enalapril and Diabetes-Mellitus--Type-1

Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The clinical implications of these new data are discussed.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enalapril; Humans; Losartan; Renin-Angiotensin System; Tetrazoles

Cardiovascular autonomic neuropathy (CAN) and abnormal circadian blood pressure (BP) rhythm are independent cardiovascular risk factors in patients with diabetes and associations between CAN, non-dipping of nocturnal BP and coronary artery disease have been demonstrated. We aimed to test if bedtime dosing (BD) versus morning dosing (MD) of the ACE inhibitor enalapril would affect the 24-hour BP profile in patients with type 1 diabetes (T1D), CAN and non-dipping.. Secondary healthcare unit in Copenhagen, Denmark.. 24 normoalbuminuric patients with T1D with CAN and non-dipping were included, consisting of mixed gender and Caucasian origin. Mean±SD age, glycosylated haemoglobin and diabetes duration were 60±7 years, 7.9±0.7% (62±7 mmol/mol) and 36±11 years.. In this randomised, placebo-controlled, double-blind cross-over study, the patients were treated for 12 weeks with either MD (20 mg enalapril in the morning and placebo at bedtime) or BD (placebo in the morning and 20 mg enalapril at bedtime), followed by 12 weeks of switched treatment regimen.. Primary outcome was altered dipping of nocturnal BP. Secondary outcomes included a measurable effect on other cardiovascular risk factors than BP, including left ventricular function (LVF).. Systolic BP dipping increased 2.4% (0.03-4.9%; p=0.048) with BD compared to MD of enalapril. There was no increase in mean arterial pressure dipping (2.2% (-0.1% to 4.5%; p=0.07)). No difference was found on measures of LVF (p≥0.15). No adverse events were registered during the study.. We demonstrated that patients with T1D with CAN and non-dipping can be treated with an ACE inhibitor at night as BD as opposed to MD increased BP dipping, thereby diminishing the abnormal BP profile. The potentially beneficial effect on long-term cardiovascular risk remains to be determined.. EudraCT2012-002136-90; Post-results.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Autonomic Nervous System; Autonomic Nervous System Diseases; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Risk Factors

Cardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes.. In a randomised, double-blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass.. The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals.. EudraCT (2012- 002136-90).

Topics: Adult; Aged; Antihypertensive Agents; Autonomic Nervous System Diseases; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Double-Blind Method; Drug Chronotherapy; Enalapril; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Multidetector Computed Tomography; Organ Size; Young Adult

Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Chemokines; Cytokines; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Administration Schedule; Enalapril; Endothelium, Vascular; Female; Hemodynamics; Humans; Losartan; Male; Middle Aged; Ontario; Oxidative Stress; Renin-Angiotensin System; Skin; Time Factors; Treatment Outcome; Vascular Stiffness

Enhancing adherence in research trials is fundamental to the proper testing of treatment hypotheses.. Regimen and follow-up adherence as well as factors associated with adherence in the Renin Angiotensin-System Study (RASS) diabetic nephropathy primary prevention trial were evaluated. Adherence to medication (i.e., pill count), follow-up visits, and follow-up renal biopsies was evaluated.. 89.8% of subjects completed the second renal biopsy. 96% of follow-up visits were attended within prescribed time windows. Mean medication adherence was 85.6%. Subgroup analyses revealed greater declines in the least adherent participants over time. Factors associated with greater adherence levels included older age, type 1 diabetes (TIDM) duration, lower HbA1c and blood pressure, GFR, ethnicity, and participants', principal investigators' (PI), and trial coordinators' (TC) baseline predictions of adherence.. T1DM patients without nephropathy were willing to take experimental medications and undergo repeat renal biopsies. Although overall adherence was excellent, patterns of adherence varied among participants, suggesting the need to better track adherence and to develop customized and targeted approaches for promoting adherence to clinical research regimens. Staff subjective predictions of adherence were imprecise, supporting need for further development of adherence predictors.

Topics: Adolescent; Adult; Antihypertensive Agents; Biopsy; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Humans; Kidney; Losartan; Male; Middle Aged; Patient Compliance; Primary Prevention

Optimal glycemic control slows diabetic retinopathy (DR) development and progression and is the standard of care for type 1 diabetes. However, these glycemic goals are difficult to achieve and sustain in clinical practice. The Renin Angiotensin System Study (RASS) showed that renin-angiotensin system (RAS) blockade can slow DR progression. In the current study, we evaluate whether glycemic control influenced the benefit of RAS blockade on DR progression in type 1 diabetic patients.. We used RASS data to analyze the relationships between two-steps or more DR progression and baseline glycemic levels in 223 normotensive, normoalbuminuric type 1 diabetic patients randomized to receive 5 years of enalapril or losartan compared with placebo.. A total of 147 of 223 patients (65.9%) had DR at baseline (47 of 74 patients [63.5%] in placebo and 100 of 149 patients [67.1%] in the combined treatment groups [P = 0.67]). Patients with two-steps or more DR progression had higher baseline A1C than those without progression (9.4 vs. 8.2%, P < 0.001). There was no beneficial effect of RAS blockade (P = 0.92) in patients with baseline A1C ≤7.5%. In contrast, 30 of 112 (27%) patients on the active treatment arms with A1C >7.5% had two-steps or more DR progression compared with 26 of 56 patients (46%) in the placebo group (P = 0.03).. RAS blockade reduces DR progression in normotensive, normoalbuminuric type 1 diabetic patients with A1C >7.5%. Whether this therapy could benefit patients with A1C ≤7.5% will require long-term studies of much larger cohorts.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Enalapril; Female; Glycated Hemoglobin; Humans; Losartan; Male; Renin-Angiotensin System; Young Adult

To examine the relationship of blood pressure (BP) and use of angiotensin-receptor blocker or angiotensin-converting enzyme inhibitor to retinal vessel diameter in normotensive, normoalbuminuric persons with type 1 diabetes mellitus.. In a randomized, controlled clinical trial, clinic and 24-hour ambulatory BPs were measured in persons with type 1 diabetes mellitus and gradable fundus photographs both at baseline (n = 147) and at 5-year follow-up (n = 124). Retinal arteriole and venule diameters were measured by a computer-assisted technique. Individual arteriole and venule measurements were combined into summary indexes that reflect the average retinal arteriole (central retinal arteriole equivalent [CRAE]) and venule (central retinal venule equivalent [CRVE]) diameter of an eye, respectively.. While controlling for age, study site, glycosylated hemoglobin level, and ambulatory pulse rate, the daytime ambulatory systolic (-0.29-microm effect per 1 mm Hg; P = .02), daytime ambulatory diastolic (-0.44-microm effect per 1 mm Hg; P = .04), nighttime ambulatory systolic (-0.27-microm effect per 1 mm Hg; P = .03), and 24-hour ambulatory systolic (-0.31-microm effect per 1 mm Hg; P = .03) BPs were cross-sectionally associated with a smaller CRAE. While controlling for age, study site, glycosylated hemoglobin level, ambulatory pulse rate, and baseline CRAE, no BP measure was associated with a change in CRAE or CRVE during 5 years of follow-up. Treatment with losartan potassium or enalapril maleate was not associated with a statistically significant change in CRAE or CRVE.. Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker therapy does not affect retinal arteriole or venule diameter in normotensive persons with type 1 diabetes mellitus. Trial Registration clinicaltrials.gov Identifier: NCT00143949.

Topics: Adolescent; Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arterioles; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Diabetes Mellitus, Type 1; Double-Blind Method; Enalapril; Female; Glycated Hemoglobin; Heart Rate; Humans; Image Processing, Computer-Assisted; Losartan; Male; Middle Aged; Retinal Vessels; Venules

Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system.. We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models.. A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.. Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)

Topics: Adult; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kaplan-Meier Estimate; Kidney Glomerulus; Logistic Models; Losartan; Male; Mesangial Cells; Renin-Angiotensin System; Retina

Angiotensin-converting enzyme inhibitors plus dihydropyridine calcium channel blockers or low-dose thiazide diuretics are considered first-line therapies in hypertensive diabetic patients as glucose metabolism is not relevantly affected. Most diabetic patients require at least two different drug classes to achieve the recommended target blood pressure of 130/85 mmHg. This controlled clinical trial investigated the calcium channel blocker lercanidipine versus hydrochlorothiazide (HCTZ) as add-on in diabetic patients with uncontrolled hypertension on enalapril monotherapy.. Overall, 174 patients (18-80 years old, well-controlled diabetes type 1 or 2, mild to moderate hypertension) were included in a 2-week placebo run-in followed by 4 weeks on enalapril 20 mg. Subsequently, 135 non-responders (90 mmHg < or = mean sitting diastolic blood pressure < or = 109 mmHg) were randomized to 20 weeks of double-blind add-on therapy to enalapril with either lercanidipine 10 mg (n = 69) or HCTZ 12.5 mg (n = 66). The primary study objective was to prove non-inferiority of lercanidipine add-on versus HCTZ add-on in reducing sitting diastolic blood pressure; response rates and tolerability data were also observed.. Both add-on treatments clearly decreased diastolic blood pressure to a greater extent than enalapril monotherapy (mean +/- SD changes at study end: lercanidipine, -9.3 mmHg; HCTZ, -7.4 mmHg); non-inferiority of lercanidipine versus HCTZ was formally proven. Blood pressure response rates reached 69.6% on enalapril plus lercanidipine as compared with 53.6% on enalapril plus HCTZ (difference between treatments, P > 0.05). Blood pressure of 130/85 mmHg or less was achieved in 30.4% of patients on lercanidipine add-on and in 23.2% of those randomized to HCTZ add-on (P > 0.05). Both treatment regimens were well tolerated.. Lercanidipine add-on showed comparable efficacy to HCTZ add-on in diabetic patients with hypertension badly controlled on angiotensin-converting enzyme inhibitor monotherapy. The blood pressure response rates seemed to be somewhat higher following enalapril plus lercanidipine than enalapril plus HCTZ.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Single-Blind Method

To examine the association of ambulatory blood pressure (ABP) and ambulatory pulse rate (APR) with diabetic retinopathy (DR) in persons with type 1 diabetes in the Renin-Angiotensin System Study (RASS), a multicenter primary diabetic nephropathy (DN) prevention trial.. Cross-sectional study.. One hundred ninety-four normotensive RASS participants in 3 centers who are 16 years of age or older with type 1 diabetes mellitus (DM) of 2 to 20 years' duration.. Ambulatory blood pressure and APR were monitored using standardized protocols. Patients were defined as nondippers if the night-to-day ratios for both systolic and diastolic blood pressures were >0.9. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of 7 standard fields using the Early Treatment Diabetic Retinopathy Study severity scale.. Severity of DR.. No DR was present in 32%, mild nonproliferative DR (NPDR) was present in 55%, and moderate to severe NPDR or proliferative DR was present in 13% of the cohort. Neither 24-hour systolic ABP or diastolic ABP, daytime systolic or diastolic ABP, nor nighttime diastolic ABP were related to severity of DR. Statistically significant associations were found between nighttime systolic ABP and mean ABP and DR. Among those with no DR, 19% were nondippers; for those with mild NPDR, 28% were nondippers; and for those with severe NPDR or proliferative DR, 36% were nondippers (P = 0.08). The ratio of nighttime to daytime APR, but not the 24-hour APR or daytime or nighttime APR, was related positively to the severity of DR. In multivariable analyses, only the nighttime systolic ABP was related to severity of DR (P<0.05).. These data suggest that ABP, especially during the night, may provide a better measure than clinical BP regarding the relationship of BP to the severity of retinopathy in normotensive persons with type 1 DM without clinical DN.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Heart Rate; Humans; Losartan; Male; Renin-Angiotensin System

To elicit the role of endothelial dysfunction in development of cardiorenal syndrome in patients with diabetes mellitus type 1 (DM1) with diabetic nephropathy (DN) and to evaluate the efficacy of endotheliotropic drugs: nebivolol (a selective beta-blocker) and enalapril (ACE inhibitor).. The trial enrolled 60 patients with DM1: 15 patients with normoalbuminuria (NAU), 15 patients with microalbuminuria (MAU), 15 patients with proteinuria (PU) and 15 with chronic renal failure (CRF). The control group consisted of 15 healthy volunteers matched by sex and age. All the patients were examined for endothelium-dependent dilation of the brachial artery (by duplex scanning in the test with reactive hyperemia), serum markers of endothelial dysfunction (endothelin-1--ET-1), Willebrand factor (WF), inflammation markers (C-reactive protein-CRP), incidence rate of ischemic heart disease (IHD). 24-h arterial pressure monitoring and echocardiography were also made. For 12 weeks the patients were given nebivolol monotherapy in a dose 5 mg/day or enalapril monotherapy in a dose 10 mg/day. The effects of these drugs on urinary excretion of albumin and protein, arterial pressure, circadial rhythm of arterial pressure and endothelial dysfunction were studied.. In DM1 patients DN advances with an increase in development of IHD: in MAU--by 13%, PU--by 33%, CRF--53%. Concentric hypertrophy and left ventricular remodeling were registered in 33, 40 and 60% of cases, respectively. A circadian rhythm disturbance correlated with DN severity. DN progression was associated with increasing endothelial dysfunction. It is shown that nebivolol and enalapril correct endothelial dysfunction, have comparable antiproteinuric and antihypertensive actions at different stages of nephropathy.. A close correlation was found between DN progression and development of cardiovascular pathology in DM1 patients. This serves the basis of cardiorenal syndrome. These two pathologies are associated with vascular endothelial dysfunction which leads to disorders in vascular tonicity regulation.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Benzopyrans; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Enalapril; Endothelium, Vascular; Ethanolamines; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Nebivolol; Syndrome

Diabetes mellitus reduces female gender-mediated protection against progression of renal disease but the mechanisms responsible for this loss of protection are unknown. The impact of gender on the diabetic hyperfiltration state has not previously been studied. Since hyperfiltration is a factor in the development of diabetic renal disease, and is influenced by hyperglycemia and renin-angiotensin system (RAS) blockade, we examined gender differences in the renal response to hyperglycemia and angiotensin-converting enzyme (ACE) inhibition in young males and females with uncomplicated type 1 diabetes mellitus.. Ten male and 12 female normoalbuminuric, normotensive, adolescents with type 1 diabetes mellitus were studied before ACE inhibition during clamped euglycemia and hyperglycemia, and then after 21 days treatment with enalapril (0.1 mg/kg daily x 1 week and then 0.1 mg/kg twice a day x 2 weeks).. During clamped euglycemia, males exhibited significantly higher effective renal plasma flow (ERPF) and renal blood flow (RBF) and a lower renal vascular resistance (RVR). During clamped hyperglycemia, females exhibited reductions in ERPF and RBF, and increased RVR and filtration fraction (FF). Males exhibited no significant renal hemodynamic changes during hyperglycemia. After ACE inhibition treatment, both genders exhibited significant declines in arterial pressure, but only females displayed a reduction in glomerular filtration rate (GFR) and FF.. The renal responses to hyperglycemia and ACE inhibition appear to differ between male and female adolescents with uncomplicated type 1 diabetes mellitus. Hyperglycemia-induced changes in RVR and FF in women may account, at least in part, for the loss of gender-based protection in diabetic renal disease.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Glucose Clamp Technique; Humans; Hyperglycemia; Hypertension, Renal; Kidney; Renal Circulation; Sex Characteristics; Treatment Outcome

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. We tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) is superior to maximal recommended dose of ACE inhibitor in type 1 diabetic patients with diabetic nephropathy (DN).. We performed a randomized, double-blind, crossover trial with 8 weeks treatment with placebo and irbesartan 300 mg (once daily), added on top of enalapril 40 mg (once daily). We included 24 type 1 patients with DN. At the end of each treatment period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were measured.. Values on ACE inhibitors + placebo were: albuminuria [mean (95% CI)], 519 (342 to 789) mg/24 hours; blood pressure [mean (SEM)], 131 (3)/74 (1) mm Hg, and GFR [mean (SEM)], 65 (5) mL/min/1.73 m2. Dual blockade of the RAS induced a reduction in albuminuria [mean (95% CI)] of 25% (15, 34) (P < 0.001), a reduction in systolic blood pressure of 8 mm Hg (4, 12) (P = 0.002), and a reduction of 4 mm Hg (2, 7) (P = 0.003) in diastolic blood pressure. GFR and plasma potassium remained unchanged during both treatment regimes. Dual blockade was safe and well tolerated.. Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN. Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Enalapril; Female; Humans; Irbesartan; Male; Middle Aged; Renin-Angiotensin System; Tetrazoles

A 5-year randomized, double blind, placebo-controlled study was carried out to determine the effect of the angiotensin-converting enzyme (ACE) inhibitor enalapril (E) on the progress of renal function and histology in subjects with type 1 diabetes and microalbuminuria. Seventy three type 1 diabetic patients with BP <140/90 and with persistent albuminuria (AER 20-200 microg/min) and normal renal function were randomly assigned to receive E (n=37) or placebo (n=36). A percutaneous renal biopsy was successfully performed in 69 patients and repeated in 59 patients after 5 years. The mean glomerular volume (MGV), mesangial volume (Vv mes) and glomerular basement membrane thickness (GBMT) were measured histomorphometrically. Before treatment, both groups had similar clinical characteristics, blood pressure, HbA(1c), albumin excretion rate (AER), glomerular filtration rate (GFR), serum creatinine and renal structural damage. Blood pressure was well controlled in both groups. In the patients treated with E, albuminuria decreased significantly (P<0.05) and only 8.1% (3/37) of subjects progressed to clinical albuminuria (AER >300 mg/24 h) compared with 30.5% (11/36) in the placebo group. The E treatment resulted in absolute risk reduction of 22.4 percentage points for the development of clinical albuminuria over a 5-year period (P<0.01). After 5 years of treatment, GBM thickness showed a consistent, though statistically insignificant, increase in the placebo group, whereas it remained stable in the E group. A significant increase in MGV and Vv mes was also observed in the placebo group on completion of the study. The present study indicates that long term therapy with E may decrease or delay the progression of structural glomerular damage in microalbuminuric diabetic subjects without marked hypertension (BP <140/90).

Topics: Adult; Albuminuria; Antihypertensive Agents; Biopsy; Blood Pressure; Diabetes Mellitus, Type 1; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Kidney Glomerulus; Male; Patient Selection; Placebos; Time Factors

We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Blood Pressure; Calcium Channel Blockers; Cell Count; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Follow-Up Studies; Glomerular Mesangium; Humans; Longitudinal Studies; Male; Middle Aged; Nifedipine

Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy, and especially, renin-angiotensin system (RAS) inhibition, slows, but may not fully arrest progression towards end-stage renal disease. Studies using hard endpoints such as doubling of serum creatinine, dialysis, or death that are initiated before emergence of any renal functional abnormalities in diabetes, would be of impractical length and size. We therefore undertook a primary prevention study (The Renin-Angiotensin System Study or RASS) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint, increase in mesangial fractional volume (Vv[Mes/glom]).. This is a parallel group, double-blind, placebo-controlled trial with 285 patients with Type 1 diabetes mellitus (95 per group) randomised to receive the angiotensin-converting enzyme inhibitor, enalapril, the angiotensin II receptor blocker, losartan, or placebo. All patients are normotensive, normoalbuminuric and have normal or increased glomerular filtration rates at study entry. The study is based on primary endpoint of change in Vv(Mes/glom) from baseline to the five-year renal biopsy, with baseline and interval measures of albumin excretion rate, glomerular filtration rate, blood pressure, and glycaemia. Baseline, mid-point, and five-year retinal fundus photography are also performed.. One thousand and sixty-five patients were interviewed, 707 refused participation and 73 were excluded. The target of 285 subjects were randomised and their clinical and demographic characteristics are described. Biopsy complications occurred in 17 (6%), only one of which required hospitalisation. There were no permanent biopsy-related sequelae.. Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Humans; Losartan; Male; Personnel Selection; Research Design

Vascular endothelial growth factor (VEGF) is thought to be instrumental in the progression of diabetic retinopathy. Indications exist that the renin-angiotensin system is involved in VEGF overexpression. We assessed the vitreous VEGF concentrations in patients and related them to anti-hypertensive treatment, with special interest in the use of ACE-inhibitors.. Samples of vitreous fluid (10-80 microl) were obtained from 39 patients both with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus and 11 non-diabetic patients undergoing intra-ocular surgery. The VEGF-A concentrations were assessed by immunoassay.. Control patients and patients without proliferative diabetic retinopathy ( n = 8) had low and comparable VEGF concentrations (medians < 50 pg/ml). In contrast, patients with proliferative diabetic retinopathy ( n = 31) had high vitreous VEGF concentrations (median 1134 pg/ml), which showed a negative correlation with the use of ACE inhibiting medication (Spearman rank-R = - 0.54; p = 0.002, n = 13). Diastolic and systolic blood pressure did not differ significantly between the two subgroups with proliferative diabetic retinopathy, i. e. those patients receiving ACE-inhibition (medians 88/160 mm Hg, respectively) and the others (90/160). For the mostly used ACE-inhibitor in the proliferative diabetic retinopathy group, i. e. enalapril ( n = 8), a linear dose-effect relation was observed (-20 +/- 4 pg x ml(-1) x mg(-1) x day(-1); p = 0.024; coefficient +/- SEM).. Treatment with ACE-inhibitors attenuates retinal overexpression of VEGF-A in patients with proliferative diabetic retinopathy, probably by interference with a local effect of angiotensin II.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enalapril; Endothelial Growth Factors; Female; Humans; Intraocular Pressure; Lymphokines; Male; Middle Aged; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vitreous Body

In the treatment of diabetic nephropathy, ACE inhibitor therapy reduces albumin excretion and slows the rate of decline in glomerular filtration rate (GFR). Our study was designed to investigate whether these effects lay in amelioration of the underlying glomerular structural abnormalities. A total of 54 type 1 diabetic patients with albuminuria and blood pressure (BP) <150/90 mmHg were randomized to receive 10 mg enalapril once daily, 10 mg nifedipine retard twice daily, or placebo in a multicenter double-blind study of 3 years' duration. Renal biopsy was performed at baseline and follow-up, and tissue was analyzed by standard morphometric methods. BP, GFR, albumin excretion rate (AER), and HbA1c were measured every 6 months. Enalapril lowered AER after 6 months by 26% (P < 0.05); however, this reduction was not sustained at 3 years. There was no significant effect of nifedipine or placebo on AER. GFR decreased by a similar average rate of 4.1 ml x min(-1) x year(-1) (95% CI 2.6-5.6) in all three groups. BP and HbA1c were unchanged throughout the study in all groups. At baseline, nearly all biopsies showed classic appearances of diabetic glomerulopathy. There was no detectable effect of enalapril compared with either nifedipine or placebo on renal structure over 3 years. However, we found that patients with increased AER have established glomerulopathy and a progressive average decline in GFR of 4.1 ml x min(-1) x year(-1) in the absence of overt hypertension, and baseline AER appeared predictive of subsequent mesangial volume fraction (r = 0.20, P = 0.0018). In this small cohort of nonhypertensive patients studied for 3 years, disease evolution appears unaffected by treatment with either enalapril or nifedipine.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cohort Studies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Double-Blind Method; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Longitudinal Studies; Middle Aged; Nifedipine; Pilot Projects; Treatment Failure

To examine the effect of low-dose losartan, an angiotensin II antagonist, on persistent microalbuminuria in normotensive Type 1 diabetes mellitus, 16 subjects with Type 1 diabetes were randomly assigned to two 2-month treatment periods, with either losartan (25 mg/day) or enalapril (5 mg/day) in a single-blind cross-over design. Urinary albumin excretion (UAE), blood pressures, lipids, glycemia, HbA1C, serum potassium and creatinine clearance were measured before and after each treatment period. The UAEs were similarly reduced after both treatments. The median UAE decreased by 27.8%, from 162 (range 65-250) to 117 (34-190) mg/day (p<0.01) after enalapril, and decreased by 25%, from 160 (60-246) to 120 (36-184) mg/day (p<0.01) after losartan. The systolic and diastolic blood pressures also decreased significantly (p<0.05), whereas serum levels of potassium increased (p<0.01) after both treatments. The levels of serum HbA1c, mean fasting glucose, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol and creatinine clearances were not significantly (p>0.05 in all) changed by either the enalapril or losartan treatment. No significant differences were found between the effects of enalapril and losartan. In conclusion, losartan treatment reduces microalbuminuria as effectively as enalapril in normotensive Type 1 diabetic patients.

Topics: Adult; Albuminuria; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Enalapril; Humans; Losartan; Reference Values; Single-Blind Method

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

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

Angiotensin-converting enzyme inhibitors (ACE-I) have different modes of action and different durations of inhibition. The effects of ACE-I on the various components of the renin-angiotensin system (RAS) at trough hours were studied in patients with diabetes mellitus receiving long-term ACE-I treatment.. Out of 86 Type 1 and 2 diabetic patients, 49 were untreated, 25 received captopril and 12 received enalapril as chronic treatment. Blood for the determination of plasma renin activity (PRA), serum ACE activity and plasma angiotensin II (Ang II) was drawn in the morning (0700-0900 hours) after an overnight fast, about 12 hours after the last dose. PRA and Ang II were measured by RIA and serum ACE activity was assayed by a radiometric assay using (3)H-hippuryl-glycyl-glycine as a substrate.. Mean age was significantly greater in the enalapril-treated patients. Systolic and diastolic blood pressures were not different between the captopril-treated and untreated groups. Serum ACE activity in the captopril-treated diabetic patients was 101.5+/-42.5 nmol/mL/min, values obtained in untreated diabetic patients (101.4+/-25.2 nmol/mL/min). In contrast, ACE activity in the enalapril-treated patients was significantly reduced (5.5+/-7.5 nmol/mL/min) compared with untreated and captopril-treated patients (p<0.00001). PRA values in the ACE-I treated patients were significantly increased. Plasma Ang II levels were significantly increased in the captopril-treated vs. untreated patients (65.1+/-50.2 vs. 36.2+/-31.7 pg/mL, p=0.006), whereas the values in the enalapril-treated patient were slightly, but not significantly, reduced (23.8+/-21.4 pg/mL). CONCLUSIONS Trough serum ACE activity is not suppressed in diabetic patients receiving captopril, compared with those receiving enalapril and we thus question the use of short acting ACE-I in these patients.

Topics: Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enalapril; Humans; Middle Aged; Peptidyl-Dipeptidase A; Renin; Time Factors

To investigate the influence of angiotensin converting enzyme inhibitors and beta blockers on the progression of early diabetic glomerulopathy.. Thirteen patients with Type I (insulin-dependent) diabetes mellitus (mean age 18.8 years) with microalbuminuria 31 (19-160) microg/min were randomised to treatment with enalapril (group 1, n = 7) or metoprolol (group 2, n = 6). Renal biopsies were taken before and after 38 (36-48) months of treatment. Albumin excretion rate, blood pressure and HbA1c were measured every third month. A reference group without antihypertensive treatment (group 3, n = 9), with similar age, diabetes duration and degree of microalbuminuria as group 1 and 2, had baseline and follow-up renal biopsies taken previously with an interval of 26-34 months, analysed at the same laboratory. Glomerular structures were measured by stereological methods.. Measurements of basement membrane thickness, mesangial and matrix volume fractions were similar among groups at baseline. Structural variables were only increased in group 3 at follow-up. Delta values in basement membrane thickness and diabetic glomerulopathy index per 24 months were lower in group 1 and 2 than in group 3 (p < 0.05). Microalbuminuria returned to normal in group 1 and 2 only. Decreased albumin excretion rate tended to inversely correlate with increased basement membrane thickness (p = 0.08) and diabetic glomerulopathy index (p = 0.05). Mean HbA1c was similar between groups. Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p < 0.01). Mean HbA1c and mean diastolic blood pressure correlated to changes in basement membrane thickness, mesangial volume fraction and diabetic glomerulopathy index (p < 0.05).. Contrary to findings in the group without antihypertensive treatment, no progression of glomerulopathy was seen in those treated with enalapril or metoprolol.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Basement Membrane; Biopsy; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney Glomerulus; Male; Metoprolol

Capillary leakage of sodium-fluorescein (NaF) in the skin reflects capillary permeability and may be a marker of diabetes-associated microcirculatory abnormalities.. We evaluated transcapillary skin NaF leakage by fluorescence videodensitometry in 10 normoalbuminuric, 10 microalbuminuric Type 1 diabetic men (diabetes duration > 10 years) and 10 healthy subjects. The microalbuminuric patients were restudied after 6 weeks treatment with the ACE-inhibitor enalapril, 10 mg once daily. All measurements were performed at a blood glucose level of 5 mmol L-1.. Transcapillary NaF leakage was strongly increased in normoalbuminuric Type 1 diabetic patients compared to healthy subjects (P < 0.001) and was still further increased in microalbuminuric Type 1 diabetic patients (P < 0.01 compared to normoalbuminuric patients). Enalapril reduced NaF leakage (P < 0.05), mean arterial blood pressure (P < 0.05) and microalbuminuria (P < 0. 05). After treatment, NaF leakage was not different from that in normoalbuminuric patients.. Capillary permeability, as determined by NaF leakage, is elevated in normoalbuminuric Type 1 diabetic patients with long-standing disease, and the excess elevation in microalbuminuric Type 1 diabetic patients is ameliorated by ACE-inhibition. Skin NaF videodensitometry seems a useful tool to document capillary permeability in intervention studies.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Capillary Permeability; Diabetes Mellitus, Type 1; Enalapril; Fluorescein; Humans; Microcirculation; Middle Aged; Skin

1. In diabetes mellitus a selective increase in the excretion of albumin generally precedes the occurrence of demonstrable loss of glomerular size-selectivity. However, even in this (microalbuminuric) phase of diabetic nephropathy a defect in glomerular barrier function can be demonstrated during infusion of atrial natriuretic peptide. 2. The aim of this study was to investigate whether angiotensin-converting enzyme inhibition could prevent the proteinuric response to atrial natriuretic peptide in these patients. We performed infusions of atrial natriuretic peptide (0.01 microgram min-1 kg-1) in 10 patients with insulin-dependent diabetes mellitus and microalbuminuria (urinary albumin excretion 90 +/- 44 mg/day), both before and after 1 month of treatment with enalapril (20 mg once daily). 3. Despite a 40% reduction in proteinuria, angiotensin-converting enzyme inhibition did not prevent the atrial natriuretic peptide-induced increase in protein excretion. Both before and during angiotensin-converting enzyme inhibition, atrial natriuretic peptide infusion resulted in a significant increase in the fractional excretion of large dextran molecules, which is compatible with an increase in flow through large unrestrictive 'shunt' pores. Atrial natriuretic peptide infusion also induced an increase in the transcapillary escape rate of albumin and angiotensin-converting enzyme inhibition also failed to prevent this effect of atrial natriuretic peptide on peripheral capillary permeability. 4. We conclude that angiotensin-converting enzyme inhibition during 1 month does not correct the capillary barrier function defect in patients with diabetes mellitus and microalbuminuria that is unmasked by atrial natriuretic peptide infusion.

Topics: Albuminuria; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Capillary Permeability; Dextrans; Diabetes Mellitus, Type 1; Enalapril; Female; Humans; Immunoglobulin G; Kidney; Male; Middle Aged

In non-diabetic subjects, an attenuated systemic norepinephrine (NE) responsiveness may contribute to the mechanisms of action of angiotensin-converting enzyme (ACE) inhibitor treatment. We determined whether ACE inhibitor treatment influences systemic and renal haemodynamic responsiveness to exogenous NE, as well as urinary albumin excretion during NE, in microalbuminuric insulin-dependent diabetic (IDDM) patients, representing a patient category that benefits by strict blood pressure control.. In seven microalbuminuric IDDM patients, systemic and renal responsiveness to NE, infused at individually determined threshold [deltamean arterial pressure (MAP)=0 mmHg], 20% pressor (deltaMAP=4 mmHg) and pressor (deltaMAP=20 mmHg) doses, were compared before and after 8 weeks treatment with enalapril, 10 mg daily. Blood glucose was clamped at 5 mmol/l and insulin was infused at 30 mU/kg/h.. Enalapril decreased MAP (P<0.05) and microalbuminuria (P<0.05), whereas effective renal plasma flow (ERPF) increased (P<0.01) and glomerular filtration rate remained unaltered. The filtration fraction tended to decline (P=0.09). The ACE inhibitor-induced fall in MAP disappeared at NE pressor dose, and the overall mean increase in MAP in response to NE was even higher with than without enalapril (P<0.05). After enalapril, the ERPF remained higher at all NE doses (P<0.05), but the magnitude of the NE-induced fall in ERPF was not altered by ACE inhibition treatment. Overnight urinary albumin excretion fell with ACE inhibition (P<0.05), but this effect was not seen during NE infusion. The angiotensin II/active renin ratio and serum aldosterone levels remained lower with enalapril at all NE doses (P<0.05).. Enalapril does not attenuate systemic and renal vascular responsiveness to exogenous NE in microalbuminuric IDDM despite adequate inhibition of the renin-angiotensin-aldosterone system. These findings suggest that the effect of NE on vasoconstriction is not counteracted effectively by ACE inhibition treatment alone.

Topics: Adult; Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 1; Enalapril; Female; Glomerular Filtration Rate; Heart Rate; Humans; Kidney; Male; Middle Aged; Norepinephrine; Vasoconstriction; Vasoconstrictor Agents

We sought to determine whether 6 months of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can improve conduit artery endothelial function in young subjects with insulin-dependent diabetes mellitus (IDDM).. Endothelial dysfunction is an early event in atherogenesis and has been demonstrated in young subjects with IDDM. ACE inhibitors have been shown to enhance conduit artery endothelial function in animal experiments and in patients with established coronary atherosclerosis, although their effect in IDDM is not known.. Ninety-one subjects (mean age 30.9 years, range 18 to 44) with stable IDDM but no clinical evidence of vascular disease were randomized to receive enalapril (20 mg once daily) (46 subjects) or placebo (45 subjects) in a randomized, double-blind, parallel-group study. Brachial artery flow-mediated dilation (FMD), an endothelium-dependent stimulus, and response to glyceryl trinitrate (GTN), which acts directly on vascular smooth muscle, were assessed noninvasively by means of high resolution external vascular ultrasound at baseline and after 12 and 24 weeks of treatment.. FMD was inversely correlated with total cholesterol (r=0.22, p=0.041) but not with any diabetic variables. Treatment with enalapril had no significant effect on FMD (p=0.67) or response to the endothelial-independent dilator GTN (p=0.45).. These data suggest that impairment of endothelial-dependent dilation in young subjects with IDDM is not improved by treatment with the ACE inhibitor enalapril. This lack of improvement may reflect the complex nature of vascular disease in IDDM, which can affect both endothelial and smooth muscle function.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Brachial Artery; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Double-Blind Method; Enalapril; Endothelium, Vascular; Female; Humans; Male; Regression Analysis; Vasodilation

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

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

Taking into account both the importance of microalbuminuria (MA) as a predictive parameter of clinical nephropathy in diabetic patients and the efficiency of exertion to show and/or to increase MA in both diabetic patients and normal individuals, we studied 37 type I diabetic patients divided into two groups: group A, with no MA at rest (n = 19), and group B, with MA at rest (n = 18). Group C comprised 10 healthy volunteers as controls. Changes of basal MA during exercise and postexercise were studied in all three groups. Normotensive patients with no metabolic disorders, normal renal function, and no proteinuria underwent an ergometric test up to 600 kg. This test was repeated after the administration of 20 mg enalapril in a single daily dose for 60 days. Body weight, systolic and diastolic arterial pressure, creatinine, and creatinine clearance were determined and showed no significant variations either between groups or with treatment. Microalbuminuria was studied in the three groups with and without administration of enalapril throughout the 2 months of the study. Determinations were performed under conditions of rest, exercise, and postexercise. Mean baseline MA values +/- SEM were as follows: at rest, 5.22 +/- 0.49, 58.36 +/- 13.24, and 4.73 +/- 0.45 micrograms/min for groups A, B, and C, respectively; with exercise, 15.19 +/- 4.43, 74.70 +/- 14.89, and 16.76 +/- 4.62 micrograms/min for groups A, B, and C, respectively; and postexercise, 32.04 +/- 6.64, 253.15 +/- 63.88, and 9.23 +/- 3.25 micrograms/min, respectively. The geometric means of the baseline to posttreatment MA ratio were as follows: at rest, 0.95, 1.59 (P < 0.01), and 1.03 for groups A, B, and C, respectively; with exercise, 1.53 (P < 0.01), 1.91 (P < 0.01), and 1.69 for groups A, B, and C, respectively; and postexercise, 2.94 (P < 0.01), 3.24 (P < 0.01), and 1.03 for groups A, B, and C, respectively. In conclusion, in the early diagnostic suspicion of diabetic nephropathy, the screening of postexercise MA during an ergometric test could be of help. Treatment with enalapril decreased MA in diabetic groups A (no MA at rest) and B (MA at rest) during exercise and postexercise, and also decreased MA in group B while at rest.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Enalapril; Exercise; Female; Humans; Male; Middle Aged

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

A longitudinal study for six months was conducted to demonstrate the influence of enalapril therapy on microalbuminuria in a group of patients with IDDM without arterial hypertension. An evaluation was also considered of its possible activity on other biochemical parameters, particularly plasma lipid levels. Thirty-four patients with IDDM were selected, with a mean age of 26.1 +/- 7.2 years and a mean clinical course of 11.8 +/- 5.6 years. Arterial blood pressure (ABP) was confirmed lower than 140/85 mmHg in all cases. Patients were administered 5 mg/day of enalapril and if a decrease in microalbuminuria higher than 25% was not achieved at the end of the first month of therapy, the dose was doubled (10 mg/day). No significant differences were found in ABP and in HbA1c throughout the study period. Albumin excretion in the initial period was 125.1 +/- 79.28 mg/24 h, at one month in the follow-up 47.6 +/- 44.1 mg/24 h, at three months 23.8 +/- 18.1 mg/24 h, and at the end of the 6th month 15.33 +/- 6.9 mg/24 h, all differences being significant. Renal function parameters and Na+ and K+ measurements remained unchanged for the follow-up period. No significant changes were detected for lipid and lipoprotein values for the length of the study. We conclude that therapy with enalapril in insulin-dependent diabetic patients without hypertension has an important effect on microalbuminuria during the first month of therapy; a stabilization in the normal range was reached in the third and sixth months of follow-up. No changes in arterial blood pressure nor in renal function were observed. Plasma lipid values were in the normal range throughout the study. Therefore, treatment for microalbuminuria with the ACEI assayed was efficient, in absence of arterial hypertension and irrespective of the metabolic control obtained. Future long-term studies are needed to evaluate the possible delay in the emergence of renal insufficiency.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Enalapril; Humans; Lipids; Longitudinal Studies

Based on animal experiments it has been proposed that antihypertensive agents may differentially influence albuminuria through their divergent effects on glomerular haemodynamics or glomerular sieving properties and may beneficially influence the progression of diabetic nephropathy even without an effect on blood pressure. However, to date this hypothesis has not been tested in normotensive patients with diabetic nephropathy. The main aim of this study was therefore to investigate the effects of the administration of two antihypertensive agents on albuminuria during rest and exercise. The study consisted of 3 x 3 randomised, cross-over periods with five days double blind administration of enalapril (E: 2.5 mg bid), nitrendipine (N: 5 mg bid) and placebo (P) on 18 Type 1 normotensive (blood pressure < 140/90 mmHg) diabetic patients with incipient diabetic nephropathy (albuminuria 30-300 mg/24 h, normal glomerular filtration rate, diabetes duration > 6 years and presence of diabetic reinopathy. The aim of this study was to investigate the effect of enalapril and nitrendipine on blood pressure values and albuminuria during exercise challenge (bicycle ergometry: 20 min at 75 W and 20 min at 100 W) in comparison to the placebo. Albumin excretion rates during pre-exercise rest (mean +/- SD; E: 6.2 +/- 6.0; N: 7.1 +/- 8.0; P: 7.7 +/- 7.0 mg/mmol creatinine) and during exercise (E: 8.7 +/- 9.4; N: 8.2 +/- 8.2; P: 11.1 +/- 11.4 mg/mmol creatinine) were comparable between the drugs and not significantly different after administration of placebo. Blood pressure values were significantly different between the medications (systolic blood pressure: p = 0.0269; diastolic blood pressure: p = 0.0021, ANOVA for repeated measurements). There were no significant correlations between blood pressure values and albuminuria at any time. In normotensive patients with incipient diabetic nephropathy low-dose administration of enalapril, nitrendipine and placebo does not result in clear cut differences in albuminuria.

Topics: Adolescent; Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Exercise Test; Female; Humans; Male; Middle Aged; Nitrendipine; Rest

Topics: Acetylglucosaminidase; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Humans; Nitrendipine; Single-Blind Method

The main aim of this study was to examine the effects of an angiotensin converting inhibitor, enalapril, and an alpha-1 (alpha-1) antagonist, doxazosin, on albumin excretion, renal haemodynamics and tubular function in insulin-dependent diabetes mellitus patients with nephropathy.. The study consisted of a four-week run-in period, a four-week active treatment period, a four-week wash-out period and a second four-week active treatment period.. The study was performed in the out-patient clinic at a university hospital.. Ten patients with insulin dependent diabetes mellitus with macroalbuminuria (> 200 micrograms min-1), mild to moderate hypertension (diastolic blood pressure 85-115 mmHg) and serum creatinine level below 200 mumol L-1 were included in the study.. The effect of the drugs on albumin and total protein excretion, beta-2-microglobulin, proximal tubular enzyme markers and renal haemodynamics.. Systolic and diastolic blood pressure were equally reduced by both drugs. Enalapril reduced albumin excretion from 1090 +/- 281 micrograms min-1 to 742 +/- 246 micrograms min-1 (P < 0.01) and total protein excretion from 2.0 +/- 0.4 g per 24 h to 1.3 +/- 0.4 per 24 h whereas doxazosin was without effect. Glomerular filtration rate and effective renal plasma flow were unchanged by either drug. Doxazosin increased filtration fraction from 0.21 +/- 0.02 to 0.23 +/- 0.01 (P < 0.05). The urinary excretion of the proximal enzyme markers N-acetyl-beta-glucosaminidase and alkaline phosphatase were elevated as well as urinary excretion of beta-2-microglobulin. However, neither the excretion of beta-2-microglobulin nor the enzyme markers were affected by either drug.. Enalapril, but not doxazosin, reduces albuminuria in insulin dependent diabetes mellitus patients with nephropathy. The drugs exert differential effects on renal haemodynamics.

Topics: Adult; Albuminuria; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Doxazosin; Enalapril; Female; Humans; Kidney Tubules; Male; Middle Aged; Renal Circulation

Topics: Adolescent; Chronic Disease; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Glycated Hemoglobin; Humans; Hypertension; Kidney

In order to compare the long-term effects of nitrendipine (CAS 39562-70-4) and enalapril (CAS 75847-73-3) on variables of glomerular and tubular function in type 1 diabetes mellitus, a single-blind, randomised comparative 1-year study was carried out in microalbuminuric patients (6 women, 14 men, age, 30-58 years, duration of diabetes, 3-41 years, HbA1 sigma 5.5-10%). 10 patients were treated with 20 mg/d nitrendipine, 10 patients were treated with 10 mg/d enalapril. On the average, urinary albumin excretion was decreased by 38 +/- 4% by nitrendipine (p < 0.01 vs. before treatment) and by 21 +/- 8% by enalapril (p < 0.05 vs. before treatment). The excretion of alpha 1-microglobulin decreased by 35 +/- 10% and by 39 +/- 9%, respectively (p < 0.05 vs. before treatment). Creatine clearance rose by 20 +/- 30% during nitrendipine treatment (p < 0.05 vs. before treatment) but was unchanged during enalapril treatment. Total kidney volume decreased by 23 +/- 4% (p < 0.01) and by 14 +/- 6% (p < 0.05), respectively. Blood pressure fell by 8 +/- 1% systolic and by 13 +/- 1% (diastolic) in nitrendipine-treated patients (both p < 0.01) and by 10 +/- 1% and 13 +/- 1% in enalapril-treated patients (both p < 0.01). Thus, nitrendipine long-term treatment of microalbuminuric type 1 diabetic appeared to be as effective as the treatment with enalapril in preventing or postponing the progression of diabetic nephropathy.

Topics: Adult; Albuminuria; Alpha-Globulins; Blood Pressure; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Heart Rate; Humans; Kidney Function Tests; Male; Middle Aged; Nitrendipine; Renin; Single-Blind Method

To determine whether long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor has a beneficial effect on the urinary microalbumin excretion and renal function in non-insulin-dependent diabetes mellitus (NIDDM) patients, enalapril (5 mg/day) was administered for 48 months.. -Fifty-two patients with NIDDM who had persistent microalbuminuria in the range of 20-300 mg/24 h, serum creatinine < 106.1 microM (1.2 mg/dl), supine systolic blood pressure (BP) < 150 mmHg, supine diastolic BP < 90 mmHg, and HbA1c < 10% were divided into four groups. Twenty-six patients with normotension were divided at random into two groups; one group received enalapril (5 mg/day) (NE group), the other did not receive enalapril (NC group). In the same way, 26 other patients who were already well-controlled with nifedipine (30 mg/day) over a long-term period (4-6 years) were divided at random into two groups; one received enalapril (5 mg/day) (HE group), the other did not receive enalapril (HC group).. After 48 months, urinary albumin excretion (UAE) was markedly reduced in group NE from 102.4 x/divided by 1.3 to 55.5 x/divided by 1.3 mg/24 h (P < 0.005), whereas no significant change occurred in group NC. In the well-controlled hypertensive groups, a significant reduction in UAE occurred in group HE (P < 0.05), whereas no significant change occurred in group HC. No changes in creatinine clearance, BP, or blood glucose control were seen during the study.. Treatment with enalapril for 48 months may have a beneficial effect on the decline of microalbumin excretion in NIDDM patients.

Topics: Acetylglucosaminidase; Albuminuria; beta 2-Microglobulin; Blood Pressure; Body Weight; Cholesterol; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Glycated Hemoglobin; Humans; Hypertension; Middle Aged; Nifedipine; Triglycerides

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

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

The effects of spirapril and isradipine on blood pressure, urinary albumin excretion and sodium-volume homeostasis in hypertensive insulin-dependent diabetic patients with nephropathy were assessed. Fifteen Type 1 diabetic patients aged 28-53 years with a diabetes duration of 19-37 years were studied. All had hypertension and diabetic nephropathy with a urinary albumin excretion of more than 300 mg/24 h. After a single blind placebo treatment period of 4 weeks the patients were randomly assigned to treatment with the calcium antagonist isradipine SRO 5 mg once daily or the ACE inhibitor spirapril 6 mg once daily for 6 months in a double-blind design. Isradipine lowered ambulatory systolic blood pressure from 152 +/- 12 to 141 +/- 11 mmHg (p < 0.05) and ambulatory diastolic pressure from 91 +/- 9 to 86 +/- 8 mmHg (p < 0.05). The blood pressure lowering effect of spirapril was similar: 156 +/- 13 vs 143 +/- 11 mmHg (p < 0.01) and 90 +/- 4 vs 84 +/- 4 mmHg (p < 0.05). The fractional albumin clearance was unchanged on isradipine but decreased after 6 months treatment with spirapril with on average 20% (p < 0.05). Total body exchangeable sodium decreased on spirapril treatment: 2994 +/- 296 vs 2636 +/- 194 meq/1.73 m2 (p < 0.05) and extracellular volume tended to do so (p = 0.12). On isradipine treatment these parameters remained unchanged. In conclusion both isradipine and spirapril lowered blood pressure in patients with diabetic nephropathy. Only the ACE inhibitor had demonstrable beneficial effects on urinary albumin excretion rate and the sodium-volume expansion seen in these patients.

Topics: Adult; Albuminuria; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Isradipine; Lipoproteins; Male; Middle Aged; Potassium; Sodium

To compare the effects of sodium depletion and of angiotensin I converting enzyme inhibition on microalbuminuria in insulin dependent diabetes.. Randomised, double blind, double dummy parallel study of normotensive diabetic patients with persistent microalbuminuria (30-300 mg/24 h) treated with enalapril or hydrochlorothiazide for one year after a three month, single blind placebo period.. Diabetic clinic in a tertiary referral centre.. 10 diabetic patients with low microalbuminuria (30-99 mg/24 h) and 11 with high microalbuminuria (100-300 mg/24 h).. 11 subjects (six with low microalbuminuria, five with high microalbuminuria) were given enalapril 20 mg plus placebo hydrochlorothiazide once daily and 10 (four with low microalbuminuria, six with high microalbuminuria) hydrochlorothiazide 25 mg plus placebo enalapril once daily.. Monthly assessment of urinary albumin excretion and mean arterial pressure; plasma active renin and aldosterone concentrations and renal function studies at 0, 6, and 12 months.. Median urinary albumin excretion decreased from 59 (range 37-260) to 38 (14-146) mg/24 h with enalapril and from 111 (33-282) to 109 (33-262) mg/24 h with hydrochlorothiazide (analysis of variance, p = 0.0436). During the last three months of treatment with enalapril five patients had persistent normoalbuminuria (2-3 times below 30 mg/24 h), five low microalbuminuria, and one high microalbuminuria; in the hydrochlorothiazide group one had normoalbuminuria, three low microalbuminuria, and six high microalbuminuria (chi 2 test = 6.7; p = 0.03). Mean arterial pressure did not differ before (98 (SD 7) with enalapril v 97 (9) mm Hg with hydrochlorothiazide) or during treatment (88 (7) with enalapril v 90 (7) mm Hg with hydrochlorothiazide (analysis of variance, p = 0.5263)). Glomerular filtration rate did not vary. The aldosterone to active renin ratio was decreased by angiotensin I converting enzyme inhibition and increased by sodium depletion, showing treatment efficacy.. Angiotensin I converting enzyme inhibition by enalapril effectively reduces microalbuminuria in normotensive diabetic patients whereas hydrochlorothiazide is not effective. Changes in blood pressure and activity of the renin-angiotensin-aldosterone system may contribute to these different effects.

Topics: Adolescent; Adult; Albuminuria; Diabetes Mellitus, Type 1; Double-Blind Method; Enalapril; Female; Humans; Hydrochlorothiazide; Male; Middle Aged

A double blind crossover trial was performed on the effect of enalapril on urinary albumin excretion (UAE) in normotensive insulin dependent diabetics. Nineteen normoalbuminuric (UAE < 30 mg/24 h) and 17 microalbuminuric patients (UAE > 30 and < 300 mg/4 h) were studied; all patients had post prandial blood glucose levels < 180 mg/dl, HbA1 < 11% and none had chronic diabetic complications. Both groups had similar age, years of diabetes, body mass index and protein ingestion (70 g/day). Fifty percent of patients in each group received 5 mg/day of enalapril or placebo during one year, and during the second year the therapy was switched. No changes were observed in blood pressure, post prandial blood glucose, HbA1 and plasma electrolytes during the study period. A reduction in creatinine clearance, within normal limits, in both groups of patients treated with enalapril and no modifications with placebo were observed. UAE decreased significantly in normo and microalbuminuric patients initially treated with enalapril from 19 +/- 8 to 8 +/- 2 and from 71 +/- 19 to 39 +/- 12 mg/24 h respectively. These values increased during the placebo period to 23 +/- 6 and 47 +/- 13 mg/24 h respectively. Among those initially treated with placebo, UAE increased only in normoalbuminurics from 19 +/- 7 to 28 +/- 9 mg/24 h. During subsequent treatment with enalapril, UAE decreased in both groups. It is concluded that, in this group of patients, enalapril decreases UAE, possibly preventing the progression to severe forms of diabetic nephropathy.

Topics: Adolescent; Adult; Albuminuria; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Humans

To investigate the effect of low doses of the angiotensin converting enzyme inhibitor enalapril on renal haemodynamics and albuminuria in normotensive and hypertensive type 1 (insulin-dependent) diabetic patients with incipient or overt nephropathy.. Twenty-two type 1 (insulin-dependent) diabetic patients with persistent microalbuminuria or macroalbuminuria and normal serum creatinine were studied. Of all patients, 16 males and 6 females, age 45 +/- 13 years, diabetes duration 19 +/- 11 years, insulin dose 38 +/- 11 U/day, 10 were normotensive and 12 were hypertensive. After 3 months of run-in period the patients were assigned to treatment with 5 mg or 10 mg enalapril based on the presence of normotension or hypertension respectively. Before and after 6 months of treatment, renal function was assessed by evaluation of glomerular filtration rate (99m Tc-DTPA), renal plasma flow (131-I iodohippurate), filtration fraction and renal vascular resistance. Mean arterial pressure, albumin excretion rate, urinary urea excretion and glycated haemoglobin were also determined.. Administration of enalapril resulted in both groups of patients in a significant fall in mean arterial pressure, albumin excretion rate, glomerular filtration rate, filtration fraction, and renal vascular resistance. Decreasing albumin excretion did not correlate with a drop in systemic blood pressure or filtration fraction. No significant variations were observed in renal plasma flow, in urinary urea excretion or in glycated haemoglobin.. Our results suggest that low doses of enalapril are effective in influencing renal haemodynamics and reducing urinary albumin excretion in both normotensive and hypertensive type 1 (insulin-dependent) diabetic patients with incipient or overt nephropathy. The lowering effect of the angiotensin converting enzyme inhibitor on albuminuria seems to be independent of the action on systemic blood pressure and renal haemodynamic changes.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged

An open, randomized, cross-over study was undertaken to assess the effects of lisinopril and nifedipine on albumin excretion, renal haemodynamics and segmental tubular reabsorption in overt diabetic nephropathy. The study consisted of a 4-week run-in period, a 3-week active treatment period, a 4-week wash-out period and a second 3-week active treatment period. Twelve patients with type 1 diabetes with albuminuria, mild to moderate hypertension and a serum creatinine level of less than 200 mumol l-1 were included. Lisinopril reduced albumin excretion from 1343 +/- 337 micrograms min-1 to 879 +/- 299 micrograms min-1 (P less than 0.01), whereas nifedipine was without effect, 1436 +/- 336 micrograms min-1 vs. 1319 +/- 342 micrograms min-1. Glomerular filtration rate (GFR) was unchanged by either drug. Both drugs increased effective renal plasma flow (ERPF) by about 20%. No differences between the drugs were observed with regard to their effect on renal haemodynamic parameters. By contrast, nifedipine exerted an inhibitory effect on several proximal tubular transport markers, whereas lisinopril was without effect. The different actions on tubular transport mechanisms exerted by lisinopril and nifedipine may contribute to the observed effect on albumin excretion.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Biological Transport; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Kidney Tubules; Lisinopril; Lithium; Male; Nifedipine; Sodium

Although angiotensin-converting enzyme (ACE) inhibitors may lower urinary protein excretion, it is not known whether these agents can completely eliminate microalbuminuria. This study examined whether the ACE inhibitor, enalapril, can abolish low levels of microalbuminuria in diabetic patients. Six men with adult-onset, insulin-dependent diabetes mellitus, most of whom had low levels of microalbuminuria, were studied in a clinical research center, where they ate a controlled diet and performed regulated exercises daily. After 2 weeks of baseline measurements, the patients received 5-15 mg/day of enalapril for 4 weeks. They were then monitored for 2 more weeks without enalapril. Urinary albumin excretion (UAE) fell in each patient with enalapril treatment and was within the normal range at some time during enalapril treatment in 5 of 6 patients. After stopping enalapril, UAE rose. UAE was 53.6 +/- 20.7 (SEM), 31.5 +/- 8.9 and 39.4 +/- 8.0 mg/24 h during the baseline, enalapril and postenalapril periods, respectively (baseline vs. enalapril, p less than 0.02; postenalapril vs. enalapril, p less than 0.01). The magnitude of fall in UAE correlated with the baseline UAE (r = 0.90). During enalapril treatment, renal plasma flow and GFR did not change, although blood pressure fell slightly. These data suggest that enalapril can reduce or abolish UAE in diabetic patients with microalbuminuria. Whether long-term treatment with enalapril will continue to suppress microalbuminuria and prevent progressive diabetic nephropathy remains to be determined.

Topics: Albuminuria; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renal Circulation

We evaluated the effects of angiotensin converting enzyme inhibition upon the urinary excretion of albumin in 36 insulin dependent normotensive diabetic patients with adequate metabolic control and no evidence of renal failure. 19 subjects had normal levels of albumin excretion (< 30 mg/24 h) and 17 showed microalbuminuria from 30 to 300 mg/24 h. Half of the patients were randomly selected in each group to receive enalapril, 5 mg/day. A progressive decrease in albumin excretion levels was observed for both enalapril treated subgroups, from 18.9 +/- 8.3 to 8.1 +/- 2.7 mg/24 h (normoalbuminurics) and from 73.1 +/- 25.0 to 40.1 +/- 26.3 mg/24 h (microalbuminurics). In contrast, an increase in albumin excretion from 19.4 +/- 6.8 to 29.4 +/- 14.2 mg/24 h was observed in non treated normoalbuminuric patients. Untreated patients with microalbuminuria remained with stable albumin excretion levels (67.4 +/- 39 to 64.8 +/- 23.4 mg/24 h). Enalapril treatment was associated to a significant (p < 0.05) decrease in creatinine clearance which remained within normal limits. Blood pressure, Na and K plasma levels and total proteins remained normal throughout the study. Thus, angiotensin converting enzyme inhibition reduces the urinary excretion of albumin in insulin dependent diabetics with normo or microalbuminuria.

Topics: Adolescent; Adult; Albuminuria; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dietary Proteins; Enalapril; Humans

The effect of enalapril on albumin excretion rate was studied in two groups of age- and sex-matched Type 1 (insulin-dependent) diabetic patients, aged 15-20 years, with persistent microalbuminuria greater than 20 micrograms/min. Group 1 contained six patients with systolic blood pressure greater than or equal to 75th percentile for age and sex, group 2 six normotensive patients. Enalapril (10-20 mg/day) was given for six months. Albumin excretion rate, glomerular filtration rate, renal plasma flow, blood pressure at rest and during exercise, and angiotensin converting enzyme activity were measured before, after three weeks' and six months' treatment and six months after treatment withdrawal. Albumin excretion rate decreased in all patients after three weeks' (mean decreases 55% in group 1, 65% in group 2) and six months' treatment (35% in group 1, 61% in group 2). Systolic blood pressure remained unchanged in both groups. Diastolic pressure was reduced after three weeks in group 1 (p = 0.001). No reduction in increment in systolic pressure during exercise test occurred in any group during treatment. Angiotensin converting enzyme activity decreased in all patients after three weeks (p = 0.001) and six months (p = 0.003). This correlated to the decrease in albumin excretion rate after three weeks (r = 0.79, p = 0.05) and six months (r = 0.59, p = 0.04). HbA1c, mean blood glucose and glomerular filtration rate remained unchanged during the study in both groups. Renal plasma flow tended to increase after three weeks' and six months' treatment in group 2 (p = 0.06, respectively) but not in group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 1; Enalapril; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Insulin; Male; Peptidyl-Dipeptidase A; Renal Circulation

Using a prospective randomised double-blind crossover design, the effect of the angiotensin converting enzyme inhibitor enalapril compared to a placebo was studied in 18 normotensive, normoalbuminuric Type 1 (insulin-dependent) diabetic children. Each patient had a high normal or clearly elevated glomerular filtration rate (145 ml.min-1.1.73 m2 or higher) in the 6 months prior to the study. Enalapril, 0.5 mg.kg-1.day-1, was given for 4 weeks followed by placebo for 4 weeks, or vice versa. At the end of each period, glomerular filtration rate, renal plasma flow, blood pressure, plasma renin activity, and converting enzyme activity were determined. Enalapril caused significant reduction (p = less than 0.001) in blood pressure and converting enzyme activity and a rise in plasma renin activity. A slight but not significant rise in glomerular filtration rate and renal plasma flow without change in filtration fraction was observed. These data suggest that the renin angiotensin system is not involved in the glomerular hyperfiltration of Type 1 diabetes, and can be interpreted as showing no evidence for the presence of intraglomerular hypertension in these patients.

Topics: Adolescent; Albuminuria; Blood Pressure; Child; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Placebos; Prospective Studies; Random Allocation; Renal Circulation

To determine the effect of enalapril maleate and low-dose hydrochlorothiazide therapy on blood pressure and glucose and lipid homeostasis in hypertensive type II diabetic patients, we treated nine of these patients sequentially with placebo, hydrochlorothiazide (25 mg/d with supplemental potassium chloride), and enalapril (10 to 20 mg/d). Sitting blood pressure fell significantly and to comparable levels with both hydrochlorothiazide and enalapril monotherapy. Enalapril monotherapy was associated with a slight, but not significant, fall in fasting blood glucose levels and with a significant fall in hemoglobin A1c levels. This improved glucose homeostasis could not be explained satisfactorily by changes in peripheral insulin sensitivity or hepatic glucose output, determined with the euglycemic clamp technique, or by changes in fasting serum insulin levels or monocyte insulin binding. In these low doses, hydrochlorothiazide did not worsen glucose homeostasis. Serum total cholesterol levels were significantly lower with enalapril therapy than with hydrochlorothiazide therapy or with placebo, and serum high-density lipoprotein cholesterol and triglyceride levels did not change significantly with either treatment. Thus, by providing effective blood pressure control and beneficial metabolic effects, enalapril therapy appears ideal for treatment of hypertension in diabetic patients. Similarly, low-dose hydrochlorothiazide therapy appears to have fewer metabolic complications in these patients and is, therefore, a logical alternative to substitute for, or add to, enalapril therapy.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Lipids; Male; Middle Aged; Random Allocation

To assess the effectiveness of inhibition of angiotensin converting enzyme in preventing diabetic nephropathy.. Randomised follow up study of normotensive diabetics with persistent microalbuminuria (30-300 mg/24 hours) treated with enalapril or its matched placebo for one year. Double blind for first six months, single blind for last six months.. Diabetic clinic in tertiary referral centre.. Treatment group and placebo group each comprised 10 normotensive diabetics with persistent microalbuminuria.. Treatment group was given enalapril 20 mg daily and controls matched placebo. Patients were given antihypertensive treatment after one year.. Albumin excretion, arterial pressure, and renal function.. In last three months of trial three of 10 patients taking placebo had diabetic nephropathy (albumin excretion greater than 300 mg/24 hours). No patients taking enalapril developed nephropathy and five showed normal albumin excretion (less than 30 mg/24 hours) (p = 0.005, Mann-Whitney test). Mean arterial pressure was reduced by enalapril throughout study (p less than 0.005) but increased linearly with placebo (p less than 0.05). Albumin excretion decreased linearly with enalapril but not placebo. An increase in albumin excretion with placebo was positively related to the increase in mean arterial pressure (r = 0.709, p less than 0.05, Spearman's rank test). With enalapril total renal resistances and fractional albumin clearances improved progressively (time effect, p = 0.0001).. Inhibition of angiotensin converting enzyme prevents development of nephropathy in normotensive diabetics with persistent microalbuminuria. This may be due to reduction in intraglomerular pressure and to prevention of increased systemic blood pressure. Future studies should compare long term effects of inhibitors of converting enzyme with other antihypertensive drugs.

Topics: Adult; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enalapril; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney; Middle Aged; Random Allocation

Glomerular filtration rate (GFR) (thalamate clearance), renal plasma flow (RPF) (hippuran clearance), and urinary albumin excretion rate (AER) were measured in 10 normoalbuminuric, normotensive insulin-dependent diabetic patients and 8 normal subjects before and during acute angiotensin converting enzyme (ACE) inhibition by means of enalapril (10 mg IV). The effect of placebo versus enalapril (30 mg day-1) was also studied for 3-month treatment periods in the insulin-dependent diabetic patients. Acute ACE-inhibition caused a decline in filtration fraction (FF) from 0.259 +/- 0.011 (+/- SE) to 0.237 +/- 0.013 (2p less than 0.01) in the diabetic patients, and from 0.210 +/- 0.010 to 0.188 +/- 0.006 (2p less than 0.02) in the normal subjects. Mean arterial blood pressure was lowered from 90 +/- 1 to 84 +/- 2 mmHg (2p less than 0.01) and from 91 +/- 1 to 86 +/- 2 mmHg (2p less than 0.05). No significant change in blood glucose, AER or fractional albumin excretion (theta Alb) was seen in either group. After 3 months of enalapril treatment FF was decreased from 0.253 +/- 0.011 to 0.235 +/- 0.011 (2p less than 0.05), AER from 5.6 x/ divided by 1.7 to 4.3 x/divided by 1.6 micrograms min-1 (2p less than 0.01) and theta Alb from 1.22 +/- 0.22 x 10(-6) to 0.92 +/- 0.12 x 10(-6) (2p less than 0.02). The decline in total renal resistance was not significant (0.175 +/- 0.013 to 0.165 +/- 0.012 mmHg ml-1 min-1) and significant changes in GFR, RPF, mean arterial pressure or HbA1c were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney; Reference Values; Renal Circulation

In diabetic patients, it has been suggested that angiotensin converting enzyme inhibitors may be associated with unexplained hypoglycaemic episodes. Such a side effect may limit the use of these drugs in diabetic hypertensive patients. Ten insulin-dependent diabetic patients mean age 38.4 +/- 13.1 years, mean diabetes duration 10.3 +/- 6.6 years (m +/- SD) were selected on the basis of good glycaemic control: HbA1: 7.6 +/- 0.9 per cent (upper limit of normal value less than 7.5 per cent) on continuous subcutaneous insulin infusion. In a double blind study, they were randomly and successively allocated for a 3 months period to enalapril 20 mg daily or placebo. Before treatment, after enalapril and placebo, mean blood glucose values, HbA1, daily insulin dosage were recorded as well as the number of clinical and biological (less than 3 mmol/l) hypoglycaemic episodes. Peripheral insulin sensitivity was assessed by euglycaemic insulin clamp technique. Compared to placebo, enalapril did not induce any modification of daily insulin dosage, glycaemic control. The incidence of hypoglycaemic episodes was similar. Neither peripheral insulin sensitivity was modified by enalapril. In the conditions of this study, enalapril did not interfere with glycaemic control in insulin-dependent diabetics in good metabolic control.

Topics: Administration, Cutaneous; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 1; Double-Blind Method; Enalapril; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin Infusion Systems; Male; Middle Aged; Random Allocation

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 1; Enalapril; Humans; Hypertension; Time Factors

Although it is known that glomerular filtration rate (GFR) declines in response to angiotensin converting enzyme (ACE) inhibition, recent observations using GFR(CYSTATIN C) have shown a paradoxical increase calling into question its validity. In this descriptive study, we aimed to reconcile this observation by simultaneously measuring GFR(CYSTATIN C), GFR(CREATININE), and gold standard GFR(INULIN) responses to ACE inhibition. Adolescents with type 1 diabetes and hyperfiltration (n = 9, GFR(INULIN) ≥ 135 mL/min/1.73 m(2)) or normofiltration (n = 11) were studied during clamped euglycemia at baseline and after 3-week enalapril therapy. In hyperfilterers, the anticipated GFR(INULIN) decline before and after enalapril was observed (174 ± 29 mL/min/1.73 m(2) to 140 ± 26 mL/min/1.73 m(2), P = .01). Although GFR(CYSTATIN C) equations tended to underestimate while GFR(CREATININE) equations tended to overestimate baseline GFR(INULIN) in hyperfilterers, both approaches generally reflected declining GFR(INULIN) responses to enalapril. Normofilterers demonstrated a trend toward rising GFR(INULIN) in response to enalapril (112 ± 16 mL/min/1.73 m(2) to 119 ± 27 mL/min/1.73 m(2), P = .35). Although all estimating equations tended to overestimate baseline GFR(INULIN), they generally reflected the rising trend in GFR(INULIN) in response to enalapril in normofilterers. Although GFR(INULIN) declines in response to enalapril among hyperfilterers, we confirm the previous observation that it demonstrates a trend to rising among normofilterers. These group trends are both reflected by cystatin C- and creatinine-based estimates.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Child; Creatinine; Cystatin C; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Predictive Value of Tests; Sensitivity and Specificity

To evaluate the frequency of normalization, the persistence of remission, and the impact on normalization of glycemic control and lipid profile, we analyzed data from a retrospective observational cohort study of type 1 diabetic children and adolescents with abnormal urinary albumin excretion (UAE).. All diabetic children and adolescents (n = 41) who had persistent abnormal UAE in the period of 1984 to 2008 and followed up until 2009 (follow-up duration = 13.1 ± 6.2 years) were included in the study. Nine patients progressed to macroalbuminuria; 24 patients were administered ACE inhibitor treatment.. The cumulative prevalence of abnormal UAE was 9%. During follow-up, 14 of 17 untreated and 19 of 24 treated patients reverted to normoalbuminuria. In the remission group compared with the nonremission group, A1C levels during follow-up decreased (7.5 ± 1.0 vs. 9.4 ± 1.2%, P < 0.0001) and serum HDL cholesterol increased (52.7 ± 11.3 vs. 42.7 ± 8.6 mg/dL, P < 0.05). The micro-macroalbuminuric patients had lower HDL cholesterol (51.0 ± 11.4 vs. 62.4 ± 13.6 mg/dL, P < 0.0001) than 134 normoalbuminuric diabetic patients.. Microalbuminuria and macroalbuminuria were not permanent in most of our diabetic children and adolescents. If abnormal UAE values are high and persist for >1 year, only long-lasting treatment with ACE inhibitors seems able to induce persistent remission, especially when associated with good metabolic control and high HDL cholesterol levels.

Topics: Adolescent; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Child; Cholesterol, HDL; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Enalapril; Follow-Up Studies; Humans; Hyperglycemia; Longitudinal Studies; Prevalence; Remission Induction; Retrospective Studies

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Humans; Losartan; Male; Prognosis; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Assessment; Tetrazoles; Treatment Outcome

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Male; Metabolic Syndrome; Ramipril; Tetrazoles; Valine; Valsartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Long-Term Care; Renal Dialysis; Telmisartan; Treatment Outcome

In patients with diabetes, altered diurnal blood pressure (BP) regulation (high night-to-day [N/D] ratio, or "nondipping") is associated with increases in albumin excretion and a decline in the glomerular filtration rate (GFR) by an unknown mechanism. Because it is known that renin angiotensin system (RAS) activation and defective glucose control contribute to adverse renal outcomes, we examined renal responses to high glucose and to manipulation of the RAS in adolescents (mean age 14 +/- 2 years) with uncomplicated type 1 diabetes, segregated into two groups on the basis of the presence or absence of normal N/D BP ratio. In the first experiment, renal hemodynamic comparisons were made during euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l), maintained by modified clamp techniques. The induction of hyperglycemia resulted in a significant increase in GFR and filtration fraction (FF) in the high N/D ratio group. In the second experiment, we examined the renal response to graded angiotensin II (Ang II) infusion while subjects were euglycemic and salt replete. High N/D ratio was associated with an enhanced FF response to Ang II. In the third experiment, the N/D ratio and GFR were assessed after 3 weeks of ACE inhibition. This maneuver corrected the high N/D ratio, but it had no effect on glomerular hyperfiltration. These results suggest that RAS activation does not explain the hyperfiltration state, nor can it explain the poor outcomes, at least in this population. However, the observed deleterious hemodynamic responses to high glucose and Ang II and the insensitivity to ACE inhibition may, taken together, provide an explanation for the adverse renal outcomes in patients with type 1 diabetes and high N/D ratio.

Topics: Adolescent; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Mass Index; Circadian Rhythm; Diabetes Mellitus, Type 1; Enalapril; Glomerular Filtration Rate; Glucose Clamp Technique; Hemodynamics; Humans; Renal Circulation; Renin-Angiotensin System; Vascular Resistance

Angioedema and cough are known side effects of angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme is a potent inhibitor of kinase II, which facilitates the breakdown of bradykinin. An increase in bradykinin levels results in continued prostaglandin E2 synthesis, vasodilation, increased vascular permeability, and increased interstitial fluid. In contrast, the angiotensin II receptor blockers (ARBs) do not increase bradykinin levels. Angioedema as a complication of ACE inhibitor therapy is not widely recognized; this complication is even less recognized with second-line ARBs. We report angioedema associated with losartan (an ARB) in a patient who had experienced angioedema secondary to enalapril (an ACE inhibitor). Almost half of patients with ARB-associated angioedema also had developed angioedema while receiving ACE inhibitor therapy. Clinicians should exercise caution when using ARBs in patients with a history of angioedema secondary to ACE inhibitors.

Topics: Adult; Angioedema; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Diabetes Mellitus, Type 1; Enalapril; Female; Humans; Losartan; Pharyngitis

Glomerular structural modifications were measured in kidney biopsies from two follow-up studies in type-1 diabetic patients with microalbuminuria and in kidney donors. Stereologic methods were used to obtain data on glomerular composition and absolute quantities per glomerulus to supplement data on diabetic glomerulopathy previously published. Diabetic patients at baseline (n=37) showed significant changes compared with controls (n=11). The volume fraction of tuft/glomerulus was increased, the proportion of capillary surface facing peripheral basement membrane was decreased (0.72+/-0.04 vs 0.77+/-0.03, P=0.0008), the ratio of mesangial surfaces, urinary/capillary, was decreased (0.67+/-0.17 vs 1.11+/-0.28, P<10(-4)), and the average capillary diameter was increased (8.9+/-0.9 microm vs 7.5+/-1.0 microm, P=0.0002). The total volume of mesangial extracellular material per glomerulus was increased (P=0.01), whereas glomerular volume was not significantly different from controls. Follow-up biopsies after antihypertensive treatment with ACE-inhibitor (n=7) or beta-blocker (n=6; 36-48 months) and after intensive insulin treatment (n=7; 24-33 months) showed no change. In a conventionally treated group (n=9), the glomerular volume, the volume of extracellular material/glomerulus, and the capillary length increased. The mean capillary diameter did not correlate with the glomerular volume. In conclusion, the development of diabetic glomerulopathy entails structural modifications of the glomerular tuft. Antihypertensive and intensified insulin treatment seem to slow the progression of ultrastructural changes.

Topics: Adult; Albuminuria; Capillaries; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Extracellular Matrix; Female; Humans; Insulin; Insulin Infusion Systems; Kidney Glomerulus; Male; Metoprolol; Microscopy, Electron; Treatment Outcome; Ultrasonography

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Severity of Illness Index

Our goal was to investigate the effect of antihypertensive drugs on the juxtaglomerular apparatus (JGA) in young type-1 diabetic patients with microalbuminuria.. Twelve patients were allocated to treatment with either an angiotensin-converting enzyme inhibitor (group 1, six subjects) or a beta-receptor blocker (group 2, six subjects). A comparable group of nine patients without antihypertensive treatment provided reference values (group 3, nine subjects). Renal biopsies were taken at baseline and after a median of 40 months (groups 1 and 2) and 30 months (group 3). Using light microscopy with 1microm serial sections of the plastic-embedded biopsies, volumes of the JGA and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were obtained.. A significant decrease of the volume of the JGA (P=0.026) and of the volume of the JGA relative to that of its corresponding glomerulus (P=0.0005) was noted in the reference group only. Negative correlations existed between the increase in the luminal area of the afferent arteriole and mean diastolic blood pressure in the study period in group 1 (P=0.024) and group 2 (P=0.032).. Our results showed that a decrease in the size of the JGA is offset by antihypertensives. The negative correlation between the change in the luminal area of the afferent arteriole and mean diastolic blood pressure in groups 1 and 2 suggest that renal protection in antihypertensive treatment may be through a better constriction of the afferent arteriole protecting the glomerulus from systemic blood pressure.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Humans; Juxtaglomerular Apparatus; Male; Metoprolol

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

Renal failure in multiple myeloma can be precipitated during hemodynamic perturbances of renal blood flow, as seen secondary to volume depletion, radiocontrast dye, and nonsteroidal anti-inflammatory agents. We report two cases of acute renal failure that developed suddenly after initiation of angiotensin-converting enzyme (ACE) inhibitor, both with biopsy-proven cast nephropathy. ACE inhibitors may contribute to the intratubular light chain cast formation and acute "myeloma kidney" in susceptible patients.

Topics: Acute Kidney Injury; Aged; Angiotensin-Converting Enzyme Inhibitors; Back Pain; Captopril; Diabetes Mellitus, Type 1; Enalapril; Humans; Hypertension; Male; Multiple Myeloma

Topics: Acute Kidney Injury; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diuretics; Electrocardiography; Enalapril; Female; Humans; Hyperkalemia; Ibuprofen; Middle Aged; Spironolactone

Acute renal failure and hyperkalemia due to angiotensin-converting enzyme inhibitors have been described in diabetic patients with other predisposing conditions. The case reported here involves a patient with type 1 diabetes mellitus, microalbuminuria and normal renal function who was treated with enalapril. Two years after initiation of this therapy, at a time when glycemic control was poor, he presented with symptomatic hyperkalemia and impaired renal function accompanied by hyporeninemic hypoaldosteronism. This case illustrates that reversible impairment of renal function and hyperkalemia can present after 2 years of treatment with angiotensin-converting enzyme inhibitors in patients with precipitating factors.

Topics: Acute Kidney Injury; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Humans; Hyperkalemia; Hypertension; Hypoaldosteronism; Male; Precipitating Factors

We postulated that nitric oxide (NO)-mediated endothelial function would be improved by acute and short-term treatment with an angiotensin converting enzyme (ACE) inhibitor in patients with type I diabetes mellitus, in whom endothelial function is depressed. Nine type I diabetic patients and eight healthy subjects underwent forearm blood flow measurement using strain gauge plethysmography during intraarterial infusion of incremental doses of endothelium-dependent (acetylcholine [ACh]) and endothelium-independent (sodium nitroprusside [SNP]) vasodilators. Pretreatment ACh responses were depressed in diabetic patients relative to the normal subjects (P < 0.05). No difference between the groups was evident in response to SNP. Acute ACE inhibition (with intrabrachial enalaprilat) enhanced ACh responses in the diabetic patients (P < 0.005), with a further improvement evident after 1 mo of oral therapy with enalapril (P < 0.001) when ACh responses were normalized. ACE inhibition did not affect SNP responses. We conclude that acute administration of the ACE inhibitor, enalaprilat, enhances NO-mediated endothelial function in type I diabetic patients, with further improvement evident after 4 wk of enalapril therapy.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Enalapril; Enalaprilat; Endothelium; Humans; Male; Middle Aged; Nitric Oxide

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 1; Enalapril; Humans; Imidazoles; Kidney Transplantation; Losartan; Male; Middle Aged; Tetrazoles; Uremia

Acetazolamide (ACTZ), a carbonic anhydrase inhibitor, causes a fall in renal plasma flow and glomerular filtration (GFR). It is generally believed that the tubuloglomerular feedback (TGF) mechanism is responsible. This study examined whether, in patients with diabetes mellitus, the renal hemodynamic response to ACTZ is intact and whether the angiotensin-converting enzyme inhibitor, enalapril, which would be expected to block TGF, attenuates this response to ACTZ. Six men with insulin-dependent diabetes mellitus lived in a clinical research center for 8 weeks and received enalapril 5-15 mg/day from the third through sixth week. At 2, 6 and 8 weeks p-aminohippurate (PAH) and inulin clearances were performed over eleven 30-min periods. ACTZ (150 mg) was given intravenously after 180 min. In both the pre- and postenalapril studies, PAH clearance fell after ACTZ administration (-60 +/- 15 and -66 +/- 20 ml/min/l1.73 m2, respectively, p < 0.05 for each study). In contrast, with enalapril treatment PAH clearance after ACTZ tended to rise (29 +/- 12 ml/ min/1.73 m2, p = 0.07). GFR after ACTZ fell during the pre- and postenalapril studies (-19 +/- 3 and -13 +/- 1 ml/min/1.73 m2, respectively, p < 0.05 for each study) but not with enalapril treatment (-6 +/- 3 ml/min/1.73 m2). After ACTZ was administered, estimated renal vascular resistance rose during both the pre- and postenalapril studies (p < 0.05 and p < 0.01, respectively) and fell with enalapril treatment (p < 0.05). These data indicate that enalapril alters the renal hemodynamic effects of ACTZ in patients with diabetes mellitus, possibly by inhibiting tubuloglomerular feedback.

Topics: Acetazolamide; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Carbonic Anhydrase Inhibitors; Diabetes Mellitus, Type 1; Enalapril; Feedback; Glomerular Filtration Rate; Humans; Kidney Tubules; Male; Middle Aged; Renal Circulation

Topics: Acute Kidney Injury; Aged; Angiotensin-Converting Enzyme Inhibitors; Bicarbonates; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diuresis; Enalapril; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Rhabdomyolysis

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of cortisol and its inactive metabolite, cortisone, and protects the mineralocorticoid receptor from activation by cortisol. Sodium and fluid retention is a well documented phenomenon in insulin-dependent diabetes mellitus (IDDM), but it is not known whether diabetes-associated alterations in cortisol metabolism contribute to its pathogenesis. Therefore, we evaluated some aspects of cortisol metabolism by measuring urinary metabolites of cortisol and cortisone in eight microalbuminuric and eight normoalbuminuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahydrocortisone (THE) was lower than that in the control group (P < 0.05 to P < 0.01). Both the allo-THF/THF ratio, a parameter of 5 alpha/5 beta-reduction of cortisol, and the cortisol to cortisone metabolite ratio (THF+allo-THF/THE), which reflects the overall direction of the cortisol to cortisone interconversion, were lower in the IDDM groups (P < 0.05 to P < 0.01). In the combined subjects (n = 24), allo-THF, allo-THF/THF, and THF+allo-THF/THE were inversely correlated with hemoglobin A1c (r = -0.69, P < 0.001; r = -0.61, P < 0.01; and r = -0.58, P < 0.01, respectively). Upper arm segmental blood volume, estimated by an electrical impedance technique, was positively correlated with the cortisol to cortisone metabolite ratio in both the control subjects (r = 0.77; P < 0.05) and the IDDM patients in whom it was measured (r = 0.56; P < 0.05; n = 13), whereas the regression line was shifted leftward in IDDM (i.e. a lower ratio at the same blood volume; P < 0.03, by analysis of covariance). In seven microalbuminuric IDDM patients, the angiotensin-converting enzyme inhibitor, enalapril (10 mg daily for 6-12 weeks), resulted in a moderate further lowering of the cortisol to cortisone metabolite ratio (P < 0.05). The present data suggest a chronic hyperglycemia-related impairment in the reduction of corticoids to tetrahydro metabolites and an imbalance in 11 beta HSD. Altered 11 beta HSD activity is unlikely to be primarily responsible for the sodium and fluid retention in IDDM. Moreover, an additional mechanism of action of angiotensin-converting enzyme inhibition might be provided by an effect on 11 beta HSD activity.

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Blood Volume; Case-Control Studies; Cortisone; Creatinine; Diabetes Mellitus, Type 1; Enalapril; Glycated Hemoglobin; Humans; Hydrocortisone; Potassium; Reference Values; Regression Analysis; Renin

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

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

The renal effects of intravenous injection of 10 mg enalapril were investigated in 16 normotensive microalbuminuric type 1 (insulin-dependent) diabetic patients. After enalapril the following changes were observed: fractional albumin clearance (theta Alb) decreased from 9.9 (3.0-23.8) to 8.2 (2.0-18.3) x 10(-6) (2 P < 0.01); filtration fraction (FF) decreased from 0.260 (0.225-0.312) to 0.253 (0.190-0.297) (2 P < 0.01); renal plasma flow (RPF) increased from 565 (411-690) to 623 (449-785) (2 P < 0.01); and glomerular filtration rate (GFR) remained stable at 149 (128-181) versus 150 (124-185) ml.min-1 (NS). These values were unchanged after placebo (n = 8), except for RFP which decreased from 606 (401-701) to 559 (381-677) ml.min-1 (2 P < 0.05) and GFR which was reduced from 148 (111-173) to 138 (111-167) (2 P < 0.05). A reduction in mean blood pressure from 94 (87-103) to 89 (79-101) mmHg (2 P < 0.05) was found in the enalapril group and a minor reduction in the placebo group from 97 (83-106) to 96 (81-104) mmHg (2 P < 0.05) was also noted. The relative changes in systolic blood pressure in the enalapril group correlated with changes in theta Alb (Spearman's r = 0.66, 2 P < 0.02) and FF (r = 0.53, 2 P < 0.05). Acute inhibition of angiotensin converting enzyme does not reduce the pathological hyperfiltration in these patients and a reduction in theta Alb and FF can not be dissociated from the reduction in blood pressure.

Topics: Adult; Albuminuria; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diastole; Enalapril; Glomerular Filtration Rate; Heart Rate; Hematocrit; Hemodynamics; Humans; Middle Aged; Renal Circulation; Systole; Urine; Vascular Resistance

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Enalapril; Glomerular Filtration Rate; Humans; Infusions, Intravenous; Kidney; Male; Renal Circulation

Topics: Adult; Captopril; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Humans; Hypertension; Hypoglycemia; Male; Nifedipine

Topics: Child; Diabetes Mellitus, Type 1; Enalapril; Glomerular Filtration Rate; Humans

The short-term effect (2 weeks) of angiotensin-converting enzyme inhibitor (enalapril) on renal hemodynamics and urinary albumin excretion was investigated in eleven normotensive patients with incipient diabetic nephropathy (IDN). Six patients had had elevated baseline glomerular filtration rate (GFR) and each responded to enalapril with a decline in the GFR, from a mean of 160.7 to 134 ml/min/1.73 m2, (p less than 0.05). Their respective filtration fraction values also decreased from a mean of 27.8 to 23.8% (p less than 0.01). Such renal hemodynamic change was accompanied by a decrease in urinary albumin excretion (33 to 19 micrograms/min, p less than 0.05). The remaining 5 patients had displayed normal baseline GFR (mean, 109.6 ml/min/1.73 m2), responded to enalapril with minimal change in the GFR (115.2 ml/min/1.73 m2) and showed no significant improvement in their microalbuminuria. It is concluded that enalapril is effective in lowering glomerular filtration pressure and ameliorating microalbuminuria in the normotensive patient with IDN only when the baseline GFR is elevated.

Topics: Albuminuria; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Renal Circulation; Time Factors

In view of the pharmacological and chemical reasons for using ACE-inhibitors to treat diabetic hypertension, a group of 40 outpatients were treated with Enalapril. The sample consisted of 20 outpatients, 6 males, 14 females aged 48-76 (mean age 63.75), 18 of whom had type II and 2 type I diabetes and 11 under treatment by diet and hypoglycaemic drugs or insulin. All these patients presented slight or moderate essential arterial hypertension (diastolic pressure less than 115 mmHg). For about one year 17 of the patients were given 20 mg/die Enalapril and the remaining three 10 mg/die in a single morning dose. In 16 cases no other treatment was given. In 4 a non-potassium conserving diuretic was also given. Check-ups before six months into and at the end of treatment showed: a statistically significant reduction in systolic (p less than 0.05) and diastolic (p less than 0.01) pressure. In contrast no significant change was noted in heart beat, glycaemia before or after meals, body weight, glycosylated haemoglobin or any other blood chemical parameter considered. In one case only there was a slight increase in proteinuria that was however present at the start of treatment. As far as side effects are concerned there was one case of cardiac palmus during treatment and one case of coughing that regressed totally when treatment was suspended but nothing else of significance. It should be noted that the antidiabetic treatment remained unchanged throughout the period considered in most cases and at most was subjected to minimal qualitative and quantitative adjustments.

Topics: Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged