enalapril and Kidney-Diseases

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

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII)-receptor antagonists suppress the effects of ATII and are effective antihypertensive agents. However, the use of ACE inhibitors is sometimes associated with intolerable side effects (eg, cough, angioedema), and patients may develop a compensatory rise in ATII levels. ATII-receptor antagonists have tolerability profiles similar to that of placebo and inhibit the effects of ATII more completely by blocking the AT1 receptor.. This review summarizes clinical studies comparing the efficacy and tolerability of the ATII-receptor antagonist telmisartan with the ACE inhibitor enalapril in patients with hypertension.. Randomized, controlled clinical trials comparing telmisartan with enalapril in patients with primary hypertension were identified through a PubMed search of the English-language literature from 1998 through 2001 and from bibliographic data provided by the manufacturer of telmisartan.. In 2 randomized, double-blind, placebo-controlled trials (total number of patients, 647), telmisartan 40 or 80 mg/d was at least as effective as enalapril 20 mg/d for lowering blood pressure (BP) in patients with mild to moderate hypertension. An open-label, titration-to-response study involving 86 patients with severe hypertension found that telmisartan 80 to 160 mg/d was as efficacious as enalapril 20 to 40 mg/d. The antihypertensive effects of telmisartan 20 to 80 mg/d and enalapril 5 to 20 mg/d were comparable in 278 elderly patients (age > or = 65 years) with mild to moderate hypertension enrolled in a 26-week, double-blind, dose-titration study. A double-blind, titration-to-response study in 71 patients with moderate renal impairment and mild to moderate hypertension found equivalent reductions in BP with telmisartan 40 to 80 mg/d and enalapril 10 to 20 mg/d without any clinically relevant decline in renal function. Telmisartan tended to be better tolerated than enalapril in this study, with fewer patients experiencing treatment-related adverse events (8.9% vs 26.9%, respectively).. Based on the literature included in this review, telmisartan and enalapril produced comparable reductions in BP in a broad range of patients with hypertension. Telmisartan appeared to have a better tolerability profile.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Clinical Trials as Topic; Enalapril; Humans; Hypertension; Kidney Diseases; Renin-Angiotensin System; Telmisartan

Chronic unilateral ureteral obstruction results in interstitial fibrosis of the affected kidney. Both an angiotensin-converting enzyme inhibitor, enalapril, and an angiotensin II receptor antagonist, SC-51316, ameliorate the increased production of extracellular matrix protein in the tubulointerstitium of the obstructed kidney. Blockade of angiotensin II synthesis or inability of angiotensin II to bind to its receptor lessened the increased levels of mRNA for transforming growth factor-beta and collagen IV found in the obstructed kidney of untreated rats. A monocyte/macrophage infiltration was present in the obstructed kidney of untreated rats or rats treated with the angiotensin II receptor antagonists. In contrast, this infiltrate was almost completely absent in the obstructed kidney of rats treated with enalapril. The reason for this different effect of enalapril compared with the angiotensin II receptor antagonist on the macrophage infiltrate seen in obstructive nephropathy has not been elucidated. We conclude that both an angiotensin-converting enzyme inhibitor (enalapril) and a receptor antagonist of angiotensin II ameliorate the tubulointerstitial fibrosis that follows complete unilateral ureteral obstruction in the rat. We suggest that an increased level of angiotensin II has a major role in the development of tubulointerstitial fibrosis following ureteral obstruction.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Collagen; Enalapril; Extracellular Matrix Proteins; Fibrosis; Kidney; Kidney Diseases; Kidney Tubules; Macrophages; Monocytes; Rats; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Triazoles; Ureteral Obstruction

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

The effects of dietary protein and converting enzyme inhibition (CEI) on chronic puromycin aminonucleoside nephropathy (PAN) were studied. PAN was induced with seven SQ injections of puromycin aminonucleoside 20 mg/kg over 10 weeks in male Sprague-Dawley rats. The rats were divided into a 22.5% protein diet group (Gr 1), a 6% protein diet group (Gr 2), and an enalapril-treated group on 22.5% protein diet (Gr 3). Group 4 animals served as age-matched controls. Both diets were isocaloric and had the same phosphorus content. Rats from groups 1, 2, and 4 were sacrificed at 12, 18 and 24 weeks. Five rats of group 3 were sacrificed at 12 weeks, and the others were divided in subgroups 3A (diet changed to 6% protein) and 3B (no changes); half of each subgroup was sacrificed at 18 and 24 weeks, respectively. Group 2 had significantly less proteinuria than group 1 at all times. Group 3 had the same proteinuria as group 1 until 12 weeks and then began to decrease. In group 3A proteinuria decreased to group 2 levels, while in group 3B the decrease was slower but still prominent. Early lesions of focal and segmental glomerular sclerosis/hyalinosis (FSH) were present in groups 1, 2, 3 at 12 weeks (16 +/- 1.2%, 15 +/- 1.3%, 7 +/- 1.3%, respectively, versus 1.3 +/- 0.4% in controls), but by 18 weeks a reversal in FSH was seen in groups 2 and 3A/B (3 +/- 1.6%, 2 +/- 0.4%, and 3 +/- 0.9%, respectively, vs. 14 +/- 1.5% in group 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dietary Proteins; Enalapril; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Diseases; Male; Microscopy, Electron; Puromycin; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

One of the major challenges for today's nephrology is to elucidate the mechanism of action of ACE-inhibitors in damaged kidneys. Clarification of the mechanisms involved will not only increase the understanding of the pathomechanisms involved in progression, but also enrich the therapeutic armamentarium available to the nephrologist.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetic Nephropathies; Enalapril; Humans; Kidney Diseases; Kidney Failure, Chronic

Structurally, lisinopril differs from captopril in that it does not contain a sulphydryl group and it differs from enalapril and related compounds in that it is not an ester prodrug. Published data on the clinical pharmacology of lisinopril are reviewed and data from new studies are presented. A radioimmunoassay has been used to study the clinical pharmacokinetics of lisinopril and 14C-lisinopril has been used in metabolism studies in man. Following oral administration, lisinopril is absorbed slowly but the absorbed drug is immediately available without any requirement for biotransformation by the liver. The plasma half-life controlling accumulation during chronic administration is 12-13 h and the absorbed drug is eliminated via glomerular filtration. These properties are consistent with once-daily dosing and uncomplicated clinical use in the treatment of hypertension and congestive heart failure.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Interactions; Enalapril; Humans; Kidney Diseases; Lisinopril

The safety profiles of the angiotensin converting enzyme inhibitors, captopril and enalapril, are the focus of this review. Adverse effects are reviewed as those associated with sulfhydryl compounds and as those considered class-specific adverse effects of angiotensin converting enzyme inhibitors. Specifically discussed are the incidences of the adverse effects of rash, taste disturbance, neutropenia, and proteinuria, which are characteristic of compounds containing sulfhydryl moieties, such as captopril. It is concluded from the review of these safety data that enalapril is well tolerated, has few class-specific adverse effects, and may offer a potential advantage over captopril by having fewer sulfhydryl-related adverse effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Clinical Trials as Topic; Dizziness; Dose-Response Relationship, Drug; Enalapril; Half-Life; Headache; Humans; Hypertension; Kidney Diseases; Neutropenia; Oligopeptides; Skin Diseases; Sulfhydryl Compounds; Taste Disorders; Teprotide

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Dipeptides; Drug Eruptions; Drug Interactions; Enalapril; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Kidney Diseases; Neutropenia; Proline; Taste Disorders

The RED LEVEL study (REnal Disease: LErcanidipine Valuable Effect on urine protein Losses) directly compares, in an explorative fashion, the effects of lercanidipine + enalapril and amlodipine + enalapril combinations on renal parameters in hypertensive subjects.. This was a 1 year, prospective, multi-center, randomized, open-label, blinded-endpoint (PROBE) study in hypertensive patients with albuminuria.. Renal function (albuminuria, serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria); blood pressure.. Albuminuria was significantly reduced, compared with baseline values, with the lercanidipine + enalapril combination over the entire study period; at month 3, month 6 and month 12, changes from baseline were: -162.5 (p-value = 0.0439), -425.8 (p-value = 0.0010), -329.0 (p-value = 0.0011) mg/24 h), respectively. On the other hand, this improvement was not observed with enalapril + amlodipine. Other parameters of renal function such as serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria did not change over the study. Both lercanidipine + enalapril and amlodipine + enalapril significantly reduced systolic and diastolic blood pressure values from baseline all over the study period with no significant differences between groups. Safety outcomes were comparable between the two groups.. Overall, the results of this explorative study lend support to the anti-albuminuric effect of the lercanidipine + enalapril combination and to the long term renal-protective effects of this combination in patients with hypertension.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Prospective Studies

Dual blockade of the renin-angiotensin system (RAS) has been claimed to have a specific renal protective effect in chronic kidney disease (CKD). The present short-term study reports on the feasibility of dual blockade in a consecutive group of patients with CKD stage 3-5.. Forty-seven CKD patients, mean age 59 years, with mean estimated glomerular filtration rate (GFR) 26 ml/min/1.73 m(2) (range 13-49) and blood pressure (BP) 133/78 mmHg, were block randomized in an open study to 16 weeks of monotherapy with increasing doses of RAS blockade aiming at enalapril 20 mg o.d. or candesartan 16 mg o.d. Thereafter, the complementary drug was added in incremental doses over a period of 5 weeks aiming at combined enalapril 20 mg and candesartan 16 mg for 3 weeks. Seventy-five percent of the patients were known to be RAS blockade tolerant. Blood samples and BP were measured every 2-3 weeks. Doses of study medication were reduced in case of hyperkalemia >5.5 mmol/l, a sustained rise in p-creatinine >30% or symptomatic hypotension.. Twenty-one patients (45%) did not tolerate dual blockade in aimed dosages due to unacceptable p-creatinine increase (n = 12, including two study withdrawals), hypotension (n = 6), general discomfort (n = 2) or unmanageable hyperkalemia (n = 1). Hyperkalemia >5.5 mmol/l was seen in seven patients (15%). The reduced-dose group had baseline lower eGFR and diastolic BP.. Forty-five percent of CKD stage 3-5 patients did not tolerate dual RAS blockade with 20 mg enalapril and 16 mg candesartan daily, primarily due to loss of renal function or hypotension. Hyperkalemia could be managed in most patients. Caution is recommended when giving this treatment to patients with advanced CKD.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chronic Disease; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Feasibility Studies; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Renin-Angiotensin System; Tetrazoles

Combination therapy with angiotensin II Type I receptor blocker 50 mg of losartan and a fixed combination of losartan (50 mg)/hydrochlorothiazide (12.5 mg) was administered to hypertensive patients with Stage 3 - 4 chronic kidney disease to investigate its renoprotective effect.. Subjects already being administered the angiotensin I-converting enzyme inhibitor enalapril and losartan 100 mg daily were enrolled in this open-labeled trial (n = 40). Administration of 100 mg losartan twice daily was replaced with losartan (50 mg)/hydrochlorothiazide (12.5 mg) once daily after the morning meal and losartan at 50 mg once daily after the evening meal for the 24-week study period.. The mixture of losartan/hydrochlorothiazide significantly reduced systolic and diastolic blood pressures by 14.7 and 7.4 mmHg, respectively, compared with the baseline values. No significant changes were observed in the serum creatinine levels and estimated glomerular filtration rate. The urinary protein/creatinine ratio was, however, significantly decreased. Similarly, the regression line of 1/serum creatinine level was significantly increased after administration of losartan/hydrochlorothiazide. None of the patients exhibited a significant increase in the occurrence of adverse effects.. Our results demonstrated that a low dose of hydrochlorothiazide had a renoprotective effect due to its blood pressure-lowering effect. We accordingly propose that a low dose of hydrochlorothiazide should be administered to those patients in whom the blood pressure is not well controlled by intensive renin-angiotensin system inhibition therapy using the maximum recommended doses of angiotensin II Type I receptor blockers and angiotensin I-converting enzyme inhibitors.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Chronic Disease; Creatinine; Drug Administration Schedule; Drug Combinations; Enalapril; Female; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Kidney Diseases; Losartan; Male; Middle Aged

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

Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors (ACEIs) decrease proteinuria and slow the progression of nondiabetic nephropathies. However, head-to-head comparisons of ACEIs and calcium channel blockers (CCBs) have shown conflicting results. Indeed, a recent metaanalysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease, particularly when using true glomerular filtration rate (GFR) as the primary outcome.. The objective of this 3-year, randomized, multicenter, double-blind, placebo-controlled study was to compare true GFR decline (measured by yearly 51Cr-EDTA blood clearance) in nondiabetic, nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2), when randomized to a CCB (amlodipine, 5-10 mg/d) or an ACEI (enalapril, 5-20 mg/d).. Patients (aged 18-80 years) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks. Add-on treatments were atenolol (50-100 mg/d), loop diuretics (furosemide, 20-500 mg/d or torsemide, 5-200 mg/d), alpha-blockers (prazosin, 2.5-5 mg/d or doxazosin, 1-16 mg/d), and centrally acting drugs (rilmenidine, 1-2 mg/d or methyldopa, 250-500 mg/d). The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance. Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit. Post hoc analyses for the change in GFR, proteinuria, and time to clinical events were also planned on baseline proteinuria subgroups (<1 and >or=1 g/d) before unblinding the database.. Three hundred eighteen patients entered the run-in period and 263 patients (156 men/107 women; mean age, 58 years) were randomized to receive either amlodipine (5 mg/d, n=132) or enalapril (5 mg/d, n=131). Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril, respectively (no between-group significance). Only 20.8% of the patients randomized to ACEI treatment received diuretics at the last observation. No statistically significant difference was found between amlodipine and enalapril in GFR decline (-4.92 and -3.98 mL/min.1.73 m(2), respectively, at last observation) and composite secondary end point after a median follow-up of 2.9 years, including in the subgroup of patients with proteinuria >1 g/d at baseline. Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics (median -270 mg/d; P<0.001) but not in patients taking amlodipine plus diuretics (-25 mg/d at last observation).. In this cohort of nondiabetic, nonnephrotic hypertensive patients, no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers, including in the subgroup of patients with proteinuria >1 g/d.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Blood Pressure; Cohort Studies; Creatinine; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Placebos; Treatment Outcome

Chronic kidney disease (CKD), anemia, and declining kidney function are recognized as risk factors for adverse outcomes in patients with heart failure. This analysis was conducted to evaluate whether anemia is a risk factor for kidney function decrease in patients with heart failure. Data from the Studies of Left Ventricular Dysfunction (SOLVD), a randomized trial of enalapril versus placebo in patients with ejection fractions or=6 ml/min/1.73 m(2)/year. Anemia was defined as baseline hematocrit <36%. Multivariate logistic regression weighted by the number of GFR assessments was used to test the relation between anemia and rapid decrease. We also evaluated whether CKD (baseline GFR

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Chronic Disease; Cohort Studies; Creatinine; Diabetes Complications; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Hematocrit; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Placebos; Risk Factors; Stroke Volume

Patients with type 2 diabetes are prone to hypertension and persistent protein leakage from the kidney (microalbuminuria or macroalbuminuria). A progressive decline in renal function can lead to overt diabetic nephropathy and ESRD. The likelihood of cardiovascular disease also is increased. Control of hypertension is paramount to prevent these life-threatening complications. Agents that target the renin-angiotensin system--angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers--have been shown to be renoprotective. The groundbreaking Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial was designed to address the absence of comparative data on the long-term effects of an angiotensin II receptor blocker versus an angiotensin-converting enzyme inhibitor on renoprotection and survival in 250 patients with hypertension and early type 2 diabetic nephropathy. The primary purpose of the 5-yr double-blind, double-dummy, randomized study was to establish whether 40 to 80 mg of telmisartan conferred similar (i.e., noninferior) renoprotection to 10 to 20 mg of enalapril as determined by the change from baseline in GFR, measured by the plasma clearance of iohexol. Secondary end points included the emergence of ESRD and all-cause mortality. Telmisartan was not inferior to enalapril in reducing the decline in GFR: Mean annual declines in GFR were 3.7 and 3.3 ml/min per 1.73 m(2) with telmisartan and enalapril, respectively. During the 5-yr study period, no patient developed a serum creatinine >200 micromol/L, and none required dialysis. There were only six deaths in each treatment group during the study, with half being due to cardiovascular events.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Creatinine; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Receptors, Angiotensin; Renin-Angiotensin System; Telmisartan

The objective of this study was to compare the effects of the angiotensin II (ang II) antagonist, losartan and the angiotensin-converting enzyme inhibitor (ACEI), enalapril on haemorheology. Twenty-nine patients with renal parenchymal disease and hypertension were enrolled in the prospective, open, parallel study that involved a 14-day washout period followed by a 120-day treatment period. Patients were allocated randomly to receive either losartan 50-100 mg/day (n = 15) or enalapril 2.5-10 mg/day (n = 14) to achieve blood pressure control <140/90 mm Hg. Blood pressure, haemorheology profile and plasma fibrinogen concentration were measured after the washout phase and after 2, 10, 60, and 120 days of treatment. The data were analysed using ANOVA with repeated measures. Twenty-seven patients completed the study. Treatment with both losartan and enalapril was associated with a significant decrease (P < 0.05) in relative high shear rate whole blood viscosity, indicating an increase in blood cell deformability. In patients taking losartan, the increase in blood cell deformability did not result in a decrease in mean whole blood viscosity due to a concomitant, significant increase in mean plasma viscosity (P < 0. 01). In contrast, the improved cell deformability in patients treated with enalapril resulted in a small and statistically insignificant decrease in mean whole blood viscosity (P = 0.06; mean change = -0.15 mPa sec). The mechanism of the increase in blood cell deformability and the rise in plasma viscosity associated with losartan remain unclear. It is possible but unproven that the improvement in intrinsic blood cell rheology with losartan and enalapril may be the result of changes in cation transport systems and/or the consequence of the protective antioxidant properties of drug metabolites.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Circulation; Blood Viscosity; Enalapril; Erythrocyte Deformability; Female; Fibrinogen; Humans; Hypertension; Kidney Diseases; Losartan; Male; Middle Aged; Prospective Studies

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalapril; Erythropoiesis; Female; Humans; Hypertension; Kidney; Kidney Diseases; Losartan; Male; Middle Aged

In this cross-over, double-blind study, 12 essential hypertensive patients (stage I, II, and III) with glomerular filtration rate (GFR) between 50 to 80 mL/min/1.73 m2, were submitted to 4 weeks of placebo followed by 12 weeks with isradipine SRO (IS) 5 mg, spirapril (SP) 6 mg, and isradipine plus spirapril (IS + SP). The study evaluated the effects of these drugs on GFR ((99m)Tc DTPA), effective renal plasma flow (ERPF) ((131)I-orthoiodohippurate), urinary sodium excretion (UNaV), urinary kallikrein excretion (UKal), urinary albumin excretion (UAE), and plasma renin activity (PRA). The three protocols significantly reduced mean blood pressure (128 v 107 mm Hg; 126 v 112 mm Hg; 129 v 104 mm Hg with IS, SP and IS + SP, respectively). ERPF and GFR did not change. UNaV increased significantly after IS (0.17 v 0.22 mEq/min) and IS + SP (0.18 v 0.24 mEq/min). UKal increased significantly after IS (58.6%) and IS + SP (53.6%). UAE decreased significantly only after SP. PRA increased significantly after IS (1.31 v 2.84 ng/mL/h), SP (1.10 v 2.15 ng/mL/h), and after IS + SP (1.23 v 3.21 ng/mL/min). In conclusion, IS, SP and IS + SP were effective in reducing blood pressure while keeping renal function stable. Only SP significantly decreased UAE. Enhanced UKal may have played a role in natriuresis observed after IS and IS + SP.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Isradipine; Kallikreins; Kidney Diseases; Male; Middle Aged; Natriuresis; Renal Circulation; Renal Plasma Flow, Effective; Single-Blind Method

We questioned the superiority of angiotensin converting enzyme (ACE) inhibitors to beta blocking drugs with regard to renal function outcome in patients with mild to moderate renal insufficiency and normal to moderately elevated blood pressure (BP). We therefore studied 89 patients in a prospective double-blind randomized trial comparing the effect of enalapril and atenolol on the slope of glomerular filtration rate (GFR). Mean baseline GFR was 53 +/- 20 ml/min, untreated BP 152 +/- 20 mm Hg systolic and 90 +/- 11 mm Hg diastolic and median proteinuria 0.6 g/24 hr (interquartile range 0.0 to 2.5). After a run-in period without antihypertensives, the test drug was titrated to lower diastolic BP to a predefined goal of 10 mm Hg below baseline and/or below 95 mm Hg. The median follow up was 3.9 years. Antihypertensive therapy resulted in a comparable decrease of BP in both study groups. Filtration fraction and proteinuria decreased in both groups. The slope of GFR over time was not different between both groups (-1.39 +/- 2.82 and -1.97 +/- 3.38 ml/min/year on atenolol and enalapril, respectively). In multiple regression analysis a higher baseline GFR, a greater decrease in GFR and in proteinuria during titration and a lower proteinuria during follow up were independently related to a better GFR slope. We conclude that the use of ACE inhibitors is not imperative in all patients with non-diabetic nephropathy.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Atenolol; Blood Pressure; Creatinine; Disease Progression; Enalapril; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Regression Analysis; Renal Circulation

Polymorphism in the gene for angiotensin-converting enzyme (ACE), especially the DD genotype, is associated with risk for cardiovascular disease. Glomerulosclerosis has similarities to atherosclerosis, and we looked at ACE gene polymorphism in patients with kidney disease who were in a trial of long-term therapy with an ACE inhibitor or a beta-blocker.. 81 patients with non-diabetic renal disease had been entered into a randomised comparison of oral atenolol or enalapril to prevent progressive decline in renal function. The dose was titrated to a goal diastolic blood pressure of 10 mm Hg below baseline and/or below 95 mm Hg. The mean (SE) age was 50 (1) years, and the group included 49 men. Their renal function had been monitored over 3-4 years. We have looked at their ACE genotype, which we assessed with PCR.. 27 patients had the II genotype, 37 were ID, and 17 were DD. 11 patients were lost to follow-up over 1-3 years. The decline of glomerular filtration rate over the years was significantly steeper in the DD group than in the ID and the II groups (p = 0.02; means -3.79, -1.37, and -1.12 mL/min per year, respectively). The DD patients treated with enalapril fared as equally a bad course as the DD patients treated with atenolol. Neither drug lowered the degree of proteinuria in the DD group.. Our data show that patients with the DD genotype are resistant to commonly advocated renoprotective therapy.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atenolol; Double-Blind Method; Enalapril; Female; Genotype; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

An open, randomised, cross-over study was performed to investigate the pharmacokinetics of enalaprilat, administered as 20 mg enalapril both as monotherapy and in combination with hydrochlorothiazide (HCTZ 12.5 mg). Three groups of 6 hypertensive patients were enrolled [untreated diastolic blood pressure (DBP) 90-115 mm Hg]; normal renal function [glomerular filtration rate (GFR) > 81 ml min-1 1.73 m-2], mild renal impairment (GFR 51-80 ml min-1 1.73 m-2), and moderate renal impairment (GFR 31-50 ml min-1 1.73 m-2). The pharmacokinetics of enalaprilat and enalaprilat plus HCTZ correlated predictably with renal impairment with increased plasma concentrations and decreased urinary elimination at lower values of GFR. The coadministration of HCTZ had no significant effect on the pharmacokinetics of enalaprilat in any group. We conclude that although the pharmacokinetics of both enalaprilat and HCTZ are related to renal function, HCTZ has no significant effect on the pharmacokinetics of enalaprilat and that dosage adjustment for both regimens should be based on renal function.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cross-Over Studies; Diuretics; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Kidney Diseases; Male; Middle Aged; Sodium Chloride Symporter Inhibitors

This study was designed to evaluate whether the angiotensin converting enzyme inhibitor enalapril could prevent cyclosporine-induced renal dysfunction in diabetic patients treated with CsA in monotherapy.. Twenty-four recent onset insulin-dependent diabetic patients without prior renal involvement were randomized to receive a 3 month course of either cyclosporine (CsA) alone (7.5 mg/kg. b.i.d. in olive oil) or CsA+enalapril (20mg p.o. oad.).. were mean arterial pressure, plasma creatinine, GFR, renal plasma flow, renal vascular resistance, sodium and lithium clearances measured before and after 3 months of treatment.. Baseline values were identical in both groups except for mean arterial pressure which was slightly higher in the subjects subsequently receiving CsA + enalapril. Three month treatment with CsA increased significantly mean arterial pressure and renal vascular resistance by 9 and 24% respectively, while decreasing significantly glomerular filtration rate and renal plasma flow by 17 and 14% respectively. Enalapril was able to prevent the decline in GFR and the increase in blood pressure induced by CsA. This effect was demonstrated despite a similar increase in renal vascular resistance suggesting a dissociation between changes in glomerular filtration rate and renal vascular resistance during angiotensin converting-enzyme inhibition.. Chronic angiotensin converting-enzyme inhibition could afford some degree of protection against CsA-induced renal dysfunction. Whether these results can be extrapolated to transplant recipients in whom CsA is usually associated to treatment by glucocorticosteroids deserves further evaluation.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Radioimmunoassay; Renal Circulation; Sodium

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

An open, prospective study was undertaken to investigate the effects of enalapril on hemorheology in patients with renal disease and complicating hypertension. Cellular and plasma determinants of blood viscosity and renal function were measured in 19 patients at baseline and 2, 60 and 120 days after treatment with enalapril (mean dose 5.4; range 2.5-20 mg/day). Within 2 days of starting enalapril there was a significant decrease in apparent blood viscosity measured at high shear rate (-0.15 mPa.s; p < 0.05) which fell further by day 60. The decrease in blood viscosity was primarily the result of hemodilution, as evidenced by a concurrent fall in plasma albumin concentration and plasma viscosity. A small, but significant decrease, in hemoglobin concentration (-7.4g/l; p = 0.03), and a trend of improved red blood cell (RBC) and white blood cell (WBC) rheological properties may have also contributed to the decrease in blood viscosity. We conclude that enalapril had a beneficial effect on hemorheology in patients with renal disease. The mechanism of the rheological changes appeared to be multifactorial and would be expected to decrease vascular resistance to blood flow.

Topics: Adult; Blood Viscosity; Enalapril; Hemoglobins; Humans; Hypertension; Kidney Diseases; Middle Aged; Prospective Studies; Serum Albumin

The angiotensin converting enzyme inhibitors constitute a major treatment modality for cardiovascular diseases, including congestive heart failure and hypertension. In addition to their beneficial hemodynamic effects, they offer other advantages, such as a relative lack of adverse effects on other cardiovascular risk factors. When used judiciously, the angiotensin converting enzyme inhibitors may also contribute to improved renal function. These agents induce vasodilation of both efferent and afferent renal vessels, which may facilitate improved renal blood flow and glomerular filtration rate in individuals whose renal insufficiency results from hyperadrenergic activity. Improvements in renal function may also be observed when angiotensin converting enzyme inhibitors are employed in other clinical conditions, such as diabetic nephropathy or proteinuric renal disease. Although the renal protective effects of the angiotensin converting enzyme inhibitors are well recognized, their use in certain circumstances may actually contribute to renal dysfunction. The factors which may predispose an individual to angiotensin converting enzyme inhibitor-induced renal dysfunction must be recognized by the clinician and appropriate interventions taken to prevent this potentially deleterious effect. This article reviews those factors which increase risk for angiotensin converting enzyme inhibitor-induced renal dysfunction and provides recommendations for prevention.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiovascular Diseases; Creatinine; Drug Interactions; Enalapril; Guidelines as Topic; Humans; Kidney; Kidney Diseases; Prospective Studies

The pharmacokinetics of spirapril and its active diacid metabolite spiraprilat were characterized in four groups of patients categorized on the basis of their renal function. No statistically significant effects of renal impairment upon the disposition of spirapril were detected. In contrast, there were significant perturbations in the pharmacokinetics of spiraprilat: The maximum plasma concentration (Cmax) values in the severely renally impaired group were 2-3 times those in the group of patients with normal renal function whereas the corresponding area under the curve (AUC) values were 5-6 times higher. However, there was no evidence of accumulation of spiraprilat in any of the groups as determined by the pharmacokinetic parameters derived after single and multiple doses. Thus, despite the evidence of a significant influence of renal impairment upon the disposition of spiraprilat, the lack of accumulation during the translation from single to multiple doses indicates that there is a considerable margin of safety for spirapril in renal impairment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Humans; Hypertension; Kidney Diseases; Single-Blind Method

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

Topics: Enalapril; Heart Failure; Humans; Kidney Diseases; Research Design

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

The pharmacokinetics of combined lisinopril and hydrochlorothiazide have been studied following single and multiple oral doses to 'young' (reference), elderly and renally impaired hypertensive patients. Tablets containing the fixed combination of lisinopril 20 mg and hydrochlorothiazide 12.5 mg were administered as a single dose followed by daily administration for 6-8 days. Serum concentration and haemodynamic measurements were made at intervals up to 48 hours after the first and last doses. The serum profiles of both drugs were comparable with observations from previous studies, showing higher concentrations in the elderly and in the renally impaired patients. Similar differences have been reported for such patient groups when the drugs were administered separately, indicating an absence of pharmacokinetic interaction. Both drugs accumulated by about 30% on multiple daily dosing. There were no differences between the patient groups in the extent of accumulation. The combination of lisinopril and hydrochlorothiazide produced the expected hypotensive response, minimum BP values being recorded 4 and 6 hours after treatment. The higher concentrations in the elderly and renally impaired patients were not associated with a greater reduction in BP. The pharmacokinetic behaviour of lisinopril and hydrochlorothiazide given together to elderly and renally impaired hypertensive patients suggests that a fixed dose combination is appropriate and that no changes to the dosage regimen additional to those used for the individual agents are necessary.

Topics: Adult; Aged; Aged, 80 and over; Aging; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Combinations; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Kidney Diseases; Lisinopril; Male; Middle Aged

To review the incidence of reversible renal insufficiency in patients with hypertensive nephrosclerosis undergoing antihypertensive therapy.. Retrospective analysis of 73 patients in a long-term blood pressure control study that compared the effects of an angiotensin converting enzyme (ACE) inhibitor plus conventional antihypertensive agents compared with placebo plus antihypertensive agents.. Hospital-based outpatient treatment center.. Patients were divided into group 1, which received enalapril plus conventional antihypertensives, and group 2, which received placebo plus conventional antihypertensives.. Blood pressure and serum creatinine levels were measured, and imaging studies of the main renal arteries were done.. In group 1, eight of 42 patients (19%, 95% CI, 9% to 34%) developed reversible renal insufficiency, defined as an unexpected increase in serum creatinine of 88 mumol/L or higher. Six episodes of reversible renal insufficiency occurred during July and August when temperatures were 32.2 degrees C to 37.8 degrees C (90 degrees F to 100 degrees F). Renal artery stenosis was excluded by renal arteriogram or ultrasonic duplex scanning. All eight group-1 patients had a significant decrease in mean arterial pressure below their baseline level during reversible renal insufficiency (mean change, -28 +/- 10 mm Hg, P less than 0.001). The increase in the serum creatinine level was inversely correlated with the decrease in the mean arterial pressure (r = -0.68, P less than 0.01). Reversible renal insufficiency was successfully managed by withdrawing or reducing enalapril as well as other antihypertensive agents. Subsequently, enalapril was tolerated by seven of the eight patients without recurrence of renal insufficiency. In contrast, none of 31 (CI, 0% to 11%) patients in group 2 developed reversible renal insufficiency despite the fact that both the incidence of decreases in mean arterial pressure in 6 of 31 patients (19%) and the magnitude of the decreases in mean arterial pressure (mean change, -33 +/- 16 mm Hg) were similar to those observed in group 1.. Reversible renal insufficiency in hypertensive nephrosclerosis associated with ACE inhibitor therapy correlates with relative hypotension, is not dependent on renal artery stenosis, and can usually be managed by dose reduction.

Topics: Aged; Blood Pressure; Creatinine; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Nephrosclerosis; Radiography; Renal Artery; Retrospective Studies; Ultrasonography

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

The safety of 738 high-risk patients treated with enalapril under various clinical programs was evaluated. High risk was defined as the presence of a collagen vascular disease; a renal disease, including renovascular hypertension; or either hypertension or refractory cardiac failure with serum creatinine greater than or equal to 1.7 mg/dl at baseline. Essential hypertension was the primary diagnosis in most of these patients. Treatment with enalapril in these patients usually continued without interruption for the length of the particular protocol. The incidence of adverse reactions resulting in discontinuation of treatment was comparable to that observed with other standard antihypertensive therapies in patients with milder forms of disease. No enalapril-related neutropenia, proteinuria, dysgeusia or ageusia were reported in these high-risk patients. The incidence of discontinuation due to rash was less than 0.5%. Resolution and/or improvement of captopril-related adverse effects was observed in many patients crossed over to treatment with enalapril. In patients with collagen vascular diseases and those with severe impairment of renal function (serum creatinine greater than or equal to 3.0 mg/dl), the incidence of discontinuation due to adverse experiences or death as well as the profile of reported adverse experiences was similar to those for the total group of high-risk patients. The data suggest that enalapril is efficacious and well tolerated by the high-risk patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Urea Nitrogen; Child; Child, Preschool; Clinical Trials as Topic; Collagen Diseases; Creatinine; Dose-Response Relationship, Drug; Enalapril; Female; Heart Failure; Humans; Hypertension; Hypertension, Renovascular; Kidney Diseases; Male; Middle Aged; Risk Factors

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

The safety profiles of the angiotensin converting enzyme inhibitors, captopril and enalapril, are the focus of this review. Adverse effects are reviewed as those associated with sulfhydryl compounds and as those considered class-specific adverse effects of angiotensin converting enzyme inhibitors. Specifically discussed are the incidences of the adverse effects of rash, taste disturbance, neutropenia, and proteinuria, which are characteristic of compounds containing sulfhydryl moieties, such as captopril. It is concluded from the review of these safety data that enalapril is well tolerated, has few class-specific adverse effects, and may offer a potential advantage over captopril by having fewer sulfhydryl-related adverse effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Clinical Trials as Topic; Dizziness; Dose-Response Relationship, Drug; Enalapril; Half-Life; Headache; Humans; Hypertension; Kidney Diseases; Neutropenia; Oligopeptides; Skin Diseases; Sulfhydryl Compounds; Taste Disorders; Teprotide

18 renovascular hypertensive patients were entered into a randomised, double-blind protocol to assess the safety and efficacy of enalapril (5 to 20 mg twice-daily) and hydrochlorothiazide (50 to 100 mg/day), versus triple-drug therapy employing hydrochlorothiazide (50 to 100 mg/day), timolol (10 to 30 mg twice-daily) and hydralazine (50 to 150 mg twice-daily). Specifically monitored were the effects of each drug regimen on blood pressure, plasma renin activity and angiotensin II, glomerular filtration rate by insulin clearance, and effective renal plasma flow by para-aminohippurate clearance. Results indicate that enalapril/hydrochlorothiazide was more effective than triple-drug therapy in lowering blood pressure. All patients on enalapril/hydrochlorothiazide had excellent control of blood pressure, and there were no adverse effects. In contrast, 50% of the patients on triple-drug therapy had either uncontrolled blood pressure or significant drug-related side effects. Patients who were uncontrolled or intolerant of triple-drug therapy were well controlled on enalapril/hydrochlorothiazide. Patients on enalapril/hydrochlorothiazide demonstrated stimulation of plasma renin activity with inhibition of plasma angiotensin II, indicating adherence with therapy. Therapy for both unilateral and bilateral renovascular hypertension with enalapril/hydrochlorothiazide did not result in reductions in either glomerular filtration rate or effective renal plasma flow, except in 1 patient with a functional solitary stenotic kidney. In contrast, triple-drug therapy was generally associated with modest reductions in glomerular filtration rate and effective renal plasma flow, with a severe reduction in glomerular filtration rate and effective renal plasma flow occurring in 1 patient with bilateral symmetrical renovascular disease. We conclude that the combination of enalapril and hydrochlorothiazide is a safer and more effective regimen, compared with triple-drug therapy, for the treatment of renovascular hypertension.

Topics: Angiotensin II; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension, Renovascular; Kidney Diseases; Male; Middle Aged; Random Allocation; Renal Circulation; Renin; Time Factors

Up to now, the experiments carried out throughout the world with enalapril have been most encouraging. The drug gives good, even excellent responses in 54 to 66 % of patients with essential hypertension, and it is at least as effective as diuretics and beta-blockers. Compared with those of diuretics, the effects of enalapril confirm that the best responders are those patients who are most dependent on the renin-angiotensin system. When a diuretic is administered concomitantly with enalapril, almost all patients respond and the therapeutic effect is well maintained in long term. Blocadren or alpha-methyldopa can be added to hydrochlorothiazide, thus providing additional benefits to patients with severe hypertension. Enalapril reduces the undesirable metabolic effects of hydrochlorothiazide, particularly hypokalaemia. Altogether, enalapril and captopril have similar effectiveness, but enalapril is better tolerated and does not seem to produce the side-effects encountered with captopril, notably skin rashes and ageusia. As expected, enalapril and other angiotensin-converting enzyme inhibitors may be associated with azotaemia in patients with bilateral renovascular hypertension.

Topics: Captopril; Clinical Trials as Topic; Drug Eruptions; Enalapril; Gout; Humans; Hypertension; Kidney Diseases; Leukocyte Count

To date, more than 5000 patients have had experience with enalapril. Over 1000 subjects have been exposed to the drug for more than one year and approximately 600 for over two years. In controlled trials, 2249 subjects, who included normal volunteers and patients with hypertension and congestive heart failure, have received enalapril alone or concomitantly with hydrochlorothiazide or other antihypertensive agents. There have been no deaths attributed to enalapril. The incidence of serious adverse experiences in controlled trials was similar to placebo, and was not higher in the elderly. The incidence of adverse experiences was not dose-related. Drug discontinuation due to adverse experiences was 3.5%, similar to placebo, and approximately half that of control drugs. Serious laboratory adverse experiences were rare. Enalapril attenuated the adverse metabolic effects of hydrochlorothiazide, particularly hypokalaemia. Skin rash occurred in approximately 1.0% of patients. One case of transient taste loss occurred on enalapril, and one on enalapril in combination with hydrochlorothiazide. Neutropenia and agranulocytosis were not encountered. Mean white blood cell counts did not change overall. Most patients (approximately equal to 80%) show no change or an improvement in renal function on enalapril. Discontinuation of concomitant hydrochlorothiazide usually normalized renal function. Enalapril is well tolerated in renal insufficiency. Azotaemia may occur in bilateral renovascular hypertension. Proteinuria was rarely seen and often improved on enalapril. Compassionate use protocols have been available to patients either resistant or intolerant to captopril. Of 68 patients admitted for captopril-related skin rashes, only five recurred on enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Captopril; Clinical Trials as Topic; Creatinine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Global Health; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Kidney Diseases; Leukopenia; Skin Diseases; Taste Disorders

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antiviral Agents; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Enalapril; Female; Kidney Diseases; Male; Mice; Sex Characteristics

To investigate the effect of Huangqi decoction on renal interstitial fibrosis and its association with the transforming growth factor-β1 (TGF-β1) / mitogen-activated protein kinase (MAPK) signaling pathway.. 120 C57/BL mice were randomly divided into six groups: sham group, Enalapril (20 mg/kg) group, 5/6 nephrectomy model group, and 5/6 nephrectomy model plus Huangqicoction (0.12, 0.36 and 1.08 g/kg respectively) groups. Detecting 24hours urinary protein, blood pressure, serum creatinine, urea nitrogen content changes. Periodic Acid-Schiff stain (PAS) and Masson's trichrome staining was used to observe the renal tissue pathological changes. Protein expression of TGF-β1, Phosphorylated P38 mitogen activated protein kinases (P-P38), Phosphorylated c-jun N-terminal kinase (P-JNK), Phosphorylated extracellular regulated proteinhnase (P-ERK), Fibroblast-specific protein-1 (FSP-1), Alpha smooth muscle actin (α-SMA), Type III collagen (Collagen III), Connective tissue growth factor (CTGF), Bcl-2 Assaciated X protein (Bax) and B cell lymphoma 2 (Bcl-2) were measured with western blot and immunohistochemical.. Both Huangqi decoction and Enalapril improved the kidney function, 24 h urinary protein and the fibrosis in 5/6 nephrectomy mice, Huangqi decoction downregulated the expressions of TGF-β1, FSP-1, α-SMA, Collagen III and CTGF in a dose-dependent manner, and it has a significant difference ( 0.01) compared with model group.Huangqi decoction downregulated the expressions of P-P38, P-JNK, P-ERK and Bcl-2 in a dose-dependent manner, while upregulated the expression of Bax.. The protective effect of Huangqi decoction for renal interstitial fibrosis in 5/6 nep-hrectomized mice the inhibition of Epithelial-Mesenchymal Transitions and downregulating the TGF-β1/ MAPK signaling pathway.

Topics: Animals; bcl-2-Associated X Protein; Drugs, Chinese Herbal; Enalapril; Fibrosis; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Nephrectomy; Signal Transduction; Transforming Growth Factor beta1; Ureteral Obstruction

This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Blood Urea Nitrogen; Collagen Type I; Creatinine; Disease Models, Animal; Enalapril; Epithelial Cells; Fas-Associated Death Domain Protein; Fibrosis; Kidney Diseases; Male; Pyridones; Random Allocation; Rats, Sprague-Dawley; Transcription Factor CHOP; Ureteral Obstruction

Renin-angiotensin system (RAS) blockade during nephrogenesis causes a broad range of renal mal-development. Here, we hypothesized that disruption of renal lymphangiogenesis may contribute to tubulointerstitial alterations after RAS blockade during kidney maturation.. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for 7 days after birth. Lymphangiogenesis was assessed via immunostaining and/or immunoblots for vascular endothelial growth factor (VEGF)-C, VEGF receptor (VEGFR)-3, Podoplanin, and Ki-67. The intrarenal expression of fibroblast growth factor (FGF)-1, FGF-2, FGF receptor (R)-1, α-smooth muscle actin (α-SMA), and fibroblast-specific protein (FSP)-1 was also determined. Sirius Red staining was performed to evaluate interstitial collagen deposition.. On postnatal day 8, renal lymphangiogenesis was disrupted by neonatal enalapril treatment. The expression of podoplanin and Ki-67 decreased in enalapril-treated kidneys. While the expression of VEGF-C was decreased, the levels of VEGFR-3 receptor increased following enalapril treatment. Enalapril treatment also reduced the renal expression of FGF-1, FGF-2, and FGFR-1. Enalapril-treated kidneys exhibited profibrogenic properties with increased expression of α-SMA and FSP-1 and enhanced deposition of interstitial collagen.. Enalapril treatment during postnatal renal maturation can disrupt renal lymphangiogenesis along with tubulointerstitial changes, which may result in a pro-fibrotic environment in the developing rat kidney.

Topics: Actins; Angiotensins; Animals; Animals, Newborn; Calcium-Binding Proteins; Collagen; Enalapril; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Fibrosis; Ki-67 Antigen; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Lymphangiogenesis; Muscle, Smooth; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Renin-Angiotensin System; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3

Renal vasoconstriction, oxidative stress, endothelial dysfunction, and apoptosis are the major causes of contrast-induced nephropathy (CIN). The aim of this study was to evaluate the protective effects of enalapril maleate and folic acid tablets on CIN in diabetic rats.. Thirty-two Sprague-Dawley rats were divided into four groups: CIN (C), CIN + enalapril maleate (CE), CIN + folic acid (CF), and CIN + enalapril maleate and folic acid tablets (CEF). CE, CF, and CEF rats were treated orally with enalapril maleate, folic acid, or enalapril maleate and folic acid tablets, respectively, for 5 days. CIN was induced in all groups followed by analyzed biochemical parameters, oxidative stress markers, endothelial dysfunction parameters, renal histopathology, and TUNEL staining.. Serum creatinine, blood urea nitrogen, and malondialdehyde levels were lower in the CEF group than in the C group. Homocysteine, superoxide dismutase, glutathione peroxidase, and nitric oxide levels were higher in the CEF group than in the C group. Histopathology scores and percentage of apoptotic kidney cells in the CEF group were significantly decreased compared with those in the C group.. These results suggest that enalapril maleate and folic acid tablets have a protective effect against CIN in diabetic rats.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Contrast Media; Creatinine; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Combinations; Enalapril; Endothelial Cells; Folic Acid; Humans; Kidney; Kidney Diseases; Nitric Oxide; Oxidative Stress; Rats

Mercuric chloride (HgCl2) induces kidney damage, in part, through oxidative stress. A role for angiotensin II (Ang II) in pro-inflammatory events in a model of acute HgCl2-induced nephropathy was reported. Ang II is a potent oxidative stress inducer; however, its role in oxidative/anti-oxidative events in HgCl2-induced nephropathy remains unknown. The aim of this study was to determine the role of Ang II in the oxidative stress and renal infiltration of CD8(+) T-cells after an acute HgCl2 intoxication. Three groups of Sprague Dawley rats were treated with a single subcutaneous dose of 2.5 mg/kg HgCl2: for 3 days prior to and for 4 days after that injection, rats in one group received Losartan (30 mg/kg), in another group Enalapril (30 mg/kg) or normal saline in the last group. Two other groups of drug-treated rats received saline in place of HgCl2. A final group of rats received saline in place of HgCl2 and the test drugs. All treatments were via gastric gavage. At 96 h after the vehicle/HgCl2 injection, blood and kidney samples were harvested. Renal sections were homogenized for measures of malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity. Frozen sections were studied for the presence of superoxide anion ([Formula: see text]) and CD8(+) T-cells. HgCl2-treated rats had increased interstitial and tubular expression of [Formula: see text], high levels of MDA, normal catalase activity and GSH content, increased levels of interstitial CD8(+) T-cells and an increased percentage of necrotic tubules. Anti-Ang II treatments diminished the HgCl2-induced increases in interstitial [Formula: see text], CD8(+) T-cells and tubular damage and increased catalase and GSH expression above that due to HgCl2 alone; the HgCl2-induced high MDA levels were unaffected by the drugs. These data provide new information regarding the potential role of Ang II in the oxidative stress and renal CD8(+) T-cell infiltration that occur during HgCl2 nephropathy.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Catalase; CD8-Positive T-Lymphocytes; Enalapril; Glutathione; Kidney; Kidney Diseases; Losartan; Male; Malondialdehyde; Mercuric Chloride; Necrosis; Oxidative Stress; Rats; Rats, Sprague-Dawley

Renal interstitial fibrosis (IF) is an important pathologic manifestation of disease progression in a variety of chronic kidney diseases (CKD). However, the quantitative and reproducible analysis of IF remains a challenge, especially in experimental animal models of progressive IF. In this study, we compare traditional polarized Sirius Red morphometry (SRM) to novel Second Harmonic Generation (SHG)-based morphometry of unstained tissues for quantitative analysis of IF in the rat 5 day unilateral ureteral obstruction (UUO) model. To validate the specificity of SHG for detecting fibrillar collagen components in IF, co-localization studies for collagens type I, III, and IV were performed using IHC. In addition, we examined the correlation, dynamic range, sensitivity, and ability of polarized SRM and SHG-based morphometry to detect an anti-fibrotic effect of three different treatment regimens. Comparisons were made across three separate studies in which animals were treated with three mechanistically distinct pharmacologic agents: enalapril (ENA, 15, 30, 60 mg/kg), mycophenolate mofetil (MMF, 2, 20 mg/kg) or the connective tissue growth factor (CTGF) neutralizing antibody, EX75606 (1, 3, 10 mg/kg). Our results demonstrate a strong co-localization of the SHG signal with fibrillar collagens I and III but not non-fibrillar collagen IV. Quantitative IF, calculated as percent cortical area of fibrosis, demonstrated similar response profile for both polarized SRM and SHG-based morphometry. The two methodologies exhibited a strong correlation across all three pharmacology studies (r2 = 0.89-0.96). However, compared with polarized SRM, SHG-based morphometry delivered a greater dynamic range and absolute magnitude of reduction of IF after treatment. In summary, we demonstrate that SHG-based morphometry in unstained kidney tissues is comparable to polarized SRM for quantitation of fibrillar collagens, but with an enhanced sensitivity to detect treatment-induced reductions in IF. Thus, performing SHG-based morphometry on unstained kidney tissue is a reliable alternative to traditional polarized SRM for quantitative analysis of IF.

Topics: Animals; Antibodies, Monoclonal; Azo Compounds; Collagen; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Kidney Diseases; Male; Mycophenolic Acid; Non-Fibrillar Collagens; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Ureteral Obstruction

You-gui Pill (YGP), a traditional Chinese medicinal prescription, was widely used to warm and recuperate "kidney-yang" clinically for hundreds of years in China. Recent studies found that YGP had a potential benefit for renoprotection.. The present study aimed to elucidate the in vivo and in vitro efficacy of YGP on renal tubulointerstitial fibrosis, and the molecular mechanism is also investigated.. Rat renal tubulointerstitial fibrosis model was elicited by unilateral ureteral obstruction (UUO). Sprague-Dawley rats underwent UUO and were studied after 14 days. Animals were randomly subjected to six groups: sham, UUO, UUO/YGP (0.14, 0.42, 1.26g/kg/d), and UUO/enalapril (10mg/kg/d). HE, Masson and ELISA were used for evaluate renal injury and function. Immunohistochemical analysis and western blot were used to detect the expressions of α-SMA, fibronectin, collagen matrix and Smads. In vitro studies were investigated in TGF-β1-stiumlated NRK-49F cell line.. Oral administration of YGP significantly decreased UUO-induced inflammatory cell infiltration, tubular atrophy and interstitial fibrosis, and there was no significant difference between YGP at 1.26g/kg and enalapril at 10mg/kg treatment (P>0.05). Meanwhile, serum creatinine and blood urea nitrogen levels were reduced dramatically (P<0.01). In coincide with the decreased of TGF-β1, α-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF-β1-stimulated NRK-49F cell line. Additionally, nuclear translocation of p-Smad2/3 was markedly down-regulated by YGP (P<0.001), with a relative mild up-regulated expression of Smad7 (P<0.05).. Our findings demonstrate that YGP had a renoprotective effect in ameliorating renal tubulointerstitial fibrosis, and this activity possibly via suppression of the TGF-β and its downstream regulatory signaling pathway, including Smad2/3.

Topics: Actins; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Drugs, Chinese Herbal; Enalapril; Fibrosis; Kidney Diseases; Male; Rats; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Up-Regulation

A high performance liquid chromatographic (HPLC) method was proposed for the simultaneous determination of four drugs for kidney disease, enalapril, triamterene, furosemide and valsartan. After proteins being removed by acetone precipitation method, freeze drying and redissolving in mobile phase, the urine samples were analyzed by HPLC. Chromatographic separation was performed on a WondaSil C18-WR (150 mm x 4.6 mm, 5 μm) in gradient elution mode using 10.0 mmol/L ammonium acetate aqueous solution (pH 3.90) and acetonitrile as mobile phases at a flow rate of 1.0 mL/min. The detection wavelength was set at 254 nm. Under the optimized conditions, good linearities were obtained in the range of 0.15-300 mg/L, 0.05-100 mg/L, 0.75-750 mg/L, 0.05-100 mg/L, and the detection limits were 1.38 x 10(-2), 7. 67x103, 3.69x 10-2, 1. 16x 10-2 mg/L for enalapril, triamterene, furosemide and valsartan, respectively. The recoveries were in the range of 89.49%-99.20% with the relative standard deviations (RSDs) among 4.12%-9.44%. The method is simple, accurate and effective, and the results showed the method is applicable for the analysis of the four drugs for kidney diseases in real urine samples.

Topics: Chromatography, High Pressure Liquid; Enalapril; Furosemide; Humans; Kidney Diseases; Triamterene; Valsartan

Angiotensin-converting enzyme inhibitors (ACEi) are commonly used for pediatric cardiology patients. However, studies examining their safety for neonates with cardiac disease are scarce. The current study aimed to test the hypothesis that ACEi-mediated nephrotoxicity occurs in neonates and may be underappreciated in this population. A retrospective review of 243 neonates with cardiac disease between 2007 and 2010 was performed. Demographic data, weight, length, captopril and enalapril dosing, serum [K⁺], serum creatinine, and concomitant medications during ACEi therapy were recorded and analyzed. Body surface area (BSA), creatinine clearance (CrCl), and change in [K⁺] were calculated. The age range of neonates at ACEi initiation was 15.9-18.1 days. The inclusion criteria was met by 206 neonates: 168 term (82%) and 38 preterm (18%) newborns. Of these neonates, 42% were female, and all the patients had a BSA smaller than 0.33 m² (a group known to have relative renal insufficiency). The mean dose of enalapril was 0.08 ± 0.007 mg/kg for the preterm neonates and 0.08 ± 0.003 mg/kg for the term neonates. The mean dose of captopril was 0.07 ± 0.009 mg/kg for the preterm neonates and 0.13 ± 0.019 mg/kg for the term neonates. A significant decrease in CrCl occurred for both the preterm (p < 0.01) and term (p < 0.001) neonates while they were receiving ACEi. However, the two groups did not differ significantly (p = 0.183). Nearly 42% of all the patients showed renal risk, with approximately 30% demonstrating renal failure by modified pRIFLE (pediatric risk, injury, failure, loss, and end-stage renal disease) criteria. Despite the lack of significantly different CrCl, the premature neonates were more likely to experience ACEi-related renal failure by pRIFLE (55%) than their term counterparts (23%; p < 0.001). Despite its common use for term neonates with cardiac disease, ACEi should be used cautiously and only when indications are clear. These results also raise the question whether ACEi should be used at all for preterm neonates.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Creatinine; Enalapril; Female; Heart Defects, Congenital; Humans; Infant, Newborn; Infant, Premature; Kidney Diseases; Male; Retrospective Studies

We tested five different angiotensin converting enzyme inhibitors (ACEI) as mitigators of experimental radiation nephropathy at drug doses calibrated to the plasma renin activity (PRA). This was done to determine whether all ACEI had the same efficacy as mitigators of radiation nephropathy when used at drug doses that gave equivalent suppression of the renin angiotensin system.. 10 Gy total body irradiation with bone marrow transplantation was used to cause radiation nephropathy in barrier-maintained rats. Equivalent ACEI doses were determined based on their effect to inhibit angiotensin converting enzyme (ACE) and raise the PRA in unirradiated animals.. PRA-equivalent doses were found for captopril, lisinopril, enalapril, ramipril and fosinopril. These doses overlap the human doses of these drugs on a body surface area basis. All ACE inhibitors, except fosinopril, mitigated radiation nephropathy; captopril was a somewhat better mitigator than lisinopril, enalapril or ramipril.. Most, but not all, ACEI mitigate radiation nephropathy at doses that overlap their clinically-used doses (on a body surface area basis). Fosinopril is known to be an ineffective mitigator of radiation pneumonitis, and it also does not mitigate radiation nephropathy. These pre-clinical data are critical in planning human studies of the mitigation of normal tissue radiation injury.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Bone Marrow Transplantation; Calibration; Captopril; Enalapril; Fosinopril; Kidney; Kidney Diseases; Lisinopril; Male; Radiation Injuries; Ramipril; Rats; Renin; Renin-Angiotensin System; Whole-Body Irradiation

Abstract Hyperglycemia, hypertension, dyslipidemia, and inflammation have been proposed to account for the development of nephropathy in diabetic subjects. The beneficial effects of enalapril on diabetic nephropathy are known. However, the effects of trimetazidine (TMZ) are still unknown. We aimed at comparing the effects of the enalapril and TMZ treatment on fibronectin expression, inducible nitric oxide synthase expression, urine proteinuria, blood glucose and glomerular, and mesangial structures of kidney in rats that take streptozotocin (STZ). In this study, 32 male Sprague-Dawley albino mature rats of 8 weeks, weighing 200-220 g were used. Diabetes was induced by intraperitoneal injection of STZ (60 mg/kg) for 24 rats. We made four groups (Group 1: control, non-diabetic rats (n = 8), Group 2: diabetes, without treatment (n = 8), Group 3: diabetes treatment with enalapril (n = 8), Group 4: diabetes treatment with TMZ (n = 8). The positive effects of renal tissue and tubules in the mesangium immunohistochemical were shown in TMZ receiving rat groups. These positive effects were in parallel with the reduction in fibronectin and I-NOS expression and reduction in the proteinuria. TMZ and enalapril treatment of diabetic rats and renal parenchyma in this study are shown to have positive effects on the different levels.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Trimetazidine

Viscum articulatum Burm. is used traditionally in Chinese medicine for treating hypertension.. The present study was designed to evaluate the antihypertensive activity of the methanolic extract of Viscum articulatum (MVA) against N(ω)-nitro-L-arginine methyl ester (L-NAME) induced hypertension in rats.. Six groups of rats were investigated for 4 weeks as normal control, L-NAME (40 mg/kg/day), L-NAME+enalapril (15 mg/kg/day), L-NAME+L-arginine (100 mg/kg/day), L-NAME+MVA (200 mg/kg/day) and L-NAME+MVA (400 mg/kg/day) for four weeks. The systolic blood pressure (SBP) and heart rate (HR) were measured weekly throughout the experimental period. The urine electrolytes concentration, cardiac mass index, serum nitrate/nitrite (NO(x)) level, serum creatinine level and lipid profile were determined.. Treatment with MVA (200 and 400 mg/kg) or enalapril delayed the rise in SBP produced by administration of L-NAME. None of the treatments had a significant effect on the depression of the serum NO(x) level caused by L-NAME. The serum creatinine and total cholesterol concentrations were elevated upon administration of L-NAME, and this elevation was prevented by MVA co-administration. The urine volume and urine potassium ion level were depressed by L-NAME administration and this effect being inhibited in MVA and enalapril groups. There was no cardiac hypertrophy and HR change after 28 day of L-NAME administration.. We conclude that MVA may have an antihypertensive effect in the NO deficient type of hypertension, which may be attributed to its diuretic, nephroprotective and hypolipidemic actions.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cholesterol; Creatinine; Drugs, Chinese Herbal; Enalapril; Hypertension; Kidney Diseases; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phytotherapy; Potassium; Rats; Rats, Wistar; Renal Agents; Urination; Viscum

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

Although accelerated atherosclerosis and arteriosclerosis are the main causes of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients, the molecular pathogenesis remains largely obscure. Our study of the aortic function in a typical CKD model of subtotal nephrectomy (SNX) rats demonstrated phenotypes that resemble CKD patients with aortic stiffness. The 2-DE analysis of rat aortas followed by MS identified 29 up-regulated and 53 down-regulated proteins in SNX rats. Further Western blot and immunohistochemistry analyses validated the decreased HSP27 and increased milk fat globule epidermal growth factor-8 (MFG-E8) in SNX rats. Functional classification of differential protein profiles using KOGnitor revealed that the two major categories involved in aortic stiffness are posttranslational modification, protein turnover, chaperones (23%) and cytoskeleton (21%). Ingenuity Pathway Analysis highlighted cellular assembly and organization, and cardiovascular system development and function as the two most relevant pathways. Among the identified proteins, the clinical significance of the secreted protein MFG-E8 was confirmed in 50 CKD patients, showing that increased serum MFG-E8 level is positively related to aortic stiffness and renal function impairment. Drug interventions with an inhibitor of the angiotensin converting enzyme, enalapril, in SNX rats improved aortic stiffness and decreased MFG-E8 depositions. Together, our studies provide a repertoire of potential biomarkers related to the aortic stiffness in CKD.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens, Surface; Aorta; Disease Models, Animal; Enalapril; HSP27 Heat-Shock Proteins; Humans; Kidney Diseases; Male; Milk Proteins; Nephrectomy; Proteomics; Rats; Rats, Sprague-Dawley

Lipoprotein glomerulopathy (LPG) is a rare hereditary disease characterized by the accumulation of much thrombi material consisting of lipoproteins at the glomerular capillary lumen. Most patients show nephrotic syndrome; nearly half progress to chronic renal failure. Intensive therapy with lipid-lowering agents reportedly engenders clinical remission with histological resolution. We report the case of a 14-year-old Japanese female patient who had been in a nephrotic condition with hematuria from 4 years old and who had been diagnosed based on pathological and molecular examination at 7 years old. We initially treated the patient with probucol, enalapril (angiotensin-converting enzyme inhibitor: ACEI), and dipyridamole from age 7, but achieved no improvement in her nephrotic status. Subsequently, we replaced probucol with bezafibrate at age 11 and added atorvastatin calcium hydrate and valsartan (angiotensin II receptor blocker: ARB) the following year. The next 3 years' treatment improved her nephrotic status, decreased serum apolipoprotein E, and markedly decreased intraglomerular lipoprotein thrombi. Early and intensive therapy with antilipidemic drugs combined with ACEI and ARB is inferred to be effective for LPG.

Topics: Adolescent; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Apolipoproteins E; Bezafibrate; Child; Child, Preschool; Enalapril; Female; Hematuria; Humans; Hypolipidemic Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Glomerulus; Nephrotic Syndrome; Probucol; Tetrazoles; Valine; Valsartan

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

Controlling hypertension by angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), mechanisms that inhibit later pathway steps in the renin-angiotensin system (RAS), have clinically afforded protection against cardiac and renal disease.. In order to determine if blocking the RAS rate-limiting step of angiotensin II generation via renin inhibition could afford similar end organ protection in a human-relevant preclinical model, this study investigated the cardiac and renal effects of a nonpeptide, piperidine renin inhibitor (RI; 100 mg/kg/day PO) in double transgenic mice (dTGM) which express both human renin and angiotensinogen genes. RI was compared to the ARB, candesartan (3 mg/kg/day PO), and to the ACEI, enalapril (60 mg/kg/day PO) in a 4-week dosing paradigm. These doses of RI, ACEI and ARB were previously found to normalize mean blood pressure (MBP) to 110 + 3, 109 + 7 and 107 + 6 mmHg, respectively, after 1 day of treatment.. In the dTGM, PRA, plasma aldosterone, GFR, microalbuminuria and left ventricular free wall thickness (LVH) were higher than in the wild type C57BL/6 mice. Microalbuminuria and LVH were significantly reduced by 93% and 9% for the RI, 83% and 13% for enalapril and 73% and 6% for candesartan, respectively. PRA and aldosterone were reduced by the RI 56% and 23%, respectively. These results suggest that the RI provides protection against cardiac and renal disease, similar to ARB and ACEI.

Topics: Administration, Oral; Albuminuria; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiotonic Agents; Drug Administration Schedule; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Structure; Piperidines; Quinolines; Renin; Renin-Angiotensin System; Tetrazoles; Time Factors; Ultrasonography

Congenital urinary tract obstruction is the most important cause of renal insufficiency in infants and children, and angiotensin-converting enzyme (ACE) inhibitors attenuate the progression of renal disease in adults. ACE inhibitors are increasingly utilized in children with progressive renal disease. Because angiotensin is necessary for normal renal development, we examined the effects of ACE inhibition both during and immediately following the period of postnatal nephrogenesis in the neonatal rat subjected to sham operation or partial unilateral ureteral obstruction (UUO) under general anesthesia within the first 48 h of life. Rats in group I received enalapril 30 mg/kg body wt (or vehicle) daily for the first 10 days, while in group II, the 10 days of treatment began 10 days after surgery. Kidneys were harvested at day 21 and analyzed for apoptosis (TUNEL), interstitial macrophages (ED-1 immunohistochemistry), myofibroblasts (alpha-smooth muscle actin), and collagen (Sirius red). Partial UUO delayed glomerular maturation and increased ipsilateral renal macrophage infiltration, alpha-smooth muscle actin and Sirius red staining. In group I, enalapril increased myofibroblast accumulation in sham-operated kidneys, but not in obstructed kidneys. In contrast, in group II, enalapril further increased macrophage, myofibroblast, and collagen accumulation following partial UUO. The relative abundance of components of the kallikrein-kinin system, measured by Western blot, was not altered by partial UUO in the 14- and 28-day-old rat. Thus, in contrast to its salutary effects at later ages, ACE inhibition can worsen injury to the partially obstructed kidney during renal maturation even after the completion of nephrogenesis.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Apoptosis; Body Weight; Cell Movement; Collagen; Contraindications; Enalapril; Kidney; Kidney Cortex; Kidney Diseases; Kidney Glomerulus; Kidney Medulla; Kidney Pelvis; Kidney Tubules; Kininogens; Macrophages; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Tissue Kallikreins; Ureteral Obstruction

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

Five-sixths-nephrectomized rats present renal functional and histological abnormalities which are attenuated by enalapril treatment. c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase, and nuclear factor-kappaB (NF-kappaB) pathways can be activated by angiotensin II which has been implicated in renal injury. The aim of this study was to investigate the effect of enalapril on the expression of NF-kappaB and JNK in renal cortices of five-sixths-nephrectomized rats.. Of the 65 rats studied, 25 underwent five-sixths nephrectomy and received no treatment, 15 underwent five-sixths nephrectomy and received enalapril, 15 were sham operated and received no treatment, and 10 were sham operated and received enalapril. On postoperative days 15 and 90, systolic blood pressure, glomerular filtration rate, and albumin excretion were determined. The rats were then killed and the kidneys removed for histology and immunohistochemistry.. In five-sixths-nephrectomized rats, we observed functional and structural renal alterations, as well as greater NF-kappaB/JNK expression and higher macrophage counts. Enalapril treatment reduced all of these changes.. The protective effect of enalapril on the kidney of five-sixths-nephrectomized rats might be related to the inhibition of NF-kappaB and JNK activation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression; JNK Mitogen-Activated Protein Kinases; Kidney; Kidney Diseases; Nephrectomy; NF-kappa B; Rats; Rats, Wistar; Tissue Distribution

The relative roles of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on cardiac and renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats were studied.. The ACE/NEP inhibitor omapatrilat (40 mg/kg per day), the ACE inhibitor enalapril (10 mg/kg per day) and the NEP inhibitor CGS 25462(100 mg/kg per day) were administrated for 3 weeks to DOCA rats. Collagen was stained with Sirius red, and mediators of inflammation were identified by immunolabeling (vascular cell adhesion molecule, nuclear factor-kappaB, infiltrating ED-1-positive macrophages and monocyte chemotactic protein-1) or by western blot (platelet-endothelial cell adhesion molecule-1).. Elevated systolic blood pressure of DOCA rats was significantly reduced (P < 0.05) by omapatrilat and CGS 25462. Omapatrilat and CGS 25462 significantly (P < 0.05) decreased interstitial collagen density in the left ventricle of DOCA rats compared with untreated DOCA rats. Enalapril only decreased the subepicardial collagen of DOCA rats. Omapatrilat significantly (P < 0.05) decreased renal mesangial collagen deposition in DOCA rats. Cardiac and renal expression of surface adhesion molecules, nuclear factor-kappaB, monocyte chemotactic protein and ED-1-positive cells were decreased in omapatrilat-treated DOCA rats compared with untreated DOCA rats. Enalapril and CGS 25462 did not alter mesangial collagen of DOCA rats.. Dual ACE/NEP inhibition was more effective than ACE or NEP inhibition in decreasing inflammatory mediators, and improving cardiac and renal fibrosis. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Cell Adhesion Molecules; Collagen; Desoxycorticosterone; Drug Therapy, Combination; Enalapril; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Metalloendopeptidases; Neprilysin; NF-kappa B; Organophosphonates; Pyridines; Rats; Rats, Sprague-Dawley; Thiazepines

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

The renal and glomerular dynamic effects of combining thiazide and angiotensin antagonists have not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme inhibitor or ANG II type 1-receptor blocker on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the N(omega)-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (l-NAME/SHR) model. HCTZ (80 mg x kg(-1) x day(-1)) alone or in combination with enalapril (30 mg x kg(-1) x day(-1)) or losartan (30 mg x kg(-1) x day(-1)) or enalapril (15 mg.kg(-1).day(-1)) plus losartan (15 mg x kg(-1) x day(-1)) was administered to l-NAME/SHR (5.0 +/- 0.10 mg x kg(-1) x day(-1)) for 3 wk. Mean arterial pressure, total peripheral resistance, renal plasma flow, glomerular filtration rate, glomerular hydrostatic pressure, afferent and efferent glomerular arteriolar resistances, single nephron plasma flow, single nephron glomerular filtration rate, serum creatinine concentration, 24-h urinary protein excretion, and glomerular and arteriolar injury scores were determined. HCTZ reduced mean arterial pressure, total peripheral resistance, glomerular hydrostatic pressure, and afferent and efferent glomerular arteriolar resistances (P < 0.05, at least) but slightly increased renal plasma flow and single nephron plasma flow associated with reduced serum creatinine concentration, urinary protein excretion, and arteriolar injury score compared with l-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in l-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Diuretics; Enalapril; Enzyme Inhibitors; Hematocrit; Hemodynamics; Hydrochlorothiazide; Kidney; Kidney Diseases; Kidney Glomerulus; Losartan; Male; NG-Nitroarginine Methyl Ester; Organ Size; Rats; Rats, Inbred SHR; Renal Circulation; Vascular Resistance

The clinical course of a 10-year-old female patient who presented with hematuria, proteinuria, and hypertension is described. Four months after being diagnosed with acute glomerulonephritis, the child was referred to a pediatric nephrologist due to persistent hematuria and unresolved proteinuria. A renal biopsy was performed due to the persistent urinary abnormalities and a family history of renal failure. The renal biopsy demonstrated pathological findings characteristic of membranoproliferative glomerulonephritis type II. The child was treated with an antihypertensive agent and steroids. Despite poor prognostic clinical and pathological features, she has minimal urinary abnormalities, normal renal function, and normal blood pressure on antihypertensive medication six years after the diagnosis of membranoproliferative glomerulonephritis type II.

Topics: Child; Clinical Chemistry Tests; Diagnosis, Differential; Drug Therapy, Combination; Enalapril; Female; Fluorescent Antibody Technique, Direct; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Hematologic Tests; Humans; Hypertension; Kidney Diseases; Kidney Glomerulus; Methylprednisolone; Prednisone; Treatment Outcome

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

Hyperthyroidism and chronic renal disease occur commonly in geriatric cats, often in association with potentially life-threatening primary or secondary hypertension. Early treatment of hypertension minimizes damage to vital organs. This case illustrates the complexity of managing hypertension in a geriatric cat with both hyperthyroidism and renal disease.

Topics: Animals; Antihypertensive Agents; Antithyroid Agents; Cat Diseases; Cats; Diagnosis, Differential; Enalapril; Female; Hypertension; Hyperthyroidism; Kidney Diseases; Methimazole; Treatment Outcome

Locally generated angiotensin II (AngII) may be involved in the pathogenic mechanisms of chronic renal diseases. Renal expression of AngII and other components of the renin-angiotensin system (RAS) were analyzed by immunohistochemistry and Western blot in a model of chronic progressive nephropathy induced by inhibition of nitric oxide synthesis. Renal injury was evaluated by histology and albumin excretion. Systemic RAS status was evaluated through plasma renin activity (PRA) and plasma AngII concentration. In addition, the effects of enalapril, losartan, and mycophenolate mofetil (MMF) on AngII expression in animals with chronic renal disease was also analyzed. Plasma renin activity and plasma AngII were not different between rats with nephropathy and controls (2.08 +/- 0.7 versus 2.03 +/- 0.5 ng/ml/h and 94.3 +/- 18 versus 78.9 +/- 16 fmol/ml, respectively). However, rats with chronic progressive nephropathy showed augmented renal content of angiotensinogen protein (13.5 +/- 3.5 versus 2.2 +/- 0.4 pixels in control rats; P < 0.05), enhanced expression of cathepsin D-a renin-like enzyme-in cortical collecting tubules (103.5 +/- 27.0 versus 66.2 +/- 3.6 cells/mm2 in controls; P < 0.01), and increased expression of AT1 receptor in interstitium (54.7 +/- 7.8 versus 1.3 +/- 0.4 cells/mm2 in controls; P < 0.001). Kidney angiotensin-converting enzyme content did not differ among the groups. Notably, an increased number of interstitial cells expressing AngII was detected in the renal interstitium (9.5 +/- 1.6 versus 1.7 +/- 0.6 cells/mm2 in controls; P < 0.05). Rats treated with Nomega-nitro-L-arginine-methyl-esther and losartan presented a decreased local AngII formation, in contrast to its known effect on plasma AngII. Moreover, mycophenolate mofetil lowered interstitial AngII expression, suggesting that inflammatory signaling may be involved in interstitial AngII generation. This study demonstrates the upregulation of local RAS in the kidney in a model of chronic progressive nephropathy.

Topics: Albumins; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Cathepsin D; Enalapril; Enzyme Inhibitors; Glomerulonephritis; Immunohistochemistry; Kidney; Kidney Diseases; Losartan; Male; Mycophenolic Acid; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Time Factors; Up-Regulation

Experimental aristolochic acid nephropathy (AAN), characterized by interstitial fibrosis, tubular atrophy, and chronic renal failure, was reported after 35-day injections of aristolochic acids (AA) to salt-depleted male Wistar rats. The link between renal fibrosis and the renin-angiotensin system (RAS) in this model remains unknown.. We investigated the impact of sodium diets (low and normal), of RAS inhibition with enalapril (ENA) alone, or combined with candesartan (CSN) for 35 days, and ENA + CSN for 65 days on AAN development. At the end of each observation period, blood pressure and renal angiotensin-converting enzyme activity were measured, as well as renal functional impairment (plasma creatinine increase, proteinuria) and histologic lesions (interstitial fibrosis, monocytes/macrophages infiltration, myofibroblasts collagens type I and IV, proliferating cells).. Sodium intake did not modify renal functional and morphologic impairment induced by AA. The RAS blockade by ENA or ENA + CSN in rats receiving AA did not result in any statistical difference in terms of renal failure, proteinuria, and interstitial fibrosis on day 35 or 65. On day 35, the monocytes/macrophages infiltration was significantly decreased by two-fold when ENA (P < 0.01) or ENA + CSN (P < 0.01) was given from day 0.. Our data demonstrate that RAS modulation by salt depletion and pharmacologic blockade do not influence renal failure and interstitial fibrosis in the rat model of AAN. We suggest that pathways of interstitial renal fibrosis may be independent of RAS at least in some conditions.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aristolochic Acids; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diet, Sodium-Restricted; Drug Synergism; Enalapril; Fibrosis; Kidney; Kidney Diseases; Male; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin-Angiotensin System; Tetrazoles

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

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

Although fitting orders to renal function avoids overdosage and therefore iatrogenic risk, dosage adjustment is rarely made. The objective of this study was to assess residents' prescribing behavior in renal impairment, through a standardized simulated clinical setting.. This criterion-referenced study was carried out in a French teaching hospital. The hospital had 118 residents; 71 of them were asked to complete a questionnaire including four vignettes, simulating drug prescription in four 'patients' with various degrees of renal impairment (16 orders). The patients had an order of gentamicin sulfate, diclofenac sodium, and amlodipine bensylate. For each drug, the resident could maintain the order, discontinue the order, or change the dosage. A fourth drug, enalapril maleate, was to be started, with three possible dosages and the possibility of not prescribing it. The reference chosen for assessment was the Vidal dictionary, which corresponds to the Physician's Desk Reference and is the French reference for prescription.. All the residents approached for the survey accepted the offer to complete the questionnaire. Among the 16 simulated orders, the median number of appropriate orders per resident was nine. Considering the renal function of their patients, 62% of residents wrote an inappropriate order for gentamicin, 42% wrote an inappropriate order for didofenac, and 52% wrote an inappropriate order for enalapril. Although no adjustment to renal function was required, 28% of the residents decreased the dosage of amlodipine and ordered an underdose.. Considering the iatrogenic risk related to the lack of dosage adjustment, attention should be drawn to increasing residents' awareness of dosage adjustment in renal impairment and to providing them with better information on patients' renal function.

Topics: Aged; Aged, 80 and over; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Cyclooxygenase Inhibitors; Diclofenac; Drug Prescriptions; Drug Utilization; Enalapril; Female; France; Gentamicins; Humans; Internship and Residency; Kidney Diseases; Male; Practice Patterns, Physicians'; Surveys and Questionnaires

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Disease Progression; Enalapril; Female; Follow-Up Studies; Humans; Kidney Diseases; Kidney Transplantation; Living Donors; Male; Postoperative Complications; Time Factors; Treatment Outcome

Vascular endothelial growth factor (VEGF) is involved in angiogenesis, wound healing and inflammation. VEGF exerts its effect via the tyrosine kinase receptors Flt-1 and KDR/Flk-1. We have previously shown that VEGF is up-regulated in a chronic cyclosporine (CsA) nephrotoxicity model. Our current study examined the role of angiotensin II (Ang II) blockade with enalapril (E) or losartan (L) on VEGF in this model.. Pair-fed salt-depleted rats were administered vehicle, CsA, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide (HCTZ), CsA + E or CsA + L, and were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to the mRNA expression of VEGF and its receptors Flt-1 and KDR/Flk-1 by Northern blot, and the protein expression of VEGF by Western blot.. While all groups achieved similar blood pressures and creatinine clearances, the amelioration in nephrotoxicity was observed only with Ang II blockade. VEGF mRNA and protein expressions increased with CsA and became significantly reduced with Ang II blockade. Flt-1 expression was similar in all groups; it decreased early and remained low. On the other hand, KDR/Flk-1 mRNA expression was higher at seven days in all groups, except in the +E and +L groups where it was significantly lower, and then became further down-regulated at 28 days.. The increased VEGF expression in chronic CsA nephrotoxicity seems to be related to up-regulation of Ang II. In addition, VEGF probably exerted its effect via the KDR/Flk-1 receptor. The actions of VEGF in this model remain speculative, but may be related to its effect on macrophage infiltration or matrix deposition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cyclosporine; Disease Models, Animal; Enalapril; Endothelial Growth Factors; Extracellular Matrix Proteins; Gene Expression; Immunosuppressive Agents; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Losartan; Lymphokines; Male; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Kidney Diseases; Scleroderma, Systemic

Spontaneously hypercholesterolemic (SHC) rats exhibit hypercholesterolemia, proteinuria and focal glomerulosclerosis with age, and they finally die as a result of renal failure. In this study, the renoprotective effects of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, and enalapril, an angiotensin I converting enzyme inhibitor, were examined in SHC rats. Candesartan cilexetil (0.1 and 1 mg /kg) and enalapril (10 mg/kg) were administered orally to 10-week-old SHC rats for a 6-week period. Candesartan cilexetil (1 mg/kg) and enalapril (10 mg/kg) significantly inhibited proteinuria and hypercholesterolemia to a similar extent. In untreated 16-week-old SHC rats, glomerulosclerosis, basophilic change, cast formation and interstitial mononuclear cell infiltration were observed. Candesartan cilexetil (1 mg/kg) inhibited all of these histological changes. Enalapril inhibited glomerulosclerosis and cast formation. These results show that candesartan cilexetil and enalapril have renal protective effects in SHC rats. Thus, angiotensin II might play an important role in renal pathogenesis in a model of focal glomerulosclerosis with hypercholesterolemia.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Body Weight; Cholesterol; Enalapril; Glomerulosclerosis, Focal Segmental; Hypercholesterolemia; Indicators and Reagents; Kidney Diseases; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apolipoproteins E; Arteriosclerosis; Enalapril; Hyperlipidemias; Hypertension; Kidney Diseases; Mice; Mice, Mutant Strains; Nitric Oxide Synthase

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

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Bone Marrow Transplantation; Captopril; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Fibrosis; Imidazoles; Kidney Diseases; Male; Radiotherapy; Rats; Tetrazoles; Time Factors

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Captopril; Child; Child, Preschool; Cough; Enalapril; Female; Humans; Infant; Kidney Diseases; Male; Perindopril; Time Factors

Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction between these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of endothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) have higher blood pressure (BP) and increased atherosclerotic lesion size but no change in plasma lipoprotein profiles compared with normotensive but atherosclerotic (NNee) mice. The nnee mice also develop kidney damage, evidenced by increased plasma creatinine, decreased kidney weight/body weight ratio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice. In striking contrast, a genetic lack of inducible NOS, which does not affect BP, has no effect on the development of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positive relationship between BP and size of atherosclerotic lesions These results suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlling hypertension in preventing atherosclerosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apolipoproteins E; Arteriosclerosis; Blood Pressure; Enalapril; Hypertension; Kidney Diseases; Mice; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organ Size

Most experimental studies on kidney proliferation and its attenuation by angiotensin-converting enzyme inhibitors were performed in the rat hypertensive remnant-kidney model with a five-sixths kidney ablation. The developing hypertension rose the objections on the hypertension and its treatment in control rats. A normotensive four-sixths remnant-kidney model (Nx) was elaborated, compared with sham-operated (S) animals, and a subantihypertensive dosage of enalapril (E) was administered for 4 weeks of intensive kidney tissue proliferation (NxE). The pair-fed groups increased their body weight and blood pressure comparably. Moderately increased plasma creatinine and urea concentrations were found in the Nx group; markedly increased levels in the NxE group. Nx increased proteinuria, and E attenuated its increase. The remnant-kidney weight (Nx 912+/-31 vs. S 1,111+/-36 mg, p<0.001) was still lower, but collagen (Col; Nx 164+/-2 vs. S 148+/-5 mg/100 g, p<0.05) and tubular protein/DNA ratio (Nx 26.2+/-10.8 vs. S 9.8+/-1. 0, p<0.05) increased markedly in the Nx group; E attenuated the kidney growth (NxE 719+/-31 vs. Nx 912+/-31 mg, p<0.01) and decreased the tubular protein/DNA ratio remarkably (NxE 15.3+/-10.5 vs. Nx 26.2 +/-10.8), but E did not inhibit the Col accumulation. Nx decreased the heart (Nx 1,002+/-28 vs. S 1,130+/-41 mg, p<0.05), but not liver weights and did not influence Col concentrations or protein/DNA ratios either in heart or liver. E potentiated the weight decrease of heart (NxE 862+/-20 vs. Nx 1,002+/-28 mg, p<0.01) and liver (NxE 8.3+/-0.44 vs. Nx 10.3+/-0.51 g, p<0.001) and Col accumulation (heart: NxE 113+/-6 vs. Nx 92+/-5 mg/100 g, p<0.01; liver: NxE 134+/-8 vs. Nx 101+/-9 mg/100 g, p<0.01). Nx did not influence either the soleus muscle weight or its Col accumulation, but it increased its protein/DNA ratio (Nx 66.3+/-4.7 vs. S 35.5+/-2. 8 mg/100 g, p<0.01). E increased the Col concentration in muscle (NxE 141+/-3 vs. Nx 110+/-5 mg/100 g, p<0.01), while it attenuated the increase in protein/DNA ratio (NxE 36.6+/-2.1 vs. Nx 66.3+/-4.7, p<0.01). In conclusion, kidney ablation nephropathy stimulating kidney proliferation evokes only minor changes in heart, liver and striated muscle. E inhibits markedly the kidney proliferation and functional recovery, but does not prevent the Col accumulation. E evokes antiproliferative changes also in the heart and surprisingly even in the liver. Alterations in soleus muscle are only borderline.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; DNA; Enalapril; Heart; Kidney; Kidney Diseases; Kidney Function Tests; Liver; Male; Muscle, Skeletal; Myocardium; Nephrectomy; Protein Biosynthesis; Rats; Rats, Wistar

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

1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Bradykinin Receptor Antagonists; Cyclosporine; Dose-Response Relationship, Drug; Drinking; Eating; Electrolytes; Enalapril; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Kallikreins; Kidney; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Renin; Sodium, Dietary; Tetrazoles; Urination; Valine; Valsartan

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Kidney; Kidney Diseases; Losartan; Nephrectomy; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

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

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

Topics: Adult; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Enalapril; Female; Glomerular Mesangium; Hemodynamics; Humans; Hypertension, Renal; Infant; Kidney; Kidney Diseases; Organ Size

Rats injected with a single, 50-mg dose of bromoethylamine (BEA) developed papillary necrosis accompanied by sever interstitial fibrosis. At 1 mo, the creatinine clearance decreased (control 0.66 versus BEA 0.33 ml/min per 100 g body wt, P = 0.02), and the urine albumin-to-creatinine ratio increased markedly (control 0.19 versus BEA 0.51, P = 0.02). In a group of animals given the angiotensin-converting enzyme inhibitor enalapril (Enal; 100 mg/L) in their drinking water for 4 wk, beginning 1 wk before BEA injection, creatinine clearance improved significantly (BEA 0.33 versus Enal + BEA 0.52 ml/min per 100 g body wt, P = 0.01) and albumin excretion fell to zero. Histologic examination revealed an 88% decrease in the area of papillary necrosis and a decrease in the degree of interstitial fibrosis in the corticomedullary junction. To determine whether this was due to changes in urine flow rate induced by enalapril, a group of animals was injected with BEA, and enalapril at the above dose was begun 1 wk later. After 1 mo, the enalapril-treated animals showed the same improvement in creatinine clearance (BEA 0.33 versus BEA + Enal 0.50 ml/min per 100 g body wt, P = 0.03) and suppression of albumin excretion. The area of papillary necrosis was reduced by 67%. In the BEA animals treated with enalapril, ED-1-positive cells, alpha-smooth muscle actin, and transforming growth factor-beta1 were decreased compared with BEA alone. It is concluded that in this model of papillary necrosis, enalapril protects renal function and decreases interstitial fibrosis mediated at least in part through an angiotensin II/bradykinin-dependent mechanism.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Creatinine; Enalapril; Ethylamines; Fibrosis; Glomerular Filtration Rate; Kidney; Kidney Diseases; Kidney Papillary Necrosis; Male; Rats; Rats, Sprague-Dawley

Topics: Adolescent; Enalapril; Female; Humans; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Lipoproteins; Nephrotic Syndrome; Postoperative Complications

Topics: Angiotensin-Converting Enzyme Inhibitors; Aorta, Abdominal; Constriction; Enalapril; Humans; Kidney Diseases

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

Insulin resistance (IR) and secondary hyperinsulinaemia are major risk factors of atherosclerosis and probably also of related glomerulosclerosis. Angiotensin converting enzyme inhibitors (ACEI), while improving IR in essential hypertension, do not improve it in patients with chronic renal disease. Thus, the combination of ACEI and low protein diet was evaluated. Thirty-eight patients with various kidney diseases and mild to moderate impairment of kidney function were included in the study. Thirteen of them suffered from IR. Their dietary protein intake was decreased from > or = 1.0 g/kg/d to 0.6-0.7 g/kg/d. Moreover, they were treated by ACEI enalapril at dosages of 2-10 mg/d depending on the absence/presence and severity of hypertension. The patients were followed for 8 months. No clinically relevant kidney disease progression (KDP) was found. IR patients improved remarkably. IR was examined by the oral glucose tolerance test and glucose, insulin and C-peptide determinations. Their increased plasma triglyceride, VLDL concentrations and proteinuria decreased, HDL concentration increased. Acid-base balance and anaemia did not change. It is concluded that protein restriction in combination with ACEI treatment improve IR and the associated dyslipoproteinaemia and proteinuria.

Topics: Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Female; Humans; Insulin Resistance; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged

This study defines the nature of the renal protective effects of calcium channel blockers (Ca blockers) and the effects of the Ca blocker, amlodipine, compared to those of the angiotensin-converting enzyme inhibitor (ACEI), enalapril, on the progression of renal injury in 5/6 nephrectomized spontaneously hypertensive rats (SHR) fed a high-salt diet. Furthermore, we studied the effects of various Ca blockers on the glomerular afferent and efferent arterioles using the isolated perfused hydronephrotic kidneys of six-week-old male Sprague-Dawley rats. In the first study, forty 6-week-old male SHRs which underwent 5/6 nephrectomy were equally divided into five groups. One group received no therapy. In two groups, therapy was started at four weeks post-nephrectomy, one with amlodipine and the other with enalapril. In the remaining two groups, amlodipine or enalapril therapy was started at eight weeks postnephrectomy. Amlodipine was more effective than enalapril in reducing proteinuria and glomerulosclerosis in the group that was started on drug therapy eight weeks after surgery. In the second study, at concentrations of 10(-6) to 10(-9) M, nifedipine, nicardipine and amlodipine dilated the afferent, but not the efferent, arteriole preconstricted with angiotensin II. On the other hand, efonidipine and manidipine clearly dilated angiotensin II-induced constriction of both the afferent and efferent arterioles. These results indicated that Ca blockers are effective at reducing renal injury in 5/6 nephrectomized SHR, and that they are more effective than ACEI in advanced stages of renal injury. The observation that only certain Ca blockers can dilate the efferent arteriole suggests that the renal protective effect of Ca blockers is not necessarily dependent on the dilation of the efferent arterioles.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Calcium Channel Blockers; Enalapril; Hydronephrosis; In Vitro Techniques; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renal Circulation

The renin-angiotensin-aldosterone system (RAAS) participates in the injury sustained by the remnant kidney. Our studies assessed the importance of aldosterone in that model and the response of aldosterone to drugs interfering with the RAAS. Initially, four groups of rats were studied: SHAM-operated rats, untreated remnant rats (REM), REM rats treated with losartan and enalapril (REM AIIA), and REM AIIA rats infused with exogenous aldosterone (REM AIIA + ALDO). The last group was maintained with aldosterone levels comparable to those in untreated REM rats by constant infusion of exogenous aldosterone. REM rats had larger adrenal glands and a > 10-fold elevation in plasma aldosterone compared to SHAM. REM AIIA rats demonstrated significant suppression of the hyperaldosteronism as well as marked attenuation of proteinuria, hypertension, and glomerulosclerosis compared to REM. REM AIIA + ALDO rats manifested greater proteinuria, hypertension, and glomerulosclerosis than REM AIIA rats. Indeed, by 4 wk of observation all of these features of the experimental disease were similar in magnitude in REM AIIA + ALDO and untreated REM. In separate REM rats spironolactone administration did not reduce glomerular sclerosis but did transiently reduce proteinuria, lowered arterial pressure, and lessened cardiac hypertrophy. In summary, aldosterone contributes to hypertension and renal injury in the remnant kidney model.

Topics: Adrenal Glands; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Disease Models, Animal; Enalapril; Imidazoles; Kidney; Kidney Diseases; Losartan; Male; Mineralocorticoid Receptor Antagonists; Nephrectomy; Organ Size; Rats; Rats, Sprague-Dawley; Spironolactone; Tetrazoles

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Collagen; Enalapril; Enzyme Inhibitors; Female; Fibrosis; Kidney; Kidney Diseases; Kidney Tubules; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Sprague-Dawley; Ureteral Obstruction

The pathogenesis of renal scarring in chronic cyclosporin nephropathy is unknown. In this study, we evaluated the effects of renin-angiotensin system blockade by enalapril and losartan in a salt-dependent model of cyclosporin-associated chronic tubulointerstitial fibrosis (TIF). Rats kept on normal or low-salt diet were given cyclosporin, cyclosporin+enalapril, cyclosporin+losartan, cyclosporin+enalapril#losartan, or vehicle for 14 and 28 days. Cyclosporin reduced glomerular filtration rate (GFR) in rats fed either diet, but only salt-depleted animals developed significant TIF. Cyclosporin also impaired renal concentrating ability and caused tubular enzymuria. Renin-angiotensin system blockade decreased blood pressure (BP) and promoted afferent arteriolar vasodilatation. Losartan reduced plasma renin activity and prevented cyclosporin-induced increment of cortical alpha 1(I) procollagen mRNA. Renin-angiotensin blockade did not improve GFR and tubular function; however, it strikingly prevented TIF development, even in presence of very low BP. Rats treated with cyclosporin, hydralazine, and furosemide achieved BP values similar to losartan or enalapril groups, but there was no protection against interstitial fibrosis development. These results suggest that cyclosporin-related chronic interstitial injury is mediated by angiotensin II and that the mechanisms promoting the interstitial scarring can be dissociated from glomerular and tubular dysfunction in cyclosporin nephropathy.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Cyclosporine; Enalapril; Furosemide; Hydralazine; Imidazoles; Kidney; Kidney Diseases; Losartan; Male; Microscopy, Electron, Scanning; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; 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

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Dose-Response Relationship, Drug; Enalapril; Humans; Hypertension; Isoquinolines; Kidney Diseases; Lisinopril; Otolaryngology; Quinapril; Tetrahydroisoquinolines

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

In Wistar rats just after weaning, 5/6 of renal parenchyma were removed surgically. Thereafter, the rats were fed either a "high-protein" (21%) or two types of a "low-protein" (6%) diet; in one of the latter the lack of protein was substituted by saccharide, in the other by fat, making the substitution "isocaloric" in either case. In all three diet groups, subgroups were formed drinking either tap water or water containing either the ACE inhibitor enalapril (Ena) or the calcium antagonist diltiazem (Dil), or both (Ena + Dil). In the high-protein diet group, increases in the weight of kidney remnants, in proteinuria and in systolic blood pressure (SBP) were seen. This was prevented by feeding either type of the low-protein diet but also by Ena and Ena + Dil. Ena and Ena + Dil not only prevented the increase in SBP but actually lowered it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and proteinuria. No additive protective action of Ena + Dil or Ena + low protein or Ena + Dil + low protein was seen, suggesting that a bottom limit of these protective action was reached by the low-protein diet alone. There was no substantial difference between either type of the low-protein diet except a small and transient decrease in body weight in the first week of fat-rich diet administration.

Topics: Analysis of Variance; Animals; Body Weight; Diet, Protein-Restricted; Diltiazem; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Kidney Diseases; Male; Nephrectomy; Rats; Rats, Wistar; Time Factors

Renal endothelin-1 (ET-1) production is diminished in spontaneously hypertensive rats. An increase has been reported of renal ET-1 production associated with progression of renal disease in rats with reduced renal mass. The purpose of the present study was to investigate the evolution over time of the urinary ET-1 excretion in an experimental model of renal mass reduction not caused by renal infarction. Rats were subjected to 2/3 nephrectomy (right nephrectomy and resection of the lower left renal pole) and thereafter randomly assigned to a no-treatment control group or to treatment with recombinant erythropoietin, recombinant erythropoietin plus verapamil, or recombinant erythropoietin plus enalapril. The urinary ET-1 excretion was decreased by week 16 after nephrectomy as compared with healthy animals and with the levels 6 weeks after nephrectomy. The temporal evolution of urinary ET-1 excretion in the various groups of rats showed a trend toward decrease in all groups except the one receiving enalapril. The urinary ET-1 excretion correlated directly with creatinine clearance and inversely with tubulointerstitial damage. We observed an inverse correlation between urinary ET-1 excretion and arterial blood pressure 16 weeks after nephrectomy. These results indicate that renal ET-1 production decreases with the progression of renal disease and in relation with the severity of tubulointerstitial damage. The decrease in renal ET-1 production might contribute to the development and perpetuation of renal disease-associated arterial hypertension; this situation may be favorably modified by the use of enalapril.

Topics: Animals; Enalapril; Endothelins; Erythropoietin; Hypertension, Renal; Kidney; Kidney Diseases; Male; Nephrectomy; Radioimmunoassay; Rats; Rats, Wistar; Recombinant Proteins; Verapamil

To investigate the role of angiotensin II (Ang II) in hypertension-induced tissue injury, we gave TCV-116 (1 mg/kg per day PO), a nonpeptide Ang II type I receptor antagonist, or enalapril (10 mg/kg per day PO) to deoxycorticosterone acetate (DOCA)-salt hypertensive rats for 3 weeks and examined the effects on tissue mRNA levels for transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix components. Tissue mRNA levels were measured by Northern blot analysis. Renal mRNA levels for TGF-beta 1; types I, III, and IV collagen; and fibronectin in DOCA-salt hypertensive rats were increased by severalfold (P < .01) compared with sham-operated rats. In the aorta of DOCA-salt hypertensive rats, TGF-beta 1 and fibronectin mRNA levels were increased, but types I, III, and IV collagen mRNAs did not increase. In the heart, increased mRNA was found only for fibronectin. Thus, these gene expressions are regulated in a tissue-specific manner. TCV-116 or enalapril did not lower blood pressure in DOCA-salt hypertensive rats. However, the increase in renal mRNAs for TGF-beta 1 and extracellular matrix components in DOCA-salt hypertensive rats was significantly inhibited by treatment with TCV-116 or enalapril, which was associated with a significant decrease in urinary protein and albumin excretions and histological improvement of renal lesions. In contrast, in the aorta and heart these gene expressions were not affected by TCV-116 or enalapril. Thus, local Ang II may contribute to renal injury of DOCA-salt hypertension by stimulating the gene expression of TGF-beta 1 and extracellular matrix components.

Topics: Angiotensin II; Animals; Benzimidazoles; Biphenyl Compounds; Collagen; Desoxycorticosterone; Enalapril; Hypertension; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Wistar; Renin; RNA, Messenger; Sodium Chloride; Tetrazoles; Transforming Growth Factor beta

Spirapril is a prodrug that is converted by esterolysis to the active (but poorly absorbed) diacid spiraprilat. After intravenous infusion, the disposition of spirapril is monophasic with a terminal half-life of 20-50 minutes. Plasma clearance was 56 l/h and renal clearance was 11 l/h; the volume of distribution was 28 litres. After intravenous infusion of spiraprilat, the disposition was biphasic with half-lives of 2 hours and 35 hours, respectively. Plasma clearance of spiraprilat was 10 l/h, of which 7.6 l/h was cleared by the kidneys. The volume of distribution was 43 litres. The bioavailability of orally administered spirapril was 50% whereas the bioavailability of orally administered spiraprilat was virtually zero. There was a significant first-pass metabolism of spirapril after oral administration. The pharmacokinetics of spirapril were linear within the dose range of 6-50 mg whereas the disposition of spiraprilat was non-linear with respect to the terminal phase. Variability of the pharmacokinetic parameters of spiraprilat were significantly less than that of spirapril. Plasma concentrations of both spirapril and spiraprilat were increased by 30% in the elderly. Similarly, in patients with impaired liver function, plasma concentrations of spiraprilat were reduced by 30%. In patients with severe renal impairment, spiraprilat concentrations were significantly increased by a factor of 3-4. Spirapril showed no clinically relevant drug interactions with either glibenclamide, diclophenac, cimetidine, rifampicin, hydrochlorothiazide or nicardipine.

Topics: Adult; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enalapril; Humans; Kidney Diseases; Liver Diseases; Reference Values

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

Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.

Topics: Animals; Atrial Natriuretic Factor; Binding Sites; Clonidine; Cyclic GMP; Enalapril; Hypertension; Hypertrophy; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

The antihypertensive efficacy of combination therapy with N-E-A was evaluated during 6 months in 15 patients with hypertension associated with mild to moderate kidney failure. After 6 months a significant reduction of SBP and DBP (p < 0.001), with improvement of creatinine clearance and with no adverse effects on ECG, heart rate and routine laboratory tests test, was observed in 3 patients treated with N 20 mg x 2/d + E 10 mg/d + A 50 mg/d and in 8 patients treated with N 20 mg x 3 + E 10 mg x 2, + A 50 mg x 2. Four patients did not respond to this therapy.

Topics: Adult; Atenolol; Chronic Disease; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Nicardipine; Treatment Outcome

Topics: Blood Pressure Determination; Enalapril; Humans; Kidney Diseases

Topics: Enalapril; Humans; Kidney Diseases; Renal Artery Obstruction

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 aim of the study was to define a therapy to be combined with an immunosuppressive drug such as cyclosporin A, in order to partially reduce the nephrotoxic and hepatotoxic effects in the treated rats. Two drugs were considered: enalapril, which is an inhibitor of the angiotensin-converting enzyme, and spironolactone, which is an antagonist of aldosterone. These two drugs interrupt the renin-angiotensinogen-angiotensin chain after this has been activated by cyclosporin A, preventing peripheral vasoconstriction and more specifically the constriction of both glomerular arterioles and hepatic vessels from occurring, thus diminishing the cyclosporin A toxicity in both liver and kidney.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclosporine; Drug Therapy, Combination; Enalapril; Kidney Diseases; Liver Diseases; Male; Rats; Rats, Sprague-Dawley; Spironolactone

Angiotensin-1-converting enzyme inhibitors have an effective and established role in the treatment of patients with congestive heart failure. However, a small number of such patients will subsequently develop renal insufficiency. These patients may be identified prior to, or shortly after, commencement of therapy by recognized criteria. This report describes 4 patients with congestive heart failure who developed severe renal insufficiency secondary to either enalapril or captopril therapy in the absence of any currently recognized predisposing factors. One patient died.

Topics: Aged; Captopril; Contraindications; Enalapril; Female; Heart Failure; Humans; Kidney Diseases; Male; Middle Aged

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

Topics: Adult; Analysis of Variance; Antihypertensive Agents; Clinical Trials as Topic; Creatinine; Drug Evaluation; Enalapril; Female; Humans; Hypertension; Kidney Diseases; Lisinopril; Male; Middle Aged

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 antihypertensive and renal effects of the angiotensin-converting enzyme inhibitor lisinopril were studied in a group of patients with moderate-to-severe hypertension and impaired renal function. After 12 weeks of treatment, most patients had good blood pressure response to lisinopril monotherapy. During this period, correlations between antihypertensive effect, drug dose, and serum drug level were observed. These correlations were no longer evident after prolonged treatment. During a 1-year follow-up period, the drug dose was lowered gradually without losing antihypertensive effect. Hyperkalemia occurred in one third of the patients. During the 1-year follow-up, the glomerular filtration rate (GFR) decreased in two thirds of the patients and remained stable in the other third. In this latter group, the pretreatment GFR was higher, and the effective renal plasma flow had increased, whereas in the patients with a decreased GFR no renal vasodilation had occurred during lisinopril therapy. Thus, lisinopril is an effective antihypertensive drug for patients with impaired renal function. The dose should be adjusted to the pretreatment GFR, and a decrease in dosage should be considered with prolonged treatment.

Topics: Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Hypertension; Kidney Diseases; Lisinopril; Male; Time Factors

Prolonged treatment with cyclosporine (CS) results in an irreversible renal lesion consisting of interstitial fibrosis and tubular atrophy, as well as prominent hyperplasia of the juxtaglomerular apparatus (JGA). Ischemia to the tubulointerstitial compartment caused by intense CS-mediated renal vasoconstriction may contribute significantly to the development of this lesion. To explore the potential role of volume contraction and activation of the renin-angiotensin system (RAS) in the genesis of this lesion, we have employed a recently described rodent model of chronic cyclosporine nephropathy (CCN). Over 28 days of CS therapy, animals received plain drinking water, 1% saline, or enalapril (ENAL), 50 mg/l in drinking water. At the end of 28 days, Na+ balance in saline-treated animals was markedly positive, and plasma volume was increased; however, glomerular filtration rate (GFR) did not change, and the tubulointerstitial lesion and JGA hyperplasia as evaluated by morphometric techniques were unaffected. Enalapril-treated animals were relatively hypotensive with lower GFR than CS controls. Enalapril conferred no protection against the development of tubulointerstitial disease and exacerbated the development of JGA hyperplasia and hyperkalemia. We conclude that volume contraction is not an important contributor to the reduced GFR, tubulointerstitial lesion, or JGA hyperplasia associated with long-term CS treatment. Blockade of the RAS also conferred no protection against the development of tubulointerstitial disease but resulted in worsening of JGA hyperplasia and hyperkalemia.

Topics: Animals; Blood Pressure; Chronic Disease; Cyclosporins; Enalapril; Kidney; Kidney Diseases; Male; Natriuresis; Plasma Substitutes; Rats; Rats, Inbred Strains; Renin; Sodium Chloride; Time Factors

Rats of the spontaneously hypertensive strain develop kidney damage that resembles the nephropathy seen in some cases of human essential hypertension. Previous studies with a triple drug antihypertensive regimen indicated that proteinuria and glomerular histopathology in spontaneously hypertensive rats might develop despite long-term effective control of systemic blood pressure. To investigate further the relation between hypertension and kidney disease, a group of spontaneously hypertensive rats were treated with enalapril at 15 weeks of age. Blood pressure, protein excretion, and kidney function were measured in those rats at regular intervals during the next year and a half and were compared with untreated spontaneously hypertensive rats and the normotensive Wistar-Kyoto parent strain. Kidney tissue samples from all three groups, collected at autopsy, were stained by immunohistochemical and conventional methods to assess the relative severity and nature of kidney damage. Although enalapril therapy was completely effective in controlling the blood pressure of spontaneously hypertensive rats, it only postponed the onset of kidney disease. Enalapril-treated spontaneously hypertensive rats eventually exhibited albuminuria as severe as that found in hypertensive rats. Kidney vessel pathology was completely prevented with enalapril, but the abnormal accumulation of mononuclear cells in tubulointerstitial and periglomerular sites was the same as in untreated spontaneously hypertensive rats. We have concluded that elevated protein excretion in rats of the spontaneously hypertensive rat strain is not a secondary consequence of systemic hypertension. Structural abnormalities of renal vessels also do not appear to contribute significantly to the pathogenesis of albuminuria in spontaneously hypertensive rats. Other explanations must be sought to account for the close link between spontaneous hypertension and kidney damage in this animal model. The clear dissociation of kidney disease from systemic hypertension exhibited by spontaneously hypertensive rats may also be relevant for human disease.

Topics: Albuminuria; Animals; Dietary Proteins; Enalapril; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Angiotensin converting enzyme (ACE) inhibitor treatment in renovascular hypertension is associated with acute compromise of renal function in patients with bilateral renal artery stenosis or with arterial stenosis to a single functioning kidney. Recent evidence has suggested that renal function is also compromised in the stenosed kidney of patients with unilateral renal artery stenosis. The long-term consequence of this reduction in renal function is not known. We have studied the effect of chronic ACE inhibition with enalapril on renal structure and function in rats with the two-kidney one-clip model of renovascular hypertension. Four weeks after placement of a clip on the left renal artery, hypertensive rats were randomized to treatment with enalapril, minoxidil, or to a no treatment group. Twelve months later split kidney function was determined by chromium 51-labeled ethylenediamine-tetraacetic acid clearance in surviving rats. Clearance of the clipped kidney was 0.0 ml/min (enalapril group), 0.26 +/- 0.23 ml/min (minoxidil group), and 0.74 +/- 0.13 ml/min (untreated group). The clipped kidney from the enalapril treated rats weighed much less than the minoxidil group or the untreated group (0.46 +/- 0.1 gm, 1.2 +/- 0.07 gm, and 1.14 +/- 0.10 gm, respectively). Enalapril treatment was stopped for 2 weeks in five rats. The clipped kidney remained small and nonfunctional. Histologic examination revealed marked interstitial fibrosis and tubular atrophy of the clipped kidneys from the enalapril treated group in contrast to minor changes in the minoxidil treated and untreated groups. After 12 months of treatment, survival in the enalapril group was 84%, 48% in the minoxidil group, and 15% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dose-Response Relationship, Drug; Enalapril; Hypertension, Renovascular; Kidney; Kidney Diseases; Minoxidil; Nephrectomy; Organ Size; Rats; Rats, Inbred Strains

Several [(1H-imidazol-1-yl)methyl]- and [(3-pyridinyl)methyl] pyrroles were prepared and evaluated in vitro as thromboxane synthetase inhibitors in human platelet aggregation studies. A number of structures, e.g. 10b,f,g,i (respective IC50 values: 1 microM, 50 nM, 42 nM, 44 nM) showed superior in vitro inhibition of TXA2 synthetase when compared to the standard dazoxiben (1). However, it was found that in vitro potency did not translate into nor correlate with in vivo activity when these compounds were evaluated in mice in a collagen-epinephrine-induced pulmonary thromboembolism model. (E)-1-Methyl-2-[(1H-imidazol-1-yl)methyl]-5-(2-carboxyprop-1-enyl) pyrrole (10b) was found to offer protection against collagen-epinephrine-induced mortality in mice, thereby demonstrating that oral administration is an effective route for absorption of this drug. Additional evidence for the oral effectiveness of 10b in lowering serum TXB2 levels was obtained by performing ex vivo radioimmunoassay experiments with rats. A 13-week study of 10b in rats with reduced renal mass was conducted in order to evaluate the role of TXA2 production in hypertension and renal dysfunction. Although serum and urinary TXB2 levels in rats were found to be lowered during this study by 10b, the levels of urinary protein excretion remained comparable to that of the control group.

Topics: Animals; Aorta; Biological Availability; Blood Platelets; Chemical Phenomena; Chemistry; Humans; Imidazoles; Inflammation; Kidney Diseases; Male; Mice; Microsomes; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pyridines; Pyrroles; Rats; Structure-Activity Relationship; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

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 safety and tolerability of lisinopril (1.25-160 mg daily) were assessed in 3,270 patients (2,688 hypertensives and 582 patients with congestive heart failure (CHF] and 280 healthy subjects. The duration of therapy ranged from a single dose to 43 months; 438 patients received lisinopril for at least 12 months (mean 20 months). In the hypertensive population, the most frequent adverse events reported were headache, dizziness, cough, nausea, diarrhoea and fatigue, although not all of these events were thought to be related to lisinopril; 6.1% discontinued lisinopril due to adverse clinical events, most commonly cough and nausea. Twelve hypertensive patients died (0.45%), but most of these were not receiving lisinopril at the time of death and none was considered to be drug-related. In CHF patients, the most frequently reported adverse events were dizziness, dyspnoea, diarrhoea, hypotension and fatigue. Again, not all of these reports were considered to be drug-related. Therapy was withdrawn in 9.6% of patients--hypotension, dizziness, diarrhoea and rash being the most frequent reasons. Fifty-three CHF patients died (9.1%) and in three cases death was considered to be related to lisinopril therapy. Hypotension, orthostatic effects or dizziness following the initial dose of lisinopril occurred infrequently (in 1.3% of the hypertensive group, including those receiving hydrochlorothiazide, and in 4.8% of CHF patients). Changes in laboratory parameters were generally minor and seldom resulted in discontinuation of therapy. Long-term treatment of hypertension and CHF with lisinopril for at least 3 years confirms that the drug is well tolerated. Overall, the side-effect profile is very similar to that of other ACE inhibitors with regard to class-specific effects. However, taste disturbance was rarely observed.

Topics: Adult; Age Factors; Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Heart Failure; Hematologic Tests; Humans; Hypertension; Hypotension; Kidney Diseases; Lisinopril; Male; Middle Aged

Comparative effects of the angiotensin converting enzyme inhibitors captopril and enalapril on progression of chronic renal disease was studied in 3/4 nephrectomized rats. Rats were divided into sham and nephrectomized groups, and treated with plain water or water containing captopril (150 mg/liter) or enalapril (50 mg/liter). Evaluations were made 4 weeks before and 0, 4, 8, and 10 weeks after nephrectomy. Endogenous creatinine clearance decreased in drug-treated, nephrectomized rats to values less than sham controls, but remained greater than water-treated rats. Significant (P less than 0.05) proteinuria developed 4 weeks post-nephrectomy in water-treated rats, 8 weeks post-nephrectomy in captopril-treated rats, but did not develop in enalapril treated rats. Regression analysis of carbamylated plasma protein values vs plasma creatinine revealed significant (P less than 0.05) relationships only in the water-treated, nephrectomized rats from weeks 0 through 8, but were otherwise unaffected by treatment. Both drugs resulted in significantly (P less than 0.05) improved scores for renal histologic lesions as compared to water treatment. Modifications of proteinuria in captopril and enalapril-treated rats occurred prior to onset of changes in systolic blood pressure, which was significantly elevated only in water-treated, nephrectomized rats at weeks 8 and 10. We conclude that angiotensin converting enzyme inhibitors may ameliorate progression of experimental renal disease through intrarenal effects, independent of modulation of systemic blood pressure, and that enalapril may be superior to captopril in some regards.

Topics: Animals; Blood Cell Count; Blood Pressure; Body Weight; Captopril; Chronic Disease; Creatinine; Drinking; Electrolytes; Enalapril; Kidney Diseases; Male; Nephrectomy; Organ Size; Rats; Rats, Inbred Strains; Urodynamics

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

Angiotensin converting enzyme (ACE) inhibitors have been recommended for the treatment of diabetic nephropathy. However, it should be remembered that diabetic patients may also develop atheromatous renal artery stenosis. In such patients ACE inhibitors may have adverse effects on renal function. Careful investigation and monitoring is essential when ACE inhibitors are used in diabetes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Complications; Enalapril; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Renal Artery Obstruction

Lisinopril, a long-acting angiotensin-converting enzyme inhibitor, is excreted unchanged by the kidney. To determine how reduced renal function affects the drug's antihypertensive efficacy and safety, we studied 26 patients with hypertension associated with impaired renal function, having glomerular filtration rates (GFRs) of 60 ml/minute or less. These patients were enrolled in an open trial of 12 weeks' duration. They were given single daily doses of lisinopril, starting with 2.5 mg in patients with a GFR of less than 30 ml/minute, and 5 mg in the other patients. The dose was titrated to a maximum of 40 mg daily according to the blood pressure response. A diuretic was then added if required. Mean sitting and standing blood pressures at four, eight, and 12 weeks of treatment were significantly reduced compared with pretreatment values. The median dose of lisinopril was 10 mg daily (range, 2.5 to 40 mg), and only four patients required the addition of a diuretic. The mean GFR was unchanged during the study (36 +/- 16.4 ml/minute at baseline, 39 +/- 20.8 ml/minute after 12 weeks of treatment). Twenty-five patients completed the study. The one patient withdrew because of nausea and vomiting due to reflux esophagitis, which was probably not drug-related. Another patient had transient angioneurotic edema and continued to receive lisinopril. No clinically significant hematologic or biochemical abnormalities were observed. Sixteen patients continued to receive lisinopril for one year. Blood pressure control and GFR were well maintained throughout. Thus, in a group of patients who are often difficult to treat, lisinopril provided highly effective blood pressure control and was generally well tolerated.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Enalapril; Female; Furosemide; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Kidney Diseases; Lisinopril; Male; Middle Aged

Topics: Adult; Drug Interactions; Enalapril; Female; Humans; Kidney Diseases; Lithium; Lithium Carbonate; Male; Middle Aged

This review focuses on recent human studies with the angiotensin-converting enzyme (ACE) inhibitor enalapril, prescribed either alone or in combination with a diuretic, to patients with essential hypertension and to patients with hypertension associated with moderate to severe renal parenchymal disease. Data suggest that enalapril therapy may provide a renal protective effect. In addition to lowering and controlling systemic arterial blood pressure, enalapril therapy is associated with stabilisation of, and/or improvement in effective renal plasma flow, glomerular filtration rate (GFR) and urinary protein excretion. Such renal protective effects are probably mediated by normalisation of both the systemic arterial blood pressure and intraglomerular capillary hydraulic pressure, and by an increase in the glomerular ultrafiltration coefficient. Drug therapy enabling control of both systemic and glomerular hypertension may prevent hypertensive renal end-organ damage and attenuate the natural progression of renal parenchymal disease.

Topics: Antihypertensive Agents; Blood Pressure; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Kidney Function Tests

The antihypertensive efficacy and safety of lisinopril, a long-acting angiotensin-converting enzyme inhibitor, were assessed in 23 patients with hypertension associated with impaired renal function (glomerular filtration rate 60 ml/min or less) in an open study of 12 weeks' duration. Lisinopril was given orally in single daily doses. The starting dose was 2.5 mg in patients with glomerular filtration rate (GFR) of less than 30 ml/min and 5 mg in all other patients. This was titrated to a maximum of 40 mg daily according to blood pressure response. A diuretic was then added if blood pressure was not controlled. Mean sitting and standing blood pressures were significantly reduced by lisinopril treatment. The median dose of lisinopril taken was 10 mg daily (range 2.5-40 mg), and only three patients required the addition of a diuretic. The mean glomerular filtration rate was unchanged during the study (38 +/- 16.4 ml/min at baseline, 41 +/- 21.0 ml/min after 12 weeks of treatment). Twenty-two patients completed the study. One patient was withdrawn because of nausea and vomiting due to reflux oesophagitis which was probably not drug related. Another patient had transient mild angioneurotic oedema and continued on lisinopril. No clinically significant haematological or biochemical changes were observed. In conclusion, lisinopril provided effective blood pressure control and was well tolerated in this group of hypertensives who are typically difficult to treat.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Furosemide; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension, Renal; Kidney Diseases; Lisinopril; Male; Middle Aged

To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chronic Disease; Enalapril; Female; Heart Failure; Humans; Hyponatremia; Kidney Diseases; Male; Middle Aged; Renin; Risk Factors; Sodium

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

If optimal dosage administration schedules are to be defined, the factors that influence the disposition of a drug in the population of patients who are likely to receive it should first be determined. Traditionally, separate groups of patients, each with different underlying disease, are given the drug and then detailed studies are performed to assess which groups have significantly different pharmacokinetic parameters and therefore require an adjustment in dose. An alternative approach, utilizing large groups of patients studied less intensively, will be described here. The analysis used the results of two multicenter trials of lisinopril: one in elderly (greater than 65 years) hypertensive patients and one in a group of hypertensive patients with impaired renal function (creatinine clearance rate less than 60 ml/min). Both protocols allowed for a stepwise increase in the dose of lisinopril until optimum control of BP was achieved. Required dosages ranged from 2.5 to 40 mg/day. During the course of therapy, regular trough concentrations were analyzed to assess compliance and a steady-state profile was determined during one dosage interval. Only patients who appeared to be compliant on the basis of multiple trough concentrations were used in the analysis. Data from a total of 53 patients were used, of whom 35 took part in the elderly study, and 18 in the renal study. There were 25 men and 28 women in this combined study group with ages ranging from 21 to 85 years (mean 65 years) and weights from 51 to 115 kg (mean 72 kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Hypertension; Kidney Diseases; Lisinopril; Male; Metabolic Clearance Rate; Middle Aged

Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.

Topics: Adult; Aged; Aged, 80 and over; Blood Urea Nitrogen; Captopril; Creatinine; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged

Topics: Adult; Aged; Enalapril; Enalaprilat; Female; Humans; Kidney Diseases; Kinetics; Male; Middle Aged; Renal Dialysis

Topics: Animals; Diabetic Nephropathies; Enalapril; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Kidney Diseases; Male; Rats; Rats, Inbred Strains

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dogs; Dose-Response Relationship, Drug; Enalapril; Kidney; Kidney Diseases; Kidney Tubular Necrosis, Acute

Topics: Animals; Blood Pressure; Captopril; Cerebrovascular Disorders; Enalapril; Hypertension, Renal; Kidney Diseases; Kinins; Male; Rats; Rats, Inbred SHR

The pharmacokinetics of enalaprilat were studied after administration of single and multiple doses of enalapril maleate to people with normal and impaired renal function. Renal impairment was associated with higher serum concentrations of enalaprilat, longer times to peak concentrations, slower decline of serum concentrations and with reduced urinary elimination. Urinary elimination of enalaprilat was closely related to renal function. In patients with severe renal impairment (GFR values below 30 ml min-1 1.73 m-2) significantly smaller doses of enalapril maleate will be required than in patients with normal or less severely impaired renal function.

Topics: Adult; Aged; Enalapril; Humans; Kidney Diseases; Kinetics; Middle Aged; Time Factors

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

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

Topics: Enalapril; Humans; Kidney Diseases; Renal Artery Obstruction

Enalapril maleate (MK-421), a nonmercapto-containing angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to enalaprilat (MK-422), the active diacid. We evaluated serum profiles and urinary excretion of oral enalapril maleate in patients with renal disease (group I, creatinine clearance less than 3 ml/min, patients undergoing dialysis, n = 10; group II, creatinine clearance 10 to 79 ml/min, n = 9) compared with healthy subjects (group III, creatinine clearance greater than 80 ml/min, n = 10). Group I received a 10 mg dose during a day while not receiving dialysis and a 10 mg dose 1 hour before dialysis 2 weeks later. Groups II and III received a single 10 mg dose. Blood samples and urine were collected for 48 hours. Impaired renal function resulted in elevated serum and plasma concentrations of enalapril maleate and decreased excretion rates and urinary recovery of enalapril maleate and enalaprilat. The data suggest an apparent increase in the extent of metabolism of enalapril maleate to enalaprilat or an increase in nonrenal elimination of unchanged enalapril maleate in renal disease compared with normal health. Enalaprilat was dialyzable.

Topics: Administration, Oral; Adult; Analysis of Variance; Blood Pressure; Creatinine; Enalapril; Enalaprilat; Female; Humans; Kidney Diseases; Kinetics; Male; Middle Aged; Pulse; Radioimmunoassay; Renal Dialysis

Worldwide experience with captopril and enalapril showed that angiotensin-converting enzyme (ACE) inhibitor monotherapy in hypertensive patients rarely caused renal dysfunction. The ACE inhibitors in combination with potent vasodilating drugs and diuretics may produce sudden systemic normotension or hypotension that may impair glomerular filtration at reduced renal perfusion pressure. Reversible renal insufficiency developed during the 13th week of hydrochlorothiazide-enalapril-alpha methyldopa therapy in patient 1 and during the 6th week of hydrochlorothiazide-enalapril treatment in patient 2. Systemic hypotension in patient 1 and routine biochemical monitoring in patient 2 was the first clue of renal insufficiency. Renal angiography was normal in both patients. Renal insufficiency resolved after stopping all drugs temporarily and did not recur on other antihypertensive drug regimens. These data suggested the importance of systemic arterial blood pressure as the best clinical determinant of renal function in hypertensive patients receiving an ACE inhibitor in combination with other antihypertensive agents.

Topics: Acute Kidney Injury; Captopril; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Hypertension, Renovascular; Kidney Diseases; Male; Middle Aged; Oligopeptides; Teprotide

In a 36-year-old woman with malignant hypertension and moderate renal insufficiency from nephrosclerosis normotension was not achieved by the combination of a beta-blocker, a vasodilator, and a loop-diuretic. The angiotensin-converting enzyme (ACE) inhibitor captopril was then added to the therapy. The blood pressure control was good. However, due to adverse reactions, captopril had to be withdrawn. Later on, the patient was successfully treated with enalapril, another ACE inhibitor, without the relapse of any adverse reactions.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Creatinine; Dipeptides; Enalapril; Female; Humans; Hypertension, Malignant; Kidney Diseases; Peptidyl-Dipeptidase A; Proline

A 74-year-old man has been known to have scleroderma for 5 years. Two months before the hospitalization, his blood pressure was rapidly elevated, and progressive renal impairment and ulcerations of the fingers manifested. Then he was diagnosed to have a crisis of scleroderma. The treatment with a new long-acting angiotensin I converting enzyme inhibitor, enalapril maleate (MK-421), normalized the blood pressure and protected the progress of renal impairment without side effects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dipeptides; Enalapril; Humans; Kidney Diseases; Male; Scleroderma, Systemic

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chlorothiazide; Dipeptides; Diuretics; Enalapril; Female; Furosemide; Humans; Kidney Diseases; Nephrosclerosis; Proline

Topics: Adult; Antihypertensive Agents; Dipeptides; Enalapril; Glycosuria; Humans; Hypertension; Kidney Diseases; Male; Uremia