIA), occurring in 1-2% of the patients. The IL-6 inhibitor tocilizumab is effective in controlling systemic signs and symptoms of sJIA and may be of therapeutic benefit in secondary amyloidosis. Herein, we report the clinical timeline of a 10-year boy with sJIA and secondary amyloidosis, who showed a sustained improvement of systemic symptoms and a reduction in proteinuria with tocilizumab. Compared to the data on adult patients affected with the secondary amyloidosis, there are very few reports on therapeutic options for the children affected with SJIA and secondary amyloidosis in the paediatric population. While doing a systematic literature search for writing this review, we could only retrieve nine case reports and one case series of the children affected with SJIA and secondary amyloidosis, including five cases which were treated with tocilizumab. We also looked into the clinical and biochemical response to various agents that have been used in the previous cases, including tocilizumab. The available literature and the present case report suggest that tocilizumab may be considered as a safe and effective option to treat SJIA-related secondary amyloidosis.

Topics: Amyloidosis; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Antirheumatic Agents; Arthritis, Juvenile; Child; Cyclophosphamide; Enalapril; Humans; Hypertension; Kidney Diseases; Male; Proteinuria

The pathogenesis of renal involvement in Wiskott-Aldrich syndrome (WAS) is unclear and renal outcome is generally poor in such situations. Here we present the case of an 8-year-old boy with WAS who developed hematuria, proteinuria, and declining renal function that did not improve with the combined use of immunosuppressive agents and angiotensin-converting-enzyme inhibitor. Renal pathology revealed IgA nephropathy (IgAN). The patient underwent splenectomy for refractory thrombocytopenia. The proteinuria remitted and renal function improved after splenectomy, long-term antibiotic prophylaxis, and tapering of immunosuppressive agents.

Topics: Angiotensin-Converting Enzyme Inhibitors; Child; Enalapril; Glomerulonephritis, IGA; Hematuria; Humans; Immunosuppressive Agents; Male; Proteinuria; Splenectomy; Thrombocytopenia; Wiskott-Aldrich Syndrome

Management of hypertension is the mainstay of prevention and treatment of diabetic renal disease; evidence suggests that tight blood pressure control slows renal disease progression in established diabetic nephropathy. Inhibition of the renin-angiotensin-aldosterone system (RAAS) has renoprotective effects over and above those achieved by lowering systemic blood pressure. To date, however, no long-term study using hard end points has directly compared current mechanisms for RAAS inhibition, angiotensin II receptor blockade (ARB) and angiotensin-converting enzyme (ACE) inhibition. This issue was addressed in the recently published Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study, a head-to-head comparison of telmisartan and enalapril in 250 patients with hypertension and type 2 diabetes mellitus and early-stage nephropathy. After 5 years' treatment, change in glomerular filtration rate (GFR), the primary efficacy end point, was equivalent in the 2 treatment groups, as were all secondary end points. The expected steep decline in GFR in the first year was followed by a lesser decrease in the second year and then almost complete stabilization of renal function at > or =3 years. Over 5 years, no patient went into end-stage renal disease or required dialysis. There were also no increases in albumin excretion rate, nor was there an increase in creatinine beyond 200 mumol/L. Incidence of cardiovascular morbidity and mortality was extremely low in both treatment groups, a remarkable outcome given that almost 50% of patients had evidence of cardiovascular disease at randomization. Inhibition of the RAAS should play a major part in management of patients with type 2 diabetes with nephropathy, for which both telmisartan and enalapril provide long-term renoprotection.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Agents; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan; Time Factors; Treatment Outcome

Blood pressure and proteinuria are important determinants of progressive renal failure in patients with renal diseases. In a 53-year-old man with hypertension and nephrotic-range proteinuria, lowering the blood pressure to a value of 125/75 mmHg resulted in a disappearance of the proteinuria. Recent literature data indicate that the treatment of blood pressure in patients with proteinuria, with emphasis on the benefits of reaching a blood pressure target of 125/75 mmHg and the use of angiotensin-converting enzyme inhibitors, may lead to a serious improvement in their prognosis.

Topics: Antihypertensive Agents; Atenolol; Chlorthalidone; Dose-Response Relationship, Drug; Enalapril; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Male; Middle Aged; Obesity; Proteinuria; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Enalapril; Heart Failure; Humans; Hypertension; Lisinopril; Proteinuria

Angiotensin-converting enzyme inhibitory therapy is widely used to treat hypertension. With long-term use, it is now being shown to have a beneficial effect on renal function and proteinuria in patients with renal insufficiency. When hypertensive patients with renal insufficiency are treated with enalapril, glomerular filtration rate is maintained, effective renal plasma flow is increased, and microalbuminuria and gross proteinuria are reduced. These beneficial renal changes with enalapril therapy differ from those of most other conventional antihypertensive medications. Clinical awareness of potential problems with hyperkalemia and increasing azotemia, particularly in the setting of salt/volume depletion, is important to assure optimal patient management. When these problems occur, they are nearly always reversible by correcting salt/volume status and/or interrupting enalapril therapy.

Topics: Aged; Blood Pressure; Captopril; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Hypertension, Renovascular; Kidney Diseases; Male; Middle Aged; Proteinuria; Time Factors

Visceral adiposity index (VAI) is a sex-specific surrogate marker of adipose tissue distribution and function. Little is known about the longitudinal relationship between VAI and proteinuria. This study aimed to examine the prospective relationship of baseline VAI with new-onset of proteinuria in hypertensive patients without major cardiovascular diseases.. A total of 10 699 hypertensive patients without proteinuria (negative urine dipstick reading) at baseline from the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT) were included. Participants were randomly assigned to a double-blind daily treatment with 10 mg enalapril and 0.8 mg folic acid or 10 mg enalapril alone. Participants were followed every 3 months after randomization. The primary outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. The secondary outcome was progression of proteinuria, defined as a urine dipstick reading of trace or ≥1+ at the exit visit.. During a median follow-up duration of 4.4 years, a total of 396 (3.7%) participants developed new-onset proteinuria, while 1236 (11.6%) participants met progression of proteinuria. When VAI was categorized into quartiles, compared with participants in quartile 1-3 (<2.99), a significantly higher risk of new-onset proteinuria (OR, 1.43; 95%CI: 1.07-1.91) and progression of proteinuria (OR, 1.23; 95%CI: 1.03-1.46) was found in those in quartile 4 (≥2.99). Moreover, the positive association was consistent in participants with or without general obesity, abdominal obesity, and dyslipidemia (all P-interactions > 0.05).. There was a positive association between VAI levels and the risk of new-onset proteinuria in hypertensive patients.

Topics: Adiposity; Aged; Antihypertensive Agents; Biomarkers; Body Mass Index; Double-Blind Method; Enalapril; Female; Folic Acid; Humans; Hypertension; Intra-Abdominal Fat; Male; Middle Aged; Obesity, Abdominal; Prospective Studies; Proteinuria

We aimed to examine whether baseline neutrophil counts affected the risk of new-onset proteinuria in hypertensive patients, and, if so, whether folic acid treatment is particularly effective in proteinuria prevention in such a setting. A total of 8208 eligible participants without proteinuria at baseline were analysed from the renal substudy of the China Stroke Primary Prevention Trial. Participants were randomised to receive a double-blind daily treatment of 10 mg of enalapril and 0·8 mg of folic acid (n 4101) or 10 mg of enalapril only (n 4107). The primary outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. The mean age of the participants was 59·5 (sd, 7·4) years, 3088 (37·6 %) of the participants were male. The median treatment duration was 4·4 years. In the enalapril-only group, a significantly higher risk of new-onset proteinuria was found among participants with higher neutrophil counts (quintile 5; ≥4·8 × 109/l, OR 1·44; 95 % CI 1·00, 2·06), compared with those in quintiles 1-4. For those with enalapril and folic acid treatment, compared with the enalapril-only group, the new-onset proteinuria risk was reduced from 5·2 to 2·8 % (OR 0·49; 95 % CI 0·29, 0·82) among participants with higher neutrophil counts (≥4·8 × 109/l), whereas there was no significant effect among those with neutrophil counts <4·8 × 109/l. In summary, among hypertensive patients, those with higher neutrophil counts had increased risk of new-onset proteinuria, and this risk was reduced by 51 % with folic acid treatment.

Topics: Aged; Antihypertensive Agents; Double-Blind Method; Enalapril; Female; Folic Acid; Humans; Hypertension; Leukocyte Count; Male; Middle Aged; Neutrophils; Proteinuria

Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children.. We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR.. SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months.. Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria.

Topics: Adult; Antihypertensive Agents; Child; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Losartan; Prospective Studies; Proteinuria; Uric Acid

The association of the combination of body mass index (BMI) and waist circumference (WC) with the risk of proteinuria has previously not been comprehensively investigated and results have been inconclusive.. To examine BMI and WC in relation to new-onset proteinuria in Chinese hypertensive patients.. Post hoc analysis of the renal substudy of the China Stroke Primary Prevention Trial (CSPPT).. 10 805 hypertensive patients without proteinuria at baseline.. The primary outcome was new-onset proteinuria, defined as a urine dipstick protein reading ≥ 1 + at the exit visit, after a median follow-up duration of 4.4 years.. When analyzed separately, increased BMI (≥ 28 kg/m2, quartile 4; odds ratio [OR], 1.36; 95% confidence interval [CI], 1.08-1.72), or increased WC (≥ 91cm for females, quartile 4; OR, 1.35; 95% CI, 1.01-1.80; and ≥ 79 cm for males, quartile 2-4; OR, 1.60; 95% CI, 1.03-2.50) were each significantly associated with higher risk of new-onset proteinuria. When analyzed jointly, participants without increased BMI and increased WC had the lowest risk, while those with both increased BMI and increased WC had the highest risk of proteinuria (OR, 1.61; 95% CI, 1.21-2.13). Notably, participants with only increased WC also had significantly increased risk of proteinuria (OR, 1.39; 95% CI, 1.04-1.85).. In Chinese hypertensive patients, increased BMI and increased WC were individually and jointly associated with a higher risk of new-onset proteinuria, underscoring the value of monitoring both BMI and WC in assessing proteinuria risk.

Topics: Aged; Antihypertensive Agents; Body Mass Index; China; Drug Therapy, Combination; Enalapril; Female; Folic Acid; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Proteinuria; Risk Factors; Waist Circumference

We aimed to evaluate whether proteinuria and estimated glomerular filtration rate (eGFR) levels can modify the efficacy of folic acid therapy on the risk of all-cause mortality among hypertensive patients in the China Stroke Primary Prevention Trial, a randomized, double-blind, and controlled trial.. A total of 20 702 hypertensive patients without a history of major cardiovascular diseases were randomly assigned to a double-blind daily treatment of a single tablet containing 10-mg enalapril and 0.8-mg folic acid (n = 10 348), or 10-mg enalapril alone (n = 10 354). All-cause mortality, a prespecified endpoint of the China Stroke Primary Prevention Trial, was the main outcome in this analysis.. Over a median treatment duration of 4.5 years, in the enalapril alone group, both heavy proteinuria [vs. absent, 10.8 vs. 2.7%; hazard ratio = 3.30; 95% confidence interval (CI): 2.10-5.18] and lower eGFR levels (<60 vs. ≥90 ml/min per 1.73 m, 13.0 vs. 2.2%; hazard ratio = 1.93; 95% CI: 1.19-3.12) were significantly associated with increased risk of all-cause mortality. Folic acid supplementation significantly reduced the risk of all-cause mortality in patients with heavy proteinuria (6.4% in the enalapril-folic acid vs. 10.8% in the enalapril alone group, hazard ratio = 0.49; 95% CI: 0.26-0.94), but not in those with absent or mild proteinuria (2.8 vs. 2.9%, hazard ratio = 0.99; 95% CI: 0.84-1.17; P for interaction = 0.040). However, eGFR levels did not significantly modify the effect of folic acid supplementation in reducing the risk of all-cause mortality (P for interaction = 0.228).. Among hypertensive patients without a history of major cardiovascular diseases, folic acid therapy could reduce the mortality risk associated with heavy proteinuria.

Topics: Aged; Double-Blind Method; Drug Combinations; Enalapril; Female; Folic Acid; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Proportional Hazards Models; Proteinuria; Risk; Vitamin B Complex

We aimed to test the hypothesis that treatment with enalapril and folic acid is more effective in preventing new-onset proteinuria than enalapril alone among hypertensive patients. This is a post hoc analysis of the renal substudy of the CSPPT (China Stroke Primary Prevention Trial). A total of 13 071 eligible participants without proteinuria were randomized to receive a double-blind daily treatment of a single tablet containing 10-mg enalapril and 0.8-mg folic acid (n=6511) or 10-mg enalapril alone (n=6560). The primary outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. Secondary outcomes included a composite of the primary outcome and all-cause death and the annual rate of estimated glomerular filtration rate decline. After a median 4.4 years of treatment, the primary event occurred in 213 (3.9%) and 188 (3.5%) participants, respectively, in the enalapril and the enalapril-folic acid group (odds ratio, 0.90; 95% confidence interval, 0.74-1.11). However, among participants with diabetes mellitus at baseline, folic acid therapy resulted in a significant reduction in the risk for the primary event (3.7% in the enalapril-folic acid group versus 7.4% in the enalapril group; odds ratio, 0.48; 95% confidence interval, 0.29-0.81) and the composite event (odds ratio, 0.62; 95% confidence interval, 0.42-0.92) and a 55% slower annual rate of estimated glomerular filtration rate decline (0.5% versus 1.1% per year;. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00794885.

Topics: Aged; Antihypertensive Agents; China; Double-Blind Method; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Enalapril; Female; Folic Acid; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Mortality; Proteinuria; Treatment Outcome; Urinalysis; Vitamin B Complex

To evaluate the efficacy of enalapril treatment on decline in glomerular filtration rate and reduction in proteinuria in children with chronic kidney disease (CKD).. Open-label, randomized controlled trial.. Pediatric nephrology clinic at a tertiary-care referral hospital.. Children with GFR between 15-60 mL/min/1.73 m2 were randomized to receive either enalapril at 0.4 mg/kg /day or no enalapril for 1 year.. Change in GFR using 99mTc-DTPA and urine protein to creatinine ratio. Secondary outcomes included occurrence of composite outcome (30% decline in GFR or end stage renal disease) and systolic and diastolic blood pressure SDS during the study period.. 41 children were randomized into two groups; 20 received enalapril while 21 did not receive enalapril. During 1 year, GFR decline was not different in the two groups (regression coefficient (r) 0.40, 95% CI -4.29 to 5.09, P=0.86). The mean proteinuria reduction was 65% in the enalapril group, significantly higher than control group. The difference was significant even after adjustment for blood pressure was 198.5 (CI 97.5, 299.3; P<0.001). 3 (17.6%) patients in enalapril and 7 (36.8%) in non-enalapril group attained the composite outcome.. Enalapril is effective in reducing proteinuria in children with CKD and might be renoprotective in proteinuric CKD.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic

A previous subgroup analysis of a 12-week, double-blind study demonstrated that losartan significantly lowered proteinuria versus placebo and amlodipine and was well tolerated in children (1-17 years old) with proteinuria secondary to Alport syndrome. The present subgroup analysis of the open-label, extension phase of this study assessed the long-term efficacy and tolerability of losartan versus enalapril.. Patients who had completed the double-blind study were re-randomized to losartan or enalapril and followed for proteinuria and renal function for up to 3 years.. Twenty-seven patients with Alport syndrome were randomized to losartan (0.44-2.23 mg/kg/day; n = 15) or enalapril (0.07-0.72 mg/kg/day; n = 12). The least-squares (LS) mean percent change from week 12 in urinary protein to creatinine ratio (UPr/Cr was +1.1 % in the losartan group versus a further 13.9 % reduction in the enalapril group (GMR [95 % CI] = 1.2 [0.7, 2.0]); the LS mean change from week 12 in estimated glomerular filtration rate (eGFR) was -6.4 ml/min/1.73 m(2) in the losartan group versus -9.1 ml/min/1.73 m(2) in the enalapril group. The adverse event incidence was low and comparable in both treatment groups.. In children with proteinuria secondary to Alport syndrome, losartan maintained proteinuria reduction, and enalapril produced a further proteinuria reduction over the 3-year study period. Both agents were generally well tolerated.

Topics: Adolescent; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Asia; Biomarkers; Child; Child, Preschool; Creatinine; Double-Blind Method; Enalapril; Europe; Female; Glomerular Filtration Rate; Humans; Infant; Kidney; Least-Squares Analysis; Losartan; Male; Nephritis, Hereditary; Proteinuria; South America; Time Factors; Treatment Outcome; United States

Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor blockers delay progression of chronic kidney disease and have antiproteinuric effects beyond their effects on blood pressure. They are routinely used in adults; however, their efficacy and safety in children, in whom the causes of chronic kidney disease are significantly different relative to adults, is uncertain. Here we assessed an open-label extension of a previous 3-month blinded trial, in which the efficacy and tolerability of losartan was compared to placebo or amlodipine in 306 normotensive and hypertensive children with proteinuria. In this study, 268 children were re-randomized to losartan or enalapril and followed until 100 patients completed 3 years of follow-up for proteinuria and renal function. The least squares percent mean reduction from baseline in the urinary protein/creatinine ratio was 30.01% for losartan and 40.45% for enalapril. The least squares mean change from baseline in eGFR was 3.3 ml/min per 1.73 m2 for losartan and 7.0 ml/min per 1.73 m2 for enalapril. The incidence of specific adverse events such as hyperkalemia and renal dysfunction was low and similar in both groups. Both were generally well tolerated and, overall, fewer drug-related adverse events occurred with losartan than with enalapril. Thus, in children with proteinuria, losartan and enalapril significantly reduced proteinuria without any appreciable changes in eGFR, effects that were maintained throughout the study. Both losartan and enalapril were generally well tolerated.

Topics: Adolescent; Age Factors; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Child; Child, Preschool; Creatinine; Cystatin C; Enalapril; Female; Glomerular Filtration Rate; Humans; Least-Squares Analysis; Losartan; Male; Proteinuria; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Proteinuria is the main indicator of renal disease progression in many chronic conditions. There is currently little information available on the efficacy, safety, and individual tolerance of patients with post-diarrheal hemolytic uremic syndrome (D+ HUS) nephropathy to therapies involving diet, enalapril, or losartan. A multicenter, double-blind, randomized controlled trail was conducted to evaluate the effect of a normosodic-normoproteic diet (Phase I) and the effect of normosodic-normoproteic diet plus enalapril (0.18-0.27 mg/kg/day) or losartan (0.89-1.34 mg/kg/day) (Phase II) on children with D+ HUS, normal renal function, and persistent, mild (5.1-49.9 mg/kg/day) proteinuria. Dietary intervention reduced the mean protein intake from 3.4 to 2.2 mg/kg/day. Of 137 children, proteinuria normalized in 91 (66.4 %) within 23-45 days; the remaining 46 patients were randomized to diet plus placebo (group 1, n = 16), plus losartan (group 2, n = 16), or enalapril (group 3, n = 14). In groups 1, 2, and 3, proteinuria was reduced by 30.0, 82.0, and 66.3%, respectively, and normalized in six (37.5%), three (81.3%), and 11 (78.6%) patients, respectively (χ(2)= 8.9, p = 0.015). These results suggest that: (1) a normosodic-normoproteic diet can normalize proteinuria in the majority of children with D+ HUS with mild sequelae, (2) the addition of enalapril or losartan to such dietary restrictions of protein further reduces proteinuria, and (3) these therapeutic interventions are safe and well tolerated. Whether these short-term effects can be extended to the long-term remains to be demonstrated.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Diarrhea; Diet Therapy; Double-Blind Method; Enalapril; Female; Hemolytic-Uremic Syndrome; Humans; Kidney Failure, Chronic; Losartan; Male; Proteinuria

The combination of an ACE inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) has been proposed for the treatment of diabetic nephropathy (DN), but doubts remain about its efficacy and safety. We compared the effects of combination therapy and ACEI monotherapy on proteinuria and on three urinary inflammatory cytokines (MCP-1, TGF-beta and VEGF).. 56 patients with macroalbuminuric DN received 40 mg/d enalapril for 4 months, followed by add-on 100 mg/day losartan or placebo for another 4 months. The primary and secondary endpoints were reduction of proteinuria and cytokine levels, respectively.. Proteinuria did not fall in either group. Repeated measures ANOVA revealed no difference between groups. A high side effect rate was observed (28.5%). Finally, unadjusted logistic regression showed no difference between groups, but after adjustments the risk of worsening proteinuria was higher in the combination therapy group (p = 0.04). The same pattern was observed for urinary MCP- 1.. These results suggest that 1) in advanced DN with severe proteinuria and poor metabolic control, angiotensin II blockade may be less effective than in other groups of CKD patients. 2) In such patients, combination therapy may not afford superior renoprotection compared to enalapril. 3) Urinary MCP-1 is a promising biomarker for the response to ACEI and/or ARB treatment and for the risk of associated unwanted effects.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Chi-Square Distribution; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Logistic Models; Losartan; Male; Middle Aged; Proteinuria; Social Class; Treatment Outcome

Blocking the renin-angiotensin system (RAS) with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors protects against renal injury in patients with chronic kidney disease (CKD). The aim of this study was to compare the chronic effects of telmisartan and enalapril on proteinuria, urinary liver-type fatty acid-binding protein (L-FABP) and endothelin (ET)-1 levels in patients with mild CKD.. Thirty CKD patients with mild to moderate renal insufficiency (20 men and 10 women; mean age, 37 years; estimated glomerular filtration rate (eGFR) > 60 mL min(-1) and blood pressure > 130/85 mmHg) were included in the study. Patients were randomly assigned to receive telmisartan at 80 mg day(-1) (n = 15) or enalapril at 10 mg day(-1) (n = 15). We measured blood pressure, serum creatinine, eGFR, urinary protein, L-FABP and ET-1 before the start of treatment and 6 and 12 months after the start of treatment.. The blood pressure reduction rate was similar between the two groups. Urinary protein, L-FABP and ET-1 levels were significantly reduced in both groups 6 and 12 months (P < 0.001) after treatment, but the reduction rates were more pronounced in patients receiving telmisartan than in those receiving enalapril (P < 0.001). Estimated glomerular filtration rate was increased similarly in both groups at 12 months.. The study results suggest that telmisartan results in a greater reduction of urinary markers than does enalapril and that this effect occurs by a mechanism independent of blood pressure reduction. It would be needed to investigate whether the differences may be distinct or not the same when other dosages are used.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Creatinine; Enalapril; Endothelin-1; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Proteinuria; Telmisartan

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) have been shown to delay the progression to proteinuria and kidney failure in hypertensive type 2 diabetic patients with diabetic nephropathy. Further synergistic effect may be obtained by combined therapy with both ARB and ACE inhibitors.. To evaluate the effect of dual blockage of the renin-angiotensin system by adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients with diabetic nephropathy.. Type 2 diabetic patients with urine protein/creatinine (UPCr) > 0.5 gm/gm and hypertension who received maximal recommended dose of ACE inhibitors (Enalapril 40 mg/day) over three months were randomized to two groups. ARB group received adding maximal recommended dose of ARB (Telmisartan 80 mg/day) and control group received previous ACE inhibitors only for 24 weeks.. Eighty patients were enrolled. ARB group led to significantly reduced UPCr from baseline at week 8, 12, and 24 (2.65 +/- 1.81, 2.24 +/- 1.85, 2.24 +/- 1.88 and 1.98 +/- 1.73 gm/gm respectively, p < 0.05) but UPCr in the control group was unchanged (1.97 +/- 1.56, 1.85 +/- 1.27, 1.97 +/- 1.11 and 1.96 +/- 1.42 gm/gm respectively, p > 0.05). ARB group induced an additional reduction in proteinuria of 29.25% (95% CI 9.68-48.82) compared with control group. By the end of the present study, glomerular filtration rate had fallen from 41.76 +/- 12.16 to 37.84 +/- 13.59 ml/min/1.73 m2 in ARB group and 50.89 +/- 29.43 to 49.41 +/- 29.85 ml/min/1.73 m2 in control group (p > 0.05). Serum potassium had changed from 4.51 +/- 0.48 to 4.58 +/- 0.13 mEq/L in ARB group and 4.60 +/- 0.58 to 4.40 +/- 0.13 mEq/L in the control group (p > 0.05). No other serious adverse effects were reported during treatment.. Adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients can reduce proteinuria more than ACE inhibitors alone. This treatment is safe and well tolerated.

Topics: Adult; Aged; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Drug Synergism; Drug Therapy, Combination; Enalapril; Female; Humans; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Telmisartan; Treatment Outcome

A prospective, open label, parallel group and randomized study was conducted to see the effect of enalapril and losartan on proteinuria in type 2 diabetic nephropathy patients. 18 patients (proteinuria 2 0.5 gm/day and serum creatinine <3 mg/dL) were selected and then randomly grouped to receive enalapril (5-40 mg/day, n=10) and losartan (25-200 mg/day, n=8) in increasing dose for 16 weeks. No statistically significant alteration in the urinary total protein, protein creatinine ratio, serum creatinine, estimated glomerular filtration rate, serum potassium and blood pressure was observed in any group. After attaining maximum dose (40 mg and 200 mg respectively), enalapril group showed significant (p < 0.04) reduction of protein creatinine ratio in comparison to losartan group. It may be concluded that 40 mg enalapril or 200 mg losartan are not sufficient to reduce proteinuria and blood pressure significantly in type 2 proteinuric diabetics with renal dysfunction although both drugs were well tolerated at high doses.

Topics: Aged; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Humans; Losartan; Middle Aged; Prospective Studies; Proteinuria

To investigate the clinical effect of combined use of enalapril (an angiotensin converting enzyme inhibitor, ACEI) and Bailing Capsule (a Chinese herbal preparation made by fermented cordyceps sinensis, BLC) on renal function in patients with chronic allograft nephropathy (CAN) for seeking an effective therapy to control CAN progression.. Eighty-four CAN patients were randomly assigned to four groups, the 22 patents in group A treated with combined treatment of enalapril (10 mg/d) and BLC (2.0 g, twice a day); 20 in group B with enalapril alone; 21 in group C with BLC alone; and 21 in group D with the previously used immunosuppressive agents for control. Levels of serum creatinine (SCr), blood urea nitrogen (BUN), clearance of creatinine (CCr), 24 h urinary protein (24 h Upro) and urinary transforming growth factor beta1 (TGF-beta1) in all patients were measured before treatment, and after 6-and 9-month treatment.. CCr was improved in patients of group A after 6-month treatment accompanied with decrease of SCr, 24 h Upro and urinary TGF-131 (P < 0.05), the latter 3 indexes were lower than in group D, and there was no difference among group A-C. These indexes in patients of group A, B, and C were further improved after treatment for 9 months (P < 0.01), whereas they worsened in patients of group B (P < 0.05). and the cases of patients with renal function improving or stable condition were more in group A than those in group B.. Combined treatment of enalapril and BLC has better efficacy than using enalapril or BLC alone in reducing excretion of urinary protein, improving or stabilizing the function of graft kidney, and retarding CAN progression.

Topics: Adult; Aged; Blood Urea Nitrogen; Capsules; Creatinine; Drug Therapy, Combination; Drugs, Chinese Herbal; Enalapril; Female; Humans; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Proteinuria; Urine; Young Adult

Randomized clinical trials on progression of renal diseases usually include patients according to criteria for BP, renal function, and proteinuria. There are no data showing that this provides groups with similar baseline rates of renal function loss. Accordingly, the impact of preintervention rate of renal function loss (slope) on outcome of studies has not been established.. Preintervention slope was established in 60 of 89 renal patients without diabetes in whom a 4-yr prospective, randomized intervention had been performed (enalapril versus atenolol), and whether (1) preintervention slope was distributed equally over the groups; (2) treatment benefit, defined as slope improvement, corresponded to study outcome; and (3) preintervention slope was a determinant of intervention slope were analyzed.. The preintervention slope was different in the groups: -3.7 +/- 3.2 in the group to receive enalapril versus -2.2 +/- 3.3 ml/min per yr in the group to receive atenolol. The intervention slopes were similar: -1.9 +/- 0.8 enalapril and -1.8 +/- 0.7 ml/min per yr atenolol. Accordingly, slope improved during enalapril only. When analyzed by angiotensin-converting enzyme (I/D) genotype, slope improvement was found only in DD genotype. On multivariate analysis, the preintervention slope was a main predictor of the intervention slope.. Differences in preintervention slope are relevant to outcome of trials and can induce bias. For future studies, allocation according to preintervention slope, although time-consuming, may be useful to allow conduction of more valid studies in a smaller number of patients.

Topics: Adult; Antihypertensive Agents; Atenolol; Blood Pressure; Creatinine; Disease Progression; Enalapril; Female; Follow-Up Studies; Genotype; Humans; Hypertension, Renal; Male; Middle Aged; Multivariate Analysis; Peptidyl-Dipeptidase A; Predictive Value of Tests; Proteinuria; Renal Insufficiency, Chronic

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cardiovascular Agents; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Interactions; Enalapril; Female; Humans; Male; Middle Aged; Proteinuria

In this study we evaluated the effect of a dual blockade with enalapril and losartan on the reduction of overt macroproteinuria and its potential mechanism(s) in hypertensive patients with type 2 diabetes. Twenty-six hypertensive patients with type 2 diabetes at the baseline were administered 5 mg of enalapril once daily for 12 weeks. At the beginning of the study, the subjects were assigned to receive an add-on of 50 mg of losartan once daily or 5 mg of enalapril once daily for another 12 weeks. Blood samples were collected at the baseline, at the beginning, and at the end of the study for the measurement of laboratory parameters, and these data, including blood pressure, were compared between the two groups. Treatment with 5 mg of enalapril significantly decreased the systolic blood pressure level in both groups, and the addition of losartan and/or enalapril further decreased the levels. There was no difference in blood pressure between the two groups. However, the addition of losartan, but not enalapril, significantly decreased the urinary protein excretion level, plasma aldosterone, and hypersensitive-C-reactive protein at the end of the study. The results established that the dual blockade of angiotensin II with enalapril and losartan has a greater clinical benefit for high-risk patients with hypertension and advanced diabetic nephropathy.

Topics: Aged; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; C-Reactive Protein; Cystatin C; Cystatins; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Natriuretic Peptide, Brain; Proteinuria; Transforming Growth Factor beta

Pharmacological blockade of the renin-angiotensin-aldosteron system ameliorates glomerular and tubulointerstitial damage. For optimal renoprotection, high doses of angiotensin II converting enzyme inhibitors and angiotensin II subtype 1 receptor antagonists are commonly recommended, but cannot always be administered. The aim of this study was to evaluate the effects of low-dose (25 mg) losartan on proteinuria and tubular injury extent.. This was an open, randomized, 12-month study on the effects of 25 mg of losartan (n=19) vs. 10 mg of enalapril (n=14) as a control on proteinuria, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), and blood pressure in patients with primary glomerulonephritis. The second part of the study was an uncontrolled assessment of the renal effects of 50-mg administration of losartan.. There were no significant differences between the groups in the effects on proteinuria and NAG excretion. Losartan and enalapril reduced proteinuria by 32.8% (p<0.029) and 40.9% (p<0.021), respectively, but did not affect NAG excretion. The antiproteinuric effect of losartan, achieved without changes in blood pressure, was particularly evident in subjects with proteinuria >1.5 g/24 h and normal blood pressure. 50 mg of losartan caused a significant decrease in NAG excretion vs. the baseline (p<0.027).. 25 mg of losartan and 10 mg of enalapril equally reduce proteinuria. The significant antiproteinuric effect of losartan was achieved despite no changes in blood pressure. There were no differences between the drugs regarding their influence on tubular injury extent. 50 mg of losartan seems to be the minimal dose to improve tubular status.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Blood Pressure; Creatinine; Enalapril; Female; Glomerulonephritis; Humans; Kidney Tubules; Losartan; Male; Proteinuria

The aim of this work was to study the effect of early administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type-I receptors blockers (ARB) on renal function and proteinuria in renal transplant recipients with good, stable renal function and mild proteinuria. Twenty four patients started ACEI/ARB therapy within 14 months after surgery (RAS-). Before (T0) and every month for 2 years after the initiation of ACEI/ARB we evaluated creatinine clearance (CrCl), proteinuria/day (UP), UP/CrCl (FUP), arterial blood pressure, and serum lipid levels. Twenty-eight patients who never received ACEI/ARB (RAS+) were studied in the same fashion. In the RAS+ CrCl was reduced after 2 years compared with T0 (64.5 +/- 2.6 vs 75.0 +/- 3.2 mL/min, P < .003); UP and FUP were both significantly increased (666 +/- 65 vs 132 +/- 20 mg/day 8.8 +/- 1.2 vs 2.6 +/- 0.6 mg/mL x 10(3); P < .001 and .002) compared with T0. Moreover, UP (P < .04), FUP (P < .03), and the percentage reduction of CrCl (11.4% +/- 5% vs 4.6% +/- 1.8%; P < .05) were greater in RAS+ than RAS- subjects at 2 years of the study. The values of other parameters did not show significant differences between the two groups. In conclusion, this study suggested that ACEI/ARB have renoprotective effects, when used in patients with good stable renal function and mild proteinuria. These drugs may play a role to prevent chronic allograft nephropathy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Creatinine; Enalapril; Follow-Up Studies; Humans; Hypertension; Kidney Function Tests; Kidney Transplantation; Losartan; Proteinuria; Ramipril; Renal Artery; Renin-Angiotensin System; Tetrazoles; Time Factors; Valine; Valsartan

We have examined, in a randomized crossover trial, the antiproteinuric effect of treatment with low- (0.2 mg/kg daily) and high-dose (0.6 mg/kg daily) enalapril in 25 consecutive patients with steroid-resistant nephrotic syndrome (SRNS). Patients in group A ( n=11) received enalapril at low doses for 8 weeks, followed by 2 weeks of washout and then at high doses for 8 weeks. Those in group B ( n=14) initially received enalapril at high and then low doses. Patients continued to receive treatment with tapering doses of prednisolone; none received concomitant therapy with daily oral or intravenous steroids, alkylating agents, cyclosporine, non-steroidal anti-inflammatory drugs, and other antihypertensive medications. The urine albumin-to-creatinine (Ua/Uc) ratio and the percentage reduction were determined for each phase of therapy. Baseline clinical, biochemical, and histological features were comparable in the two groups. In the first phase, treatment with low-dose enalapril (group A) resulted in median 34.8% Ua/Uc reduction compared with 62.9% with high doses (group B) ( P<0.01). High-dose enalapril was associated with a significant reduction in Ua/Uc ratio in both groups. The combined median Ua/Uc (95% confidence interval) reduction in the low-dose phase was 33% (-10.3% to 72.4%) and in the high-dose 52% (15.4%-70.4%) ( P<0.05). The median Ua/Uc ratio at the end of 20 weeks was 1.1 and 1.8 in groups A and B, respectively ( P>0.05). Systolic and diastolic blood pressure reductions were similar in both groups. No period or carry-over effect was found. Prolonged treatment with enalapril thus resulted in a dose-related reduction in nephrotic-range proteinuria. Titration of the dose of enalapril may be a useful strategy for achieving substantial reduction of proteinuria in children with SRNS.

Topics: Adolescent; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Cross-Over Studies; Enalapril; Female; Humans; Infant; Male; Nephrotic Syndrome; Proteinuria; Time Factors; Treatment Outcome

Ten pediatric patients with Alport syndrome received enalapril for 5 years. There were nine boys. Eight patients have the X-linked form of the disease and two the autosomal recessive form. The median age at the start of treatment was 10.25 years. Only one patient was hypertensive. The starting dose of enalapril was 0.05 mg/kg; the target dose was 0.5 mg/kg per day. The median dose given effectively was 0.24, 0.37, 0.45, 0.43, and 0.49 mg/kg per day at years of study 1, 2, 3, 4, and 5, respectively. The median urinary protein/creatinine ratio was 1.58 g/g (range 0.49-4.60) before treatment. This decreased to 0.98, 1.09, 1.35, 1.11, and 1.38 g/g after 1, 2, 3, 4, and 5 years, respectively. The median creatinine clearance at baseline was 100 ml/min per 1.73 m2 (range 82-133) and after 5 years 92 ml/min per 1.73 m2 (range 22-115). Three patients did not reach the target dose of enalapril because of orthostatic hypotension. One of them was the only patient to develop chronic renal failure within 5 years. The present study indicates that enalapril reduces urinary protein excretion and preserves glomerular filtration in Alport patients as a group. However, there was individual variation, as in most studies of patients with proteinuric nephropathies given inhibitors of the angiotensin-converting enzyme.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Child; Child, Preschool; Cholesterol; Creatinine; Enalapril; Glomerular Filtration Rate; Humans; Hypertension, Renal; Nephritis, Hereditary; Proteinuria; Serum Albumin

The benefits of angiotensin-converting enzyme inhibitors and angiotensin II (ATII) receptor antagonist therapy of diabetic nephropathy (DNP) are thought to be largely the result of attenuation of ATII effects on proteinuria. The aim of the study was to ascertain whether there is the additive anti-proteinuric effect of enalapril plus losartan in DNP. Twenty-two patients with DNP were studied. Patients were randomly assigned to enalapril 10 mg/day (11 patients) or losartan 50 mg/day (11 patients) administered in a single oral dose in the morning for 12 weeks. and then, in 10 patients (five patients from enalapril group and five patients from losartan group), combination therapy (10 mg/day enalapril and 50 mg/day losartan) was started and continued for 12 weeks. In 12 patients, initial drugs dosages were doubled (six patients 20 mg/day enalapril and six patients 100 mg/day losartan), and monotherapy was continued for 12 weeks. Blood pressure and proteinuria were measured before and after therapy. Adverse effects were recorded at every visit. Proteinuria decreased by 33% with enalapril and losartan administered alone (p < 0.05). Co-administration of enalapril and losartan decreased proteinuria by a greater extent compared with enalapril and losartan administered alone (51%, p<0.05). This proteinuria level was significantly lower than the proteinuria level of 12 weeks therapy with enalapril and losartan alone. The decrease of proteinuria was 37% in double-dose monotherapy group (p < 0.05). Reduction of mean arterial blood pressure (MAP) in co-administration of enalapril and losartan was higher than enalapril and losartan administered alone (p < 0.05). Combination of enalapril and losartan decreased proteinuria and MAP by a greater extent compared with enalapril and losartan administered alone. We have found that proteinuria reduction induced by combined therapy is maintained throughout short-term follow-up; a greater anti-proteinuric response was observed in the patients with DNP.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Humans; Losartan; Male; Middle Aged; Proteinuria

It has been reported that combined therapy of angiotensin converting enzyme inhibitor and angiotensin receptor blocker significantly decreases proteinuria in immunoglobulin A (IgA) nephropathy. However, histologic alterations following the therapy have not been reported.. A total of nine Japanese children with severe proteinuric IgA nephropathy who received a prompt immunosuppressive therapy were enrolled the study, four of whom received a combined therapy of angiotensin converting enzyme inhibitor, enalapril and angiotensin receptor blocker, losartan (Group A), while the remaining five did not (Group B). All underwent renal biopsy before and approximately 12 months after the first renal biopsy.. At presentation, urine protein excretion and the histologic indices of mean activity index, mean chronicity index and tubulointerstitial scores did not show a statistical difference between the two groups: Group A (2.6 +/- 0.6 g/day; mean activity index, 5.0 +/- 1.0; mean chronicity index, 5.0 +/- 1.0; tubulointerstitial scores, 4.3 +/- 1.0) and Group B (2.2 +/- 0.6 g/day; mean activity index, 4.8 +/- 0.8; mean chronicity index, 4.8 +/- 1.3; tubulointerstitial scores, 3.6 +/- 0.5, respectively). All had normal blood pressure and renal function. Urine protein excretion and the activity index decreased at the second renal biopsy, while the chronicity index and the tubulointerstitial scores slightly increased or remained unchanged. In comparison with Group B, a significant suppression in increasing the chronicity index and the tubulointerstitial scores obtained at the second renal biopsy were observed in Group A [Group A: 4.3 +/- 1.2 and 3.0 +/- 0.0, respectively, vs Group B: 6.0 +/- 0.7 and 4.4 +/- 0.9, respectively (P < 0.05)]. One patient in Group B developed chronic renal insufficiency thereafter.. Although only a small number of patients were examined, these clinical findings suggest that a combined therapy of enalapril and losartan may attenuate histologic progression in at least a proportion of patients with severe proteinuric IgA nephropathy.

Topics: Adolescent; Antihypertensive Agents; Biopsy; Child; Creatinine; Disease Progression; Drug Therapy, Combination; Enalapril; Female; Glomerulonephritis, IGA; Humans; Japan; Kidney; Losartan; Male; Pilot Projects; Proteinuria; Treatment Outcome

In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat.. As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml(-1) (high) (n = 17) or below 10 ng ml(-1) (low) (n = 18), and the daily dose of enalapril titrated accordingly.. Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min(-1) 1.73 m(2) in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5-10) and low (2.5-20) concentration group. At 3 months' follow-up, the dose was 10 (2.5-30) and 1.9 (1.25-5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22-244) ng ml(-1) and 9.1 (2.5-74.8) ng ml(-1) (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110-200) and 133 (110-165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105-170) and 130 (105-170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65-100) and at follow-up (60-95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR.. In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Enalapril; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Proteinuria

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Glomerulonephritis, IGA; Humans; Male; Proteinuria; Survival Analysis; Treatment Outcome

In this randomized double-blind crossover trial we compared the antiproteinuric effects of enalapril and losartan in six children with proteinuria and underlying renal injury. The primary endpoint was reduction in proteinuria during therapy. The study had two 8-week on-drug arms, with a 4-week washout period between. Baseline proteinuria was similar, enalapril 87 mg/m(2) per hour and losartan 77 mg/m(2) per hour. The mean reduction in proteinuria with enalapril was 48% (37%-57%) with a standard error of the mean of 3%; with losartan it was 31% (14%-52%) with a standard error of the mean of 7%. Although there was a significant reduction in proteinuria with the use of both drugs, the difference in reduction of proteinuria, 48% versus 31%, was not considered clinically significant. Potassium remained below 4.5 mmol/l in all patients. No patient's creatinine rose more than the standard deviation of our assay. Blood pressure (BP) control was acceptable in four of the six patients; two patients had persistently elevated or increased BP on each drug. Side effects were minimal; none requiring withdrawal, one requiring dose reduction. Studies have shown that angiotensin converting enzyme inhibitors can reduce proteinuria in children with renal disorders. No studies to date have examined the reduction of proteinuria achieved by angiotensin receptor blockers. Our study, although small, suggests that angiotensin receptor blockers may reduce proteinuria as effectively, and as safely, as angiotensin converting enzyme inhibitors.

Topics: Adolescent; Adult; Antihypertensive Agents; Blood Pressure; Child; Creatinine; Cross-Over Studies; Double-Blind Method; Enalapril; Female; Humans; Losartan; Male; Pilot Projects; Proteinuria; Treatment Outcome

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Creatinine; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Losartan; Male; Postoperative Complications; Potassium; Proteinuria; Receptor, Angiotensin, Type 1; Uric Acid

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Creatinine; Cross-Over Studies; Cyclosporine; Double-Blind Method; Doxazosin; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Postoperative Complications; Proteinuria; Uric Acid

In the outcome trials that provided information on renal function in older hypertensive patients, diuretics and beta-blockers were mostly used as first-line drugs. The long-term renal effects of calcium-channel blockers remain unclear.. To compare the changes in renal function in 2,258 treated and 2,148 untreated patients with isolated systolic hypertension, of whom 455 had diabetes mellitus and 390 had proteinuria.. We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Active treatment was initiated with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg, to less than 150 mmHg. The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault.. Serum creatinine concentration at the time when participants were randomly allocated to study groups was less than 176.8 micromol/l (2.0 mg/dl), averaging 88 micromol/l. At the time of the last serum creatinine measurement, the blood pressure difference (P< 0.001) between the two groups was 11.6/4.1 mmHg. In the intention-to-treat analysis (11,427 patient-years), serum creatinine and the calculated creatinine clearance were not influenced by active treatment. However, in the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction (serum creatinine at least 176.8 mmol/l) decreased by 64% (P= 0.04) and that of proteinuria by 33% (P= 0.03). Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients: by 71%, compared with 20% (P= 0.04). In non-proteinuric patients, active treatment did not influence serum creatinine, whereas in patients with proteinuria at entry to the study, serum creatinine decreased on active treatment (P< 0.001). Furthermore, in on-randomized treatment comparison stratified for risk at baseline, serum creatinine concentration did not change (P= 0.98) in patients continuing to receive monotherapy with nitrendipine, whereas it increased by 6.73 mmol/l (P < 0.001) in patients who received hydrochlorothiazide alone or in combination with other study medication (P < 0.001 for difference in trends).. In older patients with isolated systolic hypertension, antihypertensive treatment starting with the dihydropyridine calcium-channel blocker, nitrendipine, did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria, especially in diabetic patients.

Topics: Aged; Antihypertensive Agents; Creatinine; Diabetes Complications; Double-Blind Method; Enalapril; Europe; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Kidney; Male; Nitrendipine; Proteinuria; Systole

Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs.

Topics: Adult; Aldosterone; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cohort Studies; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Enalapril; Female; Glomerulonephritis, IGA; Humans; Linear Models; Losartan; Male; Proteinuria; Renin; Treatment Outcome

Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition.. A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined.. Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition.. The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Losartan; Male; Proteinuria; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System

Hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) have a faster progression to end-stage renal disease (ESRD) than their normotensive counterparts. The aim of this prospective, randomized study is to compare the effects of the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor enalapril as first-line therapy on blood pressure, renal function, and urinary albumin excretion in hypertensive patients with ADPKD. Twenty-four patients with ADPKD with hypertension with creatinine clearances (Ccrs) greater than 50 mL/min/1.73 m(2) were included in the study. Twelve patients received amlodipine (mean dose, 9 mg/d), and 12 patients received enalapril (mean dose, 17 mg/d). The patients were followed up for 5 years. Baseline mean arterial pressures, which were 109 +/- 3 mm Hg in the amlodipine group and 108 +/- 3 mm Hg in the enalapril group, decreased significantly after 1 year of follow-up (amlodipine, 96 +/- 3 mm Hg; P < 0.005; enalapril, 89 +/- 2 mm Hg; P < 0.0005) and remained stable at year 5 (amlodipine, 97 +/- 3 mm Hg; P < 0.0005 versus baseline; enalapril, 94 +/- 3 mm Hg; P < 0.005 versus baseline). Ccrs, which were 83 +/- 5 mL/min/1.73 m(2) in the amlodipine group and 77 +/- 6 mL/min/1.73 m(2) in the enalapril group, remained stable after 1 year of follow-up and decreased significantly at year 3 in both groups (amlodipine, 67 +/- 5 mL/min/1.73 m(2); P < 0.01 versus year 1 and baseline; enalapril, 58 +/- 4 mL/min/1.73 m(2); P < 0.05 versus year 1 and P < 0.0005 versus baseline) with no significant change thereafter. No change was observed in urinary albumin-creatinine ratio in the amlodipine group (baseline, 68 +/- 21 mg/g; year 1, 52 +/- 21 mg/g; year 5, 148 +/- 74 mg/g), whereas it decreased significantly in the enalapril group at year 1 (baseline, 23 +/- 4 mg/g; year 1, 13 +/- 3 mg/g; P < 0.05) and remained stable until the end of the study at year 5 (14 +/- 6 mg/g). The investigators concluded that blood pressure was similar in both groups but only enalapril had a significant effect to sustain decreased urinary albumin excretion for a 5-year follow-up. Although proteinuria has been considered a surrogate of renal disease progression, further studies will be necessary to confirm this hypothesis in ADPKD, because after 5 years, no differences in renal function were observed between the enalapril and amlodipine groups. In comparison with patients with ADPKD with uncontrolled hypertension, effecti

Topics: Adult; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Enalapril; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Proteinuria

Clinical proteinuria is a risk factor for both end-stage renal disease and cardiovascular disease. The prevalence of clinical proteinuria, its correlates and predictive value, and the effect of ACE inhibitors in preventing clinical proteinuria in diabetic and nondiabetic patients with left ventricular (LV) dysfunction are unknown.. The Studies of Left Ventricular Dysfunction (SOLVD) trials were analyzed to determine the baseline distribution of clinical proteinuria and related cardiovascular risk factors, the effect of baseline proteinuria on the risk of hospitalization for congestive heart failure (CHF) and mortality, and the effect of enalapril in preventing new clinical proteinuria.. A total of 5,487 out of 6,797 SOLVD participants (81%) were assessed for proteinuria at baseline. A total of 177 patients (3.2%) had baseline proteinuria. These patients had significantly higher systolic (137 vs. 125 mmHg, P < or = 0.001) and diastolic (83 vs. 77 mmHg, P < or = 0.001) blood pressure levels, a higher prevalence of diabetes (41 vs. 18%, P < or = 0.001), a lower ejection fraction (26.2 vs. 27.3%, P < or = 0.05), and greater degree of CHF (New York Heart Association [NYHA] class III/IV in 22 vs. 10%, P < or = 0.001) than patients without baseline proteinuria. Patients with baseline proteinuria also had higher rates of hospitalization for CHF (relative risk 1.81 [95% CI 1.37-2.41], P = 0.0001) and mortality (1.73 [1.34-2.24], P = 0.0001). Enalapril prevented clinical proteinuria in diabetic patients (0.38 [0.17-0.81], P = 0.0123) but not in nondiabetic patients (1.43 [0.77-2.63], P = 0.2622) without baseline proteinuria.. Clinical proteinuria is an independent predictor of hospitalization for CHF and mortality in diabetic and nondiabetic patients with LV dysfunction. Enalapril significantly reduces the risk of clinical proteinuria in diabetic patients with LV dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Female; Humans; Male; Middle Aged; Proteinuria; Ventricular Dysfunction, Left; Ventricular Function, Left

It has been postulated that angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) may decrease proteinuria in patients with glomerulonephritis by its action on the glomerular basement membrane. We therefore studied the relationship between the response of patients with IgA nephritis (IgAN) to ACEI/ATRA therapy by decreasing proteinuria and its effect on the selectivity index (SI) in these patients.. Forty-one patients with biopsy-proven IgAN entered a control trial, with 21 in the treatment group and 20 in the control group. The entry criteria included proteinuria of 1 g or more and/or renal impairment. Patients in the treatment group received ACEI/ATRA or both with three monthly increases in dosage. In the control group, hypertension was treated with atenolol, hydrallazine, or methyldopa. The following tests were performed at three monthly intervals: serum creatinine, total urinary protein, SI, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and low molecular weight (LMW) proteinuria.. After a mean duration of therapy of 13 +/- 5 months, in the treatment group, there was no significant change in serum creatinine, proteinuria, or SI, but in the control group, serum creatinine deteriorated from 1.8 +/- 0.8 to 2.3 +/- 1.1 mg/dL (P < 0.05). Among the 21 patients in the treatment group, 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30% (responders), and the other 11 did not respond (nonresponders). Among the responders, SI improved from a mean of 0.26 +/- 0.07 to 0.18 +/- 0. 07 (P < 0.001), indicating a tendency toward selective proteinuria. This was associated with an improvement in serum creatinine from mean 1.7 +/- 0.6 to 1.5 +/- 0.6 mg/dL (P < 0.02) and a decrease in proteinuria from a mean of 2.3 +/- 1.1 to 0.7 +/- 0.5 g/day (P < 0. 001). After treatment, proteinuria in the treatment group (1.8 +/- 1. 6 g/day) was significantly less than in the control group (2.9 +/- 1. 8 g/day, P < 0.05). The post-treatment SI in the responder group (0. 18 +/- 0.07) was better than that of the nonresponder group (0.33 +/- 0.11, P < 0.002). Eight out of 21 patients in the treatment group who had documented renal impairment had improved renal function compared with two in the control group (chi2 = 4.4, P < 0. 05). Of the eight patients in the treatment group who improved their renal function, three normalized their renal function compared with one from the control group.. Our data suggest that ACEI/ATRA therapy may be beneficial in patients with IgAN with renal impairment and nonselective proteinuria, as such patients may respond to therapy with improvement in protein selectivity, decrease in proteinuria, and improvement in renal function. ACEI/ATRA therapy probably modifies pore size distribution by reducing the radius of large unselective pores, causing the shunt pathway to become less pronounced, resulting in less leakage of protein into the urine.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Creatinine; Enalapril; Female; Glomerulonephritis, IGA; Humans; Kidney; Losartan; Male; Middle Aged; Proteinuria; Treatment Outcome

It was reported previously that dietary fish oil supplementation retarded the progression of renal disease in patients with IgA nephropathy in a multicenter, placebo-controlled, randomized, 2-yr clinical trial. The aim of this study was to determine the long-term influence of fish oil treatment on renal progression in observations on the study cohort of 106 patients extending beyond the 2-yr trial. Renal function was assessed by serial serum creatinine and 24-h urine protein measurements. Vital, end-stage renal disease (ESRD), and BP status and treatment beyond completion of the 2-yr trial were determined. As in the trial, the primary end point was an increase of 50% or more in the serum creatinine, and the secondary end point was ESRD. After a mean follow-up of 6.4 yr, 46 patients-17 in the fish oil group versus 29 in the placebo group-reached the primary end point (P = 0.002), and 27 patients-eight in the fish oil group versus 19 in the placebo group-developed ESRD (P = 0.009). At the end of the 2-yr trial, 75 patients (45 fish oil, 30 placebo) remained at risk for the primary end point. This is also when the double-blind part of the trial ended, allowing physicians to stop supplements, switch original placebo-assigned patients to fish oil, and continue fish oil in original fish oil-assigned patients. A significantly greater number of nonsupplemented placebo patients developed the primary end point (P = 0.02) and ESRD (P = 0.003) compared with long-term supplemented fish oil patients. Conversely, more fish oil-supplemented patients had stable renal function than nonsupplemented patients (P = 0.02). By intention, BP control, primarily treated with angiotensin-converting enzyme inhibition, was equal in the fish oil and placebo groups. Proteinuria was modestly reduced in both groups. It is concluded that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgA nephropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Creatinine; Disease Progression; Double-Blind Method; Enalapril; Female; Fish Oils; Glomerulonephritis, IGA; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Longitudinal Studies; Male; Proteinuria; Treatment Outcome

The effect of enalapril (5-10 mg/day) on the progression of chronic renal failure (CRF) was compared with that of metoprolol (40-120 mg/day) in 28 patients for 24 months in a prospective study. Throughout the study, there was no significant difference between the 2 groups in protein intake and urinary sodium excretion. But there was a significant difference between the 2 groups in diastolic and mean arterial blood pressure at 6 months. In the serum creatinine level, there was a significant difference between the 2 groups at 6, 12, 18, and 24 months. In creatinine clearance, there was a significant difference between the 2 groups at 24 months. In addition, the progression of CRF was significantly faster in the metoprolol group than the enalapril group as estimated from the slope of creatinine clearance (p < 0.05) and the slope of glomerular filtration rate (p < 0.0005). In urinary protein excretion, there was a significant difference between the 2 groups at 6 and 18 months (p < 0.05). These findings indicate that enalapril has a suppressive effect on the progression of CRF and also has an antiproteinuric effect by a mechanism independent of its antihypertensive effect.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Cholesterol, HDL; Creatinine; Diet, Protein-Restricted; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Prospective Studies; Proteinuria; Sodium; Triglycerides

Elevated urinary calcium and phosphate excretion have been observed in children with insulin-dependent diabetes mellitus (IDDM). This may be related to a defect in tubular reabsorption. It is well known that converting enzyme inhibition decreases microalbuminuria and may prevent or retard diabetic nephropathy. We investigated whether enalapril also improves the defect in calcium and phosphate reabsorption. We studied 16 children and young adults (age 12-21 years) with IDDM and persistent microalbuminuria before and during 12 weeks of enalapril treatment. Before treatment microalbuminuria, urinary calcium excretion, and fractional tubular phosphorus reabsorption (TPR) were 153+/-53 microg/min, 5.5+/-0.9 mg/kg per day, and 71.4+/-3.6%, respectively. At the end of the 12th week, microalbuminuria had decreased to 20.3+/-7.9 microg/min and calcium excretion to 3.3+/-0.4 mg/kg per day (P<0.01), while the TPR increased to 80.1+/-3.8% (NS). The renal threshold phosphate concentration increased from 1.8+/-0.15 to 2.92+/-0.23 mg/dl (P<0.01). The fasting serum glucose and hemoglobin Alc levels did not change significantly during the study. Systolic and diastolic blood pressures were 120.4+/-2.2 / 79.3+/-1.4 mm Hg and 110.5+/-1.8 / 71.3+/-0.9 mm Hg before and after 12 weeks, respectively. We conclude that enalapril treatment improves not only microalbuminuria but also abnormal calcium and phosphate excretion in microalbuminuric children with IDDM.

Topics: Adolescent; Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium; Child; Diabetes Mellitus, Type 1; Enalapril; Female; Humans; Male; Phosphates; Proteinuria

Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function.

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Enalapril; Female; Glomerulonephritis, IGA; Humans; Hypertension, Renal; Indomethacin; Irbesartan; Kidney Function Tests; Male; Middle Aged; Proteinuria; Renal Circulation; Tetrazoles; Treatment Outcome

We compared the efficacy of two classes of antihypertensive therapy on ambulatory blood pressure control and proteinuria in patients with hypertension. Furthermore, we determined the effects of the interaction of these therapies on neurohormonal activation and of the patients' ambient sodium intake on the outcomes.. Sustained-release nifedipine (nifedipine gastrointestinal therapeutic system, GITS) 30-120 mg/day was compared in a double-blind sequential randomized placebo-controlled trial with enalapril 5-30 mg/day regarding office and 24-hour blood pressure control, plasma renin activity, noradrenaline and adrenaline levels and 24-hour urinary protein and sodium in 46 elderly nondiabetic hypertensive patients in a 16- to 18-week trial.. Both nifedipine GITS and enalapril controlled ambulatory blood pressure during the day and at peak effect. Nifedipine GITS controlled ambulatory blood pressure during the early morning surge and at night time as well. Nifedipine GITS increased plasma renin activity and noradrenaline by 50 and 20%, respectively, compared to the 150 and 0% change produced by enalapril. Both nifedipine GITS and enalapril reduced proteinuria by 37%. Patients had increasing levels or proteinuria proportional to higher ambient sodium intake (r = 0.48; p < 0.01). This effect was accentuated during nifedipine GITS therapy as compared to enalapril.. Nifedipine GITS was superior to enalapril in controlling ambulatory blood pressure, but they were equivalent in reducing proteinuria (37%). They had disparate effects on neural activation and the duration of action. Raised protein excretion appears to be associated with raised sodium intake. This was apparent especially during nifedipine XL therapy.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Catecholamines; Creatinine; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Nifedipine; Proteinuria; Renin; Sodium; Sodium Chloride, Dietary

To determine whether the increase in proteinuria resulting from high dietary protein intake could be prevented by angiotensin-converting enzyme inhibition (ACEI), we performed paired studies on 8 nephrotic patients with normal GFR. They were fed sequential diets with a protein content of 0.8 (LPD) and 1.6 g/kg BW (HPD) each for 8 weeks. Patients on HPD received enalapril (ENAL) 10 mg/day. Despite the significant difference in protein intake, urinary protein excretion, at the end of the two dietary periods, was not statistically different. However, total serum protein and serum albumin increased significantly with HPD + ENAL treatment. The capability of ACEI to prevent the increase in proteinuria induced by HPD may be due to changes in glomerular hemodynamics, possibly mediated by changes in the activity of angiotensin II. Our study indicates that protein metabolism in nephrotic patients is better maintained with HPD + ENAL than with LPD alone.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Proteins; Body Weight; Creatinine; Dietary Proteins; Enalapril; Female; Food, Fortified; Humans; Male; Nephrotic Syndrome; Patient Compliance; Proteinuria; Serum Albumin; Urea

Forty-one patients with a nephrotic syndrome and biopsy-proven membranous nephropathy were administered a 3 to 6-month course of cyclosporine (CsA;4 to 5 mg/kg per day). Differential solute clearances were used to evaluate glomerular function, before and after therapy. CsA lowered median proteinuria by 56%, from 7.3 to 3.2 g/24 h (P < 0.0001). Corresponding mean increments in serum albumin, immunoglobulin G, and oncotic pressure values were 31, 32, and 26%, respectively (all P < 0.0001). Arterial pressure, GFR, and renal plasma flow remained constant, but CsA restored the dextran-sieving curve toward normal, lowering the computed fraction of shunt-like pores by 25% (P < 0.05). In 14 instances, a cross-over design was used to randomly assign patients to 3 months of CsA versus 3 months of enalapril (10 to 30 mg daily), separated by a 1-month washout interval. Although enalapril lowered arterial pressure by 8 mm Hg (P < 0.01), it had no effect on proteinuria, plasma protein composition, filtration dynamics, or dextran sieving (all P = not significant). CsA dependence of proteinuria, indicated by relapsing nephrosis after CsA withdrawal, required additional courses of CsA to maintain proteinuria subnephrotic in most patients. In six patients with declining GFR during prolonged CsA treatment, a repeat biopsy showed more prominent immune deposits and a thicker glomerular basement membrane than at baseline. It was concluded that: (1) CsA lowers proteinuria in MN in part, by enhancing barrier size-selectivity; (2) lack of comparable efficacy of enalapril suggests that the antiproteinuric effect of CsA is related to its immuno-suppressive rather than glomerulodepressor properties; but (3) judged by repeat biopsy, CsA does not prevent continuing autoantibody formation in this disorder.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cross-Over Studies; Cyclosporine; Enalapril; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Proteinuria; Time Factors

Both enalapril and long-acting diltiazem have been shown to effectively lower blood pressure (BP) in hypertensive patients. Furthermore, in clinical studies, these two agents provided beneficial renal effects in these patients when administered on a long-term basis. A combination of enalapril/diltiazem ER was evaluated in 62 patients with Stage 1-3 hypertension and coexisting renal disease. This trial used a multicenter, randomized, double-blind, parallel group design. The study consisted of a 12-week double-blind phase followed by a 6-month open-label extension phase. The combination of enalapril/diltiazem ER was shown to reduce BP following both short-term and long-term treatment phases. Patients in Renal Group I (creatinine clearance CrCl): 30-59 ml/min/1.73 m2) had decreases of -18/-16 and -25/-20 mm Hg after 12 weeks and 9 months of therapy, respectively. Those in Renal Group II (CrCl: 10-29 ml/min/1.73 m2) had similar decreases of -23/-18 and -23/-19 mm Hg at these time points. The adverse events, in both phases, were those associated with the respective monotherapies. A reduction in CrCl with a coincident decrease in proteinuria was noted for both renal groups. The combination of enalapril/diltiazem ER lowered BP and was generally well tolerated by the patients. The combination of these two agents should improve the management of hypertensive patients.

Topics: Adult; Aged; Blood Pressure; Creatinine; Delayed-Action Preparations; Diltiazem; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Proteinuria

Although post exercise proteinuria has long been known, its exact pathophysiology is unclear. Our objective was to determine whether long-term angiotensin converting enzyme (ACE) inhibition by different ACE inhibitors had an influence on post exercise proteinuria. We studied 14 patients who also had mild, chronic proteinuria caused by diabetes mellitus or chronic glomerulonephritis. We compared changes both in chronic (baseline) and post exercise proteinuria, during and after treatment with three different ACE inhibitors, with appropriate washout periods for the three drugs to all 14 patients. Proteinuria (mg/24 hours +/- SD), prior to the treatment was 682 +/- 92. Proteinuria after treatment for 30 days with benazepril was 464.4 +/- 82.6 (p < 0.001), with enalapril: 477.1 +/- 105.5 (p < 0.001), and captopril: 504.7 +/- 100.1 (p < 0.001). Proteinuria three days after discontinuing the treatment with benazepril was 532.4 +/- 113.5, (p < 0.01), with enalapril: 561.3 +/- 128.5, (p < 0.01), and with captopril: 620.8 +/- 101.8, p = n.s. Post exercise proteinuria prior to treatment (mg/min. +/- SD) was: 1.38 +/- 0.32, vs. after a 30-day treatment period with benazepril: 0.81 +/- 0.19 (p < 0.001), enalapril: 0.95 +/- 0.24, (p < 0.001), captopril: 1.09 +/- 0.27 (p < 0.02). Post exercise proteinuria three days after discontinuing the treatment was (blood pressure already back to baseline): in case of benazepril: 1.26 +/- 0.36 (p = n.s.), of enalapril: 1.17 +/- 0.46 (p = n.s.), and of captopril: 1.34 +/- 0.41 (p = n.s.). We conclude that the renin-angiotensin system plays a significant role in the pathogenesis of post exercise proteinuria; the antiproteinuric effect of ACE inhibition in exercise-induced proteinuria seems to be associated chiefly with the hemodynamic changes due to these drugs, whereas in chronic proteinuria the antiproteinuric and antihypertensive effects are, at least partially, dissociated.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Captopril; Chronic Disease; Diabetes Mellitus, Type 2; Enalapril; Exercise; Female; Glomerulonephritis; Humans; Male; Proteinuria

An earlier controlled trial showed that over an average of 26 months, enalapril slowed the progression of chronic renal failure. Following completion of the trial, the patients continued to receive antihypertensive treatment according to ordinary clinical criteria. All but four patients in the enalapril group remained on that drug, and two patients in the control group were switched to an angiotensin-converting enzyme (ACE) inhibitor. In the present study the fate of the 70 patients 44 months after termination of the trial was investigated, with a total follow-up of around 7 years. In the original enalapril group, 12 of the 35 patients (34%) were alive without renal replacement therapy versus five of the 35 patients (14%) in the control group. This difference of 20% in favour of having been in the enalapril group in the original trial was significant (P = 0.05; 95% confidence limits 0.5-39.5%). The influence of baseline proteinuria on clinical outcome was analysed. In the original control group, baseline renal clearances of albumin (Calb) and immunoglobulin G (CIgG) were significantly lower in patients surviving without renal replacement therapy at follow-up than in patients who ultimately developed end-stage renal failure (ESRF) (P < 0.05). In the original enalapril group, these baseline clearances were equal in the two renal outcome groups. In all patients, baseline Calb and CIgG were negatively correlated with the rate of change in GFR during the controlled trial (r = -0.37, P < 0.01 and r = -0.28, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Proteinuria; Sex Characteristics; Survival Analysis; Treatment Outcome

Topics: Aldosterone; Blood Pressure; Combined Modality Therapy; Diet, Sodium-Restricted; Disease Progression; Enalapril; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Nifedipine; Prospective Studies; Proteinuria; Renal Circulation; Renin; Treatment Outcome; Vascular Resistance

To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure.. Open randomised multicentre trial with three year follow up.. Outpatient departments of six French hospitals.. 100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment).. Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg.. 17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups.. In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.

Topics: Acebutolol; Adolescent; Adult; Aged; Atenolol; Blood Pressure; Body Weight; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Proteinuria

A randomized comparison of enalapril and metoprolol in patients with type 1 diabetes and nephropathy showed that the decline in kidney function was 5.6 +/- 5.9 ml/min/year in the metoprolol-treated and 2.0 +/- 3.2 ml/min/year in the enalapril-treated patients (P = 0.02). In the present study, the enalapril treated patients have been studied for two additional years. In the metoprolol-treated group, only the endpoints of death or uremia have been recorded, and six of the patients have reached end-stage renal failure and three are dead, compared to three and two, respectively in the enalapril treated group. The mean fall in glomerular filtration rate in 18 enalapril-treated patients is 8.4 +/- 9.4 ml/min/1.73 m2 after four years; 7.5 +/- 9.8 ml/min/1.73 m2, occurred during the first six months treatment. The mean decline in kidney function was 1.7 +/- 2.4 ml/min/year over the whole study period and 0.3 +/- 3.9 ml/min/year after exclusion of the first six months. In this study, long-term enalapril treatment in diabetic nephropathy was associated with a low rate of decline in kidney function.

Topics: Adult; Blood Pressure; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Metoprolol; Middle Aged; Proteinuria; Time Factors

Angiotensin converting enzyme (ACE) inhibition causes specific renal effects, such as a rise in effective renal plasma flow, a fall in filtration fraction and a lowering of proteinuria. The mechanism of these renal effects is still debated. Recent animal studies suggest that non-angiotensin (Ang) II related actions of ACE inhibition, such as bradykinin accumulation, may have a role. We therefore investigated the effects of specific intervention in the renin-angiotensin system with the Ang II receptor antagonist losartan, and compared these effects to those obtained with ACE inhibition, as this comparison might resolve the question whether or not the effects of ACE inhibition are Ang II related. The effects of losartan and enalapril were studied in eleven patients with non-diabetic proteinuria and hypertension. The protocol consisted of seven periods, each lasting one month, in which patients received once daily placebo, 50 mg losartan, 100 mg losartan, placebo, 10 mg enalapril, 20 mg enalapril, and placebo, respectively. At the end of each study period proteinuria, blood pressure, and renal function were determined. On both doses of losartan and enalapril proteinuria and blood pressure fell, whereas ERPF increased and GFR remained stable. The fall in urinary protein excretion was similar for both drugs: 46.3% (28.3% to 63.1%) on 100 mg losartan versus 51.6% (37.0% to 69.2%) on 20 mg enalapril (expressed as Wilcoxon-based estimated median with 95% CI).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin II; Angiotensin Receptor Antagonists; Biphenyl Compounds; Blood Pressure; Enalapril; Female; Humans; Hypertension; Imidazoles; Kidney; Losartan; Male; Middle Aged; Proteinuria; Renal Circulation; Renin-Angiotensin System; Tetrazoles

The aim of the study was to evaluate the efficacy of enalapril and atenolol in decreasing the severity of proteinuria in hypertensive patients suffering from insulin-dependent diabetes mellitus. We studied 20 hypertensive patients. All patients had proteinuria (> 3 g/24 h) and were receiving insulin treatment. Proteinuria was measured monthly in the run-in period (3 months) and during the active drug treatment (8 months). Glomerular filtration rate, effective renal plasma flow, filtration fraction, and total renal resistance were determined after the run-in and treatment periods. The patients were randomly assigned to treatment with enalapril 20 mg/day or atenolol 100 mg/day for 8 months. In both groups blood pressure decreased significantly. After 8 months' treatment, severity of proteinuria significantly decreased both in the enalapril-treated group and in the group receiving atenolol. Glomerular filtration rate and effective renal plasma flow significantly increased, while total renal resistance decreased in the patients given enalapril, whereas glomerular filtration rate, renal plasma flow, and total renal resistance significantly decreased in the patients given atenolol. The results of this study show that enalapril and atenolol reduce proteinuria in hypertensive diabetic patients by a mechanism related to their antihypertensive effects; furthermore, the beneficial effects of enalapril might be also linked to intrarenal effects.

Topics: Adult; Atenolol; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Energy Intake; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Potassium; Proteinuria

We evaluated the effect of enalapril on proteinuria in 20 patients with chronic glomerulonephritis (CGN) and renal insufficiency. Patients were accepted into the study according to the following criteria: 1) a serum creatinine (s-Cr) level over 1.5 mg/dl or a creatinine clearance (Ccr) under 70 ml/min; and 2) urinary protein (UP) over 1.0 g/day, expect for the cases with uncontrollable hypertension. We measured total protein (TP), albumin, s-Cr, Ccr, UP, and Ht during the elanapril therapy. After enalapril therapy, UP slowly decreased, and TP and albumin levels increased. The levels of s-Cr and Ccr did not vary. None of the patients required discontinuation of enalapril therapy caused by side effects, such as anemia or hyperkalemia. In conclusion, enalapril has the effect of decreasing in proteinuria and increasing TP and albumin in patients with CGN and renal insufficiency irrespective of the original diseases.

Topics: Adolescent; Adult; Aged; Chronic Disease; Enalapril; Female; Glomerulonephritis; Humans; Male; Middle Aged; Proteinuria; Renal Insufficiency

It is unknown if the antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors reflects attenuation in the rate of progression of diabetic nephropathy. We report the results of a randomized, double-blind clinical trial designed to evaluate the longitudinal (18-month) effect of the ACE inhibitor, enalapril (5 to 40 mg/d), versus a placebo on 24-hour urinary protein excretion and on the rate of progression of renal disease in 33 patients with clinical diabetic nephropathy. Systemic blood pressure was controlled throughout the trial with conventional antihypertensive drugs. Glomerular filtration rate (GFR), determined by Tc99mDTPA renal clearance, and urinary protein excretion were monitored at 3-month intervals. Enalapril, in contrast to placebo therapy, was associated with an initial (40%) and sustained (33%) decrease in urinary protein excretion. Patients randomized to both enalapril or placebo experienced mean decreases in GFR, from 1.01 mL/s/1.73 m2 (61 mL/min/1.73 m2) to 0.85 mL/s/1.73 m2 (51 mL/min/1.73 m2), and from 1.06 mL/s/1.73 m2 (64 mL/min/1.73 m2) to 0.97 mL/s/1.73 m2 (58 mL/min/1.73 m2), respectively. Eleven of 18 patients (61%) randomized to enalapril, and 10 of 15 (66%) patients randomized to placebo, had a decrease in GFR; their rates of progression were -1.18 mL/min/1.73 m2/mo and -1.00 mL/min/1.73 m2/mo, respectively. In the absence of changes in blood pressure, the addition of an ACE inhibitor to patients with clinical diabetic nephropathy could not be shown to confer a unique renal protective effect. A prolonged decrease in 24-hour protein excretion could not be shown to predict attenuation in the progression of established clinical diabetic nephropathy.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Placebos; Potassium; Prospective Studies; Proteinuria; Sodium

To determine whether inhibition of angiotensin converting enzyme can reduce the rate of decline in kidney function more than reducing blood pressure with other antihypertensive treatment.. Prospective, open randomised study lasting a mean of 2.2 years in patients with diabetic nephropathy.. Three outpatient nephrology clinics.. 40 patients with insulin dependent diabetes and diabetic nephropathy with reduced renal function.. Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide.. Rate of decline in glomerular filtration rate measured as chromium-51 edetic acid clearance.. Glomerular filtration rate declined a mean of 2.0 (SD 3.2) ml/min/year in the group given enalapril and 5.6 (5.9) ml/min/year in the control group. The mean arterial blood pressure during the study was 102 (5) mm Hg in the patients given enalapril and 103 (5) mm Hg in the patients given metoprolol. Urinary albumin excretion during treatment with enalapril was 60% lower than during treatment with metoprolol.. Enalapril has an antiproteinuric effect independent of the effect on systemic blood pressure. Treatment with enalapril can reduce the rate of decline in kidney function in patients with diabetic nephropathy more than equally effective antihypertensive treatment with metoprolol. This points to a specific renal protective effect of angiotensin converting enzyme inhibitors in diabetic nephropathy.

Topics: Adult; Blood Pressure; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Metoprolol; Middle Aged; Prospective Studies; Proteinuria

Nephropathy may develop in patients with sickle cell disease. We determined the prevalence of proteinuria and renal insufficiency in a group of patients with sickle cell disease and investigated the renal pathologic changes and the effects of an angiotensin-converting-enzyme inhibitor (enalapril) on protein excretion in patients found to have nephropathy.. We prospectively screened 381 patients with sickle cell disease for the presence of proteinuria and renal insufficiency. Renal biopsy and measurements of glomerular filtration rate, effective renal plasma flow, and urinary protein excretion were performed in 10 patients with mild nephropathy before and after the administration of enalapril, and again two to three weeks after its discontinuation.. Of the 381 patients with sickle cell disease, 26 (7 percent) had serum creatinine concentrations above the normal range and 101 (26 percent) had proteinuria of at least 1+. The renal lesions in the 10 patients who had biopsies consisted of glomerular enlargement and perihilar focal segmental glomerulosclerosis. The mean (+/- SD) glomerular area in these patients was 28.7 +/- 4.1 x 10(3) micron 2, as compared with 15.8 +/- 4.3 x 10(3) micron 2 in 10 control patients without renal disease who had died of trauma (P less than 0.0001). During the administration of enalapril, the mean 24-hour urinary protein excretion decreased 57 percent (range, 23 to 79 percent) below the base-line value (P less than 0.001), and it increased to 25 percent below the base-line value after enalapril was discontinued. The glomerular filtration rate and effective renal plasma flow did not change significantly.. Approximately 25 percent of patients with sickle cell disease have proteinuria. Treatment with enalapril reduces the degree of proteinuria in these patients, suggesting that glomerular capillary hypertension may be a pathogenic factor in sickle cell nephropathy.

Topics: Adult; Anemia, Sickle Cell; Angiotensin-Converting Enzyme Inhibitors; Child; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Prospective Studies; Proteinuria

The effects of a nonselective beta-adrenergic blocking drug with beta-2 agonist activity (dilevalol 200 mg) on proteinuria and renal hemodynamics were evaluated in a double-blind crossover study versus an ACE inhibitor (enalapril 5 mg) in eight patients with glomerulonephritis, moderate renal function impairment and proteinuria greater than 1 g/24 hr. Patients were studied after a one week placebo phase while off all other medications, except steroids in a few cases, and after three weeks of treatment. A 10-day placebo washout perod was included between the various drug treatments. During each period renal hemodynamics were measured by clearance techniques, and urinary protein excretion as well as fractional clearance of albumin and IgG were determined. Both drugs reduced mean arterial pressure and proteinuria to a similar extent [mean arterial pressure: placebo 108 +/- 13 mm Hg; dilevalol 103 +/- 11 mm Hg (P less than 0.05); enalapril 103 +/- 12 mm Hg (P less than 0.05); protein excretion: placebo 5.1 +/- 4.2 g/day; dilevalol 3.3 +/- 3.0 g/day (P less than 0.05); enalapril 2.8 +/- 2.8 g/day (P less than 0.05)]. The antiproteinuric effect was greater with enalapril than dilevalol. Dilevalol reduced GFR [baseline inulin clearance: 73.3 +/- 38 ml/min/1.73 m2; after dilevalol: 63.3 +/- 28 ml/min/1.73 m2 (P less than 0.05)] and the decrease of proteinuria correlated positively with the reduction of GFR. Enalapril did not significantly lower the GFR (inulin clearance during enalapril 66.8 +/- 23 ml/min/1.73 m2) and the reduction of proteinuria did not correlate with the lowering of the GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Labetalol; Male; Proteinuria; Renal Circulation

Angiotensin converting enzyme inhibitors and calcium antagonists are effective agents for controlling high blood pressure in diabetic patients. We selected 30 type II diabetic patients with proteinuria and evaluated the effect of these drugs on renal function and proteinuria. In a double-blind trial, patients received either 40 mg/day enalapril or 40 mg/day nifedipine during 12 months. They also received a hypoproteic diet with 0.8 g/kg wt/day of protein. In the enalapril group (10 men and eight women), mean arterial blood pressure was 112.0 +/- 12 mm Hg, creatinine clearance was 58.6 +/- 12.4 ml/min, and 24-hour proteinuria was 4.36 +/- 3.23 g/24 hr before treatment. After treatment, mean arterial blood pressure was 82.0 +/- 8.30 mm Hg (p less than 0.001), creatinine clearance was 66.6 +/- 13.8 ml/min (NS), and 24-hour proteinuria was 0.56 +/- 0.78 g/24 hr (p less than 0.001). In the nifedipine group (six men and six women), mean arterial blood pressure was 114.0 +/- 8.0 mm Hg, creatinine clearance was 67.8 +/- 19.6 ml/min, and 24-hour proteinuria was 2.84 +/- 1.31 g/24 hr before treatment. After treatment, mean arterial blood pressure was 86.0 +/- 7.0 mm Hg (p less than 0.001), creatinine clearance was 51.4 +/- 7.9 ml/min (p less than 0.001), and 24-hour proteinuria was 2.66 +/- 0.89 g/24 hr (NS). These results show a similar hypotensive action and different renal effects between these two drugs after 12 months of treatment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Creatinine; Diabetes Complications; Diabetes Mellitus; Enalapril; Female; Humans; Hypertension; Hypotension; Kidney; Male; Nifedipine; Potassium; Proteinuria

1. Both the angiotensin-converting enzyme inhibitor, lisinopril, and the non-steroidal anti-inflammatory drug, indomethacin, lower urinary protein excretion in renal disease and improve the selectivity of the residual proteinuria. Despite the clearly different renal haemodynamic profiles of the two drugs, we hypothesize that the antiproteinuric effect has a final common pathway that is a reduction in glomerular filtration pressure. 2. We studied the effects of lisinopril and indomethacin, separately and in combination, on urinary protein excretion, selectivity of proteinuria and renal haemodynamics in nine non-diabetic patients with overt proteinuria. 3. Urinary protein excretion was 5.4 +/- 2.5 g/24 h in the control period. Lisinopril monotherapy lowered urinary protein excretion by 53 +/- 26%. During indomethacin treatment urinary protein excretion was reduced by 63 +/- 24%. After adding indomethacin to lisinopril, urinary protein excretion fell by a further 58 +/- 23%, resulting in a 79 +/- 17% decrease during combined therapy. 4. Although both lisinopril and indomethacin monotherapy appeared to result in an improvement in glomerular protein permeselectivity, no further improvement was seen during the combination therapy. 5. The change in proteinuria were associated with changes in glomerular filtration rate, which showed a pronounced fall with combination therapy. The renal haemodynamic profiles during the different therapies suggest a post-glomerular vasodilatation by lisinopril and a pre-glomerular vasoconstriction by indomethacin, and the combination of both during the combined treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Indomethacin; Lisinopril; Male; Middle Aged; Proteinuria

Control of hypertension improves the course of renal disease. We compared the renal hemodynamic and permselective responses to an angiotensin-converting enzyme inhibitor (CEI) (enalapril) and an alpha 1-antagonist (prazosin) in 14 patients with established glomerular disease. A single-blinded, randomized, cross-over design was used consisting of a 3-week baseline period followed by two 4-week treatment periods, which were separated by a 4-week washout period. During the treatment periods, the CEI or alpha 1-antagonist was added to the patients' baseline antihypertensive medications. Mean arterial pressure (MAP) was reduced to similar levels by both drugs, although the time-averaged blood pressure throughout the study was higher with the alpha 1-antagonist. Twenty-four-hour urinary protein, albumin, and IgG excretion were not significantly different at the end of the CEI and alpha 1-antagonist periods. However, compared with baseline values, significant decreases in total protein and IgG excretion occurred only during the CEI period, while albumin excretion decreased with both drugs. A 22% decrease in the fractional clearance of albumin (4.95 +/- 1.44 to 3.88 +/- 1.57 x 10(-3); P less than 0.01) and a 49% decrease in the fractional clearance of IgG (1.58 +/- 0.42 to 0.81 +/- 0.28 x 10(-3); P less than 0.001) occurred during CEI therapy with no significant changes in these parameters being seen with alpha 1-antagonist therapy (albumin: 4.95 +/- 1.44 to 4.48 +/- 1.51 x 10(-3), P = NS; IgG: 1.58 +/- 0.42 to 1.71 +/- 0.70 x 10(-3), P = NS). At the time of the fractional clearance measurements, MAP proved to be lower on the CEI. Reanalysis of the data for the subgroup of 11 patients without differences in MAP during the clearance period demonstrated a beneficial effect favoring CEI. Except for the greatest decreases in blood pressure (21 to 30 mm Hg), a greater antiproteinuric effect for a given decrease in blood pressure was seen with the CEI. Additionally, reduction in proteinuria occurred in a subset of seven patients whose baseline MAP was in the normotensive range. In conclusion, lowering MAP improves proteinuria. CEI appears to exert a more favourable effect even at similar MAP. Reductions in blood pressure, even within the accepted normal range, lessen permselective defects.

Topics: Adult; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Prazosin; Proteinuria; Renal Circulation; Renin; Single-Blind Method

Angiotensin converting enzyme (ACE) inhibitors are known to lower urinary protein excretion in human renal disease. This proteinuria lowering effect of ACE inhibition has been hypothesized to be a result of renal hemodynamic changes due to the inhibition of angiotensin II (Ang II) production. To test this hypothesis we studied the short-term effects of different doses of exogenous Ang II (5%, 10% and 20% of the pressor dose) on renal hemodynamics and urinary protein excretion in comparison with placebo infusion in six non-diabetic normotensive proteinuric patients, both before and after three months treatment with the ACE inhibitor, lisinopril. Lisinopril lowered proteinuria from 7.5 +/- 1.9 to 2.7 +/- 0.6 g/24 hr and induced a fall in blood pressure, renal vascular resistance and filtration fraction, whereas plasma Ang II levels were similar to the pre-treatment values. Ang II infusion induced typical effects which appeared to be similar before and during lisinopril treatment: a dose-related fall in renal plasma flow and rise in systemic blood pressure, renal vascular resistance and filtration fraction, while the glomerular filtration rate remained relatively stable. However, neither before nor during lisinopril therapy did any changes in urinary protein loss occur during the infusions of Ang II, despite the fact that Ang II reversed the long-term systemic and renal hemodynamic changes induced by the ACE inhibitor. We conclude that the long-term antiproteinuric effect of the ACE inhibitor, lisinopril, is neither mediated through changes in circulatory Ang II levels nor influenced by acute changes in systemic and renal hemodynamics, suggesting a non-hemodynamic mechanism of action.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Humans; Lisinopril; Male; Middle Aged; Proteinuria; Renal Circulation

To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM).. After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk.. Verapamil or enalapril alone normalized blood pressure to less than 90 mmHg diastolic in 30 patients; verapamil decreased mean +/- SE blood pressure from 159/98 +/- 3/1 to 146/87 +/- 3/2 mmHg (n = 18, P less than 0.001) and enalapril from 166/99 +/- 5/2 to 146/86 +/- 3/1 mmHg (n = 12, P less than 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 +/- 4/2 to 152/90 +/- 4/2 mmHg (P less than 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified.. In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Proteinuria; Verapamil

Arterial hypertension and proteinuric nephropathy are common features in diabetic patients. In streptozotocin-diabetic rats, it has been possible to reduce the blood pressure and proteinuria by converting enzyme inhibitors, and so slowing the decline of kidney function. These results have been confirmed in diabetic patients affected by arterial hypertension and persistent proteinuria. However, up to now it has not been clear if these favorable renal effects are related specifically to converting enzyme inhibition. In the attempt to clarify this last point, from a practical as well as from a speculative point of view, 12 type 2 diabetic outpatients affected by mild to moderate arterial hypertension and persistent macroalbuminuria (greater than 250 mg/daily, at least on three consecutive occasions) without any other signs of renal diseases were studied. In a randomized sequence and in a double blind fashion, after a washout period of 3 weeks, the patients underwent pharmacological treatment which consisted of enalapril 20 mg o.d., chlorthalidone 12.5 mg o.d., atenolol 50 mg o.d. and placebo o.d. Each treatment lasted 45 days. Kidney function, blood pressure and heart rate were checked at the beginning and at the end of each treatment, while urinary albumin excretion was measured at the end of the 4th, 5th, and 6th week of each treatment. Blood pressure significantly decreased in a similar fashion after each active treatment, while kidney function did not change significantly. Urinary albumin excretion rate significantly decreased after enalapril and atenolol, but did not change after chlorthalidone. According to these results we can hypothesize that the inhibition of tissue angiotensin formation and its related change on the glomerular permeability, rather than renal and systemic hemodynamic features, seem to be the common mechanisms by which both enalapril as well as atenolol decrease the albuminuria in our patients.

Topics: Atenolol; Blood Pressure; Chlorthalidone; Chronic Disease; Diabetic Nephropathies; Diabetic Retinopathy; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Proteinuria

To compare the antihypertensive, renal haemodynamic and antiproteinuric effect of enalapril and atenolol in patients with proteinuria of non-diabetic origin.. Prospective, double blind, randomised 16 week study after a pretreatment period of at least three weeks.. Outpatient nephrology and hypertension unit.. 27 patients with proteinuria (greater than 300 mg protein/day) of non-diabetic origin, moderately impaired renal function (creatinine clearance 30-90 ml/min), and a pretreatment diastolic blood pressure of greater than 80 mm Hg.. Treatment with enalapril (10 mg/day, adjusted between 5 and 40 mg, if necessary) or atenolol (50 mg/day, adjusted between 25 and 100 mg if necessary) titrated against a target fall in diastolic blood pressure to less than 95 mm Hg or of greater than 10 mm Hg, or both.. Blood pressure, renal haemodynamics, and urinary protein excretion.. No differences were detected between the two groups before treatment. The falls in systolic and diastolic blood pressures during treatment were not significantly different between both groups. Proteinuria fell slightly with atenolol but significantly more with enalapril (mean change -0.38 (95% confidence interval -0.78 to 0.03) v -1.2 (-1.70 to -0.69) g/day respectively, p less than 0.02) as did filtration fraction (mean change -1.8 (-2.9 to -0.7) v -3.8 (-4.9 to -2.8)% respectively. Serum potassium concentration increased with enalapril (mean change 0.63 (SD 0.51) v 0.19 (0.47) mmol/l, p less than 0.05).. Enalapril lowers proteinuria more than atenolol in patients with non-diabetic renal disease despite a similar blood pressure lowering effect of both drugs, and its antiproteinuric effect seems to be associated with the characteristic renal haemodynamic effect of angiotensin converting enzyme inhibitors.

Topics: Adult; Atenolol; Blood Pressure; Double-Blind Method; Enalapril; Female; Hemodynamics; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Circulation; Sodium; Urea

Both angiotensin-converting enzyme inhibitors and dietary protein restriction have been reported to reduce urinary protein losses in patients with chronic glomerular diseases. We evaluated these two therapies in 12 such patients ingesting a constant metabolic diet containing 1.6 g protein/kg body weight per day. After a steady-state was achieved during a 3-week baseline period, patients were randomly assigned to either enalapril, titrated to reduce mean arterial pressure by 10 mm Hg, or an isocaloric 0.8 g/kg protein diet. Five patients in each group completed 3 additional weeks of observation during the treatment period. Enalapril resulted in an average reduction in urinary protein and albumin losses of 26% and 33%, respectively, without reducing creatinine clearance. Albumin synthesis was unchanged and nitrogen balance increased slightly (+142.8 +/- 85.7 mmol/d [+2.0 +/- 1.2 g/d], P = 0.075). Dietary protein restriction had no consistent effect on proteinuria or albuminuria, whereas albumin synthesis (25.9 +/- 3.4 v 21.5 +/- 2.9 g/d/1.73 m2, P less than 0.05) and nitrogen balance (-135.6 +/- 92.8 mmol/d [-1.9 +/- 1.3 g/d], P = 0.10) decreased. Both therapies resulted in a modest increase in plasma potassium concentration. Whether the maintenance of albumin synthesis in the presence of a reduction in urinary protein losses will convey a long-term advantage to treatment of proteinuric patients with angiotensin-converting enzyme inhibitors remains to be determined.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Dietary Proteins; Enalapril; Female; Humans; Male; Middle Aged; Proteinuria

The therapeutic effect of long-term enalapril administration was studied in 20 patients with severe essential hypertension (EH), resistant to intensive therapy with a combination of 3 or 4 antihypertensive drugs. Addition of enalapril (Renitec MSD from 5 to 40 mg/day) to the previous therapy allowed to maintain blood pressure within limits not exceeding 150/95 mmHg during a 12-month study in more than 80% of previously resistant patients. Left ventricular hypertrophy regressed in all patients and dilatation of the left ventricle seen in 4 patients disappeared during enalapril treatment. Serum sodium creatinine did not change significantly. Serum potassium increased slightly but remained within the normal range. Proteinuria had a tendency to diminish and N-acetyl-beta-D-glucosaminidase activity in the urine dropped within normal limits. Based on their results, the authors conclude that enalapril is suitable for the long-term treatment of patients with severe EH, resistant to intensive antihypertensive therapy, with minimal side effects, good tolerance and a tendency for amelioration of cardiac and renal function.

Topics: Adrenergic beta-Antagonists; Cardiomegaly; Diuretics; Drug Therapy, Combination; Echocardiography; Enalapril; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Proteinuria

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diabetes Complications; Diltiazem; Enalapril; Female; Humans; Lisinopril; Male; Middle Aged; Prospective Studies; Proteinuria

To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment.. Prospective, open randomised study lasting eight weeks in patients with diabetic nephropathy.. Outpatient nephrology clinics.. 40 Patients with type I diabetes and diabetic nephropathy with reduced renal function.. Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide.. Arterial blood pressure and urinary excretion of albumin and protein.. Arterial blood pressure after eight weeks was 135/82 (SD 13/7) mm Hg in the group given enalapril and 136/86 (16/12) mm Hg in the group given metoprolol. Proteinuria and albuminuria were similar in both groups before randomisation. After eight weeks' treatment, the geometric mean albumin excretion was 0.7 (95% confidence interval 0.5 to 1.2) g/24 h in the patients given enalapril and 1.6 (1.1 to 2.5) g/24 h in the patients given metoprolol (p less than 0.02). The proteinuria was 1.1 (0.7 to 1.7) and 2.4 (1.6 to 3.6) g/24 h respectively (p less than 0.02).. Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol. This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent of the effect on systemic blood pressure.

Topics: Adult; Albuminuria; Blood Pressure; Diabetic Nephropathies; Enalapril; Humans; Metoprolol; Middle Aged; Prospective Studies; Proteinuria; Random Allocation

We studied the efficacy of the ACE inhibitor lisinopril in treating overt proteinuria in comparison with the NSAID indomethacin, and evaluated some of the conditions that could influence this antiproteinuric effect. In 12 patients with a proteinuria varying from 3.2 to 10.5 g/24 hr, a diastolic BP ranging from 64 to 105 mm Hg, and a GFR varying from 34 to 127 ml/min, the effect of different lisinopril doses and of changing dietary sodium intake was evaluated. Proteinuria fell by 27 +/- 20% from 6.1 +/- 2.1 to 4.5 +/- 1.9 g/24 hr on a low dose (median 5 mg/day) lisinopril and by 50 +/- 17% to 3.1 +/- 1.4 g/24 hr on a higher dose (median 10 mg/day), irrespective of initial proteinuria, BP, or GFR. This antiproteinuric effect was abolished by increasing salt intake from 50 to 200 mmol/day, and was recovered again by re-instituting the sodium restricted diet. The antiproteinuric effect of 10 mg/day lisinopril was comparable to the reduction in proteinuria (by 57 +/- 21% to 2.8 +/- 2.0 g/24 hr) on 150 mg/day indomethacin, while adverse effects were less and renal hemodynamic effects were more favorable during lisinopril. In some patients it took several weeks before the effect of the ACE inhibitor on proteinuria was stabilized. Thus, the antiproteinuric effect of the ACE inhibitor lisinopril appears to be dose and time related, and is strongly dependent on dietary sodium restriction, whereas it does not depend on initial proteinuria, BP, or GFR. The effect is comparable to that of indomethacin, while adverse effects are less.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diet, Sodium-Restricted; Enalapril; Female; Glomerular Filtration Rate; Humans; Indomethacin; Kidney Diseases; Lisinopril; Male; Proteinuria; Renal Circulation; Sodium, Dietary; Vascular Resistance

To evaluate the effect of enalapril on proteinuria, 16 normotensive type II diabetics with persistent proteinuria were studied. At random, the patients were allocated to enalapril (5 mg once a day) or placebo, in a double-blind fashion, for 12 months. Blood pressure, heart rate, urinary albumin excretion, plasma renin activity and aldosterone, blood glucose, serum fructosamine, urine urea and body weight were checked monthly during the run-in period and every 2 months during the treatment period. The kidney function was studied at the beginning of the study and during the sixth and 12th months. Enalapril decreased urinary albumin excretion in our patients in the absence of any effect on blood pressure and kidney function. Our data may be interpreted on the basis of a direct vascular effect of enalapril that is probably related to a tissue mechanism consisting of reduced angiotensin formation, increased kinins, or both, or of other unknown factors.

Topics: Albuminuria; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Heart Rate; Humans; Proteinuria; Randomized Controlled Trials as Topic

Angiotensin II is the main regulator of both glomerular haemodynamics and glomerular capillary permeability. An alteration in the function of intrarenal angiotensin II seems to be the cause of diabetic glomerulopathy in animals and humans. In order to investigate the renal effects of the angiotensin converting enzyme (ACE) inhibitor enalapril (5 mg once a day), 24 normotensive diabetic patients with persistent proteinuria, after a 3-month run-in period, were randomly allocated to receive the active drug (12 patients) or the corresponding placebo, for the 6 months. Effective renal plasma flow, glomerular filtration rate, renal vascular resistance and filtration fraction were measured at the end of the run-in and the treatment periods. Blood pressure, heart rate, urinary albumin excretion, plasma renin activity and aldosterone, blood glucose, serum fructosamine and body weight were checked monthly during the run-in and every 2 months during the treatment period. Enalapril decreased urinary albumin excretion in the normotensive diabetic patients without any changes in systemic blood pressure or glomerular haemodynamics. These results indicate that ACE inhibition interferes with the glomerular capillary permeability induced by angiotensin II.

Topics: Adult; Diabetes Mellitus; Enalapril; Female; Hemodynamics; Humans; Male; Middle Aged; Proteinuria

The safety and tolerability of lisinopril were assessed in 1,476 patients [1,165 hypertensives and 311 patients with congestive heart failure (CHF)] and 211 normal volunteers. The duration of lisinopril therapy ranged from 1 day to 16 months, with a mean duration of 105 days. In the hypertensive population, the most frequent clinical adverse experiences on lisinopril alone were headache, dizziness, cough, and diarrhea. Not all of these adverse experiences were thought to be drug related. Five percent of patients were discontinued because of adverse clinical experiences; cough and dizziness were the most common reasons for discontinuation. Two of 1,165 (0.17%) hypertensive patients treated with lisinopril died, compared to 0.41% of hypertensive patients on other therapies. Neither case was considered to be drug related. In patients with CHF, the most frequent clinical adverse experiences were dizziness, diarrhea, hypotension, fatigue, headache, and rash. Not all of these adverse experiences were thought to be drug related. The percent of CHF patients discontinuing because of an adverse clinical experience was 7.4%; the most frequent causes for discontinuation were hypotension, dizziness, or renal impairment. Twelve deaths occurred in 311 CHF patients treated with lisinopril (3.9%) compared to 4/104 (3.8%) of CHF patients treated with placebo and 2/65 (3.1%) treated with captopril. Hypotension, orthostatic effects, or dizziness following the initial lisinopril dose occurred infrequently in patients treated with lisinopril. In hypertensive patients with normal renal function, including those treated previously or concomitantly with diuretic therapy, a first-dose hypotensive episode was reported in six of 955, or 0.6%. The incidence was higher (6.7%) in hypertensive patients with impaired renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Cell Count; Clinical Trials as Topic; Creatinine; Drug Tolerance; Enalapril; Female; Hemoglobins; Humans; Hypertension; Lisinopril; Male; Middle Aged; Potassium; Proteinuria

Enalapril is the result of a targeted research programme to develop a non-mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. Over 3500 patients world-wide have received enalapril or enalaprilat. Long-term experience at present includes over 2500 patients. While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril-type side-effects, particularly the skin rash, taste loss, leukopenia and proteinuria. Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension.

Topics: Captopril; Clinical Trials as Topic; Dipeptides; Drug Eruptions; Enalapril; Enzyme Inhibitors; Heart Failure; Humans; Hypertension; Leukocyte Count; Proteinuria; Taste; Uremia

Enalapril and enalapril/hydrochlorothiazide are effective in treating mild to moderate essential hypertension, and efficacy has been demonstrated for up to 48 weeks. The frequency of adverse clinical effects was similar in all three treatment groups, and serious adverse clinical effects were rare.

Topics: Adult; Aged; Analysis of Variance; Black or African American; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Potassium; Proteinuria; Random Allocation; Sodium Chloride

The proactive management of spina bifida (SB), especially of its severe form, myelomeningocele (MMC), has contributed to decreasing chronic kidney disease (CKD). The objective of this study is to present the evolution of 5-year-old patient with MMC followed from birth with a proactive approach.. This retrospective study included 55 cases with MMC of up to 5 years of age. All of them were admitted at birth and followed by a multidisciplinary group, with a proactive approach: CIC and anticholinergics. In the same group, the variables were compared within the first year and the within the fifth year of life. Chronic kidney disease (CKD) was defined by: alterations on renal DMSA scintigraphy; alterations in microalbuminuria/creatininuria ratio, proteinuria 24 hs and decrease in glomerular filtration rate (GFR) calculated with Schwartz bedside equation.. Although overactivity, UTI and VUR decreased throughout the first 5 years (49, 9 and 12%), reduced cystometric capacity, DLPP >40 cm of water and end-filling pressure (Pdet) >20 cm of water increased (41, 27 and 61%). All patients at 5 years of age required CIC. Reduced cystometric capacity and VUR were more significant with abnormal DMSA (36%) at 5 years old ( p: 0.03). Proteinuria and CKD increased to 25% and 49%. Similarly, the need for enalapril increased from 10% to 27%. The microalbuminuria/creatininuria ratio was pathological in 27.3%. 48 patients (87%) remained unchanged on DMSA scan and the other 7 underwent modifications (4 new cases with altered DMSA) over time. Of the 32 normal DMSA cases without changes, 81% did not present proteinuria and 88% continued to respond favorably to oxybutynin. GFR <90 ml/min/1.72m 2 was found in only 3 cases with abnormal DMSA. There was a RR 1.91 (IC95% 1.15-3.16) greater of renal compromise in cases that were anticholinergic-resistant compared to non-refractory cases.. Over time, some patients suffered loss of bladder wall compliance, despite the proactive approach. There is an association between abnormal renal DMSA, reduced bladder capacity, and VUR at 5 years of age. Although proteinuria, CKD and enalapril requirement increased over 5 years, almost 90% did not show changes in renal DMSA status.. Over time, some patients suffered loss of bladder wall compliance. Hence, even if a proactive approach is followed since birth, it is essential to continue with the ongoing monitoring of the renal status and thus avoid greater renal deterioration.

Topics: Child; Child, Preschool; Enalapril; Humans; Infant; Infant, Newborn; Meningomyelocele; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies; Spinal Dysraphism; Succimer; Vesico-Ureteral Reflux; Water

The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting.. We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX.. While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria.. These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anilides; Animals; Disease Models, Animal; Disease Progression; Enalapril; Glomerular Filtration Rate; Hypertension; Kidney; Nephrectomy; Postoperative Complications; Proteinuria; Rats; Renal Insufficiency, Chronic; Sirtuin 1; Thiazoles

To reduce the progression of chronic kidney disease (CKD) and cardiovascular risk, the guidelines recommend the blockade of the renin-angiotensin-aldosterone system (RAAS) in patients with proteinuria.. To assess the frequency of enalapril or losartan use in diabetics or hypertensive patients with stage 3 CKD.. Review of clinical records of patients with CKD in an urban primary care clinic.. We identified 408 subjects aged 40 to 98 years (66% women) with stage 3 CKD. Sixty six percent had only hypertension and 34% were diabetic with or without hypertension. Seventy four percent received RAAS blockers (52% used enalapril, 45% losartan and 2% both medications). RAAS blockers were used in 70% of hypertensive and 78% of diabetic patients. The prescription in hypertensive diabetics with microalbuminuria was lower than in those without microalbuminuria (72% vs 87%, p < 0.05), but the opposite occurred in pure hypertensive patients with and without microalbuminuria (88% vs 69%, p < 0.05). There were no significant differences in blood pressure levels, microalbuminuria or serum potassium levels between RAAS blocker users and non-users. No differences were observed either between enalapril and losartan users.. The adherence to clinical guidelines is insufficient and users of the recommended drugs did not achieve the expected goals.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diabetes Mellitus; Disease Progression; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Renin-Angiotensin System; Treatment Adherence and Compliance

MYH9-related disease is a rare genetic disorder characterized by macrothrombocytopenia, with frequent proteinuric nephropathy, hearing loss, and cataract. Although proteinuric nephropathy usually progresses to renal failure, there is no established treatment for the nephropathy. We herein describe the case of a 19-year-old man carrying an E1841K MYH9 mutation, who developed persistent proteinuria. The patient was diagnosed with early-stage MYH9-related nephropathy based on the histological examination of a kidney biopsy specimen. The patient was treated with enalapril, which significantly reduced the proteinuria with no decline in his renal function. The early administration of renin-angiotensin system blockade therapy may have beneficial effects on MYH9-related nephropathy in patients with E1841K mutations. We also briefly summarize previously published cases of MYH9-related nephropathy treated with renin-angiotensin system (RAS) blockade therapy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biopsy; DNA; DNA Mutational Analysis; Enalapril; Hearing Loss, Sensorineural; Humans; Kidney; Male; Mutation; Myosin Heavy Chains; Proteinuria; Renin-Angiotensin System; Thrombocytopenia; Young Adult

Renal dysfunction (RD) is associated with reduced survival in HF; however, not all RD is mechanistically or prognostically equivalent. Notably, RD associated with "pre-renal" physiology, as identified by an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), identifies a particularly high risk RD phenotype. Proteinuria, another domain of renal dysfunction, has also been associated with adverse events. Given that several different mechanisms can cause proteinuria, we sought to investigate whether the mechanism underlying proteinuria also affects survival in HF.. Subjects in the Studies of Left Ventricular Dysfunction (SOLVD) trial with proteinuria assessed at baseline were studied (n=6439). All survival models were adjusted for baseline characteristics and estimated glomerular filtration rate (eGFR). Proteinuria (trace or 1+) was present in 26% and associated with increased mortality (HR=1.2; 95% CI, 1.1-1.3, p=0.006). Proteinuria >1+ was less common (2.5%) but demonstrated a stronger relationship with mortality (HR=1.9; 95% CI, 1.5-2.5, p<0.001). In patients with BUN/Cr in the top tertile (≥17.3), any proteinuria (HR=1.3; 95% CI, 1.1-1.5, p=0.008) and >1+ proteinuria (HR=2.3; 95% CI, 1.7-3.3, p<0.001) both remained associated with mortality. However, in patients with BUN/Cr in the bottom tertile (≤13.3), any proteinuria (HR=0.95; 95% CI, 0.77-1.2, p=0.63, p interaction=0.015) and >1+ proteinuria (HR=1.3; 95% CI, 0.79-2.2, p=0.29, p interaction=0.036) were not associated with worsened survival.. Analogous to a reduced eGFR, the mechanism underlying proteinuria in HF may be important in determining the associated survival disadvantage.

Topics: Aged; Blood Urea Nitrogen; Enalapril; Female; Glomerular Filtration Rate; Heart Failure; Humans; Male; Middle Aged; Prognosis; Proteinuria; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Factors; Survival Analysis; Ventricular Dysfunction, Left

Chronic allograft fibrosis is the major cause of graft loss in kidney transplantation. Progression can only be reduced by inhibition of the renin-angiotensin system (RAS). We tested the hypothesis that the protection provided by angiotensin-converting enzyme (ACE) inhibition also decreases capillary rarefaction, lymphangiogenesis, and podocyte injury in allograft fibrosis. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats treated with enalapril (60 mg/kg per day) (ACE inhibitor, ACEi) or vehicle. Proteinuria, blood urea nitrogen, and plasma creatinine were regularly assessed, and grafts were harvested for morphological and immunohistological analysis at various times up to 32 wk. In the vehicle group, many new lymphatic capillaries and severe and diffuse mononuclear infiltration of allografts were observed already 1 wk after transplantation. Lymphangiogenesis increased until week 4, by which time inflammatory infiltration became focal. Lymphatic capillaries were often located at sites of inflammation. Progressive interstitial fibrosis, glomerulosclerosis, capillary rarefaction, and proteinuria appeared later, at weeks 4-12 The number of lymphatic capillary cross sections strongly correlated with the interstitial fibrosis score. Podoplanin immunostaining, a marker of healthy podocytes, disappeared from inflamed or sclerotic glomerular areas. ACEi protected from lymphangiogenesis and associated inflammation, preserved glomerular podoplanin protein expression, and reduced glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, and blood capillary rarefaction at 32 wk. In conclusion, ACEi considerably decreased and/or delayed both glomerulosclerosis and tubulointerstitial injury. Prevention of glomerular podoplanin loss and proteinuria could be attributed to the known intraglomerular pressure-lowering effects of ACEi. Reduction of lymphangiogenesis could contribute to amelioration of tubulointerstitial fibrosis and inflammatory infiltration after ACEi.

Topics: Allografts; Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Enalapril; Fibrosis; Kidney; Kidney Glomerulus; Kidney Transplantation; Lymphangiogenesis; Lymphatic Vessels; Male; Membrane Glycoproteins; Podocytes; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew

The aim of our study was to investigate the effect of high-salt diet on the renal expression of renalase and the potential role of the local renin-angiotensin system in this process.. Sprague-Dawley (SD) rats were divided into groups according to salt content in diet and drug treatment as follows: normal-salt diet (NS), high-salt diet (HS), high-salt intake with hydralazine (HS+H), high-salt diet with enalapril (HS+E), and high-salt diet with valsartan (HS+V). The dietary intervention and drugs were given for four weeks. Renin activity and angiotensin II type 1 receptor (AT1R) levels were detected by real-time PCR. Renalase mRNA and protein were also measured.. After four weeks, systolic blood pressure and proteinuria were significantly increased in the HS group with respect to the NS group. Dietary salt intake caused a dramatic decrease in renalase expression in the rat kidneys. Renal cortex renin and AT1R increased significantly in the HS and HS+H groups. Urinary protein was positively correlated with renal renin and AT1R levels. However, in the HS+E and HS+V groups, enalapril and valsartan failed to influence renal renalase expression but abolished the increase in proteinuria, renal cortex renin, and AT1R levels with respect to the HS group.. This study indicates that high salt intake reduces renal expression, and renal RAS may be not involved in the regulation of renalase in SD rats fed with high-salt diet.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Diet; Enalapril; Hydralazine; Kidney; Male; Monoamine Oxidase; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Valsartan

To evaluate the efficacy and safety of losartan and enalapril in pediatric kidney transplant recipients.. A retrospective review was performed in 31 pediatric kidney transplant recipients who were treated with losartan (50 mg/d, oral) for 1 to 6 months because of mild hypertension and persistent proteinuria. All patients were treated concurrently with enalapril (5 or 10 mg daily, oral), and 12 patients (39%) also were treated with amlodipine (5 or 10 mg daily, oral). Demographic and clinical characteristics of the patients were reviewed.. Losartan use was associated with a significant decrease in mean systolic (before losartan was started, 123 ± 14 mm Hg; before losartan was stopped, 111 ± 10 mm Hg; P ≤ .001) and diastolic blood pressure (before losartan was started, 78 ± 11 mm Hg; before losartan was stopped, 69 ± 10 mm Hg; P ≤ .001) and urinary protein excretion (before losartan was started, 51 ± 45 mg/m2/h; before losartan was stopped, 28 ± 34 mg/m2/h; P ≤ .001). However, losartan therapy was associated with a significant mean increase in serum potassium level (before losartan was started, 4.0 ± 0.4 mmol/L; before losartan was stopped, 5.7 ± 0.5 mmol/L; P ≤ .001) and decrease in pH (before losartan was started, 7.35 ± 0.0; before losartan was stopped, 7.23 ± 0.0; P ≤ .001). Losartan was stopped because of hyperkalemia and acidosis earlier in patients who were on tacrolimus than cyclosporine immunosuppression (tacrolimus, 3 ± 1 mo; cyclosporine, 4.7 ± 0.8 mo; P ≤ .001).. Losartan and enalapril may be beneficial in pediatric kidney transplant recipients by decreasing blood pressure and proteinuria, with maintenance of stable graft function, but may be associated with serious adverse events including hyperkalemia and life-threatening acidosis.

Topics: Acidosis; Adolescent; Age Factors; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Child; Child, Preschool; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrogen-Ion Concentration; Hyperkalemia; Hypertension; Kidney Transplantation; Losartan; Male; Potassium; Proteinuria; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

The objective of this study was to compare renal function in diabetic hypertensive chronic kidney disease patients receiving enalapril or losartan.. This was a retrospective analytic cohort study.. Kenyatta National Hospital, Nairobi, Kenya.. Two hundred adult patients with hypertension and diabetic nephropathy.. One hundred and sixteen participants received an enalapril regimen while 84 were on a losartan regimen.. Time to doubling of serum creatinine and changes in the levels of proteinuria.. There was a higher risk of doubling of serum creatinine with losartan (Adjusted HR = 1.572; [95% CI: 1.015-2.434]; p = 0.043) than enalapril. There was a significant difference in time to doubling between the two arms--losartan 18 months, enalapril 36 month (p = 0.046). The changes in the levels of proteinuria between the two arms were not statistically significant for most of the follow up period except at the 15th month from treatment initiation (p = 0.05).. Enalapril was found to be more reno-protective compared to losartan. Where feasible, we suggest local use of enalapril as opposed to losartan for diabetic hypertensive chronic kidney disease patients.

Topics: Adult; Aged; Antihypertensive Agents; Creatinine; Diabetic Nephropathies; Enalapril; Female; Humans; Hypertension; Kenya; Kidney Function Tests; Losartan; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies

Alport syndrome (AS) is a progressive hereditary glomerular disease. Recent data indicate that aldosterone promotes fibrosis mediated by the transforming growth factor-β1 (TGF-β1) pathway, which may worsen proteinuria. Spironolactone (SP) antagonizes aldosterone and this study aimed to evaluate the efficacy of SP in reducing proteinuria and urinary TGF-β1 excretion in proteinuric AS patients.. The study involved ten children with AS, normal renal function, and persistent proteinuria (>6 months; uPr/uCr ratio >1). SP 25 mg once a day for 6 months was added to existing ACE inhibitor treatment with or without angiotensin-II receptor blockade. Urine and blood samples were examined monthly. Urinary TGF-β1 levels were measured twice before and three times during SP treatment. Plasma renin activity (PRA) and serum aldosterone levels were also measured. In eight patients, uProt/uCreat was also assessed after 9 months and 12 months of SP treatment.. After beginning SP therapy, all patients showed significant decrease in mean uProt/uCreat ratio (1.77 ± 0.8 to 0.86 ± 0.6; p < 0.001) and mean urinary TGF-β1 levels (104 ± 54 to 41 ± 20 pg/mgCreatinine; p < 0.01), beginning after 30 days of treatment and remaining stable throughout SP administration. PRA remain unchanged, and mean serum aldosterone increased from 105 ± 72 pg/ml to 303 ± 156 pg/ml (p < 0.001). The only side effect was gynecomastia in an obese boy. After 1 year of therapy, mean uProt/uCreat remains low (0.82 ± 0.48).. Addition of SP to ACE-I treatment with or without angiotensin II receptor blokers (ARB) significantly reduced proteinuria. This was mediated by decreased urinary TGF-β1 levels and not associated with major side effects.

Topics: Adolescent; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Child; Creatinine; Enalapril; Female; Humans; Kidney Function Tests; Male; Mineralocorticoid Receptor Antagonists; Mutation; Nephritis, Hereditary; Proteinuria; Spironolactone; Transforming Growth Factor beta1; Treatment Outcome; Young Adult

Angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers decrease postdiarrheal hemolytic uremic syndrome (D + HUS) sequelar proteinuria. However, proteinuria may persist in some patients. In nephropathies other than D + HUS, an additive antiproteinuric effect with coadministration of both drugs has been observed.. To assess such an effect in D + HUS, 17 proteinuric children were retrospectively studied. After a median period of 1 year post-acute stage (range 0.5-1.9) patients received enalapril alone for a median of 2.6 years (range 0.33-12.0) at a median dose of 0.4 mg/kg/day (range 0.2-0.56). As proteinuria persisted, losartan was added at a median dose of 1.0 mg/kg/day (range 0.5-1.5) during 2.1 years (range 0.5-5.0).. The decrease in proteinuria with enalapril was 58.0 %, which was further reduced to 83.8 % from the initial value after losartan introduction. The percentage of reduction was significantly greater with the association of both drugs (p = 0.0006) compared with the effect of enalapril exclusively (p = 0.023). Serum potassium, glomerular filtration rate, and blood pressure remained unchanged.. Our results suggest that adding losartan to persisting proteinuric D + HUS children already on enalapril is safe and reduces proteinuria more effectively. Whereas this effect is associated with long-term kidney protection, it should be determined by prospective controlled studies.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Diarrhea; Drug Therapy, Combination; Enalapril; Female; Hemolytic-Uremic Syndrome; Humans; Infant; Losartan; Male; Proteinuria; Retrospective Studies; Time Factors; Treatment Outcome

Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.

Topics: Aldehydes; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Enalapril; Ergocalciferols; Female; Glomerulonephritis; Kidney; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Proteinuria; Rats; Receptors, Calcitriol; Superoxide Dismutase; Uremia

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Enalapril; Female; Humans; Losartan; Male; Proteinuria; Social Class

Topics: Antihypertensive Agents; Dihydropyridines; Drug Combinations; Electrocardiography; Enalapril; Humans; Hypertension; Kidney Function Tests; Proteinuria

The incidence of hypertension and progression of renal disease are greater in men than in women. Data suggest that there is a dimorphic response to angiotensin II (Ang II) in rats, with male rats exhibiting a greater increase in mean arterial pressure (MAP) than females. However, during endogenous renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibition, female rats have a greater MAP response to Ang II. We tested whether female mice exhibit a greater MAP response to chronic Ang II during ACE inhibition.. Twenty-week-old male and female C57BL/6J mice (n > or = 6/group), treated with enalapril (40 mg/kg/day in drinking water), were assigned to groups receiving either Ang II (800 ng/kg/min) or saline for 2 weeks. Enalapril treatment began 4 days before and continued throughout the experiment.. MAP was higher in male mice than female mice treated with enalapril and Ang II (male: 144 +/- 3 vs. female: 121 +/- 6 mm Hg, P < 0.05) and was not different between mice treated with enalapril alone (male: 99 +/- 3 vs. female: 100 +/- 3 mm Hg). F2-isoprostanes were not increased by Ang II; however, female mice had significantly higher levels than males. Renal cortical expression of catalase and Cu/Zn-superoxide dismutase (SOD) was not different between experimental groups. Urinary protein was higher in male mice when compared to females, but was not changed after treatment with Ang II in either group.. These data suggest that there are species and sex-specific differences in the mechanism of the blood pressure response to Ang II, even during ACE inhibition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Catalase; Drug Synergism; Enalapril; F2-Isoprostanes; Female; Kidney Cortex; Male; Mice; Mice, Inbred C57BL; Proteinuria; Sex Characteristics; Superoxide Dismutase; Vasoconstrictor Agents

Renal fibrosis is the final common pathway of chronic kidney disease, and its progression predicts the degree of renal dysfunction. We investigated the renoprotective properties of pirfenidone in a remnant kidney model of chronic renal failure to determine its pharmacological potency compared to enalapril. Five-sixths nephrectomized rats were fed diet containing pirfenidone (approximately 700mg/kg/day) for 8weeks. Pirfenidone steadily inhibited the progression of proteinuria, but not to a significant degree. Pirfenidone prevented the elevation of plasma creatinine and blood urea nitrogen. At the end of the experiment, pirfenidone had reduced systolic blood pressure by means of its renoprotective effect. In a histological study, pirfenidone improved interstitial fibrosis in the renal cortex. These effects were supported by the suppression of the expression of TGF-beta and fibronectin in the mRNA of the kidney. In contrast, pirfenidone had little effect on the expression of alpha-smooth muscle actin, which is one of the proteins responsible for epithelial-mesenchymal transition. This property was confirmed by the TGF-beta-induced transdifferentiation observed in cultured normal rat kidney tubular epithelial NRK52E cells. These results suggest that pirfenidone improves the progression of chronic renal failure via its antifibrotic action, although pirfenidone has less effective TGF-beta-induced epithelial to mesenchymal transdifferentiation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Differentiation; Cell Line; Chronic Disease; Disease Progression; Enalapril; Epithelial Cells; Fibrosis; Kidney; Kidney Failure, Chronic; Male; Mesoderm; Nephrectomy; Proteinuria; Pyridones; Rats; Rats, Wistar; Transforming Growth Factor beta

Combinations of antiproteinurics, including angiotensin I-converting enzyme inhibitors + angiotensin II receptor antagonist + statins, are promising choices in the treatment of steroid-resistant nephrotic syndrome. We aimed to investigate the effects of high doses of immunoglobulin in addition to these combinations in rats with adriamycin-induced nephrosis. The study included 40 rats allocated into five groups: control, nephrotic syndrome without treatment, dual therapy (DT) with enalapril + losartan, triple therapy (TT) with enalapril + losartan + simvastatin, and quadruple therapy (QT) with enalapril + losartan + simvastatin + a high dose of immunoglobulin. The proteinuria levels were not statistically different between DT, TT and QT groups at weeks 5, 8, 12 and 16. At week 16, serum creatinine levels in the QT group were significantly lower than those in the control, DT and TT groups. The glomerulosclerosis index in the DT group was significantly lower than in the TT and QT groups. The scores for interstitial fibrosis and TGF-beta staining were similar among treatment groups. In conclusion, we showed that quadruple therapy including immunoglobulin had a beneficial effect on renal function in the late phase, but it had no additional effects in reducing proteinuria or in glomerulosclerosis score in experimental nephrotic syndrome. Further studies with angiotensin I-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs) and immunoglobulin combinations would offer some benefits in the treatment of nephrotic syndrome.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Creatinine; Drug Therapy, Combination; Enalapril; Immunoglobulins; Immunologic Factors; Losartan; Male; Nephrotic Syndrome; Proteinuria; Rats; Rats, Wistar; Simvastatin; Time Factors; Treatment Outcome

TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Blood Urea Nitrogen; Cells, Cultured; Creatinine; Curcumin; Disease Models, Animal; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Macrophages; Mesangial Cells; Nephrectomy; Nephritis; NF-kappa B; PPAR gamma; Proteinuria; Rats; Rats, Sprague-Dawley; Transfection; Tumor Necrosis Factor-alpha

The renoprotective effect of cilnidipine ((+/-)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, CAS 132203-70-4), a L/N-type calcium channel antagonist, on puromycin aminonucleoside (PAN)-induced nephrosis was investigated in rats. In the Experiment I, rats were given an intravenous injection of PAN (70 mg/kg). Cilnidipine (3 mg/kg/day) and enalapril (CAS 75847-73-3, 5 mg/kg/day) were administered orally from 6 days after treatment with PAN (day 6) to day 26, and urinary analysis was performed on days 9, 15, 20 and 27. In the Experiment II, nephrosis was also induced by intravenous injection of PAN (70 or 100 mg/kg) in rats which were treated with cilnidipine and enalapril from days 6 to 10. Systolic blood pressure was measured on day 7 and urinary analysis was performed on day 10. On day 11, serum was collected and the kidneys were removed for immunofluorescence staining for nephrin and podocin proteins. In PAN-treated rats, the daily urinary protein excretion was dramatically elevated on day 5, reached a peak on day 9 and gradually returned to a normal level from days 15 to 27. Cilnidipine (3 mg/kg/ day) significantly suppressed the increase in proteinuria on day 9 and also improved the decrease in creatinine clearance without evident effect on the blood pressure. Furthermore, the elevations in serum total cholesterol and triglyceride tended to be suppressed by cilnidipine. The expression of nephrin and podocin proteins in PAN-treated rats showed the granular pattern in the glomeruli, while the intensity of staining seemed to be dependent on the urinary protein excretion level in the cilnidipine-treated rats. The results obtained in this study suggest a renoprotective effect of cilnidipine in PAN-induced nephrosis in rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antimetabolites, Antineoplastic; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Enalapril; Fluorescent Antibody Technique; Male; Membrane Proteins; Nephrosis; Protective Agents; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley

The objective was to evaluate structural changes of glomeruli during aging and the role of chronic renin-angiotensin system inhibition (RASi) on these changes; starting RASi on Wistar rats at two different moments: the first group after weaning and the second at the midpoint of their lifespan (12 months).. Thirty rats were divided, after weaning, into three groups of 10: group 1: control (C); group 2 : 30 mg/kg/day losartan (L); group 3 : 10 mg/kg/day enalapril (E). At 18 months, rats were placed in metabolic cages to evaluate proteinuria, then killed. Another group of 24 rats, 12 months old, were divided into three groups of eight: group 1: C; group 2: L; group 3: E. At 18 months the same procedure described above was carried out. Finally, a third group of 20 rats was studied as healthy controls and killed: 10 rats at 7 months and ten at 12 months of age. Tissue samples were collected after sacrifice. To evaluate glomerular fibrotic changes, both focal and periglomerular sclerosis, and mesangial matrix expansion, a scoring scale was established. We also evaluated anti-alpha-SM-actin and anti-collagen-III immunolabeling. Glomerular area was measured using an image analyzer.. Proteinuria and serum creatinine increased with age but were reduced in treated animals. Main glomerular changes present in 18-month-old rats were reduced by half in treated animals. Glomerular area showed significant increase with normal aging and all treatment strategies protected against it.. RAS plays a central role in natural process of renal aging, probably by producing effects influencing the biology of aging, the effects of which can be attenuated by RASi.

Topics: Actins; Age Factors; Aging; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Collagen Type III; Creatinine; Enalapril; Fibrosis; Kidney Glomerulus; Losartan; Male; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Weaning

Blockade of the renin-angiotensin system (RAS), the standard treatment for chronic proteinuric nephropathy, slows but may not halt progression of the disease, particularly when therapy is started late. Because vasopressin may also play a role in the progression of renal disease, we measured the effect of a dual V(1a) and V(2) vasopressin receptor antagonist (RWJ-676070) alone or combined with angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor blockade on proteinuria and renal disease progression during overt nephropathy. Twenty-one days after renal mass reduction, a time of established injury, rats were given vehicle, RWJ-676070, enalapril, losartan, RWJ-676070 plus enalapril, or losartan in drinking water for an additional 39 days. RWJ-676070 returned the blood pressure to pre-treatment levels, which were significantly lower than those in vehicle-treated rats. Enalapril, losartan, and the combined therapies reduced blood pressure to a greater extent. RWJ-676070 afforded a partial antiproteinuric effect, which was enhanced by the addition of enalapril or losartan. Renal functional impairment, and glomerular and tubular changes were partially ameliorated by RWJ-676070; parameters significantly improved with either enalapril or losartan alone and improved to a greater extent with the combined therapies. Our findings suggest that vasopressin receptor antagonists could be of additional therapeutic value in the treatment of chronic proteinuric nephropathy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Biomarkers; Blood Pressure; Body Weight; Chronic Disease; Disease Models, Animal; Disease Progression; Diuresis; Drinking; Drug Therapy, Combination; Eating; Enalapril; Hormone Antagonists; Kidney; Kidney Diseases; Losartan; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Renin-Angiotensin System; Spiro Compounds; Time Factors

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria and edema. It is believed that nephrin and podocin are involved in the development of proteinuria. The proteinuria and effects of eplerenone alone or combined with enalapril on nephrin/podocin abundance in rats with NS have not yet been studied. Therefore, the present study was designed to examine the early (beginning 2 days before NS induction) and late (beginning 2 wk after NS induction) effects of eplerenone and enalapril, alone or combined, on proteinuria and nephrin/podocin abundance in rats with adriamycin-induced NS. Adriamycin caused a significant increase in daily protein excretion (U(pr)V; from 26.96 +/- 3.43 to 958.57 +/- 56.7 mg/day, P < 0.001) and cumulative proteinuria [from 900.33 +/- 135.5 to 22,490.62 +/- 931.26 mg (P < 0.001)] during 6 wk. Early treatment with enalapril significantly decreased U(pr)V from 958.6 +/- 56.7 to 600.31 +/- 65.13 mg/day (P < 0.001) and cumulative proteinuria to 12,842.37 +/- 1,798.17 mg/6 wk (P < 0.001). Similarly, early treatment with eplerenone produced a profound antiproteinuric effect: U(pr)V decreased from 958.57 +/- 56.7 to 593.38 +/- 21.83 mg/day, P < 0.001, and cumulative proteinuria to 16,601.84 +/- 1,334.31 mg/6 wk; P < 0.001. An additive effect was obtained when enalapril and eplerenone were combined: U(pr)V decreased from 958.57 +/- 56.69 to 424.17 +/- 38.54 mg/day, P < 0.001, and cumulative protein excretion declined to 10,252.88 +/- 1,011.3 mg/6 wk, P < 0.001. These antiproteinuric effects were associated with substantial preservation of glomerular nephrin and podocin. In contrast, late treatment with either enalapril or eplerenone alone or combined mildly decreased U(pr)V and cumulative proteinuria. Thus pretreatment with eplerenone or enalapril is effective in reducing daily and cumulative protein excretion and preservation of nephrin/podocin. More profound antiproteinuric effects were obtained when enalapril and eplerenone were combined.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Urea Nitrogen; Drug Synergism; Electrolytes; Enalapril; Eplerenone; Immunohistochemistry; Lipids; Male; Mineralocorticoid Receptor Antagonists; Nephrotic Syndrome; Proteinuria; Rats; Rats, Sprague-Dawley; Spironolactone

Fetal exposure to angiotensin-converting enzyme inhibitors (ACEIs) is associated with increased neonatal morbidity and mortality. Long-term follow-up of three patients with fetal ACEI exposure revealed impaired renal function in two, severe hypertension and proteinuria in one and isolated polycythaemia in all three. Careful long-term follow-up of children with ACEI fetopathy is recommended.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Child; Enalapril; Female; Fetus; Humans; Hypertension; Kidney Diseases; Male; Polycythemia; Pregnancy; Prenatal Exposure Delayed Effects; Proteinuria

The traditional management of children with proteinuric kidney disease is treatment with high dose steroids regardless of comorbid conditions such as obesity. This study evaluated the effect of angiotensin blockade (AB) alone as the sole management of children with non-diabetic proteinuric kidney disease.. Retrospective chart analysis was performed in 146 children. Seventeen were identified to have received angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker exclusively for management of proteinuria. Total proteinuria (Upr/cr), albuminuria (Ualb/cr), estimated glomerular filtration rate (eGFR), serum potassium and blood pressure were assessed at baseline and at 3-month intervals for over 24 months.. Mean age was 11.2+/-4.8 years with 12 females. Eleven of 17 patients (65%) were overweight or obese. There was a significant decline in total proteinuria and albuminuria after 3-6 months of AB therapy and a further decline with longer duration of treatment (P<0.001). Although single vs dual AB were similarly effective in lowering total proteinuria, dual therapy was more effective in lowering albuminuria (single 57+/-23% vs dual 71+/-15%; P<0.02). The eGFR decreased from 'hyperfiltration' levels prior to initiation of AB to normal at the end of the treatment period (145+/-41-111+/-17 ml/min/1.73 m2; P=0.01). Systemic blood pressures remained normal throughout the study period.. Angiotensin blockade alone appears to effectively control proteinuria and stabilize kidney function in children. This may provide an alternative to more toxic therapies, especially corticosteroids, in children with glomerular disorders such as those associated with obesity.

Topics: Adolescent; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Losartan; Male; Proteinuria; Retrospective Studies; Tetrazoles

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Enalapril; Ergocalciferols; Female; Macrophages; Nephrectomy; Parathyroid Hormone; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Insufficiency; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Uremia; Vitamin D

It is suggested that appropriate chronic exercise (EX) may produce improvements of the physical strength in patients with chronic renal failure (CRF). Because acute exercise causes proteinuria and decreases the renal blood flow and glomerular filtration rate, it is necessary to consider the influence of EX on renal function. Therefore, we assessed the renal and peripheral effects of moderate to intense EX as well as the effects of the combination of EX and enalapril (ENA) in a rat model of CRF.. Male 5/6-nephrectomized Wistar-Kyoto rats were divided into six groups according to the following treatment: 1) no exercise (C); 2) ENA (2 mg/kg/day, subcutaneously); 3) moderate exercise with treadmill running (20 m/min for 60 min/day, 5 days/week) (EXm); 4) intense exercise with treadmill running (28 m/min for 60 min/day, 5 days/week) (EXi); 5) EXm+ENA; and 6) sham operation (S). The rats were then treated for 12 weeks.. Both EX and ENA blocked the development of hypertension, blunted increases in proteinuria, reduced serum creatinine and blood urea nitrogen, and improved the index of glomerular sclerosis (IGS) and the relative interstitial volume of the renal cortex (RIV). Moreover, IGS and RIV in the EXm+ENA group were the lowest among all other nephrectomized groups. Furthermore, EXm+ENA enhanced capillarization as well as the proportion of type-I fiber in the soleus muscle.. These results suggest that EX and ENA have renoprotective effects. The findings also suggest that EXm+ENA provided greater renoprotective effects than those of ENA alone, and that EXm+ENA had some additional peripheral effects without any complications in this rat model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Cortex; Kidney Failure, Chronic; Male; Muscle, Skeletal; Nephrectomy; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Inbred WKY

Pax2 is a transcription factor with important functions during kidney development . Ectopic expression of Pax2 in podocytes has been reported in various glomerular diseases , but the functional relevance remains unknown. We developed an inducible mouse model that allows activation of Pax2 specifically in podocytes. Persistent expression of Pax2 did not interfere with the initial differentiation of podocytes, but mice ectopically expressing PAX2 developed end-stage renal failure soon after birth. Similarly, activation of PAX2 in healthy adult animals resulted in renal disease within 3 weeks after podocyte-specific induction of a deleter Cre. PAX2 activation caused repression of the podocyte key regulator molecule Wt1 and consequently a dramatic reduction of nephrin expression. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. Finally, treatment of mice with an angiotensin-converting enzyme (ACE) inhibitor normalized renal function and induced upregulation of the important structural molecule nephrin via a Wt1-independent pathway. Our data demonstrate the functional significance of PAX2 reexpression in mature podocytes for the development of glomerular diseases and suggest that reactivation of PAX genes in terminally differentiated cells leads to a more dedifferentiated phenotype.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression Regulation; Kidney Failure, Chronic; Male; Membrane Proteins; Mice; PAX2 Transcription Factor; Podocytes; Proteinuria; WT1 Proteins

In diabetic rats with maximal activation of RAS induced by uninephrectomy, late treatment with anti-TGFbeta antibody limited renal injury only when combined with ACE inhibitor. We investigated whether in a two-kidney diabetic model the time at which treatment started predicted the response to TGFbeta antagonist.. 27 weeks after streptozotocin injection, animals had mild proteinuria and were randomized to receive irrelevant antibody, anti-TGFbeta antibody (1D11) or enalapril till 52 weeks (early treatment). The effect of agents alone or combined was also evaluated at the time of overt proteinuria (late treatment, 52-61 weeks).. When given early, 1D11 displayed marked antihypertensive and antiproteinuric effects. Glomerulosclerosis was reduced to the extent that a remarkable percentage of glomeruli without sclerosis appeared after treatment. Podocyte number was normalized. Renoprotection of 1D11 was comparable to enalapril. Despite control of blood pressure, in late treatment single agents did not reduce proteinuria significantly. Glomerulosclerosis and podocyte loss were partially limited by 1D11 or enalapril, but full protection was achieved by combination.. Renoprotective effect of TGFbeta antagonism crucially depends on the time at which treatment started. Effectiveness of early treatment with 1D11 would indicate that TGFbeta is a major mediator of damage in early diabetes. To tackle the renal damage in the phase of advanced disease, a combined treatment with ACE inhibitor is needed.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Kidney Glomerulus; Male; Podocytes; Proteinuria; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta

Vasopressin, mainly through the V1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure. To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I).. After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7).. In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44+7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67+7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30+18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21+20% and 0%, respectively), ACE-I significantly lowered proteinuria (92+2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed.. These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Body Weight; Enalapril; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney; Male; Nephrectomy; Piperidines; Proteinuria; Rats; Rats, Wistar

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Body Weight; Disease Progression; Drug Interactions; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Male; Mycophenolic Acid; Nephrectomy; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Wistar; Thy-1 Antigens; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study sought to assess the effects of Quercetin and Enalapril on urinary protein excretion and amount of platelet-derived growth factor-B (PDGF-B) and vascular endothelial growth factor-1 (VEGF-1) in renal tissue of diabetic rats. 29 streptozotocin-induced diabetic rats were divided into 3 groups, diabetic control group (group D, n=12); Enalapril group (group E, n=10); Quercetin group (group Q, n=7). In addition, there was one normal control group (group N, n = 5). The urinary protein excretion of 24 hours was measured at 4, 8, 12 weeks. All rats were sacrificed at 12 weeks. The amounts of PDGF-B and VEGF-1 in renal tissue were measured by immunohistochemical techniques. The 24-h levels of urinary protein excretion of D,Q and E groups were higher than that of N group; the level of Q, E groups were lower than that of D group; there was no difference between Q and E group. The expression levels of PDGF-B and VEGF-1 in renal tissue of D, Q, and E groups were significantly higher than that of N group the levels of Q and E groups were significantly lower than that of D group, no difference was found between Q and E group. The protective role of Quercetin and Enalapril in lowering urinary protein excretion may be related to the decreased amounts of PDGF-B and VEGF-1 in renal tissue.

Topics: Animals; Diabetes Mellitus, Experimental; Enalapril; Kidney; Male; Proteinuria; Proto-Oncogene Proteins c-sis; Quercetin; Random Allocation; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A

An important explanatory theory for the mechanism of postexercise proteinuria is that angiotensin II could be inhibited by angiotensin converting enzyme inhibitors. Because of the kininase effect of the angiotensin converting enzyme, it is unclear whether the kallikrein-kinin system contributes to the effect of angiotensin converting enzyme inhibitors on postexercise proteinuria. The aim of this study was to evaluate any possible involvement of the kallikrein-kinin system in the therapeutic effect of angiotensin converting enzyme inhibitors on postexercise proteinuria. We evaluated urinary protein levels in exhausted rats receiving an angiotensin converting enzyme inhibitor (enalapril) or an angiotensin II type I receptor antagonist (losartan). Enalapril (30 mg/kg/day, two days) or losartan (20 mg/kg/day, two days) were given to animals using an intragastric catheter. Urinary protein levels increased (41 %) in rats which were exhausted via treadmill running (p < 0.05). In animals that received drug treatment (enalapril or losartan), but did not exercise to exhaustion, urinary protein levels were not different from the control group. Urinary protein levels were found to be significantly lower (p < 0.05) in animals which performed acute exhaustive exercise after enalapril or losartan administration, compared to rats which were exhausted without drug administration. Inhibition of postexercise proteinuria by either enalapril or losartan suggested that angiotensin II plays an important role in postexercise proteinuria, however, it appears the kallikrein-kinin system is not involved in angiotensin converting enzyme inhibitors effect.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Kallikrein-Kinin System; Losartan; Male; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Wistar

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) reduces proteinuria and the rate of renal function deterioration in diabetic nephropathy and other glomerular diseases, but its role in quiescent lupus nephritis has not been established. We conducted a retrospective study to investigate the effects of ACEI/ARB on proteinuria and renal function in patients with persistent proteinuria (>1 g/day) despite resolution of acute lupus nephritis following immunosuppressive treatment. Fourteen out of 92 patients were included. The duration of treatment with ACEI/ARB was 52.1 +/- 35.7 months. The levels of proteinuria, serum albumin, serum creatinine, systolic and diastolic blood pressure were 1.10 to 6.90 g/day, 35.8 +/- 3.6 g/L, 102.54 +/- 34.48 micromol/L, 137.6 +/- 10.9 and 81.9 +/- 9.2 mmHg at baseline. Proteinuria and serum albumin showed significant sustained improvements after 6 and 24 months of treatment. Comparison of slopes for serial proteinuria, albumin and reciprocal of serum creatinine before and after treatment showed significant improvements in six (43%), eight (57%) and two patients, respectively. At last follow-up proteinuria remained significantly lower (0.36 g/day, P = 0.043) and albumin higher (41.3 +/- 2.2 g/L, P = 0.023). Eleven (78.6%) patients had proteinuria improved by >50%, and five had insignificant proteinuria at last follow-up. Systolic blood pressure was significantly reduced from 6 months onwards, but this did not correlate with proteinuria reduction. Diastolic blood pressure, serum creatinine, creatinine clearance, anti-dsDNA, C3 and haemoglobin were not altered. We conclude that ACEI/ARB effectively reduces proteinuria and improves serum albumin in patients with persistent proteinuria despite quiescent lupus nephritis.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Enalapril; Female; Follow-Up Studies; Humans; Losartan; Lupus Nephritis; Male; Proteinuria; Ramipril; Retrospective Studies; Serum Albumin

We investigated the renal structural and functional consequences of nitric oxide (NO) deficiency co-treated with angiotensin-converting enzyme inhibitor (ACEi) in 20 adult male Wistar rats and 20 spontaneously hypertensive rats (SHR). The animals were separated into eight groups (n = 5) and treated for 30 days: Control, L-NAME (NO deficient group), Enalapril, L-NAME + Enalapril. The elevated blood pressure in NO deficient rats was partially reduced by enalapril. Serum creatinine was elevated in L-NAME-SHRs and effectively treated with enalapril. The proteinuria was significantly higher only in L-NAME-SHRs, and this was reduced by treatment with ACEi. The glomerular volume density (Vv(gl)) in L-NAME rats, both Wistar and SHR, was greater than in matched control rats, and enalapril treatment effectively prevented this Vv(gl) increase. No significant differences were observed in tubular volume density, Vv(tub), or tubular surface density, Sv(tub), in all Wistar groups. The Vv(tub) was smaller in L-NAME-SHRs than in control SHRs, and this tubular alteration was not prevented by enalapril. The Sv(tub) was not different among the SHR groups. In Wistar rats no changes were seen in vascular surface density, but a greatly increased cortical vascular volume density was seen in the enalapril treated rats. The vascular length density was greatly diminished in NO deficient rats that was effectively prevented with enalapril treatment. The vascular cortical renal stereological indices are normally reduced in SHRs. Administration of enalapril, but not L-NAME, changed this tendency. However, enalapril was not totally effective in preventing vascular damage in SHR NO deficient animals.

Topics: Algorithms; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Creatinine; Enalapril; Enzyme Inhibitors; Hypertension; Kidney; Kidney Function Tests; Kidney Glomerulus; Kidney Tubules; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Proteinuria; Rats; Rats, Inbred SHR; Rats, Wistar; Renal Circulation

Nephrotic syndrome has long been treated in China with two herbs, Astragalus mongholicus and Angelica sinensis, which may have antifibrotic effects.. Rats with chronic puromycin-induced nephrosis were treated with Astragalus and Angelica 3 mL/d (n = 7) or enalapril 10 mg/kg/d (n = 7). Normal control rats (n = 7) received saline rather than puromycin, and an untreated control group (n = 7) received puromycin but no treatment. After 12 weeks, stained sections of the glomerulus and tubulointerstitium were evaluated for injury. Immunohistochemistry staining measured extracellular matrix components, transforming growth factor-beta1 (TGFbeta1), osteopontin, ED-1-positive cells, and alpha-actin. TGFbeta1 mRNA was assessed by in situ hybridization. Renin, ACE activity, angiotensin, and aldosterone were measured by radioimmunoassay or colorimetry. In the untreated rats, chronic renal injury progressed to marked fibrosis at 12 weeks. Astragalus and Angelica significantly reduced deterioration of renal function and histologic damage. Expressions of type III and IV collagen, fibronectin, and laminin also decreased significantly. This anti-fibrotic effect was similar to that of enalapril. The herbs had no effect on the renin-angiotensin system but did reduce the number of ED-1-positive, and alpha-actin positive cells and expression of osteopontin compared to untreated controls. The combination of Astragalus and Angelica retarded the progression of renal fibrosis and deterioration of renal function with comparable effects of enalapril. These effects were not caused by blocking the intrarenal renin-angiotensin system, but associated with suppression of the overexpression of TGFbeta1 and osteopontin, reduction of infiltrating macrophages, and less activation of renal intrinsic cells [corrected].

Topics: Angelica sinensis; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Astragalus Plant; China; Drugs, Chinese Herbal; Enalapril; Fibrosis; Humans; Kidney; Male; Medicine, Chinese Traditional; Nephrosis; Phytotherapy; Plant Preparations; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Regression Analysis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Five patients with severe hemolytic uremic syndrome (HUS) were followed for 10-18 years. Because of proteinuria, arterial hypertension, and reduced glomerular filtration rates, they received either captopril (n=2) or enalapril (n=3), or both (n=1) for 8-15 years. Blood pressure was normalized and proteinuria reduced in all; glomerular filtration improved in three patients and fell moderately in two. Four of the five patients have reached adult age with body weight and height, blood pressure, and serum creatinine levels within the normal range. At the last evaluation, median proteinuria was 220 mg/24 h (range 0-310) and glomerular filtration rate 56 ml/min per 1.73 m(2)(range 40-127). This long-term study indicates a renoprotective effect of angiotensin-converting enzyme inhibitors in patients with sequelae after HUS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Child, Preschool; Creatinine; Enalapril; Follow-Up Studies; Glomerular Filtration Rate; Hemolytic-Uremic Syndrome; Humans; Hypertension; Kidney; Proteinuria; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Kidney; Kidney Diseases; Male; Proteinuria; Ureteral Obstruction

The mechanism(s) underlying greater renoprotection of combined blockade of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) by vasopeptidase over ACE inhibitors are ill defined. We previously found that progressive renal disease is associated with increased renal synthesis of endothelin-1 (ET-1) in the face of reduced generation of renal nitric oxide (NO) in the remnant kidney model. Here we compared changes in urinary excretion of ET-1 and nitrite/nitrate, markers of renal ET-1, and NO synthesis, respectively, and urinary cGMP, an indirect index of renal atrial natriuretic peptide (ANP) synthesis, after administration of vasopeptidase or ACE inhibitor in rats with renal mass reduction (RMR).. Twenty-one days after 5/6 nephrectomy, after the onset of hypertension and overt proteinuria, rats were divided in 3 groups (N= 7-8) and given daily by gavage: vehicle, the vasopeptidase inhibitor AVE7688 (3 mg/kg bid), or enalapril (5 mg/kg bid) until day 90. Normal rats (N= 5) served as control rats.. Systolic blood pressure in RMR rats was equally controlled by AVE7688 and enalapril. AVE7688 resulted in a significant antiproteinuric effect, with urinary protein levels being reduced on average by 83% in respect to vehicle (88 +/- 28 vs. 518 +/- 27 mg/day, P < 0.0001). Enalapril achieved a 47% reduction in proteinuria (277 +/- 81 mg/day, P < 0.01 vs. vehicle) to levels that remained higher (P < 0.01), however, than those after AVE7688. Renal function impairment and glomerular and tubular changes were significantly (P < 0.05 vs. vehicle) ameliorated by AVE7688, and partially affected by enalapril. AVE7688 reduced the abnormal urinary excretion of ET-1 of RMR animals (98 +/- 8 vs. vehicle: 302 +/- 50 pg/24 h, P < 0.001) more than enalapril (159 +/- 14 pg/24 h, P < 0.05 vs. AVE7688). Consistently, AVE7688 was more effective than enalapril in augmenting renal synthesis of NO (2487 +/- 267 and 1519 +/- 217 vs. vehicle: 678 +/- 71 nmol/15 h; P < 0.001, AVE7688 vs. vehicle, P < 0.01 AVE7688 vs. enalapril). AVE7688 significantly increased urinary cGMP (78 +/- 6 vs. vehicle 45 +/- 9 nmol/24 h; P < 0.01).. The superior renoprotection achieved by AVE7688 over enalapril in progressive renal injury is due to the correction of the altered balance of vasoconstrictor/vasodilator mediators in the kidney.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Enalapril; Endothelin-1; Heterocyclic Compounds, 3-Ring; Kidney; Kidney Diseases; Male; Nephrectomy; Neprilysin; Nitrates; Nitric Oxide; Nitrites; Proteinuria; Rats; Rats, Sprague-Dawley

Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor beta 1 (TGF-beta 1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-beta 1 in diabetic rats.. Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days.. Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558).. Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-beta 1.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Drug Synergism; Enalapril; Hypertrophy; Kidney; Losartan; Male; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Transforming Growth Factor beta; Transforming Growth Factor beta1

The proteinuria is frequently the initial insult to the kidney and it usually followed by a progressive decline in the glomerular filtration rate. The angiotensin II mediate by glomerular permeselective function via the opening of large pores after elevations in transmembrane pressure and by acting on the glomerular pressure, too. There is evidence that angiotensin-converting enzyme inhibitors alone or with the angiotensin receptor-blockade may improve the glomerular size-selective function and the hemodynamic intrarenal accounted output of plasma proteins. We evaluated the Enalapril action only in two progressive doses (stage 1: 0.2 mg/kg/day and stage 2: 0.4 mg/kg/per day, respectively) and then we evaluated the combinated treatment (stage 3) with Enalapril (0.2 mg/kg/per day) + Losartan (0.8 mg/kg/day) in thirteen patients (2 female/ 11 male, mean age 12 yrs, r: 10y-16y) normotensive with middle or heavy proteinuria and normal glomerular filtration rate. The study lasted six months. In the three stages occurred decrease of the urinary protein, but only the stage 2 and 3 was significant (p < 0.05). And the three stages had significant reduction of the mean blood pressure, too (p < 0.05). On the other hand there has a good correlation between the less proteinuria and the descent of the mean blood pressure in the stage I (r: 0.75, p < 0.05) and the stage 2 (r: 0.70, p < 0.05), but this did not occur in the stage 3 (r: 0.37, p < 0.1). No patient had raise serum potassium; neither did they have decrease glomerular filtration rate or anaemia.. The coadministration of Enalapril and Losartan was the most efficient treatment antiproteinuric effect. It was not only by the drug related reduction in systemic blood pressure. There weren't any adverse side effects in any patient dependent of the medication.

Topics: Adolescent; Antihypertensive Agents; Blood Pressure; Child; Drug Therapy, Combination; Enalapril; Female; Humans; Losartan; Male; Proteinuria

PGE(2) and PGI(2) reduce extracellular matrix deposition and their production is altered after ACE inhibitor (ACEi) treatment. We therefore hypothesized that cyclooxygenase (COX)-2 inhibition would exacerbate renal injury and antagonize the effects of ACEi. To test these hypotheses, WKY and SHR were uninephrectomized (UNX) and treated with either vehicle, enalapril, NS398 or enalapril+NS398. NS398 did not affect systolic blood pressure nor antagonize the antihypertensive effect of enalapril. Urinary protein excretion in UNX WKY was significantly decreased after treatment with either enalapril or NS398. In UNX SHR, enalapril reduced proteinuria, but NS398 alone had no effect. Administration of both drugs, however, further reduced proteinuria. In UNX WKY, treatment with either NS398 alone or both drugs reduced glomerular volume and similar results were observed in SHR. Surprisingly, these results disprove our original hypothesis and suggest that inhibition of COX-2 provides additional renoprotection to that of enalapril alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Collagen Type II; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enalapril; Hypertrophy; Isoenzymes; Kidney Diseases; Male; Nephrectomy; Nitrobenzenes; Organ Size; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sulfonamides

Renin-angiotensin-aldosterone system blockade has been shown to protect against renal damage in salt-supplemented, stroke-prone spontaneously hypertensive rats (SHRsp). Based on intermittent tail-cuff blood pressure (BP) measurements, it has been claimed that such protection is BP-independent and mediated by a blockade of the direct tissue-damaging effects of angiotensin and/or aldosterone. BP radiotelemetry was performed for 8 weeks in approximately 10-week-old male SHRsp who received a standard diet and either tap water (n=10) or 1% NaCl to drink. Saline-drinking SHRsp were either left untreated (n=12), received enalapril (50 mg/L) in drinking fluid (n=9), or had subcutaneous implantation of time-release 200-mg pellets of aldactone (n=10). The average systolic BP (mean+/-SEM) during the final 3 weeks was significantly higher (P<0.05) in untreated saline-drinking (215+/-6 mm Hg) SHRsp but not aldactone-treated (198+/-4 mm Hg) or enalapril-treated treated SHRsp (173+/-1 mm Hg), as compared with tap water-drinking SHRsp (197+/-3 mm Hg). Histological renal damage scores at 8 weeks paralleled the BP in all groups, with an excellent correlation (r=0.8, P<0.001, n=41). Moreover, a renal damage score of >5 was only observed in SHRsp whose average systolic BP during the final 3 weeks exceeded 200 mm Hg, indicating a threshold relation with BP. These data show that protection by renin-angiotensin-aldosterone system blockade in this model is BP-dependent and mediated by preventing the severe increases in BP seen in untreated salt-supplemented SHRsp and further underscore the limitations of interpretations based on conventional tail-cuff BP measurements.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Delayed-Action Preparations; Enalapril; Hypertension; Kidney; Linear Models; Male; Mineralocorticoid Receptor Antagonists; Proteinuria; Rats; Rats, Inbred SHR; Sodium Chloride; Spironolactone; Time Factors

Although graft dysfunction has been increasingly reported in post-transplant IgA nephropathy (Tx-IgAN), intragraft morphological changes have been largely overlooked. We evaluated glomerular changes in Tx-IgAN to identify the histological features pertaining to significant proteinuria and therapeutic response to enalapril.. Fifty-four renal allograft biopsies, diagnosed as Tx-IgAN at a median of 46 months after transplantation, were the subject of the study. In 10 patients, glomerular morphometry was performed. In 14 patients who have been treated with enalapril for more than 12 months, we correlated the therapeutic response to enalapril with allograft histology.. No uniform pattern was found in the glomeruli of Tx-IgAN. The glomerular mesangium was mostly indistinct. Interstitial fibrosis was negative or mild in 88.9%. By morphometry, the glomerular tuft areas and mesangial areas were significantly larger in Tx-IgAN than those of the normal native kidney (p < 0.05), but were not different from transplant cases without glomerulonephritis. Proteinuria of >/=1 g/24 h was correlated with glomerulosclerosis, interstitial fibrosis and interstitial inflammation at time of biopsy (p < 0.005). The presence of segmental sclerosis (SS) correlated well with the amount of 24-h proteinuria (p < 0.001). After treatment with enalapril, the amount of proteinuria reduced in 64.3%. Therapeutic response to enalapril tended to be less effective in patients having SS (28.6 versus 71.4%), but this finding did not reach a statistical significance.. Significant proteinuria was associated with advanced chronic injury, especially with the presence of SS in Tx-IgAN, but anti-proteinuric effect of enalapril was not affected by graft histology. It remains to be clarified whether glomerular mesangial expansion plays a role in graft dysfunction in a subset of Tx-IgAN showing prominent mesangial changes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Case-Control Studies; Creatinine; Enalapril; Female; Glomerulonephritis, IGA; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Kidney Transplantation; Male; Proteinuria; Retrospective Studies

Cystinosis, a rare autosomal recessive disease, manifests with renal Fanconi syndrome during the first year of life. Interstitial damage is a major cause of renal failure in patients with cystinosis. We presume that albuminuria contributes to the development of renal failure in these patients. The aim of this study was to examine whether the administration of ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis.. Five patients with cystinosis aged 4 - 9 years were studied. All patients had Fanconi syndrome and were treated with cysteamine. Median creatinine clearance was 48 ml/min/1.73 m2 (range 21 - 61). The excretion of albumin and alpha1 microglobulin as well as arterial blood pressure and serum creatinine were evaluated before and at 3 months on oral administration of enalapril (0.15 mg/kg once daily).. At 3 months on enalapril, albuminuria decreased in all patients (1,042 vs 629 mg per 24 h, p < 0.05). The median reduction of albuminuria was 43% (range: 4 - 72%, p < 0.05). Urinary excretion of alpha1 microglobulin remained constant. Systolic blood pressure decreased from median 110 - 100 mmHg (p < 0.05), while diastolic blood pressure remained stable (median 60 mmHg). Creatinine clearance decreased from median 48 - 45 ml/min/1.73 m2 (p < 0.05) and returned to previous values after discontinuation of enalapril.. ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis and might be used in these patients in order to slow the progression of renal insufficiency attributed to proteinuria.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Child; Child, Preschool; Creatinine; Cystinosis; Enalapril; Humans; Proteinuria; Statistics, Nonparametric; Treatment Outcome

Glomerular endothelial dysfunction is believed to be responsible for the proteinuria and nephronal damage, namely tubulointerstitial fibrosis and glomerulosclerosis, observed in severe nephrosis such as focal segmental glomerulosclerosis. A dysfunctioning glomerular endothelium is likely to be induced by oxidative stress and oxidized LDL as well as altered immunocirculatory balance with a defective anti-inflammatory pathway. A defective release of vasodilator inconjunction with enhanced production of angiotensin II induces hemodynamic maladjustment by preferential constriction at the efferent arteriole. Such a hemodynamic maladjustment exerts two significant hemodynamic impacts. Close to the efferent constriction, it induces intraglomerular hypertension and glomerulosclerosis. Far from the efferent constriction, it reduces peritubular capillary flow, which eventually leads to tubulointerstitial fibrosis. Treatment with a vasodilator improves the hemodynamic maladjustment but does not completely suppress proteinuria. A successful suppression of proteinuria is accomplished by using Ganoderma lucidum and vitamins C and E. The beneficial effect of Ganoderma lucidum appears to be multifactorial, including the modulation of immunocirculatory balance, antilipid, vasodilator, antiplatelet and improved hemorheology. Together with vitamins C and E, this helps to neutralize oxidative stress and suppress the toxic effect to the glomerular endothelial function.

Topics: Adrenal Cortex Hormones; Angiotensin II; Ascorbic Acid; Calcium Channel Blockers; Dipyridamole; Drug Evaluation; Drug Resistance; Drug Therapy, Combination; Enalapril; Endothelial Cells; Glutathione; Humans; Kidney Function Tests; Kidney Glomerulus; Malondialdehyde; Nephrosis; Oxidative Stress; Phytotherapy; Plants, Medicinal; Platelet Aggregation Inhibitors; Proteinuria; Reishi; Renal Circulation; Treatment Outcome; Vasodilator Agents; Vitamin E

Angiotensin-converting enzyme (ACE) inhibitors effectively reduce proteinuria; however, the optimal antiproteinuric dose is still unknown. We conducted this study to determine whether an increase in ACE-inhibitor dose above the maximal antihypertensive effect has additional antiproteinuric potential.. Twenty-three proteinuric patients were administered the ACE inhibitor spirapril at a starting dose of 3 to 6 mg/d. The dose was increased every 6 weeks until the maximal antihypertensive effect, assessed by 24-hour ambulatory blood pressure (ABP) monitoring, was achieved (spir(max)), then increased to a supramaximal dose (spir(supramax)). Renal parameters, urinary protein excretion, and systemic activity of the renin-angiotensin system were compared between baseline, spir(max), and spir(supramax). Glomerular filtration rate and renal plasma flow were determined before the administration of spirapril and after administration of the supramaximal dose.. Median ABP and proteinuria decreased significantly between baseline and spir(max) (median, 102 mm Hg; range, 82 to 122 mm Hg versus 97 mm Hg; range, 82 to 113 mm Hg; median protein, 2.56 g/d; range, 1.05 to 22.1 g/d versus 1.73 g/d; range, 0.42 to 4.7 g/d). Both creatinine level and creatinine clearance remained unchanged. Suppression of angiotensin II formation led to a significant increase in renin and angiotensin I concentrations and a nonsignificant decrease in aldosterone levels. The increase in spirapril to a supramaximal dose had no further effect on serum renin or angiotensin I levels or proteinuria. There was an additional slight decrease in aldosterone levels and, subsequently, a significantly lower level than at baseline.. Our results show that the antiproteinuric effect of spirapril is associated with its antihypertensive effect. Although high-dose ACE-inhibitor therapy has no additional influence on proteinuria, a possible beneficial long-term effect cannot be ruled out.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Proteinuria; Reference Standards

Nephropathy has long been recognized as a potential complication of cyanotic congenital heart disease (CCHD). There have been few large-scale studies or clinical reports on renal impairment in patients with CCHD; similarly, very few studies have examined the drug treatment of nephropathy in CCHD. We examined the clinical characteristics and effectiveness of enalapril, an angiotensin-converting enzyme inhibitor (ACE-I), in patients with CCHD complicated with significant proteinuria.. The clinical records of 37 patients with CCHD were evaluated; all were older than 10 years of age (median 19, range from 10 to 27) and had regular check-ups, including urinalysis. The treatment criteria for enalapril administration included significant proteinuria (urinary excretion > 1.0 g/24 h), stable cardiac condition and blood pressure within the normal range.. Eleven patients (29.7%) had persistent proteinuria, 6 patients met the enalapril treatment criteria and 5 patients were treated for more than 12 months. Enalapril apparently reduced the urinary protein excretion in 4 of the 5 patients (80%). No consistent improvement of renal function, as evidenced in the glomerular filtration rate (GFR), renal plasma flow (RPF) or filtration fraction (FF) was found in these patients, but neither were any significant adverse effects noted.. The incidence of nephropathy among patients with CCHD was about 30%, which was consistent with previous studies. It is worth considering the use of ACE-I when nephropathy accompanies CCHD.

Topics: Adolescent; Adult; alpha-N-Acetylgalactosaminidase; Angiotensin-Converting Enzyme Inhibitors; beta 2-Microglobulin; Biomarkers; Biopsy; Blood Pressure; Child; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Heart Defects, Congenital; Hexosaminidases; Humans; Japan; Kidney; Kidney Function Tests; Male; Nephrotic Syndrome; Proteinuria; Renal Plasma Flow; Serum Albumin; Treatment Outcome

Topics: Adolescent; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Drug Therapy, Combination; Enalapril; Humans; Hyperkalemia; Losartan; Proteinuria; Receptor, Angiotensin, Type 1

Whereas angiotensin converting enzyme inhibitors and angiotensin type 1 receptor antagonists have beneficial effects in the remnant model of renal failure, calcium channel blockers do not consistently improve renal disease in this model. This study examined whether these different means of blood pressure reduction have different effects on renal levels of angiotensin (Ang) and bradykinin peptides.. Rats subjected to five-sixths nephrectomy were divided into groups with similar hypertension and proteinuria at 4 to 5 weeks. They then received either no treatment, or enalapril, losartan or nifedipine for 2 weeks. Following repeat measurements of proteinuria and blood pressure, Ang II and bradykinin peptides were measured in the remnant kidney and renin, Ang II, and aldosterone were measured in the plasma.. All three drugs had equivalent blood pressure-lowering effects. Enalapril and losartan reduced proteinuria but nifedipine did not. Reduction of proteinuria in rats treated with enalapril and losartan was associated with a reduction in Ang II levels in both the peri-infarct and intact portions of the remnant kidney. By contrast, nifedipine increased Ang II levels in the intact portion of the remnant kidney. Losartan reduced bradykinin levels in the peri-infarct portion of the remnant kidney while enalapril reduced bradykinin levels in the intact portion of the remnant kidney. Nifedipine had no effect on intrarenal bradykinin levels.. The differential effects of enalapril, losartan and nifedipine on proteinuria and intrarenal Ang II and bradykinin levels suggest that the ability of an antihypertensive to decrease proteinuria may depend on its ability to decrease kidney Ang II and bradykinin levels.

Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Creatinine; Enalapril; Kidney; Losartan; Male; Nephrectomy; Nifedipine; Proteinuria; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Vasodilator Agents

The antiproteinuric effect of KD3-671 (2-propyl-8-oxo-1-[(2'-(H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-tetrahydrocycloheptimidazole), an angiotensin II type 1 receptor antagonist, was compared with that of enalapril, an angiotensin 11-converting enzyme inhibitor, using an experimental model of membranous nephropathy. KD3-671 (3, 10 and 30 mg/kg per day) and enalapril (30 mg/kg per day) were given p.o. for 40 days, respectively. KD3-671 (30 mg/kg per day) inhibited the elevation of proteinuria and plasma total cholesterol. On the other hand, enalapril showed only a tendency to diminish these parameters. KD3-671 had an antiproteinuric effect in rats with accelerated passive Heymann nephritis. These findings provide considerable encouragement for the clinical development of KD3-671.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Urea Nitrogen; Cholesterol; Enalapril; Glomerulonephritis; Imidazoles; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrazoles

Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl, show severe hypertension, organ damage, and early death. Preventive treatment with angiotensin II type 1 (AT1) receptor antagonists is known to be effective. Previously, we found that angiotensin converting enzyme (ACE) inhibition could reduce cerebral edema when treatment was started after manifestation of either proteinuria or cerebral edema. In this study AT1 receptor blockade was started at the same time points to evaluate whether this had an effect superior to ACE inhibition. SHRSP drank 1% NaCl. Group 1 served as controls. Group 2 and 3 rats were started on losartan and enalapril after proteinuria exceeded 40 mg/day. Group 4 and 5 rats were started on losartan and enalapril after the first observation of cerebral edema with T2-weighted magnetic resonance imaging scans. In controls, median survival was 54 days (range, 35 to 80 days) after the start of salt loading. With early-onset losartan and enalapril, survival increased to 305 days (range, 184 to 422 days) and 320 days (range, 134 to 368 days) (both P < .01 v group 1). Cerebral edema formation was prevented in all but two rats, one from each treatment modality. Development of proteinuria was markedly reduced. With late-onset treatment with losartan and enalapril, survival was 290 days (range, 120 to 367 days) and 264 days (range, 154 to 319 days) (both P < .01). Both losartan and enalapril decreased cerebral edema to baseline levels. Ultimately cerebral edema reoccurred, despite continued treatment, in 75% of the rats. Systolic blood pressure did not decrease after losartan treatment, but, similarly to early-onset treatment, decreased transiently after enalapril treatment. Cerebral edema and proteinuria were prevented and reduced in SHRSP treated with either an AT1 receptor antagonist or an ACE inhibitor. Survival was markedly and similarly prolonged by both treatments, whether initiated directly before or after development of cerebral edema. In rats where treatment was initiated after manifestation of cerebral edema, both cerebral edema and proteinuria reappeared despite continued treatment. Apparently, when hypertension is sustained, reappearance of target organ damage may not be entirely dependent on angiotensin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Brain Edema; Drug Administration Schedule; Enalapril; Genetic Predisposition to Disease; Hypertension; Losartan; Male; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Survival Analysis

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Enalapril; Endothelin-1; Interleukin-1; Kidney Cortex; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

Angiotensin-converting enzyme (ACE) inhibitors exert a renoprotective effect in both diabetic and nondiabetic renal disease with variable efficacy. Proteinuric patients with nondiabetic renal disease, normotension, and restricted protein and sodium intake were treated with ACE inhibitors without diuretics. Fifty-nine patients were treated with either lisinopril (10 mg/d; 36 patients) or enalapril (5 mg/d; 23 patients) over a period of 37.7 +/- 20.7 months. Urinary protein excretion decreased to less than 50% of pretreatment values after 1 to 37 months (6.9 +/- 8.8 months) of therapy in 33 patients (56%); in 29 patients, it reached less than 0.5 g/d of protein. Urinary protein levels remained low in 19 of the 33 patients (57.5%) throughout the entire posttreatment period (30.8 +/- 17.7 months). However, in the remaining 14 patients, escape from the antiproteinuric effect was detected after 19.2 +/- 13.4 months, evidenced by a decrease in the rate of change in creatinine clearance from 0.052 +/- 0.114 mL/min/mon during the low-proteinuria period to -0.697 +/- 1.101 mL/min/mon after the lapse of antiproteinuric effect (P: < 0.001). Although ACE inhibitors reduce the severity of proteinuria in patients with nondiabetic renal disease, our results show that a proportion of patients escape the antiproteinuric effect and subsequently develop an exacerbation of renal dysfunction.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dietary Proteins; Disease Progression; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Proteinuria; Sodium, Dietary

Wistar fatty (WF) rats have a genetic predisposition to hyperglycemia, polyuria, hyperinsulinemia, hyperlipidemia, obesity and nephropathy. These phenotypic characteristics are similar to those observed in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) nephropathy. In this study, the effects of two types of renin-angiotensin system inhibitors, an angiotensin II type 1-receptor antagonist (AT1A) and an angiotensin I-converting enzyme inhibitor (ACEI), on renal injury in WF rats were studied during the progressive phase of diabetic nephropathy. An AT1A, candesartan cilexetil (1 mg/kg), and an ACEI, enalapril (10 mg/kg), were administered orally once a day for 12 weeks, beginning when the rats were 27-week-old and already showed diabetic nephropathy and obesity. Both drugs prevented an increase in proteinuria during the experimental period. Furthermore, after 4-week intervention, the levels of proteinuria were markedly lower in drug-treated rats. At the end of the experiment, both drugs prevented the development of glomerular lesions without affecting glucose metabolism and obesity. In conclusion, the inhibition of angiotensin II activity ameliorated both existing proteinuria and the progression of proteinuria, resulting in preservation of glomerular structure. Thus angiotensin II plays important roles in the development and the progression of nephropathy in genetically obese diabetic WF rats.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Disease Progression; Enalapril; Glomerular Mesangium; Male; Proteins; Proteinuria; Rats; Rats, Wistar; Rats, Zucker; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Triglycerides

Regardless of the pattern of renal involvement, increased urinary protein excretion rate is the best independent predictor of progression of chronic nephropathies and short-term reduction in proteinuria has been reported to be renoprotective in the long term. Despite such evidence, however, the therapeutic target in renoprotection is almost exclusively on blood pressure control. We report the clinical course of a patient with chronic nephropathy after the institution of a multidrug treatment titrated against urinary protein excretion to achieve renoprotection. The present findings indicate that adjusting renoprotective therapy according to the decline in protein excretion in a multidrug strategy may stabilize or even reverse renal disease progression. This approach should be formally explored in prospective studies.

Topics: Adult; Algorithms; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Kidney Diseases; Kidney Failure, Chronic; Losartan; Lupus Nephritis; Proteinuria; Sodium Chloride Symporter Inhibitors

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Synergism; Drug Therapy, Combination; Enalapril; Glomerulonephritis, IGA; Humans; Losartan; Proteinuria; Renin; Treatment Outcome

There is little information on the significance of angiotensin-converting enzyme (ACE) genotypes and medical treatments in children with primary focal segmental glomerulosclerosis (FSGS).. A multicenter retrospective study was performed on the role of ACE genotypes and medical treatments in 43 Japanese children with FSGS (20 males and 23 females), including 17 children who progressed to end-stage renal failure during the mean observation period of 6.9 +/- (SD) 5.0 years.. The incidence of the D allele of the ACE gene was higher in the whole group of 43 children with FSGS and in a subgroup of 28 steroid-resistant FSGS children (p < 0.05) than in the 130 children of the healthy control group (0.48, 0.48, and 0.33, respectively). ACE genotypes did not affect renal survival in the whole FSGS group nor in the steroid-resistant subgroup. Among the 28 steroid-resistant children, treatment with ciclosporin was effective in delaying the development of end-stage renal failure (p = 0.044), independently of other treatment regimens.. The present study of Japanese children with FSGS showed that the D allele of the ACE gene is associated with the development of FSGS, but not associated with the progression of FSGS which was greatly ameliorated with ciclosporin, irrespective of ACE genotypes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Benzazepines; Captopril; Child; Disease Progression; Drug Resistance; Enalapril; Female; Glomerulosclerosis, Focal Segmental; Humans; Incidence; Japan; Kidney Failure, Chronic; Male; Peptidyl-Dipeptidase A; Prednisolone; Proteinuria; Regression Analysis; Retrospective Studies; Survival Rate

No data are available about the effects of AT1 receptor antagonist losartan on the skeleton and there is also little information on the activity of an ACE inhibitor enalapril on bone metabolism. It is widely believed that the vasculature plays an important role in bone remodeling under normal and pathological conditions. We treated 14-week-old female Wistar rats with losartan, enalapril or saline. Administration of the ACE inhibitor enalapril and angiotensin II antagonist losartan had no effect on total malondialdehyde (MDA) in the blood and on urinary excretion of some eicosanoids and their metabolites. The administration of enalapril and losartan in a dose recommended for the treatment of hypertension did not cause significant changes in bone density, the ash and mineral content or morphometric parameters of the femur compared to the values found in control female rats.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Bone Density; Dinoprost; Dinoprostone; Enalapril; F2-Isoprostanes; Female; Femur; Losartan; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Thromboxane B2

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Drug Therapy, Combination; Enalapril; Female; Humans; Kidney Diseases; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Proteinuria; Spironolactone

Patients with chronic renal failure are restricted to mild physical activity and tend to a lack of exercise. However, there have been few reports regarding the influence of chronic exercise on the progression of renal disease. Similarly, there are few animal models concerned with the effect of exercise training on improving renal function. Therefore, we assessed the renal effects of moderate chronic treadmill exercise in a remnant kidney model of spontaneously hypertensive rats (SHR) with chronic renal failure. We also assessed the effects of exercise and antihypertensive therapy on renal function.. Eight-week-old SHR were subjected to 5/6 nephrectomy by removal of the left kidney and excision of two-thirds of the right kidney. The rats were divided into four groups: (i) no exercise (Non-EX); (ii) moderate exercise with treadmill running (20 m/min, 0 grade incline for 60 min) (EX); (iii) EX with an angiotensin converting enzyme (ACE) inhibitor, enalapril (2 mg/kg per day, i.p.); and (iv) EX with an angiotensin receptor antagonist, losartan (5 mg/kg per day, i.p.), for 4 weeks.. Chronic EX significantly attenuated the increase in proteinuria (P < 0.01) and significantly protected against increases in the index of glomerular sclerosis (IGS). Both enalapril and losartan with EX significantly decreased blood pressure (P < 0.001), and further decreased the IGS. In the stepwise multiple regression analysis, only antihypertensive drug remained in the model as a significant predictor of IGS (P < 0.0001). In contrast, exercise, antihypertensive drug and mean systolic blood pressure (weeks 1-4) remained in the model as a significant predictors of mean proteinuria (weeks 1-4) (all P < 0.0001).. These results suggest that exercise does not worsen renal function and has renal-protective effects in this model of rats. Moreover, the antihypertensive therapy has additional renal-protective effects in this model of rats.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Enalapril; Hypertension; Kidney; Kidney Failure, Chronic; Losartan; Male; Motor Activity; Proteinuria; Rats; Rats, Inbred SHR; Time Factors

Prolonged proteinuria is a risk factor for renal damage. Angiotensin-converting enzyme (ACE) inhibitors can reduce proteinuria in adults with different types of nephropathy.. We evaluated treatment with low doses of ACE inhibitors (captopril and enalapril) in nine children with proteinuria due to chronic glomerular nephropathy. The patients' diagnoses were Henoch-Schönlein nephropathy, Berger's disease, Alport's disease, and chronic glomerulonephritis (GN) (membranous GN, focal and segmental GN, and membranoproliferative GN). None of the patients were receiving concomitant treatment. Those who had received corticoids, immunosuppressive or hypotensive drugs during the previous 3 months were excluded. The medication was administered over a prolonged period (mean 26.6 6.36 months).. Proteinuria was initially in the nephrotic range (M = 55.34 10.44 mg/m2/h). In all patients concentrations fell significantly after 6 months and at the end of the treatment(p = 0.01 and p = 0.05). No adverse reactions to the medication were observed. The decrease in glomerular filtration rate was not significant. No significant changes in arterial pressure were found during treatment.. ACE inhibitors could be an effective alternative for reducing proteinuria in children with prolonged nephropathy. These inhibitors do not produce the adverse effects associated with other drugs and can therefore be used for long periods.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Captopril; Child; Child, Preschool; Enalapril; Female; Humans; Male; Proteinuria; Time Factors

Previous data strongly support a role for androgens in promoting the gender difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but the mechanism is not clear. Because males develop higher blood pressures than do females, we hypothesize that androgens may affect the renin-angiotensin system to promote the development of hypertension in male SHR. The present study was performed to determine the effect of converting enzyme inhibition (CEI) on the development of hypertension in SHR. Male, female, castrated male, and ovariectomized (ovx) female SHR (n=10 per gender per treatment group) received enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein excretion and mean arterial pressure were measured. By 13 weeks of age, male rats had higher systolic blood pressures by tail plethysmography than did the other rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to 19 weeks, the same trend was found by direct measurement of mean arterial pressure. The ovx females treated with testosterone had serum testosterone and blood pressure levels similar to those found in males. CEI reduced mean arterial pressure to similar levels in all gender groups. Untreated males and ovx females given testosterone had significantly higher levels of urinary protein excretion than did the other groups, and CEI had no effect on proteinuria in any of the rats. These data suggest that the development of hypertension in SHR regardless of sex steroids is mediated by the renin-angiotensin system. However, the data further suggest that androgens promote the exacerbation of hypertension in male SHR via a mechanism involving the renin-angiotensin system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Female; Hypertension; Kidney; Male; Orchiectomy; Organ Size; Ovariectomy; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sex Characteristics; Testosterone

Despite considerable progress in immunosuppression, the incidence of chronic renal allograft rejection has not decreased. Recent studies have revealed that angiotensin-converting enzyme (ACE) inhibition ameliorates graft arteriosclerosis, glomerulosclerosis, and tubular atrophy. Moreover, it decreases systemic and glomerular capillary hydrostatic pressure in a rat kidney allograft model. We evaluated the effects of the ACE inhibitor enalapril on cytokine and growth factor expression in chronically rejecting rat kidney allografts.. Kidneys of Fisher (F344) rats were orthotopically transplanted into Lewis (Lew) rats. To prevent acute rejection, cyclosporine A (1.5 mg/kg/day) was given to all recipients during the first 10 days after transplantation. Enalapril (60 mg/L) or vehicle was added to the drinking water 10 days after transplantation. Animals were harvested 20 weeks after transplantation for histologic and immunohistologic studies, as well as for evaluation of cytokine and growth factor mRNA by semiquantitative polymerase chain reaction.. Controls developed severe signs of chronic rejection, such as glomerular and vascular lesions, associated with a large number of infiltrating leukocytes. Enalapril-treated animals developed less proteinuria and other signs of chronic rejection. The mRNA levels of transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor A and B chain (PDGF A and B), insulin-like growth factor-I (IGF-I), interleukin-1 (IL-1), and monocyte chemoattractant protein-1 (MCP-1) were significantly reduced in the enalapril group and were most pronounced for IL-1 and PDGF A. In addition, we found an increased level of renal angiotensinogen mRNA after treatment with enalapril.. Treatment with enalapril attenuated the development of proteinuria, ameliorated morphological damage, decreased leukocyte infiltration, and prevented a rise in renal mRNA levels of growth factors and cytokines in kidney grafts in a rat model of chronic renal allograft rejection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Diuresis; Enalapril; Graft Rejection; Growth Substances; Kidney; Kidney Transplantation; Male; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; RNA, Messenger

Reduction of proteinuria is a prerequisite for successful long-term renoprotection. To investigate whether individual patient factors are determinants of antiproteinuric efficacy, we analyzed individual responses to different modes of antiproteinuric intervention in nondiabetic and diabetic patients, obtained in prior studies comparing the efficacy of various pharmacological regimens. The individual antiproteinuric response to angiotensin-converting enzyme (ACE) inhibition positively correlated to the response to angiotensin type I (AT1) receptor blockade in diabetic (r = 0.67, P < 0.01, N = 16) as well as nondiabetic patients (r = 0.75, P < 0.01, N = 12). This corresponded to the correlations for antihypertensive efficacy between ACE inhibition and AT1 receptor blockade in diabetic (r = 0.73, P < 0.001) as well as nondiabetic patients (r = 0.55, P < 0.05). Remarkably, the antiproteinuric response to ACE inhibition also correlated positively to the antiproteinuric response to indomethacin (r = 0.63, P < 0.05, N = 9). Thus, patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs, supporting a main role for individual patient factors in responsiveness or resistance to antiproteinuric intervention. In the search for strategies to improve response in these high risk patients, combination-treatment (combining different drugs, and combining drugs with dietary measures like sodium and protein restriction), and the use of higher doses may provide more fruitful strategies to optimize renoprotection than shifting to other classes of the available drugs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Diabetic Nephropathies; Enalapril; Humans; Indomethacin; Kidney Diseases; Lisinopril; Losartan; Proteinuria

We have previously shown that cyclooxygenase-2 (COX-2) expression is low in the renal cortex of adult rats, but is increased in macula densa/cortical thick ascending limb and in glomerular podocytes after subtotal renal ablation.. To evaluate the functional consequences of this increased COX-2 expression, male rats were subjected to subtotal renal ablation and divided into four groups: (1) treatment with the selective COX-2 inhibitor SC58236, (2) treatment with vehicle, (3) treatment with the angiotensin-converting enzyme inhibitor enalapril, and (4) treatment with enalapril + SC58236. The administration of drugs was begun on the third day after ablation and continued for 6 to 10 weeks.. Within one week after ablation, vehicle-treated rats developed hypertension. Although enalapril led to significant reductions in blood pressure, either alone or in combination with the COX-2 inhibitor, SC58236 alone did not significantly alter ablation-induced hypertension. However, the SC58236-treated animals exhibited levels of proteinuria at six weeks after ablation that were comparable to those seen with enalapril (vehicle, 47 +/- 4; enalapril, 27 +/- 2; SC58236, 30 +/- 2 mg/day; N = 7, P < 0.01, each group compared with vehicle), and continued SC58236 treatment led to persistent reductions in proteinuria at 10 weeks after renal ablation (vehicle, 77 +/- 4; SC58236, 50 +/- 4 mg/day; N = 6, P < 0. 01). SC58236 treatment also significantly reduced the percentage of glomeruli exhibiting segmental or global sclerosis at 10 weeks (32.6 +/- 7.8% vs. 10.9 +/- 2.8%, N = 6, P < 0.03). Furthermore, SC58236 treatment partially inhibited increases in transforming growth factor-beta1 mRNA expression and increases in collagen III and collagen IV mRNA expression.. These studies indicate that chronic treatment with a specific COX-2 inhibitor may retard the progression of progressive renal injury, and suggest that such compounds can be used in combination with angiotensin-converting enzyme inhibitors. Further studies are required to determine the mechanism by which COX-2 inhibition is renoprotective.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Combinations; Enalapril; Hypertension; Isoenzymes; Kidney; Kidney Glomerulus; Male; Nephrectomy; Prostaglandin-Endoperoxide Synthases; Proteinuria; Pyrazoles; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sclerosis; Sulfonamides

The present study was designed to establish the antiproteinuric effect of ACE-I (enalapril).. Six children with steroid-resistant nephrotic syndrome (SRNS) and one patient affected by Alport syndrome and nephrotic-range proteinuria received enalapril (mean dose 0.3 mg/kg/day) during a mean period of 2 years. Before initiation of therapy, blood pressure was normal in all but one patient, the latter showed normal values with enalapril treatment.. Five patients showed a significant increase of albumin levels after the treatment. Creatinine clearance remained stable during the study in all but one patient affected by Alport syndrome.. In five patients (71.4%) enalapril therapy resulted in an important reduction ofproteinuria, in one patient the treatment was stopped after one year for relapse. In patient with Alport syndrome the fall in creatinine clearance, may simply reflect the natural course of the disease.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Child; Enalapril; Female; Glucocorticoids; Humans; Male; Nephritis, Hereditary; Nephrotic Syndrome; Prednisone; Proteinuria

The present study compared renoprotective effects of angiotensin II type I receptor antagonist (AT1RA) with angiotensin converting enzyme inhibitor (ACEI), and their influence on the renin-angiotensin-system (RAS). Experimental nephrotic syndrome was induced in SD rats by repeated peritoneal injections of puromycin. Twenty-eight rats were randomly divided into four groups: normal control, nephrotic control, ACEI-treated, and AT1RA-treated groups. Serum, urine, and renal tissue were collected for study at the end of 12 weeks. Compared with those of the nephrotic control group, urinary protein was less and renal function was better in both treated groups. The glomerular and interstitial damage indexes of both ACEI- and AT1RA-treated rats were lower than those of nephrotic control rats, with no significant difference observed between the two treated groups. Local renal ACE activity and angiotensin II concentration were elevated in nephrotic rats (p< 0.01). However, there is no significant difference in circulating RAS, renal tissue renin, and aldosterone between the normal control and nephrotic control rats. As expected, enalapril inhibited the local renal ACE activity and significantly decreased angiotensin II (p< 0.01). Intrarenal ACE activity and angiotensin concentration returned to normal levels after treatment with irbesartan (p< 0.01). In conclusion, AT1RA and ACEI have comparable renal protective effects, and these protective effects were associated with the inhibition of intrarenal ANG II.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Enalapril; Fibrosis; Irbesartan; Kidney; Male; Nephrotic Syndrome; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Tetrazoles

The important contribution of hypertension to the progression of renal failure is well realized. However, it have been less discussed which drugs are suitable for the different stages of progressive renal failure. The present study examined the effects of timing of antihypertensive therapy using calcium channel blocker and angiotensin converting enzyme inhibitor in 5/6 nephrectomized spontaneously hypertensive rats (SHRs). Forty male 6 week old SHRs were divided into 5 groups (n=8 in each group), and they were placed on a high salt diet after 5/6 nephrectomy. Group 1, high salt diet without any drug. Group 2 received 0.2 mg/kg/day of amlodipine and group 3 received 0.2 mg/kg/day of enalapril mixed in the high salt diet from week 6 respectively. Similarly group 4 received the same doses of amlodipine, and group 5 received the same doses of enalapril from week 10. Each drug protected from increasing blood pressure in 4 groups, and no significant difference was observed between the effects of amlodipine and enalapril. Proteinuria was reduced with both drugs. In histopathological evaluation, glomerulosclerosis was controlled only in group 2, and arterio/olosclerosis was significantly suppressed in all treated groups except group 5. From these results, both amlodipine and enalapril are renal protective in early stage of renal failure with hypertension. However, in advanced stage of renal failure, amlodipine is superior in its renal protective effect.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Inbred SHR; Sodium, Dietary

Kidney function and structure were compared in control rats (group 1) and in 3 groups of rats made hypertensive by administration of aldosterone and saline for 8 weeks (groups 2, 3, and 4). Group 2 rats received only aldosterone and saline, while group 3 also received losartan and group 4 also received enalapril. Rats in all groups were subjected to uninephrectomy before beginning the experiment. Hypertension and proteinuria in rats given aldosterone and saline were not affected by losartan or enalapril (8-week values for blood pressure in mm Hg: 135+/-3 group 1, 193+/-4 group 2, 189+/-4 group 3, 189+/-5 group 4; P<0.05 groups 2, 3, and 4 versus 1; 8-week values for proteinuria in mg/d: 44+/-8 group 1, 278+/-34 group 2, 267+/-37 group 3, 289+/-36 group 4; P<0.05 groups 2, 3, and 4 versus 1). Vascular, glomerular, and tubulointerstitial injury accompanied hypertension and proteinuria at 8 weeks. Losartan and enalapril did not prevent vascular injury, which was characterized by thickening of arterial and arteriolar walls and by fibrinoid necrosis and thrombotic microangiopathy. Likewise, losartan and enalapril did not reduce the prevalence of glomerular segmental sclerosis (1+/-1% group 1, 10+/-2% group 2, 11+/-2% group 3, 13+/-2% group 4; P<0.05 groups 2, 3, and 4 versus 1) or limit tubulointerstitial injury as reflected by the volume fraction of the cortical interstitium (15+/-1% group 1, 20+/-1% group 2, 21+/-1% group 3, 21+/-1% group 4; P<0.05 groups 2, 3, and 4 versus 1). These findings suggest that local angiotensin II activity does not contribute to the development of renal injury in mineralocorticoid-salt hypertension.

Topics: Administration, Oral; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Disease Models, Animal; Enalapril; Hypertension, Renal; Kidney; Kidney Function Tests; Losartan; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency; Sodium Chloride

The effect of enalapril and low prednisone doses on the urinary protein electrophoretic pattern was studied in 13 pediatric patients with glomerular diseases and steroid-resistant nephrotic syndrome. Enalapril was administered at doses of 0.2-0.6 mg/kg per day for 24-84 months, and prednisone was introduced 2 months later in 11 patients at doses of 30 mg/m2 on alternate days. The urine protein electrophoretic pattern showed a reduction of 80% and 70% in the total protein and albumin, respectively, after enalapril. Total urinary protein decreased from 5.46 to 1.1 g/m2 per day (P<0.001). A marked change from a pattern of non-selective urinary protein loss to an albumin-selective proteinuria was observed. Mean total plasma proteins increased from 4.7 to 5.43 g/dl (P<0.001). Four patients became free of proteinuria 24 months after enalapril was started, but only 2 remained free of proteinuria at 48 months of follow-up. The other 11 patients had persistent albuminuria of between 0.5 and 2.6 g/m2 per day with a selective urinary electrophoretic pattern. No additional decrease was observed after steroids were introduced. A clinical improvement in edema was observed in all children. Three patients developed transient acute renal failure, during the course of an infectious disease; 2 developed peritonitis and 1 pneumopathy. In these patients withdrawal of enalapril was necessary until a complete recovery of renal function was observed. Four patients were hypertensive on admission, achieving normal blood pressure 1 month after enalapril was started. No episodes of systemic arterial hypotension were seen. Creatinine clearance and serum potassium showed no statistically significant change.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Proteins; Child; Child, Preschool; Creatinine; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Electrophoresis, Agar Gel; Enalapril; Glucocorticoids; Humans; Infant; Kidney Diseases; Kidney Glomerulus; Male; Nephrotic Syndrome; Prednisone; Proteinuria; Steroids

The systemic renin-angiotensin system (RAS) is suppressed in normal aging, but the activity of the tissue RAS is not well defined. We examined the systemic and intrarenal RAS status of aging normal rats and responses to suppression and stimulation of the production of endogenous ANG II. Studies were performed in young (3 mo) and early aging (15 mo) male Sprague-Dawley rats. Angiotensin-converting enzyme inhibitors modestly decreased mean arterial pressure (MAP) in young (3 mo) and early aging (15 mo) rats and limited proteinuria in the older rats. There were no significant age-related effects on renal function or on endogenous RAS activity. Intravenous infusion of the precursor ANG I led to comparable increases in MAP in younger and older rats. In contrast, the renal effects (reduction in glomerular filtration and plasma flow rates) were exaggerated in the older animals. Intrarenal arterial ANG I did not affect MAP in any group. In young rats, there were no significant hemodynamic effects in either the ipsilateral (infused) or the contralateral (noninfused) kidney. In the older rats, both kidneys had a significant fall in renal renal plasma flow rate (RPF) with left renal arterial infusion of ANG I. Accordingly, these studies early in the course of aging found only subtle changes in the activity, responsiveness, and metabolism of the RAS. Thus early aging is associated with a modest but important increase in sensitivity to RAS stimulation.

Topics: Aging; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Flow Velocity; Blood Pressure; Enalapril; Glomerular Filtration Rate; Infusions, Intra-Arterial; Infusions, Intravenous; Kidney; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Topics: Adult; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Humans; Losartan; Proteinuria

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cholesterol; Disease Models, Animal; Enalapril; Glomerulosclerosis, Focal Segmental; Immune System; Immunosuppressive Agents; Interleukin-2; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Tacrolimus; Tetrazoles; Triglycerides

The effects of two weeks of oral administration of the angiotensin-converting enzyme inhibitors captopril (a sulphydryl-containing drug) and enalapril (which lacks the sulphydryl group) on skeletal muscle glucose uptake, arterial blood pressure, cardiac hypertrophy, proteinuria and aortic vascular reactivity in obese Zucker rats were evaluated. Captopril (50 mg kg(-1) once daily) and enalapril (10 mg kg(-1) did not modify body weight gain or food or water intake. Both drugs decreased systolic blood pressure (157+/-6, 133+/-4 and 136+/-3 mm Hg, in vehicle-, captopril- and enalapril-treated rats, respectively), blood glucose (172+/-8 vs. 151+/-7 and 158+/-5 mg dl(-1), respectively), proteinuria (46+/-10 vs. 17+/-2 and 18+/-2.5 mg dl(-1), respectively) and heart weight (2.17+/-0.03, 1.98+/-0.02 and 1.99+/-0.04 mg g(-1)of body weight, respectively). Plasma insulin concentration was significantly increased by enalapril (17+/-2 ng ml(-1) vs. 9+/-2) but not by captopril (12+/-1). In the absence of insulin, the diaphragms from captopril- or enalapril-treated rats showed a significantly higher glucose uptake than that of controls (31% and 30% vs. control group, respectively). The presence of insulin in the incubation medium did not stimulate peripheral glucose uptake in the control group but significantly increased glucose uptake in diaphragms from captopril- or enalapril-treated rats (enhancement of glucose uptake vs. control: 52% and 43%, respectively). Endothelium-intact aortic rings from control Zucker rats showed a poor relaxant response to acetylcholine (maximal relaxation of 38.4+/-4.7%). Captopril significantly improved the endothelium-dependent vascular relaxation responses to acetylcholine and the endothelium-independent relaxation to the nitric oxide donor sodium nitroprusside whereas enalapril did not modify these relaxant responses. Neither captopril nor enalapril significantly affected the vascular contractile responses to the vasoconstrictors noradrenaline or KCl. In conclusion, the angiotensin-converting enzyme inhibitors captopril and enalapril reversed insulin resistance and the associated cardiovascular complications (cardiac hypertrophy, hypertension and proteinuria) in the obese Zucker rat, an animal model of non-insulin-dependent (type II) diabetes mellitus. However, only captopril, but not enalapril, improved the impaired endothelium-dependent and independent relaxant responses in the isolated rat aorta.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Captopril; Cardiomegaly; Diabetes Mellitus, Type 2; Diaphragm; Enalapril; Female; Glucose; In Vitro Techniques; Insulin; Muscle, Skeletal; Nitroprusside; Norepinephrine; Organ Size; Potassium Chloride; Proteinuria; Rats; Rats, Zucker

We have investigated the influence of a novel angiotensin II type 1 receptor antagonist, candesartan cilexetil, on the oxidative state of renal tissue and renal function in 5/6 nephrectomized rats, and compared its effects with those of an angiotensin-converting enzyme inhibitor, enalapril. Candesartan cilexetil (1 and 5 mg/kg per day), enalapril (5 mg/kg per day) and vehicle were orally administered once daily for 16 weeks after 5/6 nephrectomy. There was a marked degree of proteinuria evident prior to treatment, an average of 5.69 mg/mg creatinine in the nephrectomized rats, vs 1 to 2 mg/mg creatinine in the control group matched for species and body weight. Inhibition of development of proteinuria by candesartan cilexetil was dose dependent. Enalapril also significantly blunted the rise in urinary protein. Malondi-aldehyde content in the homogenate from the renal cortex increased significantly in the nephrectomized rats compared to control animals. This elevation of malondi-aldehyde content was unaffected by administration of either candesartan cilexetil or enalapril. Antioxidative enzyme (glutathione peroxidase, superoxide dismutase, and catalase) activities in the renal tissue were not affected by any active treatment. Elevation of lipid peroxide in remnant renal tissue suggests that oxidative stress may contribute to the progression of renal injury in the nephrectomized rats. Neither candesartan cilexetil nor enalapril affected antioxidant defenses in renal tissue in nephrectomized rats, indicating that mechanisms other than alteration in oxidative stress are involved in the renoprotective effects of candesartan cilexetil and enalapril.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Catalase; Disease Models, Animal; Disease Progression; Enalapril; Glutathione Peroxidase; Kidney; Kidney Function Tests; Male; Nephrectomy; Organ Size; Oxidation-Reduction; Prodrugs; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Superoxide Dismutase; Tetrazoles; Thiobarbituric Acid Reactive Substances; Treatment Outcome

Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats.. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria.. In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not.. These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Creatinine; Dinoprostone; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Tetrazoles; Transforming Growth Factor beta

Glomerular macrophage accumulation in diabetes implicates monocyte recruitment mechanisms in the pathogenesis of diabetic nephropathy. To test the hypothesis that overexpression of monocyte chemoattractant protein-1 (MCP-1), a monocyte chemoattractant, is attenuated by renin-angiotensin system (RAS) inhibition, we assessed expression of genes regulating monocyte transmigration in the glomeruli of diabetic rats.. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to semiquantitate mRNA expression in glomeruli harvested by sieving at serial intervals after the induction of diabetes by streptozotocin in Munich-Wistar rats. Although subject to limitations, competitive RT-PCR provides an objective measure suited to the minute quantities of RNA extractable from glomerular isolates.. Time-dependent elevation of MCP-1 expression was dramatically suppressed by treatment with the angiotensin-converting enzyme inhibitor enalapril or the AT1 receptor antagonist candesartan, and was closely associated with effects on proteinuria and glomerular macrophage number. By contrast, no sustained suppression of the cell adhesion molecules intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 or the classic MCP-1 stimulators tumor necrosis factor-alpha or interleukin-1beta followed RAS inhibition, and suppression of transforming growth factor-beta1 expression was transient.. These data suggest that glomerular macrophage recruitment in experimental diabetes is largely determined by angiotensin-stimulated MCP-1 expression. We conclude that the RAS is an important regulator of local MCP-1 expression, either directly or through glomerular hemodynamic effects, and that our data strongly implicate macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Benzimidazoles; Biphenyl Compounds; Chemokine CCL2; Cytokines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; DNA Primers; Enalapril; Gene Expression; Growth Substances; Kidney Glomerulus; Macrophages; Male; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles

A 72-year-old woman had been treated for hypertension and hyperthyroidism by a local doctor. In May 1998, she came to this institution with a chief complaint of leg edema. Based on the clinical findings, she was diagnosed as having nephrotic syndrome with massive proteinurea, hypoproteinemia and hyperlipidemia. Renal biopsy findings showed minimal change nephrotic syndrome (MCNS). No substantial improvement was obtained by steroid therapy. We therefore additionally administered angiotensin-converting enzyme inhibitor (enalapril maleate). The urinary protein concentration significantly decreased. On decreasing the dose of steroids, the urinary protein concentration increased. Cyclophosphamide helped us to decrease the steroid dosage. This treatment resulted in type II incomplete remission. The final diagnosis was refractory MCNS. During steroid therapy, she developed hyperglycemia. She had no histology of diabetes mellitus. There is therefore a possibility that steroids can induce hyperglycemia even in patients without a history of diabetes mellitus. These results suggest that careful monitoring of plasma glucose is necessary during steroid therapy and that the administration of an angiotensin-converting enzyme inhibitor is effective in elderly patients with refractory primary nephrotic syndrome.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Enalapril; Female; Humans; Hypoproteinemia; Nephrosis, Lipoid; Prednisolone; Proteinuria

Increased permeability of glomerular capillary wall in adriamycin nephropathy may be mediated by increased generation of free radicals and possibly also by the non-enzymatic production of isoprostanes induced by oxidative stress. ACE inhibitors may reduce proteinuria, possibly due to the decrease of intraglomerular pressure and increased permselectivity of the glomerular capillary wall. These effects may be partly mediated by the inhibition of the degradation of kinins. It is not clear if newly available angiotensin II antagonists have the same antiproteinuric and renoprotective effects.. We compared the effect of an ACE inhibitor (enalapril, 0.4 mg/kg bw i.p. daily for 3 weeks) and angiotensin II antagonist (losartan, 2 mg/kg bw in the same way) on experimental nephrotic syndrome induced in rats by the administration of adriamycin (5 mg/kg bw i.v. in a single dose). To elucidate the potential differences between these two drugs we also measured total malondialdehyde in blood and urinary excretion some eicosanoids and their metabolites (TxB2, 6-keto-PGF1alfa, bicyclo-PGE2 and 8-isoprostane). Proteinuria increased in adriamycin treated rats after 3 weeks from 0.18 +/- 0.01 to 0.44 +/- 0.14 g/mmol creat, p < 0.01. This increase was not prevented by losartan (increase from 0.18 +/- 0.12 to 0.50 +/- 0.11 g/mmol creat, p < 0.05), but tended to be partly blunted by enalapril (increase from 0.20 +/- 0.10 to only 0.32 +/- 0.08 g/mmol creat, p < 0.05). Similarly there was no increase of serum cholesterol, only in enalapril treated rats. On the other hand, both losartan (1.27 +/- 0.13 vs. 1.91 +/- 0.30 mumol/l, p < 0.05) and enalapril (0.93 +/- 0.06 mumol/l, p < 0.001) prevented adriamycin induced increase of total MDA in serum, but urinary excretion of 8-isoprostane was increased in nephrotic rats treated by losartan compared to controls. Enalapril induced increase of urinary excretion of bicyclo-PGE2 (4.32 +/- 0.62 vs. 1.66 +/- 0.81 ng/mmol creat, p < 0.001) was possibly mediated by kinins. There was no significant difference in the urinary excretion of other eicosanoids between different groups, but proteinuria correlated positively with urinary excretion of 8-isoprostane (p < 0.01). Proteinuric rats had also significantly higher urinary excretion of 8-isoprostane than non-proteinuric rats (44.8 +/- 7.1 vs. 26.7 +/- 3.4 ng/mmol. creat, p < 0.05).. Our data suggest that proteinuria in adriamycin nephropathy may mainly depend on free radical generation and the formation of 8-isoprostane. Haemodynamic parameters (glomerular pressure) do not seem to be so important. The mild antiproteinuric effect of enalapril may suggest a contributory role of the inhibition of kinin degradation in this model of nephrotic syndrome.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Dinoprost; Doxorubicin; Eicosanoids; Enalapril; F2-Isoprostanes; Losartan; Male; Nephrotic Syndrome; Proteinuria; Rats; Rats, Wistar

A retrospective study was performed in 48 normotensive proteinuric children to evaluate the effect of enalapril (n = 17), a combination of enalapril and prednisone (n = 11) and prednisone alone (n = 20) on urinary protein excretion and systemic blood pressure. Enalapril treatment was associated with significant and persistent diminution of proteinuria from 1.32 +/- 0.23 to 0.53 +/- 0.11 and 0.44 +/- 0.07 g/day on the 4th and 8th week of treatment, respectively. Combined therapy with enalapril and prednisone resulted in a comparable significant reduction of proteinuria from a pre-treatment value of 2.06 +/- 0.42 to 0.63 +/- 0.22 and 0.52 +/- 0.17 g/day on the 4th and 8th week of treatment, respectively. In contrast to this, in the group treated with prednisone alone, proteinuria decreased significantly only from the 6th week of therapy (p < 0.02). Consequently, these children had significantly higher urinary protein losses at the 4th week of treatment as compared to patients on enalapril treatment (given either alone or combined with prednisone) (p < 0.01 and p < 0.05, respectively). Importantly, the enalapril-induced reduction of proteinuria was unrelated to variations in arterial blood pressure and no significant changes in this parameter were observed. The results indicate that enalapril can be used safety and effectively for symptomatic treatment of proteinuria in normotensive children with preserved renal function. ACE inhibitor provides additive antiproteinuric effect to corticosteroids by accelerating the rate of diminution of proteinuria. Its combination with prednisone may be of particular importance in those cases, where the degree of hypoproteinemia is a concern. (Tab. 2, Fig. 1, Ref. 29.)

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Child; Enalapril; Female; Humans; Male; Nephrotic Syndrome; Proteinuria; Retrospective Studies

Glomerular hyperfiltration and renal hypertrophy are both considered important in the progression of diabetic nephropathy. The aim of this study was to compare the effects of an equivalent reduction in blood pressure produced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPI) and an antihypertensive triple drug combination of hydralazine, reserpine and hydrochlorothiazide (HRH) on kidney function, proteinuria and renal structure in hypertensive diabetic rats.. Four groups of animals were evaluated in short-term and long-term studies. In both studies one group served as a non-diabetic hypertensive control (H). The other three groups were rendered diabetic and were allocated to one of the following groups: the first diabetic group received no specific therapy (HD), the second diabetic group was treated with SPI (HD-SPI) and the third diabetic group was treated with HRH (HD-HRH). In each of the two studies the systolic blood pressure (SBP), 24 h urinary total protein, glomerular filtration rate (GFR), glomerular area, proximal tubular area and glomerular sclerosis were evaluated.. The blood pressure reduction was equal in rats receiving either SPI or HRH. The GFR, proteinuria, glomerular area and tubular area were significantly increased in the HD group, both in the short-term and the long-term study. In the HD-SPI group the diabetic hyperfiltration and renal hypertrophy responses were prevented. In the HD-HRH group the GFR and proteinuria were slightly reduced in the later phases of diabetes, while the glomerular area and tubular area were not affected. Semiquantitative analysis of renal lesions showed that SPI was more effective than HRH in the prevention of the development of glomerulosclerosis.. The results of this study suggest that the control of early adaptive hyperfiltration and renal hypertrophy by SPI may be relevant in the prevention of glomerulosclerosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Diuretics; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Hydralazine; Hydrochlorothiazide; Hypertension; Hypertrophy; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Reserpine; Sodium Chloride Symporter Inhibitors

Most studies on the antiproliferative action of angiotensin converting enzyme inhibitors (ACEI) were performed in a rat hypertensive remnant kidney model with 5/6 kidney ablation which raised objections about the antihypertensive effect of ACEI and the influence of other antihypertensive drugs administered to remnant kidney control rats. To prevent these objections, a normotensive 4/6 remnant kidney model was elaborated and a subantihypertensive dosage of enalapril was used to evaluate its antiproliferative action. Subtotally nephrectomized rats (Nx) markedly increased the remnant kidney weight during a 4-week period and this rise was prevented by the treatment with enalapril (NxE) (Nx +297+/-35 mg vs. sham-operated +145+/-32 mg, p<0.001; NxE +154+/-35 mg vs. Nx p<0.001). While collagen concentration in the kidney cortex was not increased in sham-operated rats (Sham) in comparison with the control group (Ctrl) at the beginning of the study, the subsequent increase was significant in the Nx group and enalapril did not attenuate this increase (Sham 148+/-5 mg/100 g w.w. vs. Nx 164+/-2 mg/100 g w.w., p<0.01; NxE 161+/-4 mg/100 g w.w. vs. Sham p<0.05). The tubular protein/DNA ratio increase, which was significant in the Nx group, was inhibited by enalapril (Nx 26.2+/-10.5 vs. NxE 15.3+/-2.6, p<0.05). The protein/DNA ratio was much lower in glomeruli, with no significant changes in either the Nx or NxE groups. Serum urea concentrations were slightly higher in the Nx group than in the sham-operated group, but markedly elevated in the NxE group (Nx 10.71+/-0.76 mmol/l vs. Sham 6.10+/-0.33 mmol/l, p<0.001; NxE 28.9+/-2.6 mmol/l vs. Sham p<0.001). Creatinine concentrations in the Nx group were increased in comparison with the sham-operated group and markedly increased in the NxE group (Nx 63.7+/-3.56 micromol/l vs. Sham 37.2+/-2.84 micromol/l, p<0.001; NxE 107.0+/-5.2 micromol/l vs. Sham p<0.001). The clearance of creatinine was lower in the Nx group than in the sham-operated group and was markedly reduced in the NxE group (Nx 0.89+/-0.06 ml/min.g kidney wt. vs. Sham 1.05+/-0.16 ml/min x g kidney wt., p<0.01; NxE 0.58+/-0.029 ml/min x g kidney wt. vs. Sham, p<0.001). Enalapril improved proteinuria in comparison with the Nx group (NxE 5.6+/-0.6 mg/24 h vs. Nx 16.1+/-3.4 mg/24 h, p<0.05). Thus remnant kidney proliferation is substantial even in normotensive rats. It includes both proliferation and collagen accumulation with partial recovery of kidney weight and func

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Urea Nitrogen; Cell Division; Collagen; Creatinine; Dose-Response Relationship, Drug; Enalapril; Hyperplasia; Hypertension, Renal; Hypertrophy; Kidney; Male; Nephrectomy; Organ Size; Proteinuria; Rats; Rats, Wistar

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AT1RA) slow the rate of progression of experimental renal disease. Although the end result of both classes of drugs is to block the renin-angiotensin system (RAS), ACEI and AT1RA act at different sites in the RAS cascade. The aim of this study was to compare the effects of an ACEI (enalapril) and AT1RA (losartan), alone or in combination, in slowing the progression of experimental renal disease in a model of reduced renal mass. Two weeks after 5/6 renal ablation, rats were divided into five groups matched for body weight, systolic BP (SBP), and urinary protein excretion rate (UprotV). The effects on SBP and UprotV of treatment with 25 and 40 mg/L enalapril (groups I and II; both n = 7), 180 mg/L losartan (group III, n = 8), or a combination of enalapril (25 mg/L) + losartan (180 mg/L) (group IV, n = 9) versus vehicle (group V, n = 9) were studied for 12 wk. Remnant kidneys were then assessed histologically for evidence of focal and segmental glomerulosclerosis and hyalinosis (FSGS), and interstitial fibrosis. There were no significant differences (NSD) in body weight among the groups at any time. Combination therapy reduced SBP (122 +/- 8 mmHg) significantly at 12 wk to levels similar to losartan (127 +/- 3 mmHg) or enalapril (40 mg/L) alone (124 +/- 5 mmHg) (P < 0.05 versus vehicle controls). With equivalent antihypertensive effects, no differences in frequency of FSGS were discerned among the treatment groups (groups II through IV; F = 1.7, NSD). Tubulointerstitial injury scores followed a similar pattern. BP was highly correlated with the extent of FSGS, both among individual rats (r = 0.68, P = 0.05) and the group means (r = 0.99, P = 0.001). We conclude that the renoprotective effects of enalapril, losartan, or combination therapy are similar in this model over the 12 wk of the study, and are closely related to the magnitude of their antihypertensive effects.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Drug Therapy, Combination; Enalapril; Glomerulonephritis; Kidney; Kidney Diseases; Linear Models; Losartan; Male; Nephrectomy; Organ Size; Proteinuria; Rats; Rats, Wistar

The combination of captopril and indomethacin has been shown to control nephrotic proteinuria in an infant with congenital nephrotic syndrome of the Finnish type. We report the satisfactory control of congenital nephrotic syndrome by enalapril, maintaining normal serum albumin levels without albumin infusions. The haplotype data of our patient were consistent with the diagnosis of a Finnish-type nephrotic syndrome. After 21 months, during which daily infusions of albumin allowed partial control of the symptoms, captopril treatment was started. No adverse effects were noted. Serum creatinine levels remained normal. Within 8 weeks, albumin infusions were completely stopped. After 1 month the treatment was changed to a single dose of enalapril (0.8 mg/kg per day). During the next 15 months, the serum protein concentration was maintained around 6.5-7 g/dl, although proteinuria persisted (0.3-0.5 g/day). Weight and length gain are now satisfactory. We conclude that enalapril may be safely used in infants with severe forms of congenital nephrotic syndrome and might allow the avoidance of aggressive treatments for prolonged periods.

Topics: Angiotensin-Converting Enzyme Inhibitors; Child, Preschool; Enalapril; Female; Finland; Follow-Up Studies; Haplotypes; Humans; Molecular Biology; Nephrotic Syndrome; Proteinuria

We assessed the renal effects of moderate treadmill exercise in the spontaneously hypertensive rats (SHR) remnant kidney model of chronic renal failure (CRF). The effects of chronic administration of a specific endothelin (ET) subtype A (ETA) receptor antagonist, FR139317 (32 mg/kg/day i.p.) and an angiotensin-converting enzyme inhibitor, enalapril (2 mg/kg/day i.p.), in combination with moderate exercise were also investigated. Eight-week-old SHR were subjected to 5/6 nephrectomy. One week after surgery the rats were divided into five groups: (a) no treadmill running; (b) moderate treadmill running, 20 m/min for 60 min (Ex) per day; (c) Ex plus FR139317; (d) Ex plus enalapril; and (e) m-Ex plus enalapril in combination with FR139317, for 4 weeks. In SHR-CRF, Ex significantly attenuated the increase in urinary protein excretion. Enalapril significantly attenuated the increase in systolic blood pressure and urinary protein excretion. FR139317 at this dose did not show any antihypertensive or renal protective effect in this model. These results suggest that moderate exercise may protect renal function in SHR CRF. They also suggest that FR139317 may not have an additional antihypertensive and renal protective effect in this exercise model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Blood Pressure; Body Weight; Enalapril; Endothelin Receptor Antagonists; Indoles; Kidney Failure, Chronic; Nephrectomy; Physical Exertion; Proteinuria; Rats; Rats, Inbred SHR; Receptor, Endothelin A

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalapril; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renovascular; Kidney Glomerulus; Male; Proteinuria; Radiography; Renal Artery Obstruction

Topics: Adolescent; Ambulatory Care; Angiography; Antihypertensive Agents; Captopril; Diagnosis, Differential; Enalapril; Female; Humans; Hypertension, Renal; Kidney; Proteinuria; Renal Artery; Ultrasonography, Doppler; Urodynamics

Angiotensin-converting enzyme (ACE) inhibitors are known to reduce blood pressure and proteinuria in a variety of different glomerular diseases. Nonetheless, a marked interindividual difference in the efficacy of these agents exists. The activity of the ACE and therefore of the renin-angiotensin-aldosterone system (RAAS) has been shown to be under genetic influence. Patients with a deletion genotype at the intron 16 of the ACE gene have been shown to exhibit higher activity of plasmatic ACE when compared to patients with the insertion genotype. We therefore studied prospectively the hemodynamic and antiproteinuric effect of a 6-month therapy with enalapril in patients with biopsy-proven proteinuric glomerular diseases and the DD (n = 10) and ID/II (n = 26) genotype. Although patients with the DD genotype received a slightly higher dose of enalapril, blood pressure and proteinuria did not change significantly. However, both were significantly reduced in the II/ID group after 10 weeks and 6 months of therapy. Creatinine clearance decreased steadily in DD patients. In II/ID patients, creatinine clearance was reduced significantly after 10 weeks of therapy but increased again thereafter and the value at 6 months was again comparable to the one obtained in the DD patients. We conclude from our study that the ACE genotype influences the blood pressure-lowering and antiproteinuric effect of enalapril in patients with proteinuric glomerular disease.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Creatinine; DNA; Enalapril; Female; Follow-Up Studies; Genotype; Hemodynamics; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Prospective Studies; Proteinuria; Sodium; Treatment Outcome

Dietary sodium restriction enhances the antiproteinuric and blood pressure lowering effect of ACE inhibition. In clinical practice, however, long-term compliance to a low-sodium diet may be difficult to obtain. We therefore investigated whether the blunting of the antiproteinuric and blood pressure lowering efficacy of ACE inhibition by high sodium intake can be restored by the addition of a diuretic.. Seven proteinuric patients with non-diabetic renal disease on chronic ACE inhibition were studied during three consecutive 4-week periods: low sodium (50 mmol/day), high sodium (200 mmol/day) and high sodium plus hydrochlorothiazide (50 mg o.i.d.).. During low sodium intake proteinuria was 3.1 (0.7-5.2) g/day, during high sodium intake proteinuria increased to 4.5 (1.6-9.2) g/day (P < 0.05). Interestingly, addition of hydrochlorothiazide again reduced proteinuria to 2.8 (0.6-5.8) g/day (P < 0.05). Mean arterial blood pressure was 89 (84-96), 98 (91-104) and 89 (83-94) mmHg (P < 0.05) during the three periods, respectively.. Addition of hydrochlorothiazide can overcome the blunting of the therapeutic efficacy of ACE inhibition on proteinuria and blood pressure by a high sodium intake.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diet, Sodium-Restricted; Diuretics; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Lisinopril; Male; Middle Aged; Proteinuria; Sodium; Sodium Chloride Symporter Inhibitors; Sodium, Dietary

Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl intake, show severe hypertension, organ damage, and early death. Preventive treatment with an angiotensin-converting enzyme (ACE) inhibitor is known to reduce mortality. Previously we found that proteinuria always precedes cerebral edema in SHRSP. Hence, in this study ACE inhibition was started later, ie, directly after manifestation of either proteinuria or cerebral edema.. SHRSP were subjected to 1% NaCl intake. Group 1 served as a control. In group 2 early-onset treatment with the ACE inhibitor enalapril was initiated after proteinuria was >40 mg/d. In group 3 late-onset ACE inhibition was started after the first observation of cerebral edema with T2-weighted MRI. Cerebral edema was expressed as the percentage of pixels with an intensity above a defined threshold.. In controls median survival was 54 days (range, 32 to 80 days) after start of salt loading. The terminal level of cerebral edema was 19.0+/-3.0%. Under early-onset enalapril, median survival increased to 320 days (range, 134 to 368 days; P<0.01 versus group 1). Cerebral edema was prevented in all but 1 rat. Systolic blood pressure was slightly and transiently reduced at day 14. Proteinuria was markedly reduced (52+/-7 versus 190+/-46 mg/d in group 1 at day 7; P<0.05). Under late-onset enalapril, median survival was 264 days (range, 154 to 319 days; P<0.01 versus group 1). Cerebral edema decreased to baseline levels (9.6+/-2.9 at day 0 to 3.4+/-0.5% at day 3; (P<0.05). Ultimately cerebral edema reoccurred in 6 of the 8 rats. SBP decreased slightly at day 7 only. Proteinuria decreased from 283+/-27 at day 0 to 116+/-22 mg/d at day 7 (P<0.05). Complete remission of the original locus of cerebral edema was confirmed histologically.. In SHRSP with proteinuria, treatment with an ACE inhibitor both prevented the development of cerebral edema and reduced manifest cerebral edema and proteinuria. Survival was markedly prolonged. These findings support the use of ACE inhibition for treatment in hypertensive encephalopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Brain Edema; Cerebrovascular Disorders; Drinking; Eating; Enalapril; Magnetic Resonance Imaging; Male; Proteinuria; Rats; Rats, Inbred SHR; Sodium, Dietary; Survival Analysis

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Cytokines; Enalapril; Fibrin; Fibrinolysin; Fibrosis; Gene Expression Regulation, Enzymologic; Growth Substances; Imidazoles; In Situ Hybridization; Kidney; Male; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; RNA, Messenger; Tetrazoles; Thrombosis; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Vasoconstrictor Agents

Topics: Angiotensin-Converting Enzyme Inhibitors; Cyclosporine; Enalapril; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl CoA Reductases; IgA Vasculitis; Immunosuppressive Agents; Lovastatin; Male; Methylprednisolone; Middle Aged; Nephrotic Syndrome; Plasmapheresis; Prednisone; Proteinuria

We previously reported that mRNA levels for extracellular matrix (ECM) components and endothelin (ET)-1 are upregulated in glomeruli of puromycin aminonucleoside (PAN) nephrosis. Angiotensin-converting enzyme (ACE) inhibitors are effective in experimental models of renal injury, including PAN nephrosis. This study was designed to assess whether the glomerular expression of mRNA for ECM components, ET-1, metalloproteinases (MMP), and a tissue inhibitor of metalloproteinases (TIMP) is modulated by a specific endothelin receptor A antagonist (FR139317) or angiotensin-converting enzyme inhibitor (enalapril) in PAN-injected rats.. Animals were divided into six groups. Group 1 consisted of PAN-injected rats given no treatment. In group 2, PAN-injected rats were given enalapril 35 mg/l. In group 3, PAN-injected rats were given an intraperitoneal injection of FR139317. Group 4 consisted of saline-injected rats given no treatment. In group 5, saline-injected rats were given enalapril. In group 6, saline-injected rats were given FR139317. We prepared glomerular RNA and performed Northern blot analysis in all groups.. In PAN nephrosis, glomerular mRNA levels for alpha 1 (IV) collagen chain, laminin B1 and B2 chains, ET-1, MMP-2 and TIMP-1 increased at the peak of proteinuria on day 8 and then decreased to the control level by day 20, whereas those for alpha 1 (I) and alpha 1 (III) collagen chains, MMP-1, MMP-3 and GAPDH showed little change in PAN nephrosis throughout the experimental periods. In contrast, mRNA levels for heparan sulphate proteoglycan (HSPG) decreased on day 8 and then increased to the control level by day 20. Both enalapril and FR139317 attenuated the increases in mRNA levels for alpha 1 (IV) collagen chain (P < 0.01), laminin chains (P < 0.01), and ET-1 (P < 0.01), and attenuated the decreases in mRNA levels for HSPG (P < 0.01) in glomeruli of PAN-injected rats. Enalapril had little effect on increased glomerular mRNA levels for MMP-2 and TIMP-1 in PAN nephrosis, whereas FR139317 attenuated the increases in glomerular mRNA levels for MMP-2 (P < 0.01) and TIMP-1 (P < 0.01).. These data suggest that the beneficial effects of enalapril and FR139317 may be related to modulation of glomerular mRNA expression of ECM components and ET-1 and that these agents may follow a different mechanism in regulating the glomerular mRNA expression for MMP-2 and TIMP-1 in PAN nephrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Extracellular Matrix; Gelatinases; Glycoproteins; Indoles; Kidney Glomerulus; Male; Matrix Metalloproteinase 2; Metalloendopeptidases; Nephrosis; Protease Inhibitors; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Tissue Inhibitor of Metalloproteinases

The renal response to ACE inhibition is known to vary between individuals. The ACE genotype is a determinant of the ACE concentrations in plasma and tissue, and therefore might affect the renal response to ACE inhibition in renal patients.. To test this hypothesis we studied the short-term response to ACE inhibition (enalapril or lisinopril 10/20 mg/d) in 61 stable proteinuric patients (> 1.0 g/day) in relation to the ACE genotype (DD N = 16, ID N = 32, II N = 13).. Baseline values were not significantly different for the three groups. ACE inhibition significantly reduced proteinuria, mean arterial pressure, GFR and FF in all genotype groups. The reduction in proteinuria, MAP, GFR and FF was not different between the genotype groups. ERPF increased significantly and to the same extent in all three groups.. We conclude that in proteinuric patients the short-term responses to ACE inhibition of proteinuria, blood pressure, and renal haemodynamics are not determined by ACE genotype. Thus, ACE gene polymorphism does not account for the known interindividual variation in the short-term renal response to ACE inhibition.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Genotype; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Proteinuria; Time Factors

The von Willebrand factor (vWF) has been used as a marker of endothelial dysfunction in several diseases. We measured plasma vWF in patients with immunoglobulin A nephropathy (IgAN). In a group of 10 IgAN patients with normal renal function, normal blood pressure, and no proteinuria, vWF plasma levels were significantly higher than in a group of 21 healthy volunteers (134% +/- 38% v 80% +/- 22%; P < 0.01). In another group of 16 IgAN patients with normal renal function and proteinuria ranging between 0.3 and 3.8 g/d, vWF levels were also significantly higher than in the control group (148% +/- 63% v 80% +/- 22%; P < 0.001). Afterward, we studied the effects of enalapril administered for 4 weeks on vWF levels and proteinuria in a group of 11 IgAN patients with normal renal function and proteinuria > or = 1 g/d. After 2 weeks on enalapril treatment, both vWF levels and proteinuria had significantly decreased (vWF: 158% +/- 122% to 117% +/- 72%, P < 0.05; proteinuria: 1.6 +/- 0.7 g/d to 0.9 +/- 0.4 g/ d, P < 0.05). After enalapril withdrawal, both vWF and proteinuria significantly increased. A significant correlation between the variations in vWF levels and proteinuria was observed (r = 0.6; P < 0.05). No correlations between blood pressure and changes in vWF or proteinuria were found. We conclude that endothelial dysfunction is observed in patients with IgAN. This abnormality is already present in some patients with normal blood pressure, normal renal function, and absence of proteinuria. Angiotensin-converting enzyme inhibition induced a significant decrease in both vWF levels and proteinuria.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerulonephritis, IGA; Humans; Male; Proteinuria; von Willebrand Factor

In recent years, hepatitis C virus infection has been reported to be typically associated with membranoproliferative glomerulonephritis and less frequently with membranous nephropathy. Treatment of hepatitis C with interferon-alpha can reduce viremia and improve renal disease. After liver transplantation for hepatitis C virus-associated liver failure, standard immunosuppressive protocols result in a significant increase in hepatitis C viremia. In this report we describe a patient with end-stage liver disease and biopsy-proven hepatitis C-associated glomerulonephritis who underwent liver transplantation. Within 1 month after transplantation, he developed a severe nephrotic syndrome that paralleled a marked increase in viremia. We discuss the possible pathogenic relationship between hepatitis C virus infection and the nephrotic syndrome that followed liver transplantation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Glomerulonephritis; Hepacivirus; Hepatitis C; Humans; Kidney Transplantation; Liver Transplantation; Middle Aged; Nephrotic Syndrome; Postoperative Complications; Proteinuria; Reoperation; RNA, Viral; Time Factors; Viremia

The renal protective properties of candesartan cilexetil (TCV-116), an angiotensin II type 1 receptor antagonist (AT1A), and enalapril, an angiotensin I converting enzyme inhibitor (ACEI), were investigated in 5/6 nephrectomized (NX) rats. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were administered orally to 5/6 NX rats for four weeks (during the early phase of disease development) or 16 weeks (through the late phase). In vehicle-treated rats, proteinuria, glomerulosclerosis, interstitial mononuclear cell (MNC) infiltration and interstitial fibrosis developed. Moreover, immunohistological studies showed enhanced expression of transforming growth factor-beta 1 (TGF-beta 1) in the injured glomeruli. Both drugs inhibited these adverse changes in the early phase. In the late phase, the progressive proteinuria, interstitial MNC infiltration were attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta 1 and the interstitial fibrosis, while enalapril did not. Candesartan cilexetil and enalapril showed comparable hypotensive effects after the 16-week administration. These results indicate that candesartan cilexetil shows a more potent protective effect than enalapril against the progression of renal injury in the late phase. Thus, an AT1A might be more useful than an ACEI for the treatment of patients with chronic renal failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Disease Progression; Enalapril; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrazoles; Transforming Growth Factor beta

The hereditary nephritides are often progressive, resulting in kidney failure and the need for renal replacement therapy. There is no currently known beneficial treatment for these disorders. We observed three patients with hereditary glomerulonephritis with plasma creatinine concentrations ranging from 1.7 to 2.0 mg/dL who were treated with angiotensin-converting enzyme inhibitors (ACEIs) for 3.5 to 6 years. Angiotensin-converting enzyme inhibitor therapy was accompanied by a decrease in the mean arterial pressure (MAP) from 115 +/- 10 mm Hg to 93 +/- 2 mm Hg (+/- SD), a decrease in the mean urinary protein/creatinine ratio from 2,910 +/- 1,720 mg/g to 391 +/- 355 mg/g, and stabilization of the decline of creatinine clearance with time in two of the three patients. Based on this apparent benefit of ACEIs in hereditary nephritis, we suggest that a prospective controlled trial of ACEIs should be undertaken among a large group of such patients. Pending the results of such a study, ACEIs should be considered for the treatment of patients with proteinuric and progressive hereditary nephritis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Disease Progression; Enalapril; Glomerulonephritis; Humans; Lisinopril; Male; Middle Aged; Pedigree; Proteinuria; Time Factors

TCV-116 and enalapril were given in two stages: (early phase) for 6 to 10 weeks to 5/6 nephrectomized (NX) rats two weeks after nephrectomy, 12-week-old Wistar fatty (WF) rats and 7-week-old spontaneously hypercholesterolemic (SHC) rats; and (late phase) for 6 to 16 weeks to 5/6 NX rats 11 weeks after nephrectomy, 27-week-old WF rats and 10-week-old SHC rats. Urinary albumin, blood pressure (BP), glomerular filtration rate (GFR) and renal histology were examined. In the early phase, both agents inhibited proteinuria and tended to inhibit glomerulosclerosis. TCV-116 also inhibited interstitial inflammation. The antiproteinuric effects did not necessarily correlate with the BP-lowering effects. In the late phase, both agents showed equal antiproteinuric and antihypertensive effects. In 5/6NX and WF rats, TCV-116 inhibited tubulointerstitial inflammation/fibrosis, glomerulosclerosis and renal dysfunction, but enalapril had little effect on these parameters. In the SHC rats, TCV-116 inhibited renal tubulointerstitial inflammation and glomerulosclerosis, but enalapril inhibited only glomerulosclerosis. After drug administration, there was a positive correlation between proteinuria and BP, and a negative correlation between the severity of tissue damage and GFR, but not BP. These findings suggest that initial BP-independent tubulointerstitial inflammation may enhance glomerulosclerosis in the late phase, and TCV-116 might prevent the development of glomerulosclerosis through inhibition of angiotensin II-mediated tubulointerstitial damage in these models.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Glomerular Filtration Rate; Glomerulonephritis; Hypercholesterolemia; Kidney Glomerulus; Nephritis, Interstitial; Prodrugs; Proteinuria; Rats; Rats, Wistar; Tetrazoles

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diuresis; Enalapril; Female; Kallikrein-Kinin System; Kallikreins; Placenta; Pregnancy; Pregnancy in Diabetics; Proteinuria; Rats; Rats, Wistar

The present study was undertaken to investigate whether the development of proteinuria in the borderline hypertensive rat (BHR) is influenced by the Y chromosome and to determine if the onset of proteinuria in the BHR is delayed when blood pressure is lowered with enalapril, an angiotensin I converting enzyme inhibitor. Male F1, rats were the first-generation offspring of the mating of spontaneously hypertensive (SHR) females and Wistar-Kyoto (WKY) males and the mating of SHR males and WKY females. At 20 weeks of age, enalapril (125 mg/l) was added to the drinking water. Untreated BHR and enalapril-treated BHR (BHRE) were followed to 90-100 weeks of age. Urine was collected every 10-20 weeks for determination of protein, albumin, and nitric oxide (NO2/NO3) metabolite excretion. Indirect blood pressure in BHR from both crosses was approximately 175 mm Hg from 20 to 90-100 weeks of age. Enalapril lowered blood pressure by about 30 mm Hg, but was ineffective in reducing urinary protein or albumin excretion rates at any age. Urinary excretion of nitric oxide metabolites was similar in all groups at all time periods. There were significant differences in the percent of glomerulosclerosis between the two matings. Based on these results, renal injury in the BHR is not associated with the Y chromosome and can be dissociated from hypertension. Further studies using congenic and transgenic technology will be necessary to identify functions of genes and associations with hypertension in order to understand the kidney disease in this model of hypertension.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Enalapril; Female; Hypertension; Kidney; Male; Nitric Oxide; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sex Chromosomes; Y Chromosome

Either calcium channel blocker (CCB) or angiotensin converting enzyme inhibitor (ACEi) is used as an antihypertensive agent, and we are recommended to use them in combination to refractory hypertension with evidence dependent on clinical observations. We examined the renal protective effect of the combined therapy with calcium channel blocker (amlodipine) and angiotensin converting enzyme inhibitor (enalapril) against hypertensive renal injury in 5/6 nephrectomized spontaneously hypertensive rats (SHRs) with salt loading, comparing with monotherapy of each drug. Forty males SHRs with 5/6 nephrectomy and salt loading were divided to five groups: group 1 as control (n = 8), group 2 received 0.2 mg/kg/day of amlodipine (n = 8), group 3 received 0.2 mg/kg/day of enalapril (n = 8), group 4 (n = 8) and group 5 (n = 8) that were treated with 0.1 mg/kg/day and 0.2 mg/kg/day of each drug in combination respectively. Either amlodipine or enalapril had remarkable effects on reducing the increases in blood pressure and urinary protein excretion. In histopathological examination, it also suppressed renal injury significantly. Additional significant effect of combined therapy was not observed in blood pressure and urinary protein. There were not remarkable, additional effects of the combination of CCB and ACEi on protecting the remnant kidney in 5/6 nephrectomized SHRs fed a high-salt diet, possibly because sodium retention was not alleviated by the combination.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Diuresis; Drug Combinations; Enalapril; Hypertension; Kidney; Male; Natriuresis; Proteinuria; Rats; Rats, Inbred SHR

The effect of enalapril on urinary protein excretion and renal function was studied in six paediatric patients with various renal diseases causing nephroticrange proteinuria. In three younger children (aged 7-9 years) with steroid-resistant nephrotic syndrome, enalapril at a dose of 0.5 mg/kg per day given for 24 months yielded a temporary reduction of proteinuria in one child, a moderate and steady decrease in another and a complete disappearance of proteinuria in the third. Three adolescents, aged 17 years, took enalapril for 24 months at a dose of 20 mg/day. We observed no effect on proteiuria in one patient with Alport syndrome, a complete disappearance of urinary protein in one patient with membranoproliferative glomerulonephritis and a moderate decrease in the third patient who had idiopathic steroid-resistant nephrotic syndrome. Enalapril therapy resulted in an important reduction of proteinuria in two patients and a moderate decrease in three others. However this therapy was accompanied by a fall in glomerular filtration in all subjects, which was very marked in two patients. This fall in glomerular filtration may, however, simply reflect the natural course of the disease.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Child; Creatinine; Enalapril; Glomerular Filtration Rate; Humans; Proteinuria; Serum Albumin

The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Enalapril; Irbesartan; Kidney Failure, Chronic; Kidney Glomerulus; Nephrectomy; Proteinuria; Rats; Rats, Inbred SHR; Tetrazoles

This study was performed to evaluate the effect of angiotensin-converting enzyme inhibitor (ACEI) therapy and dietary protein restriction on nephropathy involving a remnant kidney.. Five patients with proteinuria > or = 5 years following partial removal of a solitary kidney were treated with a low-protein diet and an ACEI agent. Four patients had biopsy-proven focal segmental glomerulosclerosis. The daily urinary protein excretion ranged from 1240 to 10,032 mg. The serum creatinine levels ranged from 1.2 to 3.1 mg/dL.. The post-treatment follow-up interval ranged from 18 to 30 months. The treatment regimen was well tolerated in all patients. Four patients experienced a reduction in the urinary protein level while maintaining stable overall renal function. In 1 patient, the urinary protein level increased and renal function gradually deteriorated following ACEI therapy.. These preliminary data suggest that ACEI therapy and a low-protein diet may mitigate nephropathy associated with a remnant kidney.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Kidney Diseases; Lisinopril; Male; Middle Aged; Nephrectomy; Proteinuria

The effect of an angiotensin-converting enzyme inhibitor, enalapril, and a Japanese medicinal plant named sairei-to, after administration either alone or in combination, on survival-time due to the protection of proteinuria and the preserving of renal function, was studied in the rat with subtotal nephrectomy. Resection of 2/3 of the left kidney and removal of the right kidney was performed in 28 male Wister rats (220-250 g). The rats were divided into four groups: (1) control (without sairei-to or enalapril); (2) with sairei-to (2.5% in rat chow); (3) with enalapril (50 mg/l in drinking water); and (4) the combination of enalapril and sairei-to. The actual survival-times until natural death after renal ablation in these four groups were 92 +/- 3, 128 +/- 8, 199 +/- 19, and 194 +/- 13 days, respectively. Urinary protein excretion and renal function were markedly protected in the enalapril-treated rats. Urinary endothelin excretion was also attenuated in enalapril-treated rats. Statistical analysis revealed the absence of benefits with sairei-to alone or in combination treatment. In conclusion, enalapril provides protection of proteinuria and preserves renal function, which results in a longer survival-time in the rats having subtotal nephrectomy. However, sairei-to does not show such beneficial effects.

Topics: Animals; Drug Therapy, Combination; Drugs, Chinese Herbal; Enalapril; Endothelins; Kidney Diseases; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Survival Analysis; Time

To investigate the role of the renin-angiotensin system (RAS) on nephrosclerosis in salt-loaded, partially nephrectomized spontaneously hypertensive rats (SHR), we evaluated the effects of angiotensin II (ANGII) blockade on the progression of nephrosclerosis with an angiotensin type 1 receptor (AT1rec) antagonist [TCV-116 (TCV)] and an angiotensin-converting enzyme (ACE) inhibitor (enalapril) at the doses equivalent in reducing systemic blood pressure (BP). SHR were five/sixths nephrectomized and were fed a high-salt diet. In addition to being significantly preventive against an increase in systolic BP, both TCV and enalapril significantly attenuated the increases in proteinuria and the renal histopathological alterations. Transcription of AT1rec mRNA in the remnant kidney was enhanced with the progression of nephrosclerosis, but was inhibited by TCV as well as enalapril. In these aspects, there were no apparent differences between effects of TCV and enalapril. The RAS system plays an important role in nephrosclerosis in partially nephrectomized SHR despite a high-salt diet, and direct ANGII blockade certainly protected the kidney against hypertensive injury in this model.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blotting, Northern; Body Weight; Enalapril; Hypertension; Kidney; Male; Nephrectomy; Nephrosclerosis; Proteinuria; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Sodium, Dietary; Tetrazoles; Transcription, Genetic

Converting enzyme inhibitors (CEI) reduce proteinuria in nephrotic humans and animals, but the mediator(s) of this effect has not been identified definitively. To determine whether enhanced kinin activity contributes to the antiproteinuric action of CEI, rats with passive Heymann nephritis were treated with the B2 kinin receptor antagonist HOE 140, 300 micrograms/kg per day, for 3 days and then the CEI enalapril (ENAL), 35 mg/kg per day, was given for another 4 days while HOE 140 was continued (HOE/ENAL). Additional groups of nephrotic rats were untreated (CON), received HOE 140 only (HOE), or received ENAL only. ENAL alone produced a > 60% decrease in albuminuria after 4 days, whereas HOE 140 alone had no effect on albuminuria. In HOE/ENAL, pretreatment with HOE 140 prevented the decrease in albuminuria observed in ENAL. GFR increased significantly over time in all groups but was not different among the groups on any day. The clearance of albumin decreased significantly in ENAL (P < 0.001) and was significantly lower than in CON, HOE, or HOE/ENAL on Day 10. The fractional clearance of albumin decreased in all groups as a result of the increase in GFR but was significantly lower in ENAL compared with the other three groups at Day 10 and was not different between CON, HOE, and HOE/ENAL. Plasma renin activity and concentration were increased significantly in both ENAL and HOE/ENAL, indicating that converting enzyme was effectively inhibited in both groups. It was concluded that enhanced kinin activity contributes to the antiproteinuric action of CEI in this model of nephrotic syndrome.

Topics: Animals; Blood Pressure; Bradykinin; Enalapril; Glomerular Filtration Rate; Glomerulonephritis; Kinins; Male; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Sprague-Dawley; Serum Albumin; Time Factors

Previous studies of glomerular permselectivity have indicated that both size selectivity and charge selectivity changes play a role in the pathogenesis of proteinuria. In this study, we measured Ficoll sieving coefficients, hemodynamic parameters, and urinary protein excretion rates in the FHH strain of fawn-hooded rats. These animals spontaneously develop systemic and glomerular hypertension, proteinuria, and focal and segmental glomerulosclerosis at a relatively young age. Three groups of FHH rats were studied: two-kidney controls (2K), untreated uninephrectomized rats (CON-NX), and uninephrectomized rats treated with the angiotensin I converting enzyme inhibitor enalapril (ENA-NX). CON-NX rats had higher glomerular transcapillary pressures (delta P) and higher urinary excretion rates of both total protein (UpV) and albumin (UaV) than did 2K rats, whereas treatment with enalapril prevented both glomerular hypertension and the increased proteinuria. Ficoll sieving coefficients were significantly higher in both groups of NX rats compared with 2K rats only for Stokes-Einstein radii (rs) > or = 46 A. Fits of sieving data to pore models showed a small increase in the number of large, nonselective pores in NX, which was not prevented by enalapril treatment. Total clearances of Ficoll with rs = 36 A (the size of albumin) in CON-NX and ENA-NX groups were unchanged compared with 2K animals. In contrast, UaV in CON-NX rats was more than six times that of 2K and ENA-NX rats. Across groups, UpV, UaV, and the ratio (UaV)/(UpV) all correlated strongly with delta P.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Animals; Blood Pressure; Enalapril; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Hemodynamics; Hypertension; Kidney; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Mutant Strains

Porteinuria was quantitatively measured in twenty-five controls and eighty-one newly detected patients of essential hypertension without renal insufficiency. Hypertension was treated with enalapril, enalapril and nifedepine and nifedepine alone. Mean proteinuria was more in patients of hypertension as compared to controls (P < .001). Proteinuria decreased significantly (P < .001) after six weeks of control of hypertension. Patients treated with enalapril alone had maximum reduction in proteinuria than those with enalapril and nifedepine, and nifedepine alone.

Topics: Adult; Aged; Colorimetry; Creatinine; Drug Combinations; Enalapril; Humans; Hypertension; Middle Aged; Nifedipine; Proteinuria; Renal Insufficiency

A 61-year-old man developed renovascular hypertension characterized by nephrotic-range proteinuria. When he was treated with a calcium channel blocker, glomerular filtration fraction was 0.26 and massive proteinuria ranging from 10 to 15 g/day persisted. An angiotensin-converting enzyme inhibitor markedly reduced the proteinuria to 1-2 g/day with a filtration fraction of 0.20. After the antihypertensive drug was switched to a beta-blocker, the filtration fraction was 0.23 and urinary protein excretion was 3-4 g/day. Blood pressure control was comparable by each drug. These findings suggest a role of intraglomerular hydraulic mechanism in the etiology of massive proteinuria in renovascular hypertension.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bisoprolol; Calcium Channel Blockers; Enalapril; Glomerular Filtration Rate; Humans; Hypertension, Renovascular; Male; Middle Aged; Nifedipine; Proteinuria

Antiproteinuria effects of angiotensin-converting enzyme (ACE) inhibitors was studied in 23 patients with chronic nephritis (CN) and 32 patients with diabetic nephropathy (DN). CN patients received Capoten, DN patients were given enalapril. The drugs were also examined for the action on systemic arterial pressure, renal function and intrarenal hemodynamics. Significantly decreased urinary excretion of protein occurred in DN patients on the treatment month 1, in CN subjects on month 3. In both groups ACE inhibitors produced marked hypotensive effect, did not affect renal function, noticeably improved intraglomerular hemodynamics. Hypotensive and antiproteinuria activity of the drugs were unrelated. The mechanism of antiproteinuria action of ACE inhibitors works via normalization of intrarenal hemodynamics. Systemic arterial hypertension seems to be an additional factor aggravating disturbances of intrarenal circulation and provoking proteinuria.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chronic Disease; Diabetic Nephropathies; Drug Evaluation; Enalapril; Female; Glomerulonephritis; Hemodynamics; Humans; Male; Middle Aged; Nephrotic Syndrome; Proteinuria

In 47 patients with diabetic nephropathy (29 type I, 18 type II) renal function and blood pressure (BP) (treated with or without an angiotensin-converting enzyme [ACE] inhibitor, enalapril [10 mg], in 38 hypertensive patients) were followed over 4 years. A percutaneous renal biopsy was performed in all patients initially and repeated in a representative 19 patients with treated hypertension after 4 years. Mean glomerular volume (MGV), interstitial fibrosis (IF), capillary volume, and sclerosed glomeruli (GS) were measured histomorphometrically. Mean fall in creatinine clearance (CCr) was 11.8% after 4 years with no difference between treatment groups or type of diabetes. BP both initially and during treatment correlated with initial and final serum creatinine and CCr (P < 0.01). There were no histomorphometric differences between type I and type II patients or hypertension treatment groups. Initial IF correlated with initial and final serum creatinine and CCr (P < 0.05) in all patients and type I patients alone, MGV correlated inversely with CCr in type I patients (P < 0.05). After 4 years, IF (24.8 vs. 30.0%, P < 0.01) and GS (26 vs. 37%, P < 0.05) increased significantly, and increase in IF correlated with fall in CCr (P < 0.01). Proteinuria and HbA1 did not correlate with indexes of function or structure. In this longitudinal study of patients with diabetic nephropathy, there was a close relation between BP and renal function but no difference between treatment with enalapril and other hypertensive agents. The correlations between renal function and histology at entry and after 4 years suggest that IF is a co-determinant of renal function in diabetic nephropathy.

Topics: Adolescent; Adult; Aged; Blood Glucose; Capillaries; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Glycated Hemoglobin; Humans; Hypertension; Kidney; Kidney Glomerulus; Metabolic Clearance Rate; Middle Aged; Proteinuria

Renal radiation injury is a known complication of both local kidney irradiation and total body irradiation (TBI). TBI is felt to play an important role in the late-onset chronic renal failure seen after bone marrow transplantation in human beings. Two-hundred and eleven WAG/Rij/MCW rats underwent 0 to 20 Gy TBI followed by syngeneic bone marrow transplant (BMT). Rats received either no drug or verapamil, enalapril, or captopril in the drinking water starting 9 days before TBI and continuing thereafter. Follow-up continued up to 55 weeks after TBI/BMT. No-drug irradiated animals developed significant proteinuria 6 weeks after TBI, were azotemic by 9 weeks after TBI, and were hypertensive by 13 weeks after TBI. Survival was inversely related to the dose of TBI. There was a dose-related reduction in proteinuria, blood pressure, and azotemia with increasing doses of captopril. At 500 mg/L, captopril was more effective than 50 mg/L enalapril in controlling proteinuria, blood pressure, and azotemia and in enhancing survival of irradiated animals. Verapamil, 700 mg/L, did not control proteinuria, blood pressure, or the development of renal failure and did not enhance survival when compared with no-drug irradiated animals. We conclude that angiotensin-converting enzyme inhibitors are beneficial in preventing radiation nephropathy and that control of proteinuria may be of particular importance in preventing progression of renal failure in this model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bone Marrow Transplantation; Captopril; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Enalapril; Kidney; Kidney Diseases; Male; Proteinuria; Radiation Injuries, Experimental; Rats; Time Factors; Uremia; Verapamil; Whole-Body Irradiation

To evaluate the effect of delayed treatment with enalapril or lovastatin on the progression of glomerulosclerosis and to examine if the combined treatment with enalapril and lovastatin show synergistic effect, a total of 31 Sprague-Dawley rats were studied for 16 weeks following 5/6 nephrectomy (NPX). Treatment was delayed until 8 weeks after NPX. In untreated control rats (n = 8), sustained systemic hypertension with increasing proteinuria, serum cholesterol, triglyceride, BUN and widespread glomerulosclerosis and mesangial expansion were observed. Treatment with enalapril alone (R, n = 8) reversed systemic hypertension, prevented a further increase in proteinuria, and significantly reduced glomerulosclerosis relative to the control group. Treatment with lovastatin alone (L, n = 7) also reduced glomerulosclerosis and serum cholesterol compared to the controls. The drug also prevented a further increase in proteinuria and systemic blood pressure although the difference from the control rats did not reach statistical significance. Treatment with both enalapril and lovastatin (RL, n = 8) almost completely prevented glomerulosclerosis and significantly reduced mesangial expansion, systemic blood pressure, serum cholesterol, and proteinuria compared to controls. Only the combined treatment stabilized BUN and reduced mesangial expansion compared to control R, or L groups. Conclusion. Delayed treatment with enalapril or lovastatin is effective in preventing the progression of glomerulosclerosis, and combined treatment appears to show synergistic effect in 5/6 nephrectomized rat model.

Topics: Animals; Blood Pressure; Blood Urea Nitrogen; Body Weight; Cholesterol; Enalapril; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Lovastatin; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Systole; Triglycerides

Angiotensin I converting enzyme inhibition (ACEi) has been shown to lower urinary protein excretion in human renal disease. The mechanism of this antiproteinuric effect is hypothesized to be mediated by changes in renal hemodynamics. However, clinical studies suggest that the effect on renal hemodynamics is fully established immediately after the start of treatment, whereas others show the antiproteinuric effect to reach maximum only after several weeks. To clarify this issue we studied the course of renal hemodynamics, blood pressure and proteinuria during 28 days of ACEi (enalapril 10 mg oid) in nine patients with proteinuria due to non-diabetic renal disease. The effect of ACEi on blood pressure and renal hemodynamics was already maximal within few hours after start of treatment, and remained stable thereafter: MAP was lowered with 8.6 +/- 1.9%, 10.6 +/- 2.1%, 12.8 +/- 2.3% and 12.9 +/- 2.5%, while FF fell 23.0 +/- 2.0%, 17.0 +/- 2.6%, 16.8 +/- 2.8% and 15.9 +/- 4.0% on days 1, 7, 14 and 28 of ACEi, respectively. However, the antiproteinuric effect only gradually reached its maximum on day 28. Urinary protein excretion decreased with 10.9 +/- 6.1%, 32.7 +/- 6.2%, 46.3 +/- 2.5% and 54.0 +/- 2.5% on days 1, 7, 14 and 28 of ACEi, respectively. After drug withdrawal all parameters returned towards baseline. We conclude that a dissociation occurs in the course of the ACEi induced effects on hemodynamics and urinary protein excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Renal Circulation; Time Factors

The effect of inhibiting the renin-angiotensin system was evaluated in male Sprague-Dawley rats with reduced renal mass produced by right nephrectomy and infarction of two-thirds of the left kidney. Separate groups of rats were then administered the angiotensin receptor antagonists, A-81988 or losartan (DuP 753), the angiotensin converting enzyme inhibitor, enalapril, or vehicle (tap water) in their drinking water for 4 weeks. Tail cuff blood pressures and blood samples were obtained weekly. Excretory function during week 4 was evaluated using metabolic cages. Rats with reduced renal mass were characterized by a significant elevation in systolic blood pressure and urinary protein excretion along with a reduced urine osmolality. At 1 mg/kg/day, A-81988 prevented the hypertension and the development of proteinuria. A-81988 administration also improved urinary concentrating ability because urine osmolality was significantly higher in this group compared to untreated controls. The same dose of losartan or enalapril was ineffective at controlling the development of the hypertension, indicating that A-81988 is more potent in vivo. Despite the maintenance of systemic hypertension, losartan significantly blunted the proteinuria compared to vehicle-treated controls. At a dose of 10 mg/kg/day, losartan and enalapril also prevented the increase in systolic blood pressure and proteinuria and produced an increase in urine osmolality. These data support the hypothesis that angiotensin receptor antagonists have beneficial effects in forms of renal failure associated with proteinuria and diminished concentrating ability.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Enalapril; Hypertension; Imidazoles; Kidney; Losartan; Male; Nicotinic Acids; Organ Size; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Renin; Tetrazoles

This study was undertaken to determine the role of angiotensin II (AII) in the development of glomerulosclerosis, using an AII receptor antagonist in an animal model of hyperlipidemia. Hyperlipidemic Imai rats were employed because they spontaneously develop glomerulosclerosis; this is especially true in males. Group 1 (n = 5) received no specific therapy. Group 2 (n = 5) was treated with enalapril at a dosage of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) and group 4 (n = 6) were treated with the AII receptor antagonist DuP 753 at a respective dosage of 15 mg/l (low-dose DuP) and 150 mg/l (high-dose DuP) in drinking water. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were measured and compared among the groups from 12 to 24 weeks of age. Enalapril and high-dose DuP were almost equally effective in controlling systemic hypertension. Each treatment significantly reduced proteinuria (172 +/- 112 and 152 +/- 72 mg/kg/day at 24 weeks) as compared with that in the controls (421 +/- 147 mg/kg/day; p < 0.05 and p < 0.01, respectively). Hypercholesterolemia also decreased (82 +/- 4 and 89 +/- 6 mg/dl) as compared with that of the controls (141 +/- 48 mg/dl; both p < 0.05). Glomerulosclerosis index (SI) was significantly higher in the untreated control rats (55 +/- 26) than in the enalapril-treated rats (2 +/- 3; p < 0.005) and the high-dose-DuP-treated rats (6 +/- 6, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Cholesterol; Disease Models, Animal; Enalapril; Glomerulonephritis; Hyperlipidemias; Imidazoles; Kidney; Kidney Failure, Chronic; Losartan; Male; Organ Size; Proteinuria; Rats; Renin-Angiotensin System; Serum Albumin; Tetrazoles

The effects of blood pressure reduction on cyclosporine nephrotoxicity were studied over 12 months in four groups of rats. Group 1 received no drugs and served as controls. Groups 2, 3, and 4 received cyclosporine (CyA), approximately 9 mg/kg.day, in their food. In addition, Group 3 received enalapril and Group 4 received minoxidil, hydrochlorothiazide, and reserpine. Time-averaged monthly systolic blood pressure was equal in Groups 1 and 2 (136 +/- 1 and 135 +/- 1 mm Hg, respectively). Antihypertensive agents reduced average systolic blood pressure in Groups 3 and 4 (116 +/- 1 and 117 +/- 1 mm Hg, respectively). Morphometric studies showed that 12 months of CyA treatment caused interstitial fibrosis with an increase in the fractional volume of cortical interstitium (VvInt: Group 2, 20 +/- 1%; Group 1, 11 +/- 1%) and a reduction in mean glomerular volume (VG. Group 2, (2.00 +/- 0.06) x 10(6) mu 3; Group 1, (2.48 +/- 0.06) x 10(6) mu 3). These structural changes were accompanied by a significant reduction in GFR (Group 2, 2.27 +/- 0.10 mL/min; Group 1, 2.76 +/- 0.10 mL/min). Cotreatment with enalapril reduced interstitial fibrosis (VvInt, 14 +/- 1%) and maintained VG (2.23 +/- 0.08 x 10(6) mu 3) and GFR (2.56 +/- 0.08 mL/min) at near-normal values in Group 3. In contrast, the combination antihypertensive regimen increased the extent of interstitial fibrosis (VvInt, 24 +/- 1%) and further lowered VG (1.72 +/- 0.05 x 10(6) mu 3) and GFR (1.72 +/- 0.05 mL/min) in Group 4. These results show that sustained treatment with a moderate dose of CyA causes interstitial fibrosis and impairs renal function in rats. The administration of enalapril, but not minoxidil, reserpine, and hydrochlorothiazide, limits renal injury in this model.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cyclosporine; Enalapril; Glomerular Filtration Rate; Kidney; Male; Proteinuria; Rats; Rats, Inbred Strains; Systole

We studied the effect of enalapril, an inhibitor of angiotensin-converting enzyme (iACE), on proteinuria and renal function in recipients of renal allografts. Twenty-two patients with post-transplant nephrotic syndrome were treated with incremental doses of enalapril for 1 year. Urinary protein excretion decreased after 2 months of treatment from a mean of 8.9 g/day (range 4.0-18.9 g/day) to 4.5 g/day (range 0.4-10.0 g/day; P < 0.01) and remained significantly low for the rest of the study. However, in the same period, creatinine clearance did not change significantly; it went from 47.8 ml/min (range 17.1-110.3 ml/min) before treatment to 44.2 ml/min (range 16.5-88.5 ml/min) after 2 months of iACE therapy. Analysis of individual data showed that there was a significant reduction in proteinuria in 14 of the 22 patients and that the rate of deterioration of renal function did not increase in 17 of the 22 patients. We did not observe any serious side effects of enalapril administration. The results of our study prove that iACE can be used safely and effectively to reduce post-transplant proteinuria.

Topics: Adult; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Transplantation; Male; Nephrotic Syndrome; Proteinuria; Transplantation, Homologous

Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of free cholesterol, and the distribution of cholesteryl ester among lipoproteins in plasma. Alterations in these processes may play a role in the lipoprotein abnormalities associated with glomerular proteinuria. The activities of LCAT and CETP were measured using excess exogenous substrate assays in nine patients with nephrotic-range proteinuria and in 18 matched controls. The proteinuria-lowering effect of four weeks of angiotensin converting enzyme (ACE) inhibition with enalapril was also studied. Plasma very low lipoprotein and low density lipoprotein (VLDL and LDL) cholesterol, triacylglycerol and apolipoprotein B levels were significantly elevated in the patients compared with controls. High density lipoprotein (HDL) total cholesterol, free cholesterol, cholesteryl ester and the free cholesterol/cholesteryl ester ratio in HDL were lower. Total plasma apolipoprotein A1 was normal. Plasma LCAT and CETP activities were elevated in the patients by 30% (P < 0.01) and by 39% (P < 0.01), respectively, and were both inversely related to serum albumin. VLDL and LDL cholesterol levels were positively related to LCAT and CETP activities, whereas the HDL free cholesterol content was inversely related to LCAT activity. ACE inhibition resulted in a 40% reduction of proteinuria, a partial normalization of LCAT activity, and a decrease in VLDL and LDL cholesterol. In conclusion, elevated activities of LCAT and CETP may provide a mechanism that contributes to the low proportion of cholesterol in HDL relative to that in VLDL and LDL, as well as to the compositional changes of HDL seen in glomerular proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Enalapril; Female; Glycoproteins; Humans; Lipoproteins; Male; Middle Aged; Phosphatidylcholine-Sterol O-Acyltransferase; Proteinuria; Serum Albumin

Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. The aim of the present study was to clarify whether two different antihypertensive regimens (enalapril and a combination of reserpine, hydralazine and hydrochlorothiazide) would offer similar degrees of protection against glomerular injury in male hyperlipidemic Imai rats. Group 1 (n = 4) received no specific therapy. Group 2 (n = 4) was treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) was treated with the triple drug regimen (reserpine 5 mg/l, hydralazine 80 mg/l and hydrochlorothiazide 25 mg/l in drinking water). Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were checked and compared among groups. Although enalapril and triple drug therapy were almost equally effective in controlling systemic hypertension, there were striking differences between the two treated groups in proteinuria, hypercholesterolemia and glomerular injury. Enalapril treatment significantly reduced proteinuria (731 +/- 23 vs. 256 +/- 144 mg/kg/day at 36 week; p < 0.005) and hypercholesterolemia (264 +/- 17 vs. 104 +/- 17 mg/dl at 38 weeks; p < 0.001). Triple drug therapy failed to prevent the development of proteinuria (909 +/- 75 mg/kg/day at 38 weeks) and hypercholesterolemia (330 +/- 61 mg/dl at 38 weeks). The glomerulosclerosis index was significantly higher in untreated control rats (229 +/- 65) and in triple drug-treated rats (218 +/- 59) than in the enalapril-treated group (24 +/- 12; p < 0.05, and p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Cholesterol; Drug Therapy, Combination; Enalapril; Hydralazine; Hydrochlorothiazide; Hyperlipidemias; Hypertension; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Proteinuria; Rats; Reserpine; Time Factors

Both glomerular hypertension and hypertrophy have been associated with the development of glomerular injury in models of hypertension and reduced renal mass. The purpose of this study was to examine the effects of antihypertensive therapy on these parameters in the remnant kidney model of progressive glomerular sclerosis. Rats underwent 5/6 nephrectomy and were randomly assigned to receive either no therapy, the calcium entry blocker (CEB), nifedipine, or the angiotensin converting enzyme inhibitor (CEI), enalapril. Administration of either drug was associated with a reduction in systemic blood pressure and in the severity of glomerular injury assessed eight weeks after renal ablation. Micropuncture studies four weeks after ablation revealed that systemic and glomerular capillary pressure were high in untreated remnant kidney rats and reduced by enalapril. Administration of nifedipine was associated with a decline in systemic pressure, however, plasma renin levels increased, causing efferent arteriolar vasoconstriction and persistence of glomerular hypertension. Morphometric analysis showed that kidney weight, glomerular volume and glomerular capillary radius were lower in nifedipine treated rats than in the other two groups, indicating that the CEB, but not enalapril, inhibited the hypertrophic response to ablation of renal mass. Therefore, both CEIs and CEBs reduce glomerular injury in rats with remnant kidneys but they may act by different mechanisms. CEI reduce glomerular capillary pressure while CEBs inhibit compensatory kidney growth.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Enalapril; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Hypertrophy; Kidney; Kidney Failure, Chronic; Male; Nifedipine; Proteinuria; Rats; Rats, Wistar

The hypothesis that converting enzyme inhibition and a protein-restricted diet could have additive antiproteinuric effects has been tested. A group of 17 patients with proteinuria in excess of 3 g/24 h per 1.73 m2 of body surface area were submitted to a 3-wk period of study, after a 4-wk wash-out period during which protein intake was 1.0 g/kg per day and in the absence of any medication. During the first and second weeks of the study, protein intake was lowered to 0.3 g/kg per day, and in the third week, it returned to 1.0 g/kg per day. Enalapril (20 mg daily) was administered during the second and third weeks of the study. Initially and at the end of each week thereafter, we determined blood pressure, GFR (inulin clearance), RPF (para-aminohippurate clearance), plasma sodium and potassium, PRA and aldosterone, and the 24-h urine excretion of sodium potassium, protein, and urea. The low protein intake during the first week induced a significant fall of proteinuria (P < 0.01), GFR (P < 0.01), and RPF (P < 0.01) in the absence of changes in filtration fraction. The addition of enalapril induced a further decrease of proteinuria (P < 0.01) and a fall in filtration fraction (P < 0.05), whereas plasma potassium, PRA, GFR, and RPF values increased (P < 0.01). The rise in protein intake during the last week of the study induced a significant rise in proteinuria, GFR, and RPF (P < 0.01), although the first of these parameters attained values significantly lower (P < 0.05) than those observed initially.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Combined Modality Therapy; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Renal Circulation

A 65-year-old man presented proteinuria in the nephrotic range that occurs in the setting of high renin hypertension. Proteinuria persisted after normalizing blood pressure by nifedipine. In contrast, treatment with an ACE-inhibitor (enalapril) resulted in the prompt resolution of the proteinuria. Interestingly, proteinuria relapsed after removing the ACE-inhibition. These observations suggest a causal relation between the overactivity of the renin-angiotensin system in this patient and his proteinuria.

Topics: Aged; Enalapril; Humans; Hypertension, Renovascular; Male; Nephrotic Syndrome; Proteinuria; Recurrence; Renal Artery Obstruction; Renin

We examined whether the renal protective effect of the angiotensin I converting enzyme inhibitor enalapril in stroke-prone spontaneously hypertensive rats (SHRSP) is dose-related and associated with alterations in the urinary excretion of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a stable breakdown product of prostacyclin. Enalapril maleate at 1.5, 5 and 15 mg/kg/day or vehicle was chronically administered to saline-drinking SHRSP (six per group) starting at 8.1 weeks of age. Vehicle-treated SHRSP developed severe hypertension, proteinuria and strokes (age at death, 14 +/- 1 weeks; mean +/- S.E.). Enalapril prolonged survival dose-dependently and reduced proteinuria; all SHRSP given 15 mg/kg/day lived beyond 23 weeks of age without evidence of stroke or proteinuria. There was no effect of enalapril at any dose on systolic arterial blood pressure in spite of variable levels of urinary protein excretion and onset of stroke in the different groups. Likewise, urinary 6-keto-PGF1 alpha and PGE2 excretion did not differ among the groups except for an increase in 6-keto-PGF1 alpha in the 15 mg/kg/day group at one week after initiation of enalapril therapy. These results are consistent with a dose-related renal protective action of enalapril in saline-drinking SHRSP that is not closely associated with sustained alterations in urinary excretion of renal vasodilatory PGs.

Topics: Animals; Blood Vessels; Cerebrovascular Disorders; Enalapril; Hypertension; Kidney; Male; Prostaglandins; Proteinuria; Rats; Rats, Inbred SHR

The effect of a 6-week treatment with the calcium channel blocker nitrendipine or the angiotensin converting enzyme inhibitor enalapril on blood pressure, albuminuria, renal hemodynamics, and morphology of the nonclipped kidney was studied in rats with two-kidney, one clip renovascular hypertension. Six weeks after clipping of one renal artery, hypertensive rats (178 +/- 4 mm Hg) were randomly assigned to three groups: untreated hypertensive controls (n = 8), enalapril-treated (n = 8), or nitrendipine-treated (n = 10). Sham-operated rats served as normotensive controls (128 +/- 3 mm Hg, n = 8). After 6 weeks of treatment, renal hemodynamics (glomerular filtration rate and renal plasma flow) were measured in the anesthetized rats. Renal tissue was obtained for determination of glomerular size and sclerosis. Enalapril but not nitrendipine reduced blood pressure significantly. After 6 weeks of therapy, glomerular filtration rate was not different among the studied groups. Renal plasma flow increased, but albumin excretion and glomerulosclerosis did not change after enalapril treatment. In contrast, in the nitrendipine-treated group albuminuria increased from 12.8 +/- 2 progressively to 163 +/- 55 compared with 19.2 +/- 9 mg/24 hr in the hypertensive controls. Furthermore, glomerulosclerosis index was significantly increased in the nitrendipine-treated group compared with the hypertensive controls (0.38 +/- 0.1 versus 0.13 +/- 0.04). In addition, glomerular size was higher in the nitrendipine-treated group (14.9 +/- 0.17 10(-3) mm2) but lower in the enalapril-treated group (11.5 +/- 0.15 10(-3) mm2) compared with the hypertensive controls (12.1 +/- 0.17 10(-3) mm2).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Animals; Antihypertensive Agents; Blood Pressure; Drug Combinations; Enalapril; Hemodynamics; Hypertension, Renovascular; Kidney Glomerulus; Male; Nephrosclerosis; Nitrendipine; Proteinuria; Rats; Rats, Inbred Strains; Renal Circulation

In order to evaluate the effect of an ACE-inhibitor (enalapril) on nephrotic proteinuria in patients with primitive nephropathies, to determine the SACE before and after treatment and to compare the variation of SACE levels with the variations of proteinuria, seventeen patients were studied (5 F, 12 M) aged between 10 and 68 years. All patients were evaluated in basal conditions for creatinine clearance, protidaemia, proteinuria, SACE and serum electrolytes. All but one patient had a renal biopsy. After basal evaluation nine patients received enalapril, 10 mg/die, for two weeks. After one week SACE levels were re-evaluated, while the proteinuria was re-evaluated several times during the two weeks of treatment. The results obtained suggest (1) SACE levels are significantly higher in patients with nephrotic syndrome than in normal patients (21.14 +/- 8.37 nmol/ml/min; N.V.:15.60 +/- 4.73; M +/- s.d.; p less than 0.01); (2) proteinuria is unresponsive to the ACE-inhibitor action (varied from 8.00 +/- 2.70 g/24 h to 7.74 +/- 3.19 g/24 h, p = NS); (3) no correlation exists between the reduction of SACE levels and variations of proteinuria.

Topics: Adolescent; Adult; Aged; Enalapril; Female; Humans; Kidney Diseases; Kidney Glomerulus; Male; Middle Aged; Nephrotic Syndrome; Peptidyl-Dipeptidase A; Proteinuria

The effect of enalapril on renal hemodynamics and glomerular permselectivity was studied in eight patients with nephrotic syndrome secondary to biopsy-proven membranous glomerulonephritis. The patients received the drug in incremental doses (median, 5 mg) until 24-hour urinary protein excretion had decreased persistently by 30%. Median treatment duration was 6 weeks. Patients were studied three times: (I) after a 4-week run-in period, (II) on the final day of treatment, and (III) after a 4-week wash-out. Median 24-hour urinary protein excretion decreased on treatment from 10.45 g/d to 5.25 g/d and increased to pretreatment levels after the drug was stopped (P less than 0.05 for both changes). Fractional clearance of dextrans greater than 4.1 nm decreased on treatment, indicating both a reduction of macromolecules passing through the shunt pathway of the glomerular basement membrane (GBM) and a possible decrease in ultrafiltration coefficient. There were no significant changes in glomerular filtration rate (GFR), effective renal plasma flow (ERPF), or mean arterial blood pressure (MAP) throughout the study. The effect of enalapril in treating proteinuria appears therefore to be due to a specific intraglomerular action.

Topics: Adult; Aged; Blood Pressure; Dextrans; Enalapril; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Hemodynamics; Humans; Male; Middle Aged; Nephrotic Syndrome; Proteinuria; Renal Circulation; Vascular Resistance

Five patients (median age 63 years) with severe crescentic glomerulonephritis had acute renal failure (median plasma creatinine 930, range 690-1390). Following induction of immunosuppressive treatment all patients achieved recovery of adequate renal function (median creatinine 440, range 290-570 mumol/l). After 3-6 months of continuous remission, all patients, despite stable renal function developed increasing proteinuria (median 4.4 g/24 h, range 3.2-6.1), and enalapril (5-20 mg per day) was substituted or introduced as antihypertensive therapy. Immunosuppression was not altered. After 1 year, renal function remained stable in four patients and plasma creatinine increased initially in one patient before becoming stable: proteinuria was reduced substantially in all patients to a median of 0.8 g/24 h, range 0.2-1.3). Patients with severe crescentic glomerulonephritis may develop persistent or increasing proteinuria despite successful treatment of acute disease. We have used enalapril to reduce proteinuria and maintain function in such patients.

Topics: Acute Kidney Injury; Aged; Antihypertensive Agents; Creatinine; Drug Therapy, Combination; Enalapril; Glomerulonephritis; Humans; Immunosuppressive Agents; Middle Aged; Proteinuria

Spontaneously hypertensive rats (SHR) that underwent uninephrectomy (UNX) at six weeks of age were randomly assigned to receive no treatment, the calcium channel blocker, nifedipine, or the angiotensin converting enzyme inhibitor, enalapril. Both drugs reduced systemic blood pressure, however, blood pressure tended to be greater in rats given nifedipine than in those on enalapril. After six months, proteinuria and the relevance of glomerula sclerosis were significantly reduced in the two treated groups compared to values observed in untreated SHR. Kidney weight was also reduced by therapy, suggesting that both enalapril and nifedipine inhibited compensatory kidney growth. Micropuncture studies performed in similarly treated groups of rats, but at 11 weeks of age, revealed that PGC was elevated in untreated UNX SHR and reduced by both nifedipine and enalapril. These findings support the hypothesis that glomerular hypertension and renal hypertrophy are important risk factors for glomerular injury. They suggest that calcium blockers are as effective as angiotensin converting enzyme inhibitors in preventing progressive kidney damage.

Topics: Animals; Blood Pressure; Enalapril; Kidney Glomerulus; Longitudinal Studies; Nephrectomy; Nifedipine; Proteinuria; Punctures; Rats; Rats, Inbred SHR

The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereas ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.

Topics: Acute Disease; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Division; Dietary Proteins; Disease Models, Animal; Enalapril; Female; Kidney; Lymphocyte Depletion; Macrophages; Maleates; Nephritis, Interstitial; Nephrotic Syndrome; Proteinuria; Puromycin; Rats; Rats, Inbred Lew

The effect of enalapril on glomerular hemodynamics and permselectivity and on subsequent sclerosis was studied in male MWF/Ztm rats which spontaneously develop proteinuria and glomerular structural damage. Untreated group 1 and enalapril-treated group 2 (50 mg/liter, in the drinking water) underwent micropuncture studies after 2 mo of observation. After the same period of treatment, group 3 (untreated) and group 4 (enalapril treated) were used for determination of whole-kidney function and neutral dextran clearances. Group 5 (untreated) and group 6 (enalapril treated) were followed for an additional 4 mo and used for kidney function and morphological studies. Enalapril significantly lowered systolic blood pressure, which was elevated in untreated groups, and significantly reduced proteinuria (295 +/- 64 vs. 128 +/- 24 mg/24 h by the end of the study). Despite the reduced renal perfusion pressure, whole-kidney glomerular filtration rate was higher in enalapril-treated than in untreated rats (0.96 +/- 0.14 vs. 0.81 +/- 0.10 ml/min, P less than 0.05) as was the single nephron glomerular filtration rate (54 +/- 7.1 vs. 46 +/- 4.0 nl/min, P less than 0.05). The single glomerular afferent plasma flow was comparable in both groups. Enalapril reduced mean glomerular capillary hydraulic pressure from the normal value of 51 +/- 1 mmHg (untreated rats) to a value lower than normal (44 +/- 1 mmHg, P less than 0.001). These hemodynamic changes were associated with a significant reduction in afferent (approximately 23%) and efferent (approximately 26%) arteriolar resistance. The mean ultrafiltration coefficient was two times higher in the enalapril (0.126 +/- 0.027 nl/s per mmHg) than in the untreated group (0.061 +/- 0.023 nl/s per mmHg). The clearance of dextran macromolecules relative to that of inulin was significantly reduced for all molecular sizes studied (26-64 A) in enalapril-treated vs. untreated rats. Theoretical analysis of dextran fractional clearances using a heteroporous model of neutral solute transport across the glomerular capillary wall indicated that enalapril affected glomerular membrane size selective properties, reducing uniformly the radius of hypothetical membrane pores. Enalapril treatment also significantly limited (P less than 0.01) the development of glomerular structural lesions (mean percentage of sclerotic glomeruli was 4.2 +/- 3.5% [treated] vs. 28 +/- 15% [untreated] rats at the end of the study) as well as tubulo-interstitial damage.

Topics: Animals; Blood Pressure; Body Water; Dextrans; Enalapril; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Male; Metabolic Clearance Rate; Proteinuria; Rats; Renal Circulation

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Indomethacin; Lisinopril; Male; Metabolic Clearance Rate; Middle Aged; Molecular Weight; Proteinuria

Topics: Adult; Captopril; Chronic Disease; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Nigeria; Proteinuria

There is evidence to suggest that thromboxane synthesis inhibition will attenuate the hypertension and proteinuria associated with subtotal renal ablation. In the present study, the thromboxane receptor antagonist, daltroban, (30 mg/kg/day i.p.) or vehicle was administered to rats for 3 weeks starting 2 weeks after partial renal ablation (right uninephrectomy and ligation of approximately two-thirds of the blood supply to the left kidney). Renal ablation was associated with proteinuria and increased systolic blood pressure. Neither the proteinuria nor the hypertension was affected by daltroban administration. Histological examination of the remaining kidney demonstrated no beneficial effect of daltroban. In a second study, it was determined that, 2 weeks after renal ablation, urinary thromboxane excretion was significantly increased, and subsequent administration of daltroban for 2 weeks resulted in significant blockade of the effects of the thromboxane mimetic, U46619. In a third study, enalapril (50 mg/l in the drinking water) resulted in a significant attenuation of the proteinuria, hypertension and glomerular lesions associated with partial renal ablation. The data indicate that enalapril, but not daltroban, protects against the development of renal disease associated with reduced renal mass.

Topics: Animals; Enalapril; Kidney Diseases; Male; Nephrectomy; Phenylacetates; Proteinuria; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxanes

The urinary albumin excretion measured by the albumin creatinine clearance ratio (Calb/Ccreat) and the mean supine arterial blood pressure (MAP) were studied before the start of ACE inhibition, at the start and during up to 1 year of ACE inhibition with Captopril or Enalapril in 35 patients with various chronic proteinuric renal disorders with or without renal failure, arterial hypertension and nephrotic syndrome. Before the start of ACE inhibition mean Calb/Ccreat, MAP, s-albumin and s-creatinine did not change. During ACE inhibition the Calb/Ccreat was reduced from 75% (p less than 0.05) in patients with minimal albuminuria to 41% (p less than 0.005) in patients with extensive albuminuria. Average reduction of albuminuria was 44% at one year's observation time. Serum albumin increased 9% (p less than 0.05), serum creatinine did not change significantly and MAP showed a slight, not uniformly significant decrease. The reduction of Calb/Ccreat was of the same order in the different renal disorders studied and was independent of the renal function, presence or absence of nephrotic syndrome and treatment with antihypertensive or immunosuppressive drugs. The decrease in Calb/Ccreat during ACE inhibition was related to the reduction in MAP at most time intervals, but Calb/Ccreat decreased also when MAP was unchanged or increased. Thus the decrease in Calb/Ccreat during ACE inhibition does not only seem to be a consequence of a decrease in the systemic arterial blood pressure but reasonably also due to changes in the intra-renal hemodynamics and most probably a decrease in the glomerular capillary pressure.

Topics: Adolescent; Adult; Aged; Albuminuria; Blood Pressure; Captopril; Child; Creatinine; Enalapril; Female; Follow-Up Studies; Humans; Hypertension, Renal; Male; Middle Aged; Proteinuria; Serum Albumin

When choosing antihypertensive agents for the treatment of diabetic patients with hypertension, it is necessary to consider the individual characteristics of these patients. In this respect, angiotensin-converting enzyme (ACE) inhibitors constitute an attractive option for diabetic patients. The effects of enalapril alone for 16 weeks in 23 non-insulin-dependent diabetic (NIDD) patients and in 10 non-diabetic patients with mild to moderate essential hypertension (EH) [diastolic blood pressure greater than 95 mm Hg and less than 115 mm Hg] were evaluated. Similar reductions in both systolic and diastolic blood pressure were observed in 17 NIDD patients (from 155 +/- 18/100 +/-11 mm Hg to 128 +/- 12/82 +/- 8 mm Hg, respectively) and in 6 EH patients (from 155 +/- 21/100 +/- 6 mm Hg to 125 +/- 20/84 +/- 8 mm Hg, respectively) who achieved and maintained blood pressure control (diastolic blood pressure less than 90 mm Hg) for 16 weeks. In 4 NIDD and 4 EH patients blood pressure was not controlled. Two NIDD patients discontinued the medication, one because of symptomatic postural hypotension and the other, who had a plasma creatinine level of 1.8 mg/dl, because of hyperkalaemia (K = 6.1 mEq/L). In the responders, enalapril did not alter glucose tolerance, plasma or urinary excretion of creatinine, potassium, sodium and aldosterone. Plasma renin activity increased in the NIDD group only. In 11 patients (6 NIDD and 5 EH), the elevated protein or albumin excretions decreased. It is concluded that enalapril is a good therapeutic option for NIDD patients with hypertension.

Topics: Adult; Aldosterone; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Proteinuria; Renin

Chronic aminonucleoside nephrosis is variably associated with tubulointerstitial damage, depending on the route and frequency of drug administration. Recently, different groups have shown this injurious tubulointerstitial process to be reversible, coinciding with the resolution of heavy proteinuria to normal values. The authors have previously shown that a single jugular intravenous administration of puromycin aminonucleoside (PA) to male Munich-Wistar rats produces a triphasic pattern of glomerular injury and proteinuria, which culminates in focal glomerulosclerosis 70 weeks after drug administration. The authors now report the later progression of the tubulointerstitial morphologic abnormalities associated with acute nephrosis (phase I), despite spontaneous resolution of glomerular injury during the intermediate period (phase II) in this model. Although treatment of rats with the angiotensin I converting enzyme inhibitor enalapril (50 mg/l drinking water) over the 70-week period did not affect the magnitude of proteinuria during the acute nephrotic phase, enalapril prevented the recurrence of proteinuria (phase III), as well as significantly reducing the severity of interstitial fibrosis, extent of tubular dilatation, and number of intratubular casts on semiquantitative scoring at the conclusion of the study. In addition, enalapril-treated rats had less low-molecular-weight protein excretion during the recurrent phase of proteinuria, suggesting a preservation of tubular functional capacity to reabsorb these proteins. In vitro cytotoxicity studies showed only the glomerular visceral epithelial cell to be sensitive to PA, in contrast with rat tubular epithelium and other cellular controls. Although the exact pathogenetic mechanism responsible for the development of the tubulointerstitial damage remains unknown, PA in vitro does not adversely affect rat tubular epithelium; there is however a clear correlation between the magnitude of recurrent proteinuria and the severity of tubulointerstitial morphologic abnormalities, as suggested by the beneficial effect of converting enzyme inhibition on both of these untoward processes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Line; Cell Survival; Chronic Disease; Enalapril; Glomerular Filtration Rate; Kidney; Kidney Tubules; Male; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

Albuminuria (UalbV) increases in proportion to dietary protein in rats with passive Heymann nephritis. To determine whether a similar relationship existed in normal animals, 14 normal rats were switched from an 8.5% protein diet (LP) to a 40% protein diet (HP). Initially UalbV and glomerular filtration rate (GFR) increased in parallel, but GFR ceased to increase after 48 h while UalbV continued to increase, causing a significant increase in fractional renal clearance of albumin (FCalb). In contrast, HP for 4 days caused only a transient increase in GFR in nephrotic rats but effected a threefold sustained increase in UalbV. Pretreatment of nephrotic rats with enalapril blunted but did not entirely prevent the increase in UalbV after switching to HP and did not affect the increase or subsequent decline in GFR. Treatment with enalapril for 10 days reduced UalbV and FCalb in nephrotic rats fed either LP or HP. The similar pattern of changes in urinary albumin excretion in normal and nephrotic rats after dietary protein augmentation suggests that dietary protein may modify UalbV by the same process in both normal and nephrotic animals. The increases in UalbV and GFR resulting from dietary protein augmentation represent parallel but independent processes, since only the proteinuric response is modified by converting enzyme inhibition. Dietary protein restriction and converting enzyme inhibition exert an additive effect to reduce UalbV.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Dietary Proteins; Enalapril; Glomerular Filtration Rate; Kidney; Male; Nephritis; Proteinuria; Rats; Rats, Inbred Strains; Time Factors

High doses of the angiotensin converting enzyme inhibitor, captopril, is known to cause significant increases in urinary protein excretion in patients with idiopathic membranous nephropathy. To find whether other angiotensin converting enzyme inhibitors yield similar results, we prospectively examined the effect of enalapril in five consecutive patients with idiopathic membranous nephropathy, elevated arterial pressure, and proteinuria and compared them to age-matched controls receiving clonidine. Glomerular filtration rate, 24-hour urinary protein excretion, and arterial pressure were measured. All patients served as their own controls. Those who received enalapril demonstrated an initial increase in proteinuria (-0.3 +/- 0.7 delta gm/day, clonidine vs 3.9 +/- 0.9 delta gm/day, enalapril: P less than .05) despite similar decreases in arterial pressure (-18 +/- 6 delta mm Hg, clonidine vs -22 +/- 6 delta mm Hg, enalapril: NS) and glomerular filtration rate (-1.1 +/- 0.8 delta mL/min, clonidine vs -1.9 +/- 1.2 delta mL/min, enalapril: NS) when compared to the clonidine group. This increase in proteinuria, however, did not occur when these patients were rechallenged with enalapril. To our knowledge, this is the first report to document a significant increase in preexisting nephrotic range proteinuria following administration of nonsulfhydryl ACE inhibitor. This increase, however, appears to be unique to the initial treatment phase of the disease and does not affect long-term management.

Topics: Adult; Blood Pressure; Clonidine; Enalapril; Female; Glomerulonephritis, Membranous; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Proteinuria

14 patients (8 male, 6 female), aged 35 to 64 years, with glomerulopathies consisting of membranoproliferative glomerulonephritis (GN) [n = 6], membranous GN (n = 3), focal and diffuse glomerulosclerosis (n = 4), and post-streptococcal GN (n = 1) were studied. Diagnosis was established by renal biopsy in 12 of the 14 patients. All 14 patients had impaired renal function (creatinine clearance = 25 to 55 ml/min) and proteinuria (1.0 to 10.4 g/day). Five normotensive patients received enalapril 20 mg/day, whereas 9 patients with hypertension received 20 to 40 mg/day to control blood pressure. Diuretics were administered concomitantly to 8 patients. Patients attended the clinic every 14 days for 30 months and their diets were closely monitored, with sodium intake limited to between 50 and 100 mEq/day and protein to between 1.0 and 1.2 g/kg/day. Blood pressure was significantly controlled in the patients with hypertension. Serum creatinine, blood urea nitrogen, creatinine clearance and 24-hour urinary protein excretion all significantly improved during the 30-month study. No adverse clinical events were noted. Thus, over a period of time, enalapril therapy may improve the prognosis of patients with glomerulonephritis by maintaining glomerular filtration rates and decreasing proteinuria and blood pressure.

Topics: Adult; Enalapril; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Proteinuria

Ten patients (6 men, 4 women, age range 35-64 years) with glomerulopathies were studied. Diagnoses were membranoproliferative glomerulonephritis (GN; n = 4), membranous GN (n = 3), focal and diffuse glomerulosclerosis (n = 2), and poststreptococcal GN (n = 1). These were confirmed by renal biopsy in 8 of the 10 patients. All patients had reduced function (creatinine clearance 15-55 ml/min); proteinuria ranged from 1.0 to 10.4 g/day. Three normotensive patients received enalapril 10 mg once daily. Seven hypertensives received enalapril 10-40 mg once daily to control blood pressure (BP). Concomitant diuretic therapy (furosemide/bumetanide) was administered to 6 patients. There were visits every 14 days for a mean of 15.9 months (range 9-26 months). Diet was monitored, and BP was significantly controlled in the hypertensive patients but not altered in the normotensives. Serum creatinine, blood urea nitrogen, creatinine clearance, and 24-hour urinary protein improved and did not deteriorate progressively. Serum potassium did not change significantly. No adverse clinical events were noted. Enalapril therapy may improve the prognosis for GN over time by maintaining glomerular filtration rate and decreasing proteinuria.

Topics: Adult; Chronic Disease; Creatinine; Enalapril; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Proteinuria; Time Factors

It has been established previously that nephrotic hyperlipidemia is characterized by both an increase in lipid synthesis and a defect in removal of lipoproteins. The relationship between these defects and altered albumin metabolism is uncertain. One hypothesis is that hepatic lipogenesis increases in parallel with albumin synthesis. To test this hypothesis, albumin synthesis was increased in nephrotic rats fed an 8.5% protein diet (LPN) by increasing dietary protein to 40% (HPN). Proteinuria was modulated in half of the rats fed 40% protein by enalapril (HPE). Albumin synthesis was the same in both HPN and HPE, but proteinuria was reduced in HPE compared to HPN, and so were serum cholesterol and triglycerides (TG). To examine the effect of serum albumin on lipid clearance in the absence of proteinuria, plasma clearance of chylomicrons (CM) and VLDL was measured in Nagase analbuminemic rats (NAR) and found to be no different than in normal SD rats. When proteinuria was induced in NAR and in SD rats, a severe and identical defect in both CM and VLDL clearance was acquired in both groups and blood lipid levels were increased to a similar degree in both groups. Neither hyperlipidemia nor defective removal of lipoproteins from the circulation are linked to albumin synthesis or serum albumin concentration but result, at least in part, from proteinuria. Postheparin lipoprotein lipase (LPL) activity was reduced slightly in nephrotic animals compared to nonnephrotic controls, but the most striking finding was a highly significant decrease in postheraprin LPL activity in normal NAR compared to SD rats (P less than 0.001), suggesting that reduced LPL activity is not responsible for reduced clearance of CM and VLDL in nephrotic rats.

Topics: Albumins; Animals; Chylomicrons; Dietary Proteins; Enalapril; Hyperlipidemias; Lipoproteins, VLDL; Metabolic Clearance Rate; Nephrotic Syndrome; Proteinuria; Rats; Rats, Inbred Strains

The glomerular size-selective properties in a patient with "hyponatremic hypertensive syndrome" were investigated before and after administration of the angiotensin-converting enzyme inhibitor enalapril. Hyponatremic hypertensive syndrome is a rare condition of renovascular hypertension characterized by electrolyte abnormalities (hyponatremia, hypokalemia), polyuria, and high renin activity. In this patient a marked increase in urinary protein excretion was observed. Treatment with enalapril normalized BP, corrected electrolyte abnormalities, and reduced proteinuria. Glomerular filtration rate (GFR), renal plasma flow (RPF), and the clearance of neutral dextrans of graded sizes were measured before and after 6 months of enalapril (20 mg/d) administration. Theoretical analysis of dextran and inulin clearance data with a model of glomerular size selectivity were adopted to separate effects of hemodynamic changes on macromolecule filtration from changes of intrinsic membrane selective properties. After enalapril urinary protein excretion decreased, GFR was unchanged and RPF almost doubled. Fractional clearance values of dextran molecules were markedly elevated in comparison with the corresponding values measured in a group of normal controls and were normalized by enalapril. Theoretical calculation of membrane pore characteristics showed that enalapril treatment reduced the radius of all membrane pores by approximately 1 nm. Altogether these results indicate that enalapril normalized glomerular filtration of neutral macromolecules and circulating proteins in a human condition of angiotensin II-induced proteinuria. Enalapril effectively restored glomerular size-selective function, reducing dimensions of membrane pores, independently of its effect on renal hemodynamics.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Dextrans; Enalapril; Glomerular Filtration Rate; Humans; Hypertension, Renovascular; Hypokalemia; Hyponatremia; Inulin; Kidney Glomerulus; Male; p-Aminohippuric Acid; Proteinuria

We studied the effects of lisinopril on mean arterial blood pressure (MAP), plasma renin activity (PRA), and renal hemodynamics in nine patients with chronic renal disease and hypertension, before, and after three months of therapy. Lisinopril normalized blood pressure in five of nine patients (responders) and did not in the remaining four (nonresponders). PRA rose after lisinopril (4.8 +/- 2.6 ng/mL/h to 25 +/- 15 ng/mL/h, P less than 0.05) in responders, but not in nonresponders (2.0 +/- 1.4 ng/mL/h to 3.4 +/- 2.9 ng/mL/h). Glomerular filtration rate remained stable in both groups (responders: 43 +/- 11 mL/min to 43 +/- 22 mL/min; nonresponders: 39 +/- 25 mL/min to 32 +/- 21 mL/min). In the responders renal hemodynamics remained stable after lisinopril (renal plasma flow: 223 +/- 80 mL/min to 216 +/- 91 mL/min; filtration fraction: .20 +/- .04 to .20 +/- .05; renal vascular resistance: 386 +/- 179 to 326 +/- 209 units). In the nonresponders, renal plasma flow decreased (228 +/- 141 mL/min to 162 +/- 117 mL/min, P less than 0.005), filtration fraction increased (.19 +/- .08 to .24 +/- .12, P less than 0.05), and renal vascular resistance increased (695 +/- 747 to 1265 +/- 1574 units, P less than 0.05) after chronic lisinopril therapy. We conclude (1) there is a heterogeneous response to lisinopril in patients with chronic renal disease and hypertension, (2) lisinopril monotherapy may result in effective blood pressure control without renal hemodynamic compromise, and (3) an increase in PRA following converting enzyme inhibition may identify those in whom the circulating renin angiotensin system is participating in systemic hypertension and intrarenal hemodynamic changes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Drug Evaluation; Enalapril; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Diseases; Lisinopril; Middle Aged; Potassium; Proteinuria; Renin

The effect of long-term treatment with either enalapril or high dose verapamil on survival, proteinuria, blood pressure and renal morphology was studied in female Wistar rats with markedly reduced renal mass. Four weeks were allowed for remnant kidney hypertrophy before determining the response to renal ablation of individual animals regarding proteinuria and hypertension. At this time, five groups of 18 rats were formed with equal levels of proteinuria and hypertension. Groups E1 and E2 were treated with enalapril, groups V1 and V2 with verapamil, and one group served as control. The daily food allowance was 14 g/rat of a standard rat diet, containing 30% protein and 100 mmol NaCl/kg food in groups E1 and V1. NaCl content was reduced to 20 mmol/kg food in groups E2, V2 and control. The drugs were added to the drinking water, enalapril at a dose of 0.1 g/liter, verapamil at 0.5 to 0.7 g/liter. Drug intake thus amounted to 10 to 25 mg/kg for enalapril and 50 to 140 mg/kg for verapamil. Treatment was continued for 15 weeks. Three of the 18 control rats did not survive up to 15 weeks. Mortality was lower in the enalapril treated groups with a single nonsurvivor in group E1. In contrast, mortality was higher in the verapamil treated animals with seven nonsurvivors in group V1 and eight in group V2. Blood pressure control was excellent in both enalapril treated groups. and proteinuria decreased in most animals of group E1 and all of group 22. Glomerulosclerosis did not develop in the majority of the enalapril treated animals. Despite the high dose, verapamil barely lowered blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Enalapril; Female; Glomerulonephritis; Hypertension, Renal; Hypertrophy; Kidney; Nephrectomy; Proteinuria; Rats; Rats, Inbred Strains; Time Factors; Verapamil

Topics: Adult; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Middle Aged; Proteinuria

Topics: Adult; Diabetic Nephropathies; Enalapril; Female; Humans; Hypertension; Proteinuria

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Child; Child, Preschool; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Proteinuria; Time Factors

Nineteen essential hypertensive patients were entered into a protocol to assess the BP, humoral and renal effects of the angiotensin converting enzyme inhibitor, lisinopril (MK 521, 20 to 80 mg once daily), administered for 52 weeks. Specifically monitored prior to, and following 12 and 52 weeks of lisinopril monotherapy were plasma renin activity and plasma aldosterone, the clearances of creatinine, inulin and para-aminohippurate, and the 24-hour urinary excretion of protein. BP was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed throughout the entire protocol. In contrast to the reported short-term and long-term renal effects of enalapril, lisinopril (a lysine analog of enalapril) had no short-term effect on renal function: glomerular filtration rate, effective renal plasma flow, filtration fraction (FF), renal vascular resistance (RVR), and protein excretion were all unchanged. However, following long-term therapy, both FF and RVR were decreased. Lisinopril appears to convey no specific renal pharmacological benefit.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Electrolytes; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Lisinopril; Male; Proteinuria; Pulse; Renal Circulation; Renin; Vascular Resistance

Oral inhibitors of angiotensin converting enzyme (ACE) now have an established place in the treatment of hypertension and heart failure. Captopril, the first of these agents, was initially used in high doses and was associated with adverse effects including proteinuria, skin rash and taste disturbance. We report 11 patients who developed side effects during captopril therapy (proteinuria two, rash four, taste disturbance four and taste disturbance with rash one) who were subsequently treated with enalapril, a second generation angiotensin converting enzyme inhibitor. Proteinuria did not recur in either patient, skin rash resolved in all five cases and taste disturbance resolved in four of five during enalapril therapy. We conclude that the side effects of proteinuria, skin rash and taste disturbance are consequences of captopril idiosyncrasy rather than inhibition of the angiotensin converting enzyme. The reported incidence of these side effects with the current recommended dosage of captopril is low.

Topics: Captopril; Drug Eruptions; Enalapril; Female; Heart Failure; Humans; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Proteinuria; Taste Disorders

Functional and morphologic measurements were performed in Munich-Wistar rats after a single central venous injection of puromycin aminonucleoside (PA) or saline vehicle (sham). During phase I, PA rats exhibited overt nephrotic syndrome and impaired glomerular filtration, primarily due to a reduction in the glomerular capillary ultrafiltration coefficient. The morphologic counterpart of the latter consisted of effacement of glomerular epithelial cell foot processes and decrease in the number of filtration slit diaphragms. Administration of the angiotensin I converting enzyme inhibitor (CEI) enalapril to PA rats did not ameliorate glomerular dysfunction. During phase II, PA rats exhibited spontaneous resolution of proteinuria, impaired function, and morphologic abnormalities. However, PA rats now demonstrated marked glomerular capillary hypertension and continued, albeit lesser, reductions in the ultrafiltration coefficient. Concurrent CEI administration modestly lowered systemic arterial pressure, and normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. Additional rats were studied during phase III, 70 wk after injection. In PA rats, prior glomerular hypertension was associated with development of recurrent proteinuria and extensive glomerular sclerosis, whereas concurrent CEI administration limited these parameters to values comparable to those in sham rats. Glomerular hypertension thus may explain the development of glomerular sclerosis and renal failure long after an episode of acute glomerular injury.

Topics: Animals; Blood Pressure; Disease Models, Animal; Enalapril; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Male; Microcirculation; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

The antihypertensive efficacy and renal effects of enalapril maleate therapy were evaluated in 13 hypertensive patients with chronic renal failure. Enalapril was administered as follows: alone; added to furosemide, clonidine hydrochloride, or atenolol; or in combination with any of the aforementioned drugs. Three patients did not complete the study; uncontrolled hypertension was the cause in two of these patients. In the remaining ten patients, short-term (mean +/- SD, 63 +/- 9 days) enalapril maleate therapy decreased the patient's seated blood pressure from 161/98 +/- 19/8 to 130/80 +/- 13/7 mm Hg. Furosemide was administered to eight patients; the dose of concomitant sympatholytic therapy was decreased in five of five patients. Serum potassium concentration increased from 4.1 +/- 0.3 to 4.5 +/- 0.3 mmol/L. Levels of urinary total protein excretion decreased from 2.23 +/- 2.05 to 1.08 +/- 1.45 g/d. Renal function (creatinine clearance, 0.58 +/- 0.21 mL/s) did not change from baseline. During long-term therapy, the rate of progression of renal insufficiency seemed to slacken in three of four patients with diabetic nephropathy. Thus enalapril can reduce blood pressure and proteinuria in hypertensive patients with chronic renal insufficiency. The possibility that enalapril can slow the progression of diabetic nephropathy remains to be confirmed by future studies.

Topics: Adult; Aged; Blood Pressure; Creatinine; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Proteinuria

1. Lisinopril, a new orally active angiotensin converting enzyme inhibitor, was given to eight patients with stable chronic renal failure, in a dose of 5 mg 24 h-1 for 1 week. Creatinine clearance of the subjects ranged from 0.22 to 1.11 ml s-1. Lisinopril pharmacokinetics were studied over 8 days. 2. There was a close correlation between creatinine clearance and total 'area under the curve' over the 8 days of study (r = -0.88, P less than 0.05), and plateau lisinopril concentration and creatinine clearance (r = -0.77, P less than 0.05). 3. Serum angiotensin converting enzyme activity was inhibited in proportion to log serum lisinopril concentration (r = -0.99, P less than 0.001). Calculated IC50 was 47 ng lisinopril ml-1. from pooled data, with individual patients IC50 ranging from 20 to 70 ng lisinopril ml-1. 4. Creatinine clearance was unaltered by treatment. Serum potassium rose to over 5 mmol 1-1 in four patients, without adverse clinical effect.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatine; Enalapril; Female; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Proteinuria; Pulse

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Inbred Strains; Reference Values; Thromboxane-A Synthase

The renal functional alterations that occurred in streptozotocin-induced diabetes in uninephrectomized rats were studied over a three-month period. Diabetic animals had elevated systemic systolic blood pressure, creatinine clearance and urinary protein excretion. After three months, systolic blood pressure was 131 +/- 2 mmHg, creatinine clearance was 1.52 +/- 0.06 ml/min and urinary protein excretion 70.8 +/- 17.9 mg/24 h. Non-diabetic control rats had a systolic blood pressure of 117 +/- 3 mmHg (p less than 0.001), creatinine clearance of 1.15 +/- 0.05 ml/min (p less than 0.001), and protein excretion of 8.22 +/- 0.2 mg/24 h (p less than 0.001). Diabetic rats were treated with enalapril or verapamil, 5 mg.kg-1.day-1 which reduced systolic blood pressure to 108 +/- 3 mmHg (p less than 0.001) and 114 +/- 2 mmHg (p less than 0.001) respectively. Treatment with enalapril reduced the degree of proteinuria at three months (36.4 +/- 3.0 mg/24 h, p less than 0.05). Protein excretion rate in verapamil treated rats was 57.7 +/- 10.1 mg/24 h at three months, similar to that of untreated diabetic rats. Filtration fraction of untreated diabetic rats was 0.40 +/- 0.04. Treatment with enalapril lowered filtration fraction (0.26 +/- 0.02, p less than 0.01) whilst verapamil had no significant effect (0.37 +/- 0.02). The differing effects of enalapril and verapamil on renal function occurred despite similar degrees of hypotension, and may reflect the different intrarenal haemodynamic effects of these drugs.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Kidney; Proteinuria; Rats; Rats, Inbred Strains; Reference Values; Verapamil

1. Nephrotoxic serum nephritis was induced immunologically in uninephrectomized Sprague-Dawley rats (n = 24). One-half were assigned randomly to treatment with enalapril (5 mg/kg per 24 h). 2. Untreated rats (n = 12) developed a progressive fall in creatinine clearance, a progressive rise in systolic blood pressure and marked proteinuria over a 6 week period. The mortality rate was 42% at 5 weeks and 66% at 6 weeks. 3. Enalapril-treated rats (n = 12) had no significant reduction in systolic blood pressure, and a similar reduction in creatinine clearance to that in untreated rats. Mortality was 50% at 5 weeks, and 92% at 6 weeks. 4. Proteinuria but not the blood pressure rise was significantly reduced by enalapril treatment. 5. Converting enzyme inhibitors may have a specific role in the treatment of nephritic diseases.

Topics: Animals; Blood Pressure; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Kidney Failure, Chronic; Nephritis; Proteinuria; Rats; Rats, Inbred Strains

Sprague-Dawley rats subjected to subtotal (1 7/8) nephrectomy or streptozotocin diabetes were treated with an angiotensin converting enzyme inhibitor or a calcium channel blocker and their course compared with untreated control animals. Subtotal nephrectomy led to hypertension, proteinuria, reduced creatinine clearance, and glomerulosclerosis over 6 weeks. Enalapril treatment (5 mg/kg/day, n = 11) or felodipine (30 mg/kg/day, n = 11) reduced systolic blood pressure to a comparable degree. Plasma creatinine (mumol/l) was lower after enalapril treatment (110 +/- 8, p less than 0.05) than with felodipine treatment (153 +/- 27) or no treatment (173 +/- 19, n = 18). Proteinuria (mg/24 h) was lower with enalapril treatment (15 +/- 3, p less than 0.001) than with no treatment (85 +/- 22) and increased with felodipine (221 +/- 35). Glomerulosclerosis was reduced with enalapril but not felodipine treatment. Diabetic rats were treated with enalapril (5 mg/kg/day, n = 17), verapamil (5 mg/kg/day, n = 17), or untreated. Diabetic rats had increased creatinine clearance (ml/min) compared with nondiabetic controls (1.52 +/- 0.06 vs. 1.15 +/- 0.05, n = 11, p less than 0.01). Enalapril and verapamil treatment reduced blood pressure equally. Enalapril but not verapamil reduced the elevated creatinine clearance of diabetic rats (enalapril, 1.37 +/- 0.04 ml/min, p less than 0.01; verapamil, 1.49 +/- 0.5 ml/min). Proteinuria (mg/24 h) was lower (p less than 0.05) with enalapril treatment (36 +/- 3) but not with verapamil treatment (58 +/- 10) in comparison to that in untreated diabetes (71 +/- 18).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Felodipine; Hypertension; Kidney Failure, Chronic; Nephrectomy; Nitrendipine; Proteinuria; Rats; Rats, Inbred Strains; Verapamil

The effect of clonidine, on alpha 2-agonist and antihypertensive, on the progression of chronic renal disease was studied in rats subjected to partial nephrectomy. Treatments began four weeks after the removal of approximately 70% of renal mass. Clonidine was given once daily by gavage on an increasing dose schedule of 50 micrograms/kg for 4 weeks, followed by 100 micrograms/kg for 8 weeks and finally 200 micrograms/kg for 6 weeks. Measurements of renal functions were made at 4 week-intervals during treatment. After 18 weeks, clonidine-treated rats had lower levels of plasma urea nitrogen (P less than 0.05) and plasma creatinine (P less than 0.05). Urinary protein excretion rates were lower in clonidine-treated rats while receiving 100 micrograms/kg at 8 weeks (P less than 0.05) and 200 micrograms/kg at 18 weeks (P less than 0.05). At the end of the treatment period, anesthetized clonidine-treated rats had a numerically lower mean arterial pressure (p = 0.08), but no difference in the histological ranking of light microscopic lesions (P greater than 0.10). Based on the functional data, we conclude that clonidine retards the deterioration of renal function in this model of chronic renal disease. The lack of a consistent effect of clonidine on proteinuria and no reduction in the severity of morphological damage indicates that clonidine is less effective than previously reported treatment in this model with angiotensin converting enzyme inhibition. These differences in efficacy may be related to differences in intraglomerular hemodynamic alterations and could be an important consideration in the selection of therapies for individuals with hypertension and renal insufficiency.

Topics: Animals; Blood Pressure; Chronic Disease; Clonidine; Creatinine; Enalapril; Heart; Kidney; Kidney Diseases; Male; Nephrectomy; Organ Size; Proteinuria; Rats; Rats, Inbred Strains

The effects of the angiotensin converting enzyme (ACE) inhibitor enalapril on the proteinuria and degree of focal glomerular sclerosis hyalinosis (FSH) in chronic puromycin aminonucleoside nephropathy (PAN) were examined. Chronic PAN was induced in male Sprague-Dawley rats by seven subcutaneous injections of puromycin aminonucleoside (20 mg/kg) over 10 weeks (Groups I and II). Group II rats also received enalapril 10 mg/kg/day in the drinking water throughout the study (12 weeks). Group III rats served as age-matched controls. Proteinuria was similar in Groups I and II (35.5 +/- 9.7 versus 29.1 +/- 4.1 mg protein/mg creatinine, mean +/- SEM, P greater than 0.05). Serum creatinine remained unchanged in Group I, but rose from 0.7 +/- 0.04 to 1.2 +/- 0.1 mg/dl (mean +/- SEM, P less than 0.05) in Group II. FSH was 13.8% in Group I, 12.9% in Group II (P greater than 0.05), and 0.6% in Group III. There was no significant difference in glomerular lipid content and in immunofluorescence for rat albumin, fibrinogen, IgM, IgG, and C3 between Groups I and II. ACE activity was inhibited by 94% in serum, 83% in lungs, and 92% in kidneys; and blood pressure response to. Angiotensin I challenge was decreased by 50% in rats similarly treated with enalapril versus controls. In summary, proteinuria and glomerular sclerosis in this model are not affected by ACE inhibition.

Topics: Angiotensin I; Animals; Blood Pressure; Creatinine; Enalapril; Kidney; Lung; Male; Peptidyl-Dipeptidase A; Proteinuria; Puromycin; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

Munich-Wistar rats were studied 18 weeks following 5/6 renal ablation. In untreated group 1 rats maintained on standard chow containing 24% protein, sustained systemic and glomerular hypertension were associated with increasing proteinuria and widespread glomerular injury. In group 2, early treatment with the converting enzyme inhibitor enalapril prevented systemic and glomerular hypertension, and largely limited proteinuria and glomerular injury. Groups 3 and 4 received no therapy during the first eight weeks, during which they developed systemic hypertension and levels of proteinuria previously shown to be associated with significant glomerular sclerosis at this time point. Enalapril therapy begun at eight weeks in group 3 rats reversed systemic and glomerular hypertension, prevented a further rise in proteinuria, and limited glomerular lesions at 18 weeks relative to group 1. Reduction of dietary protein content to 12% at eight weeks in group 4 rats controlled glomerular but not systemic hypertension to near-normal levels, stabilized proteinuria values, and also limited glomerular lesions at 18 weeks compared to group 1. These studies support the view that glomerular hypertension is an essential hemodynamic derangement responsible for progressive glomerular injury. Furthermore, reduction of capillary pressure can arrest the progression of remnant glomerular injury even when therapy is delayed until glomerular injury is established.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Capillaries; Dietary Proteins; Enalapril; Glomerular Filtration Rate; Hypertension, Renal; Kidney Glomerulus; Male; Proteinuria; Rats; Rats, Inbred Strains

The effects of the angiotensin converting enzyme (ACE) inhibitor lisinopril on blood pressure, proteinuria and renal hemodynamics were evaluated in 13 patients with renal disease of different origin. A comparison was made with the effects of conventional antihypertensive therapy. Both drug regimens significantly lowered blood pressure, while only after 12 weeks of treatment with lisinopril, blood pressure was significantly lower than during conventional therapy. Lisinopril reduced proteinuria (by 61 +/- 40%), whereas conventional therapy had no significant effect on protein excretion. During the first eight weeks of treatment with lisinopril, there was a comparable degree of blood pressure reduction with both treatment regimens, whereas urinary protein loss was significantly less during ACE inhibition. There was only a nearly-significant positive correlation between the fall in proteinuria during lisinopril and the concomitant decrease in mean arterial pressure. Glomerular filtration rate decreased from 26.3 +/- 11.6 to 20.6 +/- 9.4 ml/min during treatment with lisinopril. This decrease was not correlated with the fall in proteinuria. A significant positive correlation existed between the fall in urinary protein excretion and both the decrease in overall renal vascular resistance, and the fall in filtration fraction. Although blood pressure lowering by itself could contribute to the antiproteinuric effect of lisinopril, our results suggest that this effect of ACE inhibition is also due to efferent (postglomerular) vasodilation. We conclude that the ACE inhibitor lisinopril effectively reduces blood pressure and proteinuria in renal disease. The latter effect is not only the result of a lower blood pressure, but is probably also due to a fall in intraglomerular capillary pressure.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Humans; Lisinopril; Male; Middle Aged; Proteinuria; Renal Circulation; Vascular Resistance

The development of proteinuria, and more rarely nephrotic syndrome, has been seen with the use of the first orally active converting-enzyme inhibitor captopril. Both of these side effects appear to occur more frequently when the drug is used at higher dose, particularly in the presence of renal impairment. We have used enalapril, a new orally active converting-enzyme inhibitor in the treatment of a patient with drug-resistant hypertension and renal impairment who previously developed nephrotic syndrome with captopril. Recurrence of the nephrotic syndrome was not seen in this patient during a period of 20 months on enalapril. On the contrary, urinary protein excretion over the same period was reduced to around 1 g in 24 hours. Our experience would suggest that enalapril may usefully be substituted for captopril in the treatment of hypertensive patients in whom the latter has caused proteinuria or nephrotic syndrome.

Topics: Adult; Captopril; Enalapril; Female; Humans; Hypertension; Nephrotic Syndrome; Proteinuria

Micropuncture and morphologic studies were performed in six groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 4 received no specific therapy. Groups 2 and 5 were treated with the angiotensin I-converting enzyme inhibitor, enalapril, 50 mg/liter, in the drinking water. Groups 3 and 6 were treated with reserpine (5 mg/liter), hydralazine (80 mg/liter), and hydrochlorothiazide (25 mg/liter). All rats were fed standard chow. Groups 1-3 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure gradient (delta P) and glomerular plasma flow rate (QA). In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained delta P at near-normal levels without significant reduction in SNGFR and QA. In contrast, triple drug therapy normalized systemic hypertension, but failed to lower delta P in group 3 rats. Groups 4-6 were followed for 12 wk after renal ablation. Untreated group 4 rats demonstrated continuous systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and frequent areas of segmental sclerosis. In group 5 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 12-wk period and dramatically limited the development of proteinuria and glomerular lesions. Despite equivalent systemic blood pressure control in group 6 rats, failure of triple drug therapy to control glomerular hypertension was associated with progressive proteinuria and glomerular lesions comparable to those seen in untreated group 4 rats. Thus, unless glomerular capillary hypertension is corrected, control of systemic blood pressure is insufficient to prevent progressive renal injury in rats with reduced renal mass.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Glomerular Filtration Rate; Hydralazine; Hydrochlorothiazide; Hypertension, Renal; Kidney Cortex; Kidney Diseases; Kidney Glomerulus; Male; Microcirculation; Natriuresis; Proteinuria; Rats; Renin; Renin-Angiotensin System; Reserpine

This review focuses on the renal effects of the angiotensin converting enzyme inhibitors, captopril and enalapril. Emphasis is placed on the renal response to these drugs in patients with primary essential hypertension, and in hypertension accompanying renal parenchymal disease. Specifically reviewed are the renal function and hemodynamic, salt and water, body fluid composition, and urinary protein excretion responses. The interruption of the renin-angiotensin-aldosterone axis has the potential to produce a variety of favorable renal responses, including reduction of renal vascular resistance, enhancement of renal blood flow, enhancement of glomerular filtration rate, acute natriuresis, sustained diuresis, and a decrease in urinary protein excretion. Data in support of these potential renal perturbations are presented and discussed. The results suggest that the angiotensin converting enzyme inhibitors are important therapeutic agents in the treatment of hypertensive disease, in that they may modify pathophysiologic renal abnormalities encountered in this disease state.

Topics: Angiotensin-Converting Enzyme Inhibitors; Body Fluids; Captopril; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Hypertension, Renal; Kidney; Oligopeptides; Proteinuria; Regional Blood Flow; Renin-Angiotensin System; Sodium Chloride; Teprotide

The purpose of this study was to define the effect of the angiotensin-converting enzyme inhibitor, enalapril maleate, on blood pressure, renal function, protein excretion, and potassium homeostasis in patients with hypertension associated with moderate to severe renal dysfunction. Nine patients, having an initial inulin clearance between 9 and 48 mL/min/1.73 m2, were treated with enalapril monotherapy (n = 6) or enalapril/furosemide (n = 3) combination therapy. Systolic and diastolic blood pressures were well controlled. Supine plasma renin activity was stimulated; the supine plasma aldosterone level was suppressed, with a resultant increase in the serum potassium level. Clinical hyperkalemia was not observed. Glomerular filtration rate, assessed by inulin and creatinine clearances, was not significantly changed. Effective renal plasma flow, assessed by paraaminohippurate clearance was significantly increased, with a resultant decrease in filtration fraction. Importantly, urinary protein excretion was markedly reduced. These results suggest that enalapril therapy produces efferent arteriolar dilitation with preservation of the glomerular filtration rate. Enalapril therapy may also blunt the effects of angiotensin II on transglomerular passage of protein, as demonstrated by reduced proteinuria. These findings suggest that interruption of the renin-angiotensin system in patients with preexisting renal disease may have renal protective effects.

Topics: Adult; Aged; Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Furosemide; Heart Rate; Homeostasis; Humans; Hypertension; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Potassium; Proteinuria; Sodium

Micropuncture and morphologic studies were performed in four groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 3 received no specific therapy. Groups 2 and 4 were treated with the angiotensin I converting enzyme inhibitor, enalapril, 50 mg/liter of which was put in their drinking water. All rats were fed standard chow. Groups 1 and 2 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure difference and glomerular plasma flow rate. In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained the mean glomerular transcapillary hydraulic pressure gradient at near-normal levels without significantly compromising SNGFR and the glomerular capillary plasma flow rate, as compared with untreated group 1 rats. Groups 3 and 4 were studied 8 wk after renal ablation. Untreated group 3 rats demonstrated persistent systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and segmental sclerosis. In group 4 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 8-wk period and significantly limited the development of proteinuria and glomerular lesions. These studies suggest that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further support the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced.

Topics: Animals; Dipeptides; Enalapril; Hypertension, Renal; Kidney Cortex; Kidney Glomerulus; Male; Microcirculation; Natriuresis; Proteinuria; Rats; Rats, Inbred Strains; Renin

Sustained increases in glomerular capillary pressure and flow accompany systemic hypertension in rats that have undergone extensive ablation of the renal mass. These intrarenal hemodynamic changes are, in turn, associated with the progressive development of proteinuria and glomerular sclerosis, leading ultimately to failure of remnant nephron units. The efficacy of antihypertensive therapy with enalapril was evaluated in this animal model of chronic renal insufficiency. A dose of enalapril sufficient to prevent systemic hypertension normalized the glomerular capillary pressure without reducing the glomerular filtration rate in the remnant kidney. Maintenance of normal capillary pressure markedly reduced the development of proteinuria and sclerotic lesions in remnant glomeruli. These results suggest that antihypertensive therapy directed at reducing the glomerular capillary pressure could retard the progressive loss of renal function in patients whose functional renal mass has been reduced by disease.

Topics: Animals; Enalapril; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney Failure, Chronic; Kidney Glomerulus; Male; Oligopeptides; Proteinuria; Rats; Rats, Inbred Strains; Teprotide

Enalapril alone, 10-40 mg given once-daily, controlled systemic hypertension long-term (mean follow-up time 19 months) in patients with renal artery stenosis. Significant, but usually modest, increases in serum creatinine and urea were observed. No serious side-effects were seen. A highly significant reduction in peripheral plasma angiotensin II was maintained 24 h after the previous dose of enalapril. Plasma active renin concentration rose 20-fold with long-term enalapril, when the stenotic kidney showed significant secretion of inactive, as well as of active renin. With enalapril therapy, the contralateral kidney showed net extraction of active renin. In unilateral renal artery stenosis, circulation on the affected side is diminished and is mainly via the juxtamedullary nephrons, which become rich in associated renin. Important intrarenal compensatory actions of the renin-angiotensin system include support of glomerular filtration, enhancement of vasa recta-mediated counter-current exchange, sustained urea excretion and maintenance of renal artery pressure distal to the stenosis. These compensatory effects are lost with converting enzyme inhibition. Thus in patients who are candidates for operation, enalapril should usually be given for no more than one month before proceeding to corrective surgery, to allow maximum blood pressure reduction without endangering the stenotic kidney for too long. Enalapril can nevertheless be given effectively long-term in patients unsuitable for corrective surgery.

Topics: Adolescent; Adult; Blood Pressure; Enalapril; Follow-Up Studies; Humans; Hypertension; Hypertension, Renovascular; Kidney; Middle Aged; Proteinuria; Renal Artery Obstruction; Renal Veins; Renin; Renin-Angiotensin System