enalapril and Diabetes-Mellitus--Type-2

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

Type 2 diabetes is reaching epidemic proportions throughout the world, which has major health implications as such patients have considerably increased risk of coronary heart disease (CHD). The renin-angiotensin-aldosterone system (RAAS) is involved in a wide range of adverse effects that contribute to the pathogenesis of CHD in diabetic patients, including vascular haemodynamic regulation, oxidative stress and hypertrophy of vascular cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. In diabetic patients ACE inhibitors and ARBs both effectively lower blood pressure, particularly in combination with low-dose thiazide diuretics, and may be considered first line therapies in the treatment of diabetic hypertension. Additionally they have important renoprotective actions independent of their blood pressure-lowering action, which is of particular benefit in diabetic patients, who are at increased risk of developing nephropathy. ARBs are generally well tolerated, but ACE inhibitor therapy is associated with some side effects such as cough and both may result in hyperkalaemia. Blockade of the RAAS with these agents appears to play an important role not only in protecting from renal disease, but it may also help to reduce morbidity and mortality from certain vascular diseases in diabetic patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Heart Failure; Humans; Randomized Controlled Trials as Topic; Renin-Angiotensin System

Diabetic nephropathy is characterised by hypertension and persistent proteinuria. If ineffectively controlled, a progressive decline in renal function can result in end-stage renal disease. Patients with diabetic nephropathy are also at greatly increased risk of cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors display additional renoprotective effects beyond systemic blood pressure lowering, perhaps due to reduction in intraglomerular pressure by inhibition of angiotensin II activity. In type 2 diabetics, ACE inhibitors have variable effects, with some studies showing a reduction in microalbuminuria, prevention of the progression to macroalbuminuria and maintenance of renal function. Randomised studies have demonstrated that angiotensin II receptor blockers (ARBs), as well as controlling systemic blood pressure, delay progression of proteinuria in patients with diabetic nephropathy. Telmisartan has a number of features that may make it particularly suitable for the treatment of diabetic nephropathy. In addition to its long duration of action and almost exclusive faecal excretion, its high lipophilicity should assist in tissue penetration. The Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study was designed to compare the long-term renal outcome of treatment with telmisartan 40.80 mg versus enalapril 10.20 mg (with titration to the higher dose after 4 weeks) in patients with type 2 diabetes, mild-to-moderate hypertension and albuminuria. The primary endpoint is the change in glomerular filtration rate after 5 years' randomised treatment. Secondary endpoints are annual changes in glomerular filtration rate, serum creatinine and urinary albumin excretion, as well as incidences of end-stage renal disease, cardiovascular events, all-cause mortality and adverse events. The groundbreaking DETAIL study revealed that telmisartan conferred comparable renoprotection to enalapril and was associated with a low incidence of mortality.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension; Longitudinal Studies; Male; Randomized Controlled Trials as Topic; Telmisartan

Enalapril, an angiotensin converting enzyme (ACE) inhibitor usually administered orally once daily, decreases blood pressure by lowering peripheral vascular resistance without increasing heart rate or output. It is effective in lowering blood pressure in all grades of essential and renovascular hypertension. Patients not responding adequately to enalapril monotherapy usually respond with the addition of a thiazide diuretic (or a calcium antagonist or beta-blocker), and rarely require a third antihypertensive agent. Enalapril is at least as effective as other established and newer ACE inhibitors, and members of other antihypertensive drug classes including diuretics, beta-blockers, calcium antagonists and alpha-blockers, but therapy with enalapril may be less frequently limited by serious adverse effects or treatment contraindications than with other drug classes. The most frequent adverse effect limiting all ACE inhibitor therapy in clinical practice is cough. This favourable profile of efficacy and tolerability, and the substantial weight of clinical experience, explain the increasing acceptance of enalapril as a major antihypertensive treatment and supports its use as logical first-line therapeutic option.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Kidney; Randomized Controlled Trials as Topic

Cardiovascular (CV) disease fatality rates are higher for women compared with men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), the ratio of adenosine-stimulated to rest myocardial blood flow (MBF), is an indicator of coronary microvascular dysfunction and predicts major adverse CV events. We performed a post hoc analysis to determine whether there was a sex disparity in coronary microvascular dysfunction among 46 men and 27 women with well-controlled type 2 diabetes and without clinical evidence of obstructive CAD. We found that women had a higher rest MBF, lower CFR, and worse diastolic function compared with men. In addition, rest MBF was positively correlated with worse diastolic function in women. We previously showed that mineralocorticoid blockade improved CFR in men and women with type 2 diabetes, implicating aldosterone in the pathophysiology of coronary microvascular dysfunction. We therefore examined aldosterone levels and found that women had larger increases in aldosterone in response to an angiotensin-II infusion than did men. In conclusion, among individuals with type 2 diabetes and good cardiometabolic control, women had worse myocardial perfusion and diastolic function compared with men. The greater aldosterone responsivity in women may be a mechanism for this sex effect.

Topics: Adolescent; Adult; Aged; Blood Flow Velocity; Coronary Artery Disease; Coronary Circulation; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Humans; Male; Middle Aged; Sex Factors; Young Adult

Plasminogen activator inhibitor-1 (PAI-1) is implicated in the pathophysiology of cardiovascular disease (CVD) and increased in individuals with type 2 diabetes mellitus (T2DM). Adipose tissue produces PAI-1, and pericardial fat is a CVD risk factor. We sought to determine the relationship between PAI-1 and pericardial fat in males and females with well-controlled T2DM.. The study population consisted of 32 males and 19 females, aged 35-70 years with T2DM, without clinical evidence of CVD or other active medical problems except for hypertension. Subjects were studied under good cardiometabolic control. Study procedures included fasting blood work and cardiovascular imaging. Cardiac magnetic resonance imaging of the heart was used to identify and quantify pericardial fat from the bifurcation of the pulmonary trunk to the last slice containing cardiac tissue.. PAI-1 was positively correlated with pericardial fat (β = 0.72, r = 0.72, P < 0.001) as well as with homeostatic model assessment of insulin resistance (r = 0.31, P = 0.03) and serum triglycerides (r = 0.27, P = 0.05). In a multivariable regression model, controlling for insulin sensitivity, triglycerides, and body mass index, pericardial fat was independently associated with PAI-1 (β = 0.80, P < 0.001).. PAI-1 is positively associated with pericardial fat in individuals with T2DM.

Topics: Adipose Tissue; Adiposity; Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Female; Humans; Male; Middle Aged; Pericardium; Plasminogen Activator Inhibitor 1; Risk Factors; Simvastatin

To examine the antihypertensive efficacy and safety of indapamide sustained-release (SR)/amlodipine compared with enalapril/amlodipine in patients 65 years and older with uncontrolled blood pressure (BP) on monotherapy, a post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria) was conducted. NESTOR randomized 570 patients (n=197, aged ≥65 years) with hypertension (systolic BP 140-180/diastolic BP <110 mm Hg) to indapamide SR 1.5 mg or enalapril 10 mg. If target BP (<140/85 mm Hg) was not achieved at 6 weeks, amlodipine 5 mg was added with uptitration to 10 mg if required. A total of 107 patients aged 65 years and older received dual therapy (53 indapamide SR/amlodipine and 54 enalapril/amlodipine). Amlodipine uptitration occurred in 22 and 24 patients, respectively. At 52 weeks, mean systolic BP (±SE) reduction was significantly greater with indapamide SR/amlodipine vs enalapril/amlodipine 6.2±2.7 mm Hg (P=.02). Indapamide SR/amlodipine was also associated with a greater BP response rate (88% vs 75%, respectively). Both regimens were well tolerated. Indapamide SR/amlodipine may be more effective than enalapril/amlodipine for lowering systolic BP in patients with hypertension aged 65 years and older.

Topics: Aged; Aged, 80 and over; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Indapamide; Male; Treatment Outcome; Vascular Stiffness

Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.. After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.. After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).. In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Renin; Stroke Volume; Treatment Failure

Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic ACE inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25 mg, hydrochlorothiazide (HCTZ) 12.5 mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race, and statin use. Treatment with spironolactone improved coronary microvascular function, raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Coronary Circulation; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Male; Microcirculation; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

Combination treatments for hypertension most often include a renin-angiotensin-aldosterone system (RAAS) inhibitor. However, systolic blood pressure (SBP) remains difficult to control. Non-RAAS-inhibiting strategies such as calcium channel blocker/thiazide-like diuretic combinations may offer effective alternatives.. Hypertensive diabetic patients with microalbuminuria were included in this retrospective, post-hoc analysis of the Natrilix SR Versus Enalapril Study in Hypertensive Type 2 Diabetics With MicrOalbuminuRia (NESTOR) trial if they were uncontrolled on monotherapy (indapamide slow release (SR) 1.5 mg or enalapril 10mg) and had been given add-on amlodipine 5 mg. Patients uncontrolled with monotherapy/amlodipine 5mg were uptitrated to 10 mg.. After 52 weeks, supine SBP/diastolic BP (DBP) decreased from baseline by 26±13/14±9 mm Hg in the indapamide SR/amlodipine group (n = 135) and by 21±14/11±9 mm Hg in the enalapril/amlodipine group (n = 156) (P = 0.006 for ΔSBP). In the amlodipine 10mg subgroup, SBP/DBP decreased from baseline by 26±13/13±9 mm Hg in the indapamide SR/amlodipine group (n = 62) and by 20±13/12±8 mm Hg in the enalapril/amlodipine group (n = 77) (P = 0.02 for ΔSBP). Treatment with indapamide SR/amlodipine was well tolerated. Few patients experienced edema, with no between-group differences. As expected with diuretics, slight changes in kalemia and in uricemia were observed in the indapamide SR/amlodipine group. Changes in fasting glucose, lipids, natremia, and creatinine clearance were similar between groups.. Indapamide SR/amlodipine results in superior SBP reduction with a safety profile in line with that of its components and tolerability equivalent to that of an angiotensin-converting enzyme inhibitor/amlodipine strategy.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Retrospective Studies; Treatment Outcome

To evaluate the impact of a 12-week combined antihypertensive therapy with enalapril + indapamide on endothelial dysfunction in patients with arterial hypertension (AH) and diabetes mellitus (DM) type 2.. 30 patients with AH stage II-III and DM type 2 age from 40 to 65 years were included into research. The combined antihypertensive therapy with enalapril 28.6 ± 1.9 + indapamide 2.5 ± 0 mg/day was assigned for 12 weeks. We studied endothelial function by determining the concentration of NO metabolites and endothelin-1 in serum and urine, the results of occlusion test.. After 12-week therapy, 100% of the patients achieved BP goals. There was no impairment of carbohydrate metabolism. Endothelial function was improved in hypertensive patients with T2DM: there were increases in both serum and urinary NO production (by 381 and 48.2%, respectively) and decreases in urinary endothelin-1 secretion (by 56.3%). The number of patients with normal microcirculation increased from 13.3 to 53.3% (p < 0.001) by reducing the number of patients with abnormal (hyperemic and stagnant-stasic) types of microcirculation.. Twelve-week treatment with the combined antihypertensive medication. The combined antihypertensive therapy with enalapril + indapamide is highly effective and safe for recovering endothelial function in hypertensive patients with T2DM.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Indapamide; Laser-Doppler Flowmetry; Male; Middle Aged; Nitric Oxide; Prospective Studies; Sodium Chloride Symporter Inhibitors; Treatment Outcome; Vasodilation

Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN).. DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need.. At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteinuria, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH-vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7±10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P=0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml.. FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Brazil; Chi-Square Distribution; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kaplan-Meier Estimate; Losartan; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Blockade of the renin-angiotensin-aldosterone system (RAAS) by either the angiotensin converting enzyme inhibitor (ACE-I) or the angiotensin II receptor blocker (ARB) has been shown to reduce albuminuria and delay the progression of diabetic nephropathy. This study evaluated the effect of dual blockade of the RAAS by adding an ACEI or an ARB to the administration of either drug alone on albuminuria in Asian type 2 diabetic patients with nephropathy.. 34 patients were randomly assigned to receive either enalapril 20 mg or losartan 100 mg once daily for eight weeks. Following this, all patients received a combination of enalapril 10 mg and losartan 50 mg daily for eight weeks, followed by enalapril 20 mg and losartan 100 mg daily for another eight weeks. The blood pressure and 24-hour urinary albumin excretion (UAE) were monitored.. Following monotherapy with enalapril, there was a mean and standard error (SE) reduction in the UAE and mean arterial pressure (MAP) of 9.8 (SE 6.8) percent (p-value is 0.061) and 5.3 (SE 2.2) mmHg (p-value is 0.026), respectively; the reduction in UAE and MAP following monotherapy with losartan was by 10.9 (SE 14.1) percent (p-value is 0.053) and 4.5 (SE 1.9) mmHg (p-value is 0.034), respectively. Combination therapy with enalapril and losartan further reduced the UAE (11.2 [SE 8.7] percent, p-value is 0.009] despite there being no significant change in the MAP (-1.2 [SE 1.47] mmHg, p-value is 0.42). The adverse effects included dry cough (seven [19.4 percent] patients, resulting in the withdrawal of medication in two patients), and transient hyperkalaemia (two [six percent] patients).. Dual blockade of the RAAS is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Asian People; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Humans; Losartan; Male; Middle Aged

Dipeptidyl peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that dipeptidyl peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum dipeptidyl peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of dipeptidyl peptidase-IV and ACE inhibition in humans.

Topics: Adult; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Enalapril; Female; Heart Rate; Hemodynamics; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Pyrazines; Renal Circulation; Sitagliptin Phosphate; Sodium; Triazoles

Although serum phosphorus, calcium, and calcium-phosphorus product levels have been associated with cardiovascular events and mortality in patients with normal kidney function, most studies have not examined the association of these minerals with outcomes when collected repeatedly over time.. We evaluated the association of serum phosphorus, calcium, and calcium-phosphorus product levels with cardiovascular events and mortality in 950 participants of the Appropriate Blood Pressure Control in Diabetes trial by both time-dependent Cox regression models using the cumulative average of minerals measured over time and fixed covariate Cox regression models with only baseline values of these minerals.. There were 42 deaths and 193 cardiovascular events among the participants, who were followed for an average of 4.8 years following randomization. A significant association was noted between baseline serum phosphorus >3.9 mg/dL and baseline calcium-phosphorus product >36.8 mg(2)/dL(2) compared with the lowest referent category with the adjusted risk of cardiovascular death (hazard ratio [HR] 5.00; 95% confidence interval [CI], 1.70-14.72) and (HR 10.01; 95% CI, 2.55-39.31), respectively. However, in time-dependent models using mineral values repeated during the course of the study, only the average of serum phosphorus remains significant (HR 4.25; 95% CI, 1.15 to 16.65).. In the Appropriate Blood Pressure Control in Diabetes cohort, serum phosphorus, but not serum calcium or calcium-phosphorus product, was associated with cardiovascular mortality in time-dependent Cox regression models. Thus, serum phosphorus levels may be more reliable in predicting cardiovascular mortality in patients with type 2 diabetes.

Topics: Antihypertensive Agents; Calcium; Cardiovascular Diseases; Cohort Studies; Comorbidity; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Male; Middle Aged; Nisoldipine; Phosphorus; Proportional Hazards Models

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

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

Therapeutic efficiency of spirapryl and its combination with carvedilol in the treatment of diastolic cardiac insufficiency in patients with type 2 diabetes and essential arterial hypertension (AH). Criteria for inclusion in the study of 86 patients (20 men and 66 women) were diastolic cardiac insufficiency diagnosed as recommended by the Working Group of European Society of Cardiologists (2002). The patients were divided into 2 groups receiving either spirapryl (n = 42) or spirapryl with carvedilol (alpha, beta-adenoblocker). The patients were examined before and 24 weeks after therapy for the evaluation of their clinical condition, tolerance of physical activity, transmitral and transcuspidal diastolic flows (ECG and Doppler-ECG). All therapeutic modalities significantly improved the patients" conditions, diastolic function, and ECG/ECG characteristics, but the best results were obtained with combined therapy that had beneficial effect on transmitral and transcuspidal diastolic flows (P < 0.01) and tolerance of physical exercises (P < 0.05). It is concluded that combined treatment with spirapryl and its combination with carvedilol is more efficient for the management of diastolic cardiac insufficiency than carvedilol monotherapy.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Carbazoles; Carvedilol; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echocardiography, Doppler, Color; Enalapril; Female; Follow-Up Studies; Heart Failure, Diastolic; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Propanolamines; Retrospective Studies; Treatment Outcome

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

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

To study the effects of enalapril and telmisartan on hemodynamic parameters and diastolic function (DF) of the left ventricle (LV) in patients with type 2 diabetes mellitus (DM) concurrent with arterial hypertension (AH).. The study included 64 patients (mean age 54.3 +/- 5.2 years) with type 2 DM. For the treatment of AH, Group 1 (n = 31) received enalapril and Group 2 (n = 33) took telmisartan (micardis). Their examination comprised 24-hour blood pressure (BP) monitoring, Holter ECG monitoring, and echocardiography. The fasting and postprandial levels of blood glucose and glycosylated hemoglobin were measured to evaluate the compensation for carbohydrate metabolism.. In patients with type 2 DM and elevated BP, LV diastolic dysfunction was detectable in the absence of reduced contractility. LF DF, isovolumetric relaxation time, and the ratio of the peak blood flow velocity during early diastolic filling to that during atrial systole were found to correlate with HbA(1c), diastolic hypertension time index, and the diurnal duration of asymptomatic ST-segment depression. During enalapril therapy, the goal level of BP was achieved in systolic BP (SBP) in 77% of the patients and diastolic BP (DBP) in 64.5%, which was accompanied by reductions in the number of nondippers and night-pickers in 45.4% of cases with no changes in HbA(1c) and LV DF.. In addition to effective SBP and DBP control with the normalization of their diurnal profiles in 87.5% of the patients with abnormal circadian rhythm, the 24-week course of telmisartan therapy ensures improvements in carbohydrate metabolism and LVDF.

Topics: Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Glucose; Blood Pressure; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Enalapril; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Telmisartan; Treatment Outcome; Ventricular Function, Left

In short-term studies, the replacement of red meat in the diet with chicken reduced the urinary albumin excretion rate (UAER) and improved lipid profile in type 2 diabetic patients with diabetic nephropathy. The present study sought to assess these effects over a long-term period, comparing the effects of a chicken-based diet (CD) versus enalapril on renal function and lipid profile in microalbuminuric type 2 diabetic patients.. This was a randomized, open-label, controlled clinical trial with a follow-up of 1 year.. The trial involved outpatients with type 2 diabetes attending a clinic of the Division of Endocrinology at a tertiary-care hospital.. Twenty-eight microalbuminuric patients completed the study and were evaluated.. Patients were randomized to an experimental diet (CD plus active placebo) or to treatment with enalapril (10 mg/day plus usual diet).. The main outcome measure was UAER (according to immunoturbidimetry). Blood pressure, anthropometric indices, and compliance were also evaluated monthly. The glomerular filtration rate ((51)Cr-EDTA), and lipid, glycemic, and nutritional indices, were measured at baseline and quarterly.. The UAER was reduced after CD (n = 13; from 62.8 [range, 38.4 to 125.1] to 49.1 [range, 6.2 to 146.5] microg/min; P < .001) and after enalapril (n = 15; from 55.8 [range, 22.6 to 194.3] to 23.1 [range, 4.0 to 104.9] microg/min; P < .001), and this was already significant at month 4. The reduction in UAER after CD (32%; 95% confidence interval, 6.7% to 57.6%) and after enalapril treatment (44.7%; 95% confidence interval, 28.3% to 61.1%; P = .366) were not significantly different.. The CD and the angiotensin-converting enzyme inhibitor enalapril promoted a similar reduction of UAER in patients with type 2 diabetes and microalbuminuria in a 12-month follow-up period.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Chickens; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet; Dietary Proteins; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Lipids; Male; Meat; Middle Aged; Nutrition Assessment; Treatment Outcome

Blood pressure control is the main influential variable in reducing microalbuminuria in patients with type 2 diabetes. In this subanalysis of the Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetics with micrOalbuminuRia (NESTOR) study, we have compared the effectiveness of indapamide sustained release (SR) and enalapril in reducing blood pressure and microalbuminuria in patients > or =65 years of age.. Of the 570 hypertensive patients with type 2 diabetes and persistent microalbuminuria in the NESTOR study, 187 (33%) individuals > or =65 years of age were included in this analysis. Of these, 95 patients received indapamide SR 1.5 mg and 92 patients received enalapril 10 mg, taken once daily in both cases. Adjunctive amlodipine and/or atenolol was added if required.. The urinary albumin-to-creatinine ratio decreased by 46% in the indapamide SR group and 47% in the enalapril group. Noninferiority of indapamide SR over enalapril was demonstrated (P = .0236; 35% limit of noninferiority) with a ratio of 0.95 (95% CI: 0.68, 1.34). Mean arterial pressure decreased by 18 mm Hg and 15 mm Hg in the indapamide SR and the enalapril groups, respectively (P = .1136). The effects of both treatments seen in these elderly patients were similar to those observed in the main population, although the extent of the reduction in microalbuminuria was slightly higher. Both treatments were well tolerated, and no difference between groups was observed regarding glucose or lipid profiles.. Indapamide SR is not less effective than enalapril in reducing microalbuminuria and blood pressure in patients aged >65 years of age with type 2 diabetes and hypertension.

Topics: Aged; Albuminuria; Antihypertensive Agents; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Indapamide; Kidney Function Tests; Male

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

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

With the aim to determine the influence of reducing systolic blood pressure in urinary TGF-beta1 of type 2 diabetes (DM2) with diabetic nephropathy (DN), 21 subjects with type 2 diabetes and proteinuria >500 mg/24 h were studied. Amlodipine and ramipril were added to their previous antihypertensive treatment for 12 weeks. Urinary TGF-beta1 (UTGF-beta1) was determined at 0, 4, 8 and 12 weeks. Plasma TGF-beta1 was determined at 0 and 12 weeks. Subjects whose mean systolic blood pressure (SBP) during treatment were under 140 mmHg were grouped as the better SBP controlled group (n = 11) and those with SBP equal to or greater than 140 mHg were grouped in a moderate SBP controlled group (n = 10). Compared to baseline, mean log UTGF-beta1 at 4, 8 and 12 weeks decreased (-0.22 +/- 0.15 pg/mg; p = 0.04) in better SBP controlled group but not in the moderate SBP controlled group (-0.12 +/- 0.08 pg/mg, p = 0.82). Mean SBP correlated with UTGF-beta1 (r = 0.458, p = 0.0357), and this effect was independent of HbA1c (p = 0.042). By controlling SBP in DM2 subjects with DN we might decrease UTGF-beta1. We propose that reduction of UTGF-beta1 is due to a decrease in renal TGF-beta1 production.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Blood Glucose; Blood Pressure; Captopril; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Potassium; Propranolol; Ramipril; Transforming Growth Factor beta1

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

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

To compare the effects of a cardioselective beta-blocker (nebivolol) with those of an angiotensin-converting enzyme inhibitor (enalapril) on parameters of insulin sensitivity, peripheral blood flow and arterial stiffness during one extended glucose clamp experiment.. A randomized, double-blind crossover trial, consisting of two 12-week treatment phases separated by a 4-week wash-out phase.. Patients with type 2 diabetes and arterial hypertension were randomly assigned to one of two treatment sequences (nebivolol-enalapril, enalapril-nebivolol). Haemodynamic, metabolic and other laboratory measurements were carried out on the first and last day of each treatment period by means of a glucose clamp experiment that also involved the measurement of blood flow and arterial stiffness.. Twelve patients were included in this study, of which two dropped out early. Efficacy parameters were therefore available for 10 patients. There was no significant difference in any of the primary efficacy parameters. Moreover, the effects on blood pressure did not significantly differ between both treatments. Six adverse events happened during treatment with nebivolol compared with two during treatment with enalapril, but only one was regarded as possibly related to the treatment.. This pilot study shows that the combined measurement of insulin sensitivity, blood flow and arterial stiffness is feasible. Nebivolol and enalapril did not show different effects with regard to these parameters in hypertensive diabetic patients. If these results are confirmed in larger clinical trials, this would argue against the reservations against beta-blockers as drugs of first choice in patients with diabetes because of potential metabolic side-effects.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Arteries; Benzopyrans; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Elasticity; Enalapril; Ethanolamines; Female; Glucose Clamp Technique; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Nebivolol; Pilot Projects; Plethysmography; Pulsatile Flow

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

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

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

Angiotensin-converting enzyme (ACE) inhibitors may reduce urinary albumin excretion (UAE) by decreasing glomerular pressure and increasing glomerular charge selectivity through preservation of glycosaminoglycans. The effect of Angiotensin II antagonism on glomerular charge selectivity remains to be determined. The aim of this study was to compare the effects of an AT1 blocker losartan and an ACE inhibitor (ACE-I) enalapril on UAE, extracellular matrix proteins, glycosaminoglycan excretion (UGAG) and red blood cell anionic charge (RBCCh) which are the indirect markers of glomerular basement membrane anionic content in hypertensive Type 2 diabetic patients. Twenty-four patients were randomised into two groups and received either enalapril (520 mg/d) or losartan (50100 mg/d). All parameters were measured at baseline and after six months of treatment. At the end of six months, systolic and diastolic blood pressures (BP), UAE rates, UGAG excretion and RBCCh were significantly and equally reduced in both treatment groups compared with baseline. RBCCh was negatively correlated with UAE (r=-0.57, p<0.0001) and UGAG excretion (r=-0.57, p<0.0001); UAE was correlated with UGAG excretion (r=0.58, p<0.0001). In conclusion, enalapril and losartan treatment were equally effective in reducing BP, UAE as well as UGAG excretion and preserving RBCCh in hypertensive Type 2 diabetic patients. ACE inhibition and AT1-receptor blockade may have favourable effects on preserving glomerular anionic content in hypertensive diabetic patients.

Topics: Acetylglucosaminidase; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Collagen Type IV; Diabetes Mellitus, Type 2; Enalapril; Extracellular Matrix Proteins; Female; Fibronectins; Glomerular Basement Membrane; Humans; Hypertension; Losartan; Male; Middle Aged

Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reduces albuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50 or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similar antialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d, patients with diabetes and a urinary albumin:creatinine ratio (UACR) > or = 50 mg/g were randomly assigned to receive enalapril plus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100). After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < or = 130/80 mmHg). The primary study end points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary end points included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic and diastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12, UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (both eplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantly different in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For the secondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4 (P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BP decreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similar decreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alone significantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Eplerenone; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Incidence; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone; Treatment Outcome; United States

Circulating adhesion molecules may have a prognostic significance as markers of endothelial damage. Drugs which inhibit the renin-angiotensin system may be effective in reducing circulating or tissue adhesion molecules, albeit data available are scarce. The aim of the study was to investigate the effects of an angiotensin-converting enzyme (ACE) inhibitor, enalapril and a highly selective angiotensin receptor blocker, candesartan cilexetil, on circulating adhesion molecules in a large sample of patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was comparative, multicenter, randomized and double blind, with two parallel groups.. NIDDM patients with a diagnosis of mild (grade 1) essential hypertension were included in the study, at the end of a 2-week placebo run-in period. The primary end-point of the study was to evaluate changes of intercellular adhesion molecule-1 (ICAM-1) plasma levels during treatment. The secondary end-points were: changes in vascular cells adhesion molecule-1 (VCAM-1), von Willebrand factor (vWF), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) circulating levels and of urinary albumin excretion rate (AER) as well; 129 patients were randomized: 66 in the candesartan group and 63 in the enalapril group, 118 of them completed the scheduled 24-week treatment period.. Candesartan and enalapril equally reduced circulating level of ICAM-1 and exerted comparable effects on changes of other adhesion molecules and coagulation factors. A similar blood pressure-lowering effect was observed with the two drugs (candesartan: from 148/90 +/- 11/8 to 132/82 +/- 12/7 mmHg, P < 0.01, enalapril: from 148/91 +/- 12/8 to 131/85 +/- 14/6 mmHg, P < 0.01). Candesartan was more effective than enalapril in the reduction of albuminuria (P < 0.05 between treatments), although urinary protein excretion can be considered normal in the majority of patients. The two drugs were comparable in terms of adverse events reported.. Candesartan and enalapril showed similar effects on blood pressure and on circulating adhesion molecules. In this study urinary protein excretion was reduced more by candesartan.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Fibrinogen; Humans; Hypertension; Intercellular Adhesion Molecule-1; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Tetrazoles; Vascular Cell Adhesion Molecule-1; von Willebrand Factor

Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus (NIDDM). However, no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM. Therefore, we have investigated the effect of an angiotensin-converting enzyme inhibitor, enalapril, and a highly selective angiotensin receptor blocker, candesartan cilexetil, on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM. Eight patients were treated with candesartan (8 to 16 mg per day) and 7 with enalapril (10 to 20 mg per day) for 1 year. Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment. Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated; moreover, endothelium-dependent vasodilation to acetylcholine was assessed. A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs. Vascular collagen content was reduced and metalloproteinase-9 was increased by candesartan, but not by enalapril. Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen. The 2 drugs equally improved endothelial function. In conclusion, antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct, at least in part, alterations in small resistance artery structure in hypertensive patients with NIDDM. Candesartan may be more effective than enalapril in reducing collagen content in the vasculature.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arteries; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Type 2; Echocardiography; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Male; Matrix Metalloproteinase 9; Middle Aged; Subcutaneous Tissue; Tetrazoles

Blood pressure reduction is associated with a reduced risk for cardiovascular events and death, particularly in patients with both hypertension and type 2 diabetes mellitus.. The aim of this study was to compare the antihypertensive efficacy, tolerability, and effect on metabolic risk factors of manidipine, a new dihydropyridine calcium channel antagonist, and enalapril, a widely used angiotensin-converting enzyme inhibitor, in patients with mild to moderate essential hypertension and type 2 diabetes.. This multicenter, double-blind trial compared manidipine and enalapril in patients with type 2 diabetes and hypertension (diastolic blood pressure [DBP] 90-104 mm Hg, systolic blood pressure [SBP] < or =190 mm Hg). Following a 3-week, single-blind placebo run-in period, eligible patients were randomized to receive either manidipine 10 mg or enalapril 10 mg once daily for 24 weeks. The dose was doubled after 3 weeks in patients who had not responded to treatment (DBP > or =90 mm Hg). The primary efficacy end point was change in DBP from baseline to the end of the study. Secondary outcomes were the responder rate (DBP <90 mm Hg and/or a DBP reduction of > or =10 mm Hg) at the end of the study. Other secondary measures were changes from baseline to the end of the study in heart rate and in the following measures obtained by ambulatory blood pressure monitoring (ABPM): 24-hour, daytime, and nighttime mean DBP and SBP, and the trough:peak ratio. Blood glucose, glycosylated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, and creatinine were measured at the end of the placebo run-in period and the end of treatment. The study had 80% power to detect a between-treatment difference in mean sitting DBP of >3 mm Hg.. One hundred twenty-four patients were enrolled in the study. After the placebo run-in period, 13 patients were excluded from the study: 4 for DBP values outside the specified limits, 7 at their request, and 2 for adverse events. Thus, 111 patients met the eligibility criteria and were randomized to treatment (53 manidipine, 58 enalapril). The population consisted of 61 men and 50 women with a mean (SD) age of 62 (11) years and a body mass index of 28.2 (2.4) kg/m2. Among patients who completed the study, drug doses were doubled in 67.6% (25/37) of patients in the manidipine group and 60.0% (24/40) of patients in the enalapril group (P = NS). Similar reductions in blood pressure were observed in both groups, from a mean (SD) of 164 (12)/97.5 (5) mm Hg at baseline to 141 (12)/84.5 (6) mm Hg at the end of the study in the manidipine group (P < 0.01), and from 159 (12)/98 (4) mm Hg to 139 (12)/86 (8) mm Hg in the enalapril group (P < 0.01). The proportion of responders was 66.7% (32/48) in the manidipine group and 60.0% (30/50) in the enalapril group; the difference between groups was not significant. Twenty-four-hour ABPM revealed significant (P < 0.01) and similar reductions in blood pressure in both groups, with a trough:peak ratio of approximately -50%. Neither drug affected heart rate. Among the statistically significant changes in metabolic parameters, significant reductions in HbA(1c) (from 6.7% [1.4%] to 6.2% [1.1%]) and blood glucose concentrations (from 152 [44] to 143 [44] mg/dL) were observed only in the manidipine group (P < 0.05). The incidence of adverse events was similar between groups.. In the present study, manidipine was as metabolically neutral and as effective as enalapril in reducing blood pressure in hypertensive patients with type 2 diabetes, providing a sustained 24-hour antihypertensive effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Lipoproteins; Male; Middle Aged; Nitrobenzenes; Piperazines

Assessment of vascular compliance may be a useful measurement of the clinical effects of antihypertensive treatment. Both angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are known to improve vascular elasticity. A study was performed to test the hypothesis that combined therapy with an ACE inhibitor and a calcium channel blocker would have additive benefits on vascular compliance at similar levels of blood pressure (BP), as compared with monotherapy with an ACE inhibitor. This 12-week, double-blind study was a substudy of a larger clinical hypertension study conducted in patients with hypertension and type 2 diabetes. Subjects (N = 20) were randomized to either a fixed-dose combination of amlodipine besylate/benazepril HCl or to enalapril monotherapy. BP, heart rate, large- and small-vessel compliance, systemic vascular resistance, and urinary microalbumin excretion were assessed at baseline and after treatment. Both treatments were similarly effective in lowering BP, reducing systemic vascular resistance, and decreasing urinary microalbumin excretion. Improvement in large-vessel compliance was significantly greater among subjects who received ACE-inhibitor/calcium channel blocker combination therapy (52%) as compared with those who received ACE-inhibitor monotherapy (32%; p < 0.05). No significant change in small-vessel compliance was observed with either treatment. Greater improvement in large-vessel compliance with combination therapy was independent of BP lowering.

Topics: Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Natriuresis; Vascular Resistance

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

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

To test whether microalbuminuria in patients with type 2 diabetes and hypertension is primarily dependent on the severity of hypertension, and to compare the effectiveness of two antihypertensive drugs with opposite effects on the renin-angiotensin system [the diuretic, indapamide sustained release (SR), and an angiotensin-converting enzyme inhibitor, enalapril] in reducing microalbuminuria.. A multinational, multicentre, controlled, double-blind, double-dummy, randomized, two-parallel-groups study over 1 year.. After a 4-week placebo run-in period, 570 patients (ages 60.0 +/- 9.9 years, 64% men) with type 2 diabetes, essential hypertension [systolic blood pressure (SBP) 140-180 mmHg, and diastolic blood pressure (DBP) < 110 mmHg], and persistent microalbuminuria (20-200 microg/min) were allocated randomly to groups to receive indapamide SR 1.5 mg (n = 284) or enalapril 10 mg (n = 286) once a day. Amlodipine, atenolol, or both were added, if necessary, to achieve the target blood pressure of 140/85 mmHg.. There was a significant reduction in the urinary albumin : creatinine ratio. Mean reductions were 35% [95% confidence interval (CI) 24 to 43] and 39% (95% CI 30 to 47%) in the indapamide SR and enalapril groups, respectively. Equivalence was demonstrated between the two groups [1.08 (95% CI 0.89 to 1.31%); P = 0.01]. The reductions in mean arterial pressure (MAP) were 16.6 +/- 9.0 mmHg for the indapamide SR group and 15.0 +/- 9.1 mmHg for the enalapril group (NS); the reduction in SBP was significantly greater (P = 0.0245 ) with indapamide SR. More than 50% of patients in each group required additional antihypertensive therapy, with no differences between groups. Both treatments were well tolerated.. Indapamide-SR-based therapy is equivalent to enalapril-based therapy in reducing microalbuminuria with effective blood pressure reduction in patients with hypertension and type 2 diabetes.

Topics: Aged; Albuminuria; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Indapamide; Male; Middle Aged; Treatment Outcome

Left ventricular hypertrophy (LVH) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients, and is highly predictive of future cardiac morbidity and mortality. In patients with hypertension and LVH, both an angiotensin converting enzyme (ACE) inhibitor and an angiotensin type 1 receptor (AT1) antagonist regress LVH. However, it remains controversial whether dual blockade of the renin-angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist. Thirty-three type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School, Saitama, Japan between 1999 and 2001. The study was carried out for 1 year. All patients were assigned randomly to three groups with equal number: group I, an ACE inhibitor, enalapril 10 mg daily; group II, an AT1 antagonist, losartan 100 mg daily; group III, combination of enalapril 10 mg and losartan 100 mg daily. All antihypertensive drugs were given 30 min after the cessation of dialysis therapy. LVH was evaluated by echocardiography before the start of administration of drugs, at 6 months and 12 months after the start of drug therapy. Systolic blood pressure levels less than 140 mmHg were the target for the three groups. Using repeated measures analysis of variance, applied to those with four echocardiograms, there were progressive decreases over time in left ventricular mass index, posterior wall thickness and interventricular septum thickness. There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups; however, dual blockade induced an additional 28% reduction in left ventricular mass index compared with any type of monotherapy. Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy. Moreover, combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Renin-Angiotensin System; Treatment Outcome

To study the effect of co-renitek monotherapy for 16 weeks on parameters of 24-h monitoring of arterial pressure, carbohydrate, lipid, purin metabolism in patients with mild and moderate arterial hypertension (AH) and diabetes mellitus (DM) type 2.. 20 patients with DM type 2, mild or moderate AH received co-renitek (1-2 tablets a day) for 16 weeks. Before the treatment and 16 weeks later the patients were examined (24-h AH monitoring, carbohydrate, lipid, purin, electrolyte metabolism).. Co-renitek treatment of DM type 2 patients with hypertension led to a significant lowering of mean systolic and diastolic pressure, improvement of 24-h AP profile and reduction of fasting glucose level. Co-renitek proved to be metabolically neutral in relation to lipid, purin and electrolyte metabolism.. Co-renitek is effective and safe antihypertensive drug for treatment of arterial hypertension in patients with diabetes mellitus type 2.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzothiadiazines; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Enalapril; Female; Humans; Hypertension; Lipid Metabolism; Lipids; Male; Middle Aged; Minerals; Purines; Sodium Chloride Symporter Inhibitors; Systole

Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes.. In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes.. After five years, the change in the glomerular filtration rate was -17.5 ml per minute per 1.73 m2 (where the minus sign denotes a decrement) in the telmisartan-treated subjects, as compared with -15.0 ml per minute per 1.73 m2 in the enalapril-treated subjects; the treatment difference was thus -2.6 ml per minute per 1.73 m2 (95 percent confidence interval, -7.1 to 2.0 ml per minute per 1.73 m2)[corrected] The lower boundary of the confidence interval, in favor of enalapril, was greater than the predefined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years.. Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events.

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Telmisartan

Long-term oral treatment of patients with acute coronary syndromes and type 2 diabetes mellitus with beta-adrenoblockers and angiotensin-converting enzyme inhibitors is associated with positive, though ambiguous changes in the left-ventricular structure and function. These changes should be the reason for choosing optimal therapy ensuring better prognosis in this patient population.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angina, Unstable; Angiotensin-Converting Enzyme Inhibitors; Bisoprolol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enalapril; Female; Heart; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis

Peripheral arterial disease (PAD) and diabetes are both associated with a high risk of ischemic events, but the role of intensive blood pressure control in PAD has not been established.. The Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years; 480 of the subjects were normotensive (baseline diastolic blood pressure of 80 to 89 mm Hg). Patients randomized to placebo (moderate blood pressure control) had a mean blood pressure of 137+/-0.7/81+/-0.3 mm Hg over the last 4 years of treatment. In contrast, patients randomized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128+/-0.8/75+/-0.3 mm Hg (P<0.0001 compared with moderate control). PAD, which is defined as an ankle-brachial index <0.90 at the baseline visit, was diagnosed in 53 patients. In patients with PAD, there were 3 cardiovascular events (13.6%) on intensive treatment compared with 12 events (38.7%) on moderate treatment (P=0.046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment (P=0.009), but not with intensive treatment (P=0.91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ankle-brachial index values, and was the same as in a patient without PAD.. In PAD patients with diabetes, intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Comorbidity; Death, Sudden, Cardiac; Diabetes Mellitus, Type 2; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Nisoldipine; Odds Ratio; Peripheral Vascular Diseases; Risk Assessment; Stroke; Treatment Outcome

Microalbuminuria in diabetes is a risk factor for early death and an indicator for aggressive blood pressure (BP) lowering. We compared a combination of 2 mg perindopril/0.625 mg indapamide with enalapril monotherapy on albumin excretion rate (AER) in patients with type 2 diabetes, albuminuria, and hypertension in a 12-month, randomized, double-blind, parallel-group international multicenter study. Four hundred eighty-one patients with type 2 diabetes and hypertension (systolic BP > or =140 mm Hg, <180 mm Hg, diastolic BP <110 mm Hg) were randomly assigned (age 59+/-9 years, 77% previously treated for hypertension). Results from 457 patients (intention-to-treat analysis) were available. After a 4-week placebo period, patients with albuminuria >20 and <500 microg/min were randomly assigned to a combination of 2 mg perindopril/0.625 mg indapamide or to 10 mg daily enalapril. After week 12, doses were adjusted on the basis of BP to a maximum of 8 mg perindopril/2.5 mg indapamide or 40 mg enalapril. The main outcome measures were overnight AER and supine BP. Both treatments reduced BP. Perindopril/indapamide treatment resulted in a statistically significant higher fall in both BP (-3.0 [95% CI -5.6, -0.4], P=0.012; systolic BP -1.5 [95% CI -3.0, -0.1] diastolic BP P=0.019) and AER -42% (95% CI -50%, -33%) versus -27% (95% CI -37%, -16%) with enalapril. The greater AER reduction remained significant after adjustment for mean BP. Adverse events were similar in the 2 groups. Thus, first-line treatment with low-dose combination perindopril/indapamide induces a greater decrease in albuminuria than enalapril, partially independent of BP reduction. A BP-independent effect of the combination may increase renal protection.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Cough; Diabetes Mellitus, Type 2; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Indapamide; Male; Middle Aged; Perindopril; Treatment Outcome

In type 2 diabetic hypertensive patients, microalbuminuria can be due to hypertension and/or diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors act preferentially on microalbuminuria due to diabetic nephropathy. The objective is to demonstrate the efficacy of a thiazide-like diuretic, indapamide sustained release (SR), at reducing microalbuminuria in hypertensive type 2 diabetic patients in comparison with an ACE inhibitor, enalapril. The study is an international multicentre, 12-month, randomized, double-blind, controlled, two parallel group study of type 2 diabetic patients with hypertension (140 mmHg < or = systolic blood pressure <180 mmHg and diastolic blood pressure <110 mmHg) and microalbuminuria. Intervention is after a 4-week placebo period, patients with microalbuminuria > or = 20 and < or = 200 microg/min are randomized to indapamide SR 1.5 mg or to enalapril 10 mg once a day for a one-year treatment period. An additional label treatment by amlodipine 5-10 mg (1st step) and atenolol 50-100 mg (2nd step) a day is permitted after 6 weeks of treatment based upon blood pressure response. The main outcome measures are microalbuminuria expressed as urinary albumin to creatinine ratio, albumin fractional clearance, and albumin excretion rate evaluated on overnight urine collections. Secondary criteria are supine and standing systolic, diastolic and mean blood pressure; and biological and clinical safety. This study will complete the knowledge of the efficacy of indapamide SR in hypertension and target organ damage and will provide valuable information on the management of type 2 diabetic hypertensives with microalbuminuria.

Topics: Adult; Aged; Albuminuria; Clinical Protocols; Creatine; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Indapamide; Male; Middle Aged

Serial decline in electrocardiographic voltage in patients with increased left ventricular mass has been associated with a lower risk of cardiovascular events.. We studied 468 patients with diabetes mellitus and hypertension in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial. Patients were randomized in a stratified design to receive initial treatment with either enalapril or nisoldipine and to either intensive or moderate treatment goals. We measured an electrocardiographic index for increased left ventricular mass, the adjusted Cornell voltage, serially by treatment group. The association between changes in electrocardiographic voltage and cardiovascular events was defined with Cox proportional hazards analysis.. In 5 years of follow-up, the decline in adjusted Cornell voltage was significantly greater for patients treated with enalapril than for patients treated with nisoldipine (repeated measures analysis of variance P =.002). In the Cox proportional hazards model, treatment assignment (enalapril vs nisoldipine) was the strongest predictor of cardiovascular events, but the presence of coronary disease at baseline, the duration of diabetes mellitus, and change in voltage were also independent predictors of cardiovascular events.. In the ABCD study, enalapril treatment was associated with a lower risk of myocardial infarction. The reduction in left ventricular mass as reflected by diminished electrocardiographic voltage may explain some, but not all, of the effect of enalapril in this study.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Electrocardiography; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nisoldipine; Proportional Hazards Models; Prospective Studies

We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system (RAS) by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an ACE inhibitor (ACEI) in patients with type 2 diabetes and nephropathy.. A total of 20 patients (17 men and 3 women) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind, randomized, two-period, crossover trial of 8 weeks of treatment with the ARB candesartan 16 mg daily and placebo added in random order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily. At the end of each treatment period, we evaluated albuminuria in three 24-h urinary collections by turbidimetry, 24-h ambulatory blood pressure (ABP) using the Takeda-TM2420, and glomerular filtration rate (GFR) by the (51)Cr-EDTA plasma-clearance technique.. During monoblockade of the RAS by ACEI treatment, albuminuria was 706 (349-1,219) mg/24 h [geometric mean (IQR)]; 24-h ABP was 138 +/- 3/72 +/- 2 mmHg (mean +/- SE); and GFR was 77 +/- 6 ml x min(-1) x 1.73 m(-2) (mean +/- SE). During dual blockade of the RAS by addition of candesartan 16 mg daily, there was a mean (95% CI) reduction in albuminuria of 28 (17-38) compared with ACEI alone (P < 0.001). There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg (-2 to 8 systolic, -2 to 5 diastolic; NS). Changes in albuminuria did not correlate to changes in ABP. Addition of candesartan 16 mg daily induced a small, insignificant decrease in GFR of 4 (-1 to 9) ml x min(-1) x 1.73 m(-2).. Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Captopril; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Kidney; Lisinopril; Male; Middle Aged; Tetrazoles; Treatment Outcome

To determine whether clinical outcomes in patients with type 2 diabetes were improved by protocol-driven care in a Diabetes Centre compared with usual outpatient care.. Descriptive analysis of a prospective cohort.. During a median 7-year observational period, 91 patients with type 2 diabetes and no cardiovascular or renal complications were monitored by a nurse and a diabetologist in a clinical trial setting according to a structured protocol. Another 81 patients with comparable clinical characteristics were monitored by generalists at the medical clinic in the same hospital. Clinical end points, defined as death and cardiovascular and renal events, were evaluated in 1997 by review of case records.. Patients receiving structured care had lower mortality (relative risk [RR] = 0.21; 95% confidence interval [CI] = 0.07, 0.65; P = .006) than the usual-care group, as well as a lower incidence of combined clinical end points (RR = 0.43; 95% CI = 0.22, 0.84; P = .01). In the usual-care group, patients who had no monitoring of glycosylated hemoglobin or plasma lipid levels during the entire observational period (8.6%) had a 14.6-fold (P < .01) and 15.7-fold (P < .01) increased risk of death and combined clinical end points, respectively, compared with those who had at least one measurement (60.5%).. Management by protocol-driven care model improved survival and clinical outcomes in patients with type 2 diabetes. Definitive studies are required to confirm these findings and compare the cost effectiveness of these care models.

Topics: Aged; Antihypertensive Agents; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Clinical Protocols; Diabetes Mellitus, Type 2; Disease Management; Drug Monitoring; Enalapril; Female; Glycated Hemoglobin; Hong Kong; Humans; Hypertension; Male; Middle Aged; Nifedipine; Outpatient Clinics, Hospital; Survival Analysis; Treatment Outcome

CARDIOVASCULAR RISK OF LEFT VENTRICULAR HYPERTROPHY: Because of the rhythmic, mechanical and ischemic risk related to it, the left ventricular hypertrophy (LVH) is considered to be a major independent risk factor for cardiovascular disease which should be screened for and treated early. In patients with type 2 diabetes, left ventricular hypertrophy is mainly due to high blood pressure, but also to reduced elasticity of the large vessels, defective vasomotricity and dysfunction of the arterial endothelium. Obesity, elevated blood viscosity, hyperinsulinism and/or autonomous cardiac neuropathy can also have a favoring effect. THE LIVE STUDY: Is the first multicentric European study comparing the efficacy of a thiazide-like diuretic, slow-release indapamid, with a converting enzyme inhibitor, enalapril 20 mg, on the reduction of the left ventricular mass index (LVMI) in hypertensive subjects with LVH. The study involved a randomized centralized reading of the echocardiograms as well as a randomized and blinded reading at the end of the study. DEMONSTRATED SUPERIORITY OF INDAPAMID SR: The LIVE study clearly demonstrated the superiority of indapamid SR over enalapril 20 mg in reducing the LVMI in hypertensive subjects with LVH while the blood pressure lowering effect was comparable for the two treatments.

Topics: Adrenergic alpha-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Doxazosin; Drug Therapy, Combination; Echocardiography; Electrocardiography; Enalapril; Humans; Hypertension; Hypertrophy, Left Ventricular; Indapamide; Placebos; Prazosin; Prognosis; Prospective Studies; Risk Factors; Time Factors

The first fundamental study devoted to the reduction of microalbuminuria with a antihypertensive diuretic (indapamide SR) in type 2 diabetes with hypertension, the Marre study (NESTOR) was designed to demonstrate that this antihypertension agent could be an interesting therapeutic alternative by comparing its efficacy on microalbuminuria with that of enalapril 10 mg during a treatment period of 52 weeks.. It was demonstrated that indapamide SR is the only diuretic providing a significant reduction (35%) in the microalbuminuria observed in hypertensive patients with type 2 diabetes. At the endpoint, comparison with the group of patients treated with enalapril, showed no significant difference in fractionated albumin clearance or in the percentage of patients with normoalbuminuria, microalbuminuria or gross proteinuria. Safety and tolerance were comparable for the two treatments.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Creatinine; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Time Factors

Although several important studies have been performed in hypertensive type 2 diabetic patients, it is not known whether lowering blood pressure in normotensive (BP <140/90 mm Hg) patients offers any beneficial results on vascular complications. The current study evaluated the effect of intensive versus moderate diastolic blood pressure (DBP) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients.. The current study was a prospective, randomized controlled trial in normotensive type 2 diabetic subjects. The subjects were randomized to intensive (10 mm Hg below the baseline DBP) versus moderate (80 to 89 mm Hg) DBP control. Patients in the moderate therapy group were given placebo, while the patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion, progression of retinopathy and neuropathy and the incidence of cardiovascular disease.. The mean follow-up was 5.3 years. Mean BP in the intensive group was 128 +/- 0.8/75 +/- 0.3 mm Hg versus 137 +/- 0.7/81 +/- 0.3 mm Hg in the moderate group, P < 0.0001. Although no difference was demonstrated in creatinine clearance (P = 0.43), a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria (P = 0.012) and microalbuminuria to overt albuminuria (P = 0.028). The intensive BP control group also demonstrated less progression of diabetic retinopathy (P = 0.019) and a lower incidence of strokes (P = 0.03). The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent.. Over a five-year follow-up period, intensive (approximately 128/75 mm Hg) BP control in normotensive type 2 diabetic patients: (1) slowed the progression to incipient and overt diabetic nephropathy; (2) decreased the progression of diabetic retinopathy; and (3) diminished the incidence of stroke.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Progression; Enalapril; Female; Humans; Male; Middle Aged; Nisoldipine; Prospective Studies; Single-Blind Method; Stroke

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

Whether angiotensin-converting enzyme (ACE) inhibitors have any clinically significant antiatherogenic effects in humans remains unproven. We undertook a prospective randomized clinical trial of 98 patients with non-insulin-dependent diabetes mellitus (NIDDM) to examine the efficacy of ACE inhibition with enalapril for preventing intima-media (IM) thickening of the carotid wall as measured ultrasonographically.. Ninety-eight NIDDM patients were randomly assigned either to enalapril at 10 mg/d (n=48) or to a control group (n=50); the planned duration of the trial was 2 years. All patients were seen at baseline (study entry) and 2 subsequent formal annual evaluations, in addition to standard clinical management for NIDDM. IM thickening and vascular lumen diameters were determined for all patients on the basis of baseline and 2 subsequent annual evaluations with carotid ultrasonography. We performed an intent-to-treat analysis to assess changes in IM thickening over the course of the study.. Annual IM thickening measurements of the right and left common carotid arteries were 0.01+/-0.02 and 0.01+/-0.02 mm/y in the enalapril-treated group and 0.02+/-0.03 and 0.02+/-0.02 mm/y in the control group, respectively (P<0.05). From regression analysis, annual IM thickening was found to be predicted by enalapril use, sex, and insulin use (F(3,94)=3.86, P=0.012). When we controlled for these other variables, enalapril use reduced annual IM thickening of right and left common carotid arteries by 0.01+/-0.004 mm/y relative to the control group over the course of this study.. Long-term treatment with an ACE inhibitor (enalapril) slows progressive IM thickening of the common carotid artery in NIDDM patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Carotid Artery Diseases; Carotid Artery, Common; Diabetes Mellitus, Type 2; Disease Progression; Enalapril; Female; Humans; Longitudinal Studies; Male; Middle Aged; Tunica Intima; Tunica Media; Ultrasonography

If hypertension in patients with diabetes mellitus type II is not adequately controlled by angiotensin-converting enzyme inhibitors (ACE-i), a beta-blocker is frequently added as second-line therapy. Recently, large randomized trials demonstrated the beneficial effect of second-generation dihydropyridine calcium-channel blockers in these patients. These compounds are increasingly being used to replace beta-blockers. Withdrawal of beta-blockers may influence diabetic control and may cause rebound hypertension. Any rebound hypertension from beta-blocker withdrawal may not occur if the beta-blocker is replaced with a calcium-channel blocker. A calcium-channel blocker will influence vascular resistance (VR) and blood pressure differently than a beta-blocker. Thirty-four patients with diabetes mellitus type II and a resting diastolic blood pressure above 90 mm Hg despite enalapril 10 mg daily (or equipotent dosages of other ACE-i) for at least 3 months were treated in an open label sequential comparison with the same ACE-i in combination with the beta-blocker metoprolol 100 mg for 3 months, and, subsequently for 3 more months with the same ACE-i in combination with the dihydropyridine calcium-channel blocker lercanidipine 10 mg once daily. After 6 weeks, patients with a diastolic blood pressure above 90 mm Hg were titrated up to 200 mg metoprolol or 20 mg lercanidipine once daily. Patients were examined every 6 weeks during the trial, and after 2 weeks while receiving lercanidipine. In addition to blood pressure measurements, VR was measured by iridium strain gauge plethysmography and expressed in units (1 unit = 1 mm Hg/mL blood/100 mL tissue per minute). Two of 34 patients did not complete the protocol because of non-compliance with the lercanidipine treatment in the first 2 weeks of treatment. Their data are included in the analysis. No rebound hypertension 14 days after the change-over of therapies was observed. (Mean arterial pressures [MAPs] were not significantly different from the point of withdrawal of the beta-blockers.) However, heart rate rose from 69+/-7 to 94+/-10 beats/min (p < 0.001). After 3 months on lercanidipine, MAP fell by 6+/-10 mm Hg (p = 0.002) compared to the point of withdrawal of the beta-blocker. Vascular resistance fell by 6.28+/-11.91 units (p<0.01), while glucosylated hemoglobin (HbA1c) rose by 0.4+/-0.5% (p<0.001) and body weight rose by 0.6+/-0.6 kg (p < 0.01). Multiple regression analysis revealed significant associations bet

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Metoprolol; Middle Aged; Regression Analysis; Vascular Resistance

The Japan Multicenter Investigation of Antihypertensive Treatment for Nephropathy in Diabetics (J-MIND) study was conducted to evaluate the effect of nifedipine retard or enalapril on nephropathy in hypertensive patients with type 2 diabetes. A total of 436 patients with normoalbuminuria [urinary albumin excretion rate (AER) <30 mg/day] or microalbuminuria [AER: 30-300 mg/day] were randomized to receive nifedipine retard or enalapril and were followed for 24 months. There were no differences in baseline characteristics between the two groups (the mean AER was 45 and 42 mg/day, respectively). Intent-to-treat analysis showed no significant difference in AER after 2 years, although the mean AER increased to 64 and 74 mg/day in the nifedipine retard and enalapril groups, respectively. The AER increased in patients with normoalbuminuria, whereas it did not change in those with microalbuminuria. There were no differences between the two groups with respect to progression from normoalbuminuria to microalbuminuria, progression from microalbuminuria to overt proteinuria, and regression from microalbuminuria to normoalbuminuria. The incidence of cardiovascular events was also similar in both groups. In conclusion, nifedipine retard and enalapril had a similar effect on nephropathy in hypertensive type 2 diabetic patients without overt proteinuria.

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Japan; Male; Middle Aged; Nifedipine; Prospective Studies; Statistics, Nonparametric

The objective of this study was to compare, at equal blood pressure (BP) reduction, the effect of two different combinations on metabolic control and albuminuria in type 2 diabetic hypertensive patients with albuminuria. This was a prospective, randomised, double-blind, parallel, controlled trial carried out in 11 Spanish hospitals. A total of 103 type 2 diabetic patients with stable albuminuria and BP not controlled on monotherapy were randomised of which 93 finished the study. After a 4-week single-blind placebo period, patients were randomised to verapamil SR/trandolapril 180/2 mg (VT) or to enalapril/hydroclorothiazide 20/12.5 mg (EH). Treatment duration was 6 months. The main outcome measures were changes in BP, 24-h albuminuria, blood glucose and glycated haemoglobin. Overall BP was significantly reduced from 157.3 +/- 12.0/98.3 +/- 6.4 mm Hg to 140.5 +/- 14.5/86.1 +/- 8.2 mm Hg (P < 0.001) and albuminuria significantly decreased from 508.6 +/- 693.8 mg/24 h to 253.4 +/- 517.2 mg/24 h (P < 0.001), both without significant differences between treatments. Glycated haemoglobin was not modified on VT: baseline, 5.91 +/- 1.43%; end of treatment, 5.94 +/- 1.62%, but increased on EH: baseline, 5.96 +/- 1.25%; final, 6.41 +/- 1.51%, (ANOVA interaction P = 0.040). At the end of the study, a blood glucose <126 mg/dL was attained in 72.7% of the VT group-improving in 29.5% and worsening in 6.8% of patients (P = 0.021)-and in 50% of the EH group, 13.6% of patients improved and 11.4% worsened (P = 1.000). There were no changes in body weight, serum creatinine, uric acid, potassium, cholesterol, tryglicerides and serum albumin. In hypertensive type 2 diabetic patients not controlled on monotherapy, both treatments similarly reduced albuminuria. The combination verapamil/ trandolapril seems to allow a better metabolic control than enalapril/hydroclorothiazide.

Topics: Aged; Albuminuria; Analysis of Variance; Antihypertensive Agents; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Indoles; Male; Middle Aged; Multivariate Analysis; Probability; Prospective Studies; Spain; Treatment Outcome; Verapamil

We compared the efficacy of treatment protocols with an angiotensin converting enzyme (ACE) inhibitor alone (enalapril, 5 mg) or angiotensin II (ATII) receptor blocker (losartan, 50 mg) or both enalapril plus losartan in patients with microalbuminuria in a prospective, randomized clinical trial. Normotensive type 2 diabetic patients with microalbuminuria documented by at least 3 consecutive urinary albumin excretion analyses were recruited for the study. Patients were grouped randomly into one of the protocols which consisted of treatment with 5 mg enalapril daily (group 1; n=12), 50 mg losartan daily (group 2; n=12) or both drugs (group 3; n=10). They were reevaluated with regard to HbA1c levels, lipid profiles, blood pressure and urinary albumin excretion rates (UAER) at 3-month intervals for 12 months. Mean age, duration of diabetes, body mass index, plasma lipid profiles and blood pressure levels were similar at the initial visit. In group 1, UAER returned to normal levels in 10 patients. Normalization of UAER occurred in 8 and 7 patients in groups 2 and 3, respectively. Percentage of reduction in UAERs at the end of 12 months were 58%, 59% and 60% (p=0.0001; p=0.0002; p=0.0003, respectively). The amount of reduction in UAER did not differ significantly among the three groups (p=0.346). ACE inhibitors and angiotensin II receptor blockers have similar efficacy in treating diabetic microalbuminuria, and the combination of the two drugs does not add any further benefit.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Glycated Hemoglobin; Humans; Losartan; Middle Aged; Prospective Studies

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.. In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.. After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).. In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006).. In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Humans; Hyperlipidemias; Hypertension, Renal; Kidney; Male; Middle Aged; Nifedipine; Peptidyl-Dipeptidase A; Prospective Studies; Renal Circulation; Treatment Outcome; Vasodilator Agents

The role of lipoprotein oxidation in promoting atherosclerosis is gaining recognition as its spectrum of effects is being unveiled. Accelerated atherosclerosis is a major cause of morbidity and mortality in diabetic patients. Treatment with ACE inhibitors reduces oxidation of low-density lipoprotein (LDL-ox) in hypertensive subjects, however, their effect on LDL-ox in diabetic patients is yet obscure. To evaluate the effect of the ACE inhibitor enalapril and the calcium channel blocker nifedipine on LDL oxidation in normotensive type 2 diabetic patients. A randomized single blinded cross-over study was conducted on 24 nonobese, metabolically stable, normotensive patients with type 2 diabetes who were randomly allocated to receive either enalapril, 10 mg/day, or nifedipine, 30 mg/day, for 4 weeks followed by a 2-week washout period. They were then crossed over to a 4-week course with the alternate drug. The oxidation of LDL was evaluated by three methods: dialdehyde analysis using the thiobarbituric acid reactive substances assay with and without the addition of CuSO(4) as well as determination of conjugated dienes in the LDL lipid extract. The propensity of the serum to oxidize LDL was reduced by enalapril by 17-28% depending on the laboratory method used (P=0.0001). Treatment with nifedipine resulted in a rise in LDL-ox of 7-11% as compared to baseline (P<0.05). The difference between the effects of enalapril and nifedipine was statistically significant with all three laboratory methods used (P=0.0001). Both drugs were equally effective in reducing systolic and diastolic blood pressure without affecting HbA(1c) levels and lipid profile. The albumin excretion rate was significantly reduced during treatment with enalapril returning to baseline levels during the washout period and the nifedipine treatment course. Our findings suggest that oxidation of LDL is attenuated by ACE inhibition and augmented by some calcium channel blockers. This observation may contribute insight into the underlying mechanism of the therapeutic effects of ACE inhibition in diabetic patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Lipid Peroxidation; Lipoproteins, LDL; Male; Malondialdehyde; Middle Aged; Nifedipine; Single-Blind Method; Thiobarbituric Acid Reactive Substances

It has been demonstrated that antihypertensive treatment of hypertensive diabetic patients is quite effective in preventing macrovascular and microvascular complications and improving prognosis. Nevertheless, the target blood pressure level of antihypertensive treatment in hypertensive diabetic patients with microalbuminuria (i.e., with early diabetic nephropathy) remains to be established. In this study, we evaluated the effect of intensive blood pressure control (diastolic blood pressure <80 mmHg) on urinary albumin excretion in hypertensive, type II diabetic patients with microalbuminuria. We examined the effects of a combination therapy using an angiotensin-converting enzyme (ACE) inhibitor plus a long-acting calcium channel blocker (amlodipine), and compared them with the effect of an ACE inhibitor alone. Thirty hypertensive, type II diabetic patients with microalbuminuria were treated with either an ACE inhibitor alone (group I, n=17) or an ACE inhibitor plus amlodipine (group II, n=13) for 32 weeks. With treatment, blood pressures in both groups were significantly reduced, and diastolic blood pressure was lowered to a much greater extent in group II (76 +/- 2 mmHg) than in group I (83 +/- 2 mmHg, p < 0.05). Although the urinary albumin excretion rate was decreased in both groups, the decrease attained statistical significance only in group II (from 141 +/- 25 mg/day to 69 +/- 18 mg/day, p < 0.05); the extent of reduction in microalbuminuria during antihypertensive treatment was significantly greater in group II (50 +/- 10%) than in group I (14 +/- 13%, p < 0.05). In conclusion, this study showed that in hypertensive microalbuminuric type II diabetic patients, the combination of an ACE inhibitor plus amlodipine resulted in a more pronounced decreased in blood pressure (diastolic blood pressure <80 mmHg) and a greater reduction in urinary albumin excretion than did use of an ACE inhibitor alone. This combination strategy should thus be a more effective tool for obtaining optimal blood pressure control in patients with diabetic nephropathy.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension, Renal; Imidazoles; Imidazolidines; Indoles; Male; Middle Aged

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diastole; Dihydropyridines; Double-Blind Method; Enalapril; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Systole; Treatment Outcome; Triglycerides; Uric Acid

The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective randomized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications. The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy, retinopathy, and neuropathy.. The 470 hypertensive subjects, defined as having a baseline diastolic blood pressure of > or = 90 mmHg, were randomized to intensive blood pressure control (diastolic blood pressure goal of 75 mmHg) versus moderate blood pressure control (diastolic blood pressure goal of 80-89 mmHg).. The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group. During the 5-year follow-up period, no difference was observed between intensive versus moderate blood pressure control and those randomized to nisoldipine versus enalapril with regard to the change in creatinine clearance. After the first year of antihypertensive treatment, creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria. In contrast, patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5-6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy. There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria (25% intensive therapy vs. 18% moderate therapy, P = 0.20) or microalbuminuria to overt albuminuria (16% intensive therapy vs. 23% moderate therapy, P = 0.28). Intensive therapy demonstrated a lower overall incidence of deaths, 5.5 vs. 10.7%, P = 0.037. Over a 5-year follow-up period, there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy. In addition, the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy.. Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period. The more intensive blood pressure control decreased all-cause mortality.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Nisoldipine; Placebos

The objectives of this study were to compare the effects of the angiotensin II receptor blocker, losartan, to those of the angiotensin-converting enzyme inhibitor, enalapril, on albuminuria and renal function in relationship to clinic and ambulatory blood pressure (ABP) in hypertensive type 2 diabetic subjects with early nephropathy. The tolerability of these agents and their effect on the metabolic profile were also evaluated.. The study was a one-year prospective, double-blind trial with losartan and enalapril administered alone or in combination with hydrochlorothiazide and other antihypertensive agents. ABP and renal and biochemical parameters were measured at baseline and after 12, 28, and 52 weeks of active treatment. Ninety-two hypertensive type 2 diabetics with early nephropathy completed the study.. Both losartan and enalapril administered alone or in combination with other agents induced significant reductions in sitting clinic (P < 0.05) and ABP (P < 0.002) without a statistical difference between groups. Geometric means for urinary albumin excretion (UAE) decreased significantly (P < 0.001) in patients treated with losartan from 64. 1 to 41.5 microg/min and in those treated with enalapril from 73.9 to 33.5 microg/min after 52 weeks of therapy. A significant relationship (P < 0.05) between changes in systolic and diastolic ABP and the decrease in UAE at 52 weeks was seen in both groups. The decline in glomerular filtration rate (GFR) was stabilized at the end of therapy and was identical in both treatment groups. Treatment with enalapril was associated with a significantly higher incidence of cough (P = 0.006) and a rise in serum uric acid (P = 0.002) compared with losartan.. Our results indicate that a one-year course of antihypertensive therapy with either losartan or enalapril significantly reduces UAE in hypertensive type 2 diabetic patients with early nephropathy. The reduction in UAE with each treatment is similarly related to decrements in ABP. In addition, the rate of decline in GFR is similar in both treatment groups.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension, Renal; Kidney; Losartan; Male; Middle Aged; Prospective Studies; Sodium Chloride Symporter Inhibitors; Uric Acid

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cholesterol; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Lipid Peroxidation; Male; Middle Aged; Triglycerides

To examine effectiveness and safety of quadropril.. Changes in blood pressure (BP), heart rate (HR), levels of glucose, potassium and creatinine, creatinine clearance were studied in 120 patients (48 males and 72 females, mean age 60.6 +/- 0.7 years) with mild to moderate arterial hypertension (AH) with average duration 13.8 +/- 0.7 years. The patients were divided into 3 groups: with AH (n = 40), AH + noninsulindependent diabetes mellitus (DM) (n = 43), AH and nephropathy (n = 37). 8-week treatment was performed with a standard dose of 6 mg/day (1 tablet of quadropril). Control examinations were made 2, 4 and 8 weeks after the treatment.. After 8 weeks of treatment a decrease in systolic blood pressure in AH group was 24.0 +/- 3.0 mm Hg and in diastolic blood pressure 16.3 +/- 1.3 mm Hg (P < 0.001). In the group with DM this decrease was 22.4 +/- 2.8 mm Hg and 15.7 +/- 1.4 mm Hg (p < 0.001), respectively. In the group with nephropathy this decrease was 26.4 +/- 2.4 and 16.5 +/- 1.3 mm Hg (p < 0.001), respectively. Heart rate changed significantly only in diabetics: from 75.1 +/- 1.7 to 72.9 +/- 1.3 beats/min. Biochemical parameters in the hypertensive and diabetic patients did not change significantly. In the nephropathy group there was a significant decrease in creatinine and increase in creatinine clearance. Their level of glucose and potassium changed insignificantly.. The treatment with quadropril results in a significant decrease in blood pressure, does not influence parameters of carbohydrate metabolism, improves nitrogen eliminating function of the kidneys.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Creatinine; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Safety; Treatment Outcome

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

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Drug Combinations; Enalapril; Follow-Up Studies; Fosinopril; Heart Diseases; Humans; Hypertension; Nisoldipine; Prospective Studies; Reproducibility of Results; Risk Factors; Treatment Outcome

Compared with other angiotensin-converting enzyme (ACE) inhibitors, the elimination of temocapril is less dependent on renal function. To investigate the metabolic and antihypertensive effects of temocapril in diabetic hypertensives, 30 patients with diabetes mellitus type 2 and mild to moderate hypertension [diastolic blood pressure (BP) 90-115 mm Hg] and without azotemia (plasma creatinine < 180 microM) were evaluated in a prospective randomized double-blind placebo-controlled study. After a 4-week placebo run-in, they received temocapril, 20 mg daily (n = 19), or placebo (n = 11) for 6 weeks. Insulin sensitivity index (SI), determined by the Minimal Model method of Bergman, serum lipoproteins, plasma renin activity, fibrinogen, and microalbuminuria were assessed at the end of the placebo run-in phase and the double-blind treatment phases. Temocapril but not placebo administration produced a significant decrease in supine BP (152/92+/-5/3 vs. 162/98+/-5/2 mm Hg; p < 0.01) and increase in plasma renin (p < 0.05). Variation of SI during temocapril treatment did not reach statistical significance (0.95+/-0.2 before vs. 1.44+/-0.4 x 10(-4)/min/mU/L after treatment). During administration of temocapril or placebo, no significant changes in fasting plasma glucose, insulin, and serum levels of total triglycerides, cholesterol, lipoprotein cholesterol fractions, or fibrinogen were observed. Microalbuminuria decreased significantly on temocapril treatment (49+/-10 vs. 79+/-17 mg/24 h; p < 0.01) but not on placebo. These findings demonstrate that in hypertensive patients with diabetes mellitus type 2, short-term treatment with temocapril is neutral to insulin sensitivity, lipoprotein metabolism, and fibrinogen, and significantly reduces microalbuminuria.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Fibrinogen; Humans; Hypertension; Kidney Function Tests; Lipoproteins; Male; Middle Aged; Patient Compliance; Prospective Studies; Thiazepines

The aim of this study was to assess the effect of angiotensin-converting enzyme (ACE) inhibition with enalapril on forearm endothelial function in subjects with type II diabetes mellitus.. Endothelial function is depressed in the presence of conventional risk factors for atherosclerosis, and various therapies, such as lipid-lowering therapy in hypercholesterolemia, can improve endothelial-mediated vasodilation. ACE inhibition has improved such function in several conditions including type I diabetes, but there is no evidence for a beneficial effect in type II diabetes.. The influence of enalapril (10 mg twice daily for 4 weeks) on endothelium-dependent and -independent vasodilator function was determined in 10 type II diabetic subjects using a double-blinded placebo-controlled crossover protocol. Forearm blood flow was measured using strain-gage plethysmography and graded intrabrachial infusion of acetylcholine (ACh), N(G)-monomethyl-L-arginine (LNMMA) and sodium nitroprusside (SNP).. Enalapril increased the response to the endothelium-dependent vasodilator, ACh (p < 0.02) and the vasoconstrictor response to the nitric oxide (NO) synthase inhibitor, LNMMA (p < 0.002). No difference was evident in the response to SNP.. In type II diabetic subjects without evidence of vascular disease, the ACE inhibitor enalapril improved stimulated and basal NO-dependent endothelial function. The study extends the spectrum of beneficial effects demonstrated to result from ACE inhibition in diabetes.

Topics: Acetylcholine; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enalapril; Endothelium, Vascular; Forearm; Humans; Middle Aged; Nitroprusside; omega-N-Methylarginine

It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study.. The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension.. Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8).. In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Logistic Models; Male; Middle Aged; Myocardial Infarction; Nisoldipine; Prospective Studies; Treatment Outcome

Angiotensin-converting enzyme (ACE) inhibitors attenuate the decline in renal function in diabetic patients with microalbuminuria. However, no data are available on the use of ACE inhibitors to prevent the decrease in renal function in normotensive, normoalbuminuric patients with type 2 diabetes.. To evaluate the effect of prolonged ACE inhibition on renal function and albuminuria in patients with type 2 diabetes.. Randomized, double-blind, placebo-controlled trial with 6-year follow-up.. Eight outpatient clinics coordinated by a department of medicine in a university hospital.. 156 patients in whom type 2 diabetes was diagnosed after 40 years of age who had a baseline mean blood pressure less than 107 mm Hg and albuminuria (albumin excretion < or = 30 mg/24 h).. Enalapril, 10 mg/d, or placebo.. Degree of albuminuria at 24 hours, creatinine clearance, blood pressure, and hemoglobin A1c values.. Enalapril therapy decreased albumin excretion from a mean +/- SD of 11.6 +/- 7 mg/24 h to 9.7 +/- 6 mg/24 h at 2 years. This was followed by a gradual increase to 15.8 +/- 8 mg/24 h at 6 years. In the placebo group, albumin excretion increased from 10.8 +/- 8 mg/24 h to 26.5 +/- 10 mg/24 h at 6 years (P = 0.001 for enalapril compared with placebo). Transition to microalbuminuria occurred in 15 of 79 (19%) placebo recipients and 5 of 77 (6.5%) enalapril recipients. Enalapril treatment resulted in an absolute risk reduction of 12.5% (95% CI, 2% to 23%; P = 0.042) for development of microalbuminuria. After 6 years, creatinine clearance decreased from 1.78 +/- 0.13 mL/s to 1.63 +/- 0.12 mL/s (mean decrease, 0.025 mL/s per year) in enalapril recipients and from 1.81 +/- 0.15 mL/s to 1.57 +/- 0.17 mL/s (mean decrease, 0.04 mL/s per year) in placebo recipients (P = 0.040). Hemoglobin A1c values decreased modestly in both groups. Mean blood pressure remained normal (< 107 mm Hg) in all patients.. Enalapril attenuated the decline in renal function and reduced the extent of albuminuria in normotensive, normoalbuminuric patients with type 2 diabetes. Further research is needed to determine whether this treatment forestalls the development of overt nephropathy.

Topics: Adult; Albuminuria; Algorithms; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Hemoglobin A; Humans; Male; Middle Aged; Placebos

To compare the effects of a calcium antagonist (nitrendipine) and an angiotensin converting enzyme inhibitor (enalapril) with those of placebo on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension.. A double-blind randomized, placebo-controlled trial.. General practitioners referred patients to the trial physician.. The study population comprised 121 patients with non-insulin-dependent diabetes mellitus. Inclusion criteria for blood pressure were diastolic blood pressure 90-115 mmHg and systolic blood pressure < or = 200 mmHg, while subjects were not being administered blood-pressure-lowering drugs for 3 weeks.. Patients were randomly allocated to receive nitrendipine (n = 40), enalapril (n = 40) or placebo (n = 41). The treatment period was 48 weeks.. The effect of nitrendipine was defined as the difference in change in left ventricular mass index from baseline between nitrendipine treatment and placebo after 48 weeks of treatment. The effects of nitrendipine compared with that of enalapril and of enalapril compared with placebo were defined similarly. Left ventricular mass was measured by M-mode echocardiography.. Use of nitrendipine and enalapril led to significant and almost identical reductions in systolic and diastolic blood pressures. During 48 weeks left ventricular mass index decreased by 5% for patients in the nitrendipine group (decrease by 12 g/m2, 95% confidence interval 1-23), remained about the same for patients in the enalapril group (decrease by 1 g/m2, 95% confidence interval decrease by 10 to increase by 9) and increased by 9% for patients in the placebo group (increase by 9 g/m2, 95% confidence interval 2-16).. These results indicate that administration of nitrendipine to patients with non-insulin-dependent diabetes mellitus and hypertension reduces left ventricular mass index. Enalapril appears not to induce regression, but perhaps prevents progression with an effect that is intermediate between those of nitrendipine and placebo.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nitrendipine

As the population ages, the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications. Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes. Results from the recent Appropriate Blood Pressure Control in Diabetes (ABCD) trial demonstrated an advantage of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) over a long-acting calcium antagonist (nisoldipine) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes. This trial was a prospective, randomized, blinded study comparing the effects of moderate blood pressure control (target diastolic pressure 80-89 mm Hg) with those of intensive control (target diastolic pressure 75 mm Hg) on the incidence and progression of diabetic vascular complications. The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes. In 470 hypertensive patients, the incidence of fatal and nonfatal myocardial infarctions was significantly (p = 0.001) higher among those receiving nisoldipine (n = 25) compared with those receiving enalapril (n = 5). Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril resulted from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine. Since these findings in the ABCD trial are based on a secondary endpoint, they require confirmation. Nevertheless, they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Myocardial Infarction; Nisoldipine; Prospective Studies; Single-Blind Method; Treatment Outcome

This study determines the long-term efficacy of the ACE inhibitor, enalapril, in reducing the progression of microalbuminuria to clinical albuminuria in normotensive patients with type 2 diabetes.. There were 103 normotensive type 2 diabetic patients with persistent albumin excretion rate (AER) 20-200 micrograms/min and normal renal function followed for 5 years in a prospective randomized single-blind placebo-controlled trial. AER, blood pressure, fasting plasma glucose, and HbA1 were measured very 3-4 months and glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary urea every 12 months.. In the patients treated with enalapril, AER decreased from 55 +/- 33 to 20 +/- 59 micrograms/min (geometric mean +/- SD), whereas in the placebo group, AER increased from 53 +/- 31 to 85 +/- 90 micrograms/min after 5 years. Within 5 years, 7.7% (4/52) of enalapril-treated subjects and 23.5% (12/51) of placebo-treated subjects progressed to clinical albuminuria defined as AER > 200 micrograms/min and at least 34% above baseline (risk reduction = 66.7%, P < 0.001). AER increased at an annual rate of 12.3% (95% CI 9.8-14.9) in the placebo group, while it declined by 16.7% (95% CI -18.3 to -15.2) in the enalapril group (P < 0.001). In addition, 8 of the 12 placebo-treated patients had evidence of coronary artery disease. The rest of the parameters remained practically unchanged in the two groups.. After 5 years of therapy with enalapril, compared with placebo, normotensive subjects with type 2 diabetes experienced significantly less progression of microalbuminuria to clinical albuminuria, reduced AER, and preserved GFR.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Dietary Proteins; Disease Progression; Enalapril; Energy Intake; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Placebos; Risk Factors; Single-Blind Method; Time Factors

There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial.. To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers.. Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp.. No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study.. Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Captopril; Cross-Over Studies; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipoproteins; Male; Middle Aged; Single-Blind Method; Time Factors

Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. Duration of diabetes, blood pressure values, and metabolic status are the major determinants of the course of nephropathy, and microalbuminuria is the hallmark of its onset. Angiotensin-converting enzyme inhibitors offer important renoprotection to hypertensive and normotensive patients with insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus. Our study extends previous observations for duration and the effect of angiotensin-converting enzyme inhibition on advanced nephropathy.. Double-blinded (first phase) and open (second phase) randomized controlled study of 7 years. Ninety-four normotensive patients with non-insulin-dependent diabetes mellitus whose serum creatinine levels were lower than 123.76 mumol/L (1.4 mg/dL) and who had microalbuminuria (30 to 300 mg/24 h) were given enalapril maleate, 10 mg/d, or placebo, for 5 years. For 2 more years they were followed up openly and given the choice to receive enalapril or no treatment.. In the enalapril-treated patients, albuminuria remained stable for 7 years. An increase from (mean +/- SD) 123 +/- 58 to 310 +/- 167 mg/24 h occurred in the untreated group after 5 years, and a further increase to (mean +/- SD) 393 +/- 223 mg/24 h occurred after 7 years. Reciprocal creatinine was unchanged in treated patients for 7 years; in the untreated patients, the mean decline was 13% at 5 years and 16% at 7 years. Treatment with enalapril resulted in an absolute risk reduction of 42% for nephropathy to develop during 7 years (95% confidence interval, 15% to 69%; P < .001, Student's t test). Glycosylated hemoglobin and body mass index remained unchanged.. Angiotensin-converting enzyme inhibition offers long-term protection against the development of nephropathy in normotensive patients with noninsulin-dependent diabetes mellitus who have microalbuminuria, and it stabilizes renal function in previously untreated patients with impaired renal function. Discontinuation of treatment results in renewed progression of nephropathy.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Humans; Male; Middle Aged; Risk; Treatment Outcome

The beneficial effect of long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor on urinary microalbumin excretion (UAE) and renal function was investigated in a 4 year, randomized prospective study in normotensive patients with non-insulin-dependent (Type 2) diabetes mellitus. Sixty-two normotensive patients with Type 2 diabetes mellitus and microalbuminuria but normal renal function were randomized to receive either enalapril 5 mg day-1 or no treatment. In the enalapril-treated patients, UAE was reduced from 115.4 +/- 80.1 to 95.6 +/- 61.7 mg 24 h-1 after 12 months (p < 0.05) and to 75.3 +/- 44.8 mg 24 h-1 after 48 months (p < 0.001). In the untreated group, UAE increased slowly from 93.9 +/- 69.9 to 150.0 +/- 144.5 mg 24 h-1 after 48 months. No changes in creatinine clearance, blood pressure or HbA1C were seen in either group during the 4-year period. In normotensive Type 2 diabetic patients with early stage of diabetic microalbuminuria. This effect is long-lasting and probably independent of the antihypertensive action of the drug.

Topics: Aged; Albuminuria; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Administration Schedule; Enalapril; Follow-Up Studies; Humans; Middle Aged; Prospective Studies

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Humans; Kidney Failure, Chronic; Middle Aged

A trial to study the efficacy, safety and tolerability of nitrendipine and enalapril in the treatment of diabetic hypertensive patients with microalbuminuria (MA) was performed to compare the effects of both drugs in the prevention of the renal impairment. Twenty-eight valid patients [13 with nitrendipine (N) and 15 with enalapril (E) with NIDDM, hypertension (diastolic blood pressure between 90 to 114 mm Hg) and MA (urinary albumin between 30 to 300 mg/24 hr) were recruited in a double blind, randomized trial. Following a placebo run-in period of two to four weeks, all eligible patients were randomly allocated to either N or E treatment. Treatment lasted six months, with two different visits at three and six months in which blood pressure (BP), heart rate (HR), renal function and MA were measured. No statistically significant differences on BP and metabolic parameters were found between both treatment groups. The geometric mean of final glomerular filtration rate (GFR) in the N group was 34.5% higher than in the E group, while the reduction on MA was most important in the E group. Eleven patients reported adverse events (AEs) and there were four dropouts, three of them due to AEs. We conclude that both treatments are a good choice for treating diabetic hypertensive patients with early altered renal function, as they reduce BP without altering metabolic parameters, increase GFR and reduce MA with a low frequency of AEs.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Nitrendipine

The effects of 3, 15, and 27 months of treatment with nitrendipine (10 to 40 mg/day) and enalapril (5 to 20 mg/day) on diastolic blood pressure (DBP), overnight urinary albumin excretion (UAE) rate, glomerular filtration rate (GFR), and renal plasma flow (RPF) were studied prospectively in a parallel group design in 13 microalbuminuric non-insulin dependent diabetic patients with mild hypertension and biopsy-proven diabetic glomerulopathy. Throughout the study period DBP decreased in both groups to < 95 mm Hg. At three months UAE, GFR, and RPF did not change significantly. At 15 and 27 months UAE (microgram/min, geometric mean and 95% C.I.) decreased respectively from 47.4 (23.4 to 95.9) to 28.6 (10.3 to 79.4), and to 22.3 (10.9 to 45.2; P = 0.0005) with nitrendipine, and from 58.3 (30.3 to 110.9) to 44.1 (22.9 to 84.8), and to 14.7 (4.4 to 49.3; P = 0.0025) with enalapril. Four patients in each group were normoalbuminuric at 27 months and none became macroalbuminuric. At 15 months the GFR (ml/min/1.73 m2, mean +/- SD) increased from 69.5 +/- 15.2 to 96.6 +/- 22.0 (P < 0.05) with nitrendipine and from 58.9 +/- 10.7 to 78.5 +/- 11.0 (P < 0.05) with enalapril. At 27 months the GFR was still numerically higher that at baseline either with nitrandipine (81.2 +/- 7.8) and with enalapril (79.9 +/- 17.7) (P = 0.7). The RPF (ml/min/1.73 m2, mean +/- SD) at baseline and at 27 months was comparable either with nitrendipine (456.6 +/- 165.3 vs. 400.9 +/- 112.9) and with enalapril (400.3 +/- 81.3 vs. 399.0 +/- 123.7). Both treatments were well tolerated. This is the first evidence that long-term effective control of arterial blood pressure by a calcium channel blocker or by an angiotensin converting enzyme inhibitor, in addition to reducing albuminuria, also improves GFR in incipient nephropathy.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Function Tests; Male; Nitrendipine; Renal Circulation

The ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is a large, prospective, randomized clinical trial of 950 patients with non-insulin-dependent diabetes mellitus (NIDDM) designed to compare the effects of intensive blood pressure control with moderate control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and neuropathy in NIDDM. The secondary objective is to determine equivalency of the effects of a calcium channel blocker (nisoldipine) and an angiotensin-converting-enzyme inhibitor (enalapril) as a first-line antihypertensive agent in the prevention and/or progression of these diabetic vascular complications. The study consists of two study populations aged 40-74 years, 470 hypertensive patients (diastolic blood pressure of > or = 90.0 mmHg at time of randomization) and 480 normotensive patients (diastolic blood pressure of 80.0 mmHg at time of randomization). The study duration is 5 years and is scheduled to end in May of 1998. Patients are randomized to receive either intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients are also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control is necessary. The primary outcome measure is glomerular filtration rate as assessed by 24-h creatinine clearance. Secondary outcome measures are urinary albumin excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated. Given the data showing the impact of hypertension on complications in NIDDM, the ABCD Trial is designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of diabetic complications in NIDDM.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Enalapril; Exercise; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Nisoldipine; Prospective Studies; Sex Characteristics

Microalbuminuria in diabetic patients is diagnostic of early renal involvement and angiotensin converting enzyme inhibitors reduce albumin excretion in these subjects.. To assess the effects of an angiotensin converting enzyme inhibitor on urinary albumin excretion in non insulin dependent diabetic patients.. Diabetic patients with normal blood pressure were randomly assigned to receive enalapril 10 mg/day or placebo and followed during 18 months. Those with high blood pressure were randomly assigned to receive enalapril or acebutolol in doses necessary to normalize blood pressure and followed during 12 months. Every three months, urinary albumin excretion was measured in a four hour urine sample by radioimmunoassay.. One hundred fifty two patients were recruited for the study and 46 were lost from follow up. In 17 subjects with normal blood pressure initial urinary albumin excretion below cutoff values (30 mg/24 h) and treated with enalapril, this parameter did not change; in 20 treated with placebo, it increased from 5.8 +/- 6.1 to 18.2 +/- 7.5 mg/24 h. In 11 patients with normal pressure and increased initial urinary albumin, this parameter did not change with enalapril and increased in 10 with placebo from 87.3 +/- 75.1 to 253.6 +/- 61.1 mg/24 h. In hypertensive patients with normal urinary albumin excretion, no changes in this parameter were observed in those treated with acebutolol (n = 10) or enalapril (n = 14). In hypertensives with high urinary albumin excretion, it decreased from 119.2 +/- 8.5 to 40.0 +/- 4.7 mg/24 h with enalapril treatment (n = 12), and no change was observed in those treated with acebutolol (n = 11).. Enalapril decreases urinary albumin excretion in non insulin dependent diabetic patients.

Topics: Adult; Aged; Albumins; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Follow-Up Studies; Humans; Middle Aged

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

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

To examine the factors that determine the blood pressure response to enalapril and nifedipine monotherapy in the treatment of hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM).. After a 6-week placebo baseline period, 102 hypertensive NIDDM patients were randomly assigned, double-blindly, to treatment with nifedipine retard (slow release) (n = 52) or enalapril (n = 50). The daily dosage of enalapril was increased, if required, from 10 to 20 to 40 mg and that of nifedipine from 40 to 60 to 80 mg at 4-week intervals during the 12-week titration period. Blood pressure, 24-h urinary albumin excretion (UAE), biochemical data, and serum angiotensin-converting enzyme (ACE) activity were measured at weeks -6, -4, 0, 4, 8, and 12. At week 0, venous blood was also sampled for baseline plasma atrial natriuretic peptide, renin, aldosterone, and serum insulin concentrations.. At week 12, the mean daily dose of enalapril was 35 +/- 11.4 mg, and 27 (57%) patients were receiving the maximum daily dose of 40 mg. In the nifedipine group, the mean daily drug dose was 50 +/- 12.9 mg, and 4 (8%) were receiving the maximum daily dose of 80 mg. Despite a dose-dependent fall in the serum ACE activity in the enalapril group, the mean arterial pressure (MAP) was reduced by only 8 mmHg throughout the 12-week titration period compared to a decline of 15, 18, and 19 mmHg at weeks 0, 4, and 12, respectively, in the nifedipine group (P = 0.01 between groups). In the enalapril group, changes in MAP between weeks 0 and 12 correlated significantly with baseline plasma glucose (r = 0.45, P = 0.001) and aldosterone concentrations (r = -0.32, P = 0.02) and UAE (r = 0.3, P = 0.04). There was no statistically significant correlation between the changes in MAP and baseline plasma renin concentration. On multivariate analysis, the baseline renal function, glycemic control, and plasma aldosterone and serum insulin concentrations were all independently related to the changes in blood pressure in the enalapril-treated patients. No such statistical associations were observed in the nifedipine group.. In hypertensive NIDDM patients, the activity of the renin-angiotensin-aldosterone system, the level of serum insulin, glycemic control, renal function, and proteinuria may be important determinants of the blood pressure response to ACE inhibition. Good glycemic control may optimize the antihypertensive efficacy of concomitant ACE inhibitor therapy.

Topics: Albuminuria; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Furosemide; Glycated Hemoglobin; Humans; Hypertension; Indapamide; Nifedipine; Placebos; Potassium; Regression Analysis; Renin; Sodium; Time Factors

Ninety-four normotensive type II diabetics with normal renal function and microalbuminuria were randomized to receive enalapril 10 mg/day or placebo and were followed for five years. In the patients treated by enalapril plasma creatinine values and albuminuria remained stable throughout the observation period. Their plasma total cholesterol decreased from an initial value of 245 +/- 27 mg/dl to mean study value of 236 +/- 29 mg/dl, and to a fifth year value of 232 +/- 27 mg/dl (P < 0.001). The changes in HDL cholesterol and triglyceride values were nonsignificant. In the placebo group there was a significant increase in albuminuria and a mean decline of 13% in reciprocal creatinine values during the five years. Plasma total cholesterol increased from an initial mean value of 246 +/- 24 to a mean study value of 252 +/- 25 mg/dl, and to a fifth year mean value of 259 +/- 32 mg/dl (P < 0.001). There was a significant correlation between both initial and mean plasma total cholesterol values, and the decline in renal function and the rise in albuminuria in the placebo treated patients. This correlation persisted after stratification for blood pressure. Treatment with enalapril did not eliminate these correlations. Cholesterol may be an additional risk factor for diabetic nephropathy. ACE inhibitors may have a modest cholesterol lowering effect in diabetic patients mediated, in part, through the decline in albuminuria.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enalapril; Follow-Up Studies; Humans; Lipids; Middle Aged; Prospective Studies

The effect of 20 mg of enalapril with and without 12.5 mg of hydrochlorothiazide on glucose metabolism insulin sensitivity and lipids was evaluated in hypertensive non-insulin-dependent diabetes. Ten mild to moderate hypertensive patients with non-insulin-dependent diabetes mellitus were treated for 8 weeks with 20 mg enalapril once a day, and then divided into two groups of 5 patients each for a second 8 weeks of treatment with enalapril alone or in combination with hydrochlorothiazide, 12.5 mg once a day. Blood pressure, fasting plasma glucose, lipids and insulin, glycosylated hemoglobin, and insulin sensitivity were measured at baseline and after 8 and 16 weeks. Results were analyzed by the ANOVA test for repeated measures and all values are given as mean +/- SD. Diastolic blood pressure decreased significantly after the first and second period of enalapril and after the combination of enalapril and hydrochlorothiazide. Glycosylated hemoglobin dropped significantly after the first and second period of enalapril monotherapy. Plasma triglycerides and fasting plasma insulin decreased significantly after the 16 weeks of enalapril. Insulin-mediated glucose uptake increased significantly after 8 and 16 weeks of monotherapy with enalapril. No significant difference was observed in any of the metabolic characteristics, including insulin sensitivity, between the values after 8 weeks of enalapril alone and the final values of the enalapril-treated and the enalapril/hydrochlorothiazide-treated groups. It is concluded that enalapril improves some of the metabolic parameters, including insulin sensitivity, of hypertensive diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Enalapril; Female; Glycated Hemoglobin; Humans; Hydrochlorothiazide; Hypertension; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Triglycerides

A double-blind, placebo-controlled, 4-week trial was performed to determine the antihypertensive and metabolic effects of enalapril (20 to 40 mg/d) in 16 hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM) aged 55 +/- 2 years and with a body mass index of 29 +/- 1 kg/m2. Glucose utilization was determined after an overnight fast and during insulin stimulation at 0 and 4 weeks (methods: euglycemic clamp, [3-3H]glucose infusion, indirect calorimetry). Enalapril decreased systolic (166 +/- 4 v 152 +/- 5 mm Hg, P < .05) and diastolic (102 +/- 2 v 95 +/- 2 mm Hg, P < .05) blood pressure. Peripheral insulin sensitivity, ie, insulin stimulation of glucose utilization, increased approximately 30%, or by 4.3 +/- 1.7 mumol/kg.min (13.1 +/- 2.0 v 17.4 +/- 3.5 mumol/kg.min, P < .05, 0 v 4 weeks) during enalapril treatment, but remained unchanged during placebo treatment (15.4 +/- 2.8 v 15.3 +/- 2.7 mumol/kg.min, respectively). The increase in glucose utilization during enalapril treatment was fully explained by an increase of 4.1 +/- 1.7 mumol/kg.min in glucose storage (4.1 +/- 1.2 v 8.1 +/- 2.9 mumol/kg.min, P < .05) while glucose oxidation remained unchanged. High-density lipoprotein (HDL) cholesterol increased by 8% (P < .05) and hemoglobin A1c (HbA1c) improved slightly (7.7% +/- 0.7% v 7.3% +/- 0.7%, P < .05) in the enalapril group, but not in the placebo group. We conclude that enalapril improves insulin sensitivity by increasing glucose storage in hypertensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Glucose; Humans; Hypertension; Insulin Resistance; Lipids; Male; Middle Aged; Peptidyl-Dipeptidase A

To compare the effect of the antihypertensive drugs nitrendipine and enalapril on the excretion of epidermal growth factor (EGF) and albumin in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) subjects.. After a 4-week washout period, mildly hypertensive (systolic blood pressure [sBP] > or = 140 mmHg and/or diastolic blood pressure [dBP] > or = 90 mmHg) NIDDM patients with albuminuria (15-200 micrograms/min) were randomized into an 8-month-long therapy with either nitrendipine (n = 11) or enalapril (n = 10). Blood pressure, EGF, and microalbumin excretion were measured at baseline and throughout the treatment period.. A significant fall in sBP was noticed in the enalapril group and in dBP in the nitrendipine group. In the enalapril group, EGF excretion progressively increased from 188 to 214 nmol/mmol creatinine after 6 weeks and to 274 after 8 months of therapy (P = 0.03). There was a significant fall in albumin excretion while patients were on enalapril, but in the nitrendipine group, neither albuminuria nor EGF excretion changed significantly. There was no correlation of improved EGF excretion with a decrease in albuminuria or BP.. The angiotensin-converting enzyme inhibitor enalapril has been effective in decreasing albumin and increasing EGF excretion. Measurement of urinary EGF may provide a new valuable index of renal function.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Epidermal Growth Factor; Humans; Hypertension; Middle Aged; Nitrendipine

In a double-blind, double-dummy, randomized, multi-centre study, the effects of bendroflumethiazide vs. enalapril on blood pressure, glycaemic control, lipoprotein concentrations and albuminuria were compared in non-proteinuric, hypertensive type 2 diabetic patients; they were treated for 20 weeks with either bendroflumethiazide 2.5-5.0 mg (n = 59) or enalapril 10-20 mg (n = 55). Age, fasting plasma glucose, HbA1c and BMI were similar in the groups. Systolic and diastolic blood pressure were reduced in both groups. Bendroflumethiazide was accompanied by minor but significant elevations in fasting plasma glucose and serum C-peptide. HbA1c was increased during both treatments. Lipoproteins and urinary albumin/creatinine ratio were stable. Bendroflumethiazide caused a decrease in serum potassium and an increase in serum urate. No significant correlations were observed between the decline in blood pressure and changes in the metabolic risk factors. Baseline levels of age, sex, BMI, blood pressure or urinary albumin/creatinine ratio were not related to changes in blood pressure, metabolic parameters or urinary albumin/creatinine ratio.

Topics: Adult; Aged; Bendroflumethiazide; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

To evaluate the effect of angiotensin-converting enzyme (ACE) inhibition on the pressor responsiveness to norepinephrine in type II diabetes.. Eight normotensive subjects, eight mild-to-moderate hypertensive type II diabetic patients, and eight nondiabetic patients with essential hypertension were studied before and after 4 weeks of being administered enalapril. The pressor response to norepinephrine was assessed by infusing the hormone in an antecubital vein at incremental doses of 30 ng.kg-1.min-1 for periods of 5 min until reaching an increase of 20 +/- 2 mmHg in mean arterial pressure (MAP) measured by an automatic device at 1-min intervals. An effective dosage of norepinephrine that increased MAP by 20 mmHg (EDNE 20) was thereafter calculated. Before and during the last minute of norepinephrine infusion at maximum dosage, a venous blood sample was drawn to determine plasma renin activity (PRA), aldosterone, and norepinephrine levels.. In the three groups of patients, blood pressure and aldosterone were reduced while PRA was raised following ACE inhibition. Basal and maximum postinfusion levels of norepinephrine were not modified by enalapril. The EDNE 20 was basally lower in diabetic patients and remained unchanged after ACE inhibition, contrary to that observed in nondiabetic patients with essential hypertension.. Both normotensive and hypertensive type II diabetic patients have an increased pressor responsiveness to norepinephrine that is not modified by therapeutic doses of enalapril, contrary to what is observed in nondiabetic patients with essential hypertension.

Topics: Adult; Aldosterone; Blood Pressure; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Echocardiography, Doppler; Electrocardiography; Enalapril; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Renin

To compare the effects of nifedipine and enalapril on carbohydrate and lipoprotein metabolism in Chinese non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension.. A 12-week, double-blind, randomized study of plasma lipid levels and glycemic control in patients treated with nifedipine (n = 52) or enalapril (n = 50) was conducted. None of the patients were treated with insulin. Diet and dosages of oral hypoglycemic agents remained unchanged during the 12-week treatment period.. Mean arterial pressure was reduced more by nifedipine than by enalapril (23.1 vs. 11.1 mmHg, P < 0.001). Similar reductions in body mass index and plasma triglycerides and increases in apolipoprotein A-I were seen with both treatments, but HbA1 was reduced more during treatment with enalapril than with nifedipine (0.49 vs. 0.20%, P = 0.035) and serum apolipoprotein B (apoB) also declined more with enalapril than with nifedipine (8.2 vs. 2.3 mg/dl, P = 0.009).. Twelve weeks of treatment with enalapril in hypertensive NIDDM patients was associated with greater improvement in glycemic control and greater reduction in serum apoB concentration, although the reduction in blood pressure was less than with nifedipine. These changes in cardiovascular risk profile warrant investigation for a longer term.

Topics: Apolipoprotein A-I; Apolipoproteins B; Biomarkers; Blood Glucose; Blood Pressure; China; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Double-Blind Method; Enalapril; Fructosamine; Glycated Hemoglobin; Hexosamines; Hong Kong; Humans; Hypertension; Lipids; Nifedipine; Triglycerides

The effect of short- (98 days) and long-term (1 year) treatment with nitrendipine (10 to 40 mg/d) and enalapril (5 to 20 mg/d) on kidney function was studied prospectively in a parallel group design in 16 microalbuminuric non-insulin-dependent diabetic patients with mild hypertension and biopsy-proven diabetic glomerulopathy. At the end of the short-term treatment period diastolic blood pressure significantly decreased from 95.4 +/- 2.5 mm Hg to 83.5 +/- 3.5 mm Hg (P < 0.001) in the nitrendipine group and from 96.7 +/- 2.5 to 86.7 +/- 5.6 mm Hg (P < 0.001) in the enalapril group. Both overnight urinary albumin excretion rate and albumin fractional clearance tended to increase in the nitrendipine group and to decrease in the enalapril group, whereas the glomerular filtration rate and the renal plasma flow were similar to baseline in both study groups. At the end of the long-term treatment period diastolic blood pressure significantly decreased from 95.4 +/- 2.5 mm Hg to 86.0 +/- 6 mm Hg (P < 0.005) in the nitrendipine group and from 96.7 +/- 2.1 to 90.8 +/- 4.3 mm Hg (P < 0.05) in the enalapril group. Overnight urinary albumin excretion and albumin fractional clearance were similar to baseline in both study groups. The glomerular filtration rate significantly increased from 70.2 +/- 14.2 to 96.8 +/- 20.4 (P < 0.05) in the nitrendipine group and from 58.9 +/- 10.7 to 78.5 +/- 11.0 (P < 0.05) in the enalapril group. The renal plasma flow also significantly increased from 456.6 +/- 165.3 to 597.2 +/- 178.9 (P < 0.01) in the nitrendipine group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nitrendipine; Pilot Projects; Prospective Studies; Time Factors; Treatment Outcome

The primary results of a three-year prospective, double-blind, placebo-controlled trial in non-insulin-dependent diabetic (NIDDM) patients show that an anti-hypertensive regimen, which includes the ACE inhibitor enalapril, preserves renal function to a greater extent than therapy with antihypertensive agents excluding ACE inhibitors (J Am Soc Nephrol 3:335, 1992). The influence of baseline urinary albumin excretion on the renal protective effects of enalapril treatment in these subjects was the objective of this further analysis. Adequate data were available in 121 patients of the 165 hypertensive NIDDM individuals studied [baseline glomerular filtration rate (GFR) 30 to 100 ml/min/1.73 m2]. Twenty-four hour urinary excretion of albumin (UAE), protein, urea nitrogen, creatinine and isotopically determined GFR were measured at baseline and six month intervals. Glycemic control and blood pressure regulation were assessed every three months. The rate of loss of GFR was significantly greater in patients with overt proteinuria at baseline (UAE > 300 mg/24 hr) as compared to patients with baseline sub-clinical proteinuria (UAE < or = 300 mg/24 hr). Antihypertensive treatment with enalapril preserved GFR significantly better (P < 0.01) in the patients with sub-clinical proteinuria at baseline (UAE < or = 300 mg/24 hr) than other antihypertensive treatments which excluded the ACE inhibitor. Furthermore, only 7% of the enalapril-treated group progressed to clinical albuminuria compared to 21% of control treated patients. Although the enalapril-treated group had a lower mean blood pressure during the maintenance period, no correlation between blood pressure (systolic, diastolic or mean arterial) and rate of change of GFR was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Prospective Studies

The primary objective of the ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is to determine the efficacy of intensive versus moderate antihypertensive control on the outcome of type II diabetic end-organ complications in normotensive and hypertensive populations. The secondary objective is to determine whether any differential effect on end-organ complications exists between an angiotensin converting enzyme inhibitor (enalapril) and a calcium channel blocker (nisoldipine).. The ABCD Trial is a prospective, controlled, randomized, double-blind trial, with a planned follow-up of 5 years.. All patients are seen at the Colorado Prevention Center, site of the ABCD Trial, for follow-up visits.. Patients are type II diabetic males and females between the ages of 40 and 74 years with entry diastolic blood pressures > or = 80 mmHg. Patients were recruited from University of Colorado-affiliated hospitals, several health maintenance organizations, and mailing lists from the Colorado affiliate of the American Diabetes Association.. Patients were randomized to intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients were also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control was necessary.. The primary outcome measure is glomerular filtration rate as assessed by 24-hour creatinine clearance. Secondary outcome measures are microalbumin urinary excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated.. Given the data showing the impact of hypertension on diabetic complications, the ABCD Trial was designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of these complications. Results from the ABCD Trial are expected to lend interpretable and clinically relevant findings with regards to the treatment of hypertension in type II diabetes.

Topics: Adult; Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Nisoldipine; Outcome Assessment, Health Care; Prospective Studies; Research Design

To evaluate the long-term effect of angiotensin-converting enzyme inhibition on proteinuria and on the rate of decline in kidney function in patients with type II diabetes mellitus and microalbuminuria.. Randomized, double-blind, placebo-controlled trial. Each patient was followed for 5 years.. Six clinics for diabetes mellitus coordinated by a department of medicine in a university hospital in Israel.. Ninety-four normotensive, type II diabetic patients with microalbuminuria and normal renal function.. The patients were randomly assigned to receive enalapril, 10 mg per day, or placebo. Any increase in blood pressure was treated with long-acting nifedipine.. Albuminuria, blood pressure, serum creatinine, fasting blood glucose, and glycosylated hemoglobin levels, every 3 to 4 months.. In the patients treated with enalapril, albuminuria decreased from 143 +/- 64 (mean +/- SD) mg/24 h to 122 +/- 67 mg/24 h during the first year. Thereafter, we observed a slow increase to 140 +/- 134 mg/24 h after 5 years. In the placebo group, albuminuria increased from 123 +/- 58 mg/24 h to 310 +/- 167 mg/24 h after 5 years. (Difference in rate of change in proteinuria [P < 0.05]). Kidney function (expressed as mean reciprocal creatinine) declined by 13% in the placebo group and remained stable (-1%) in the enalapril group (P < 0.05). Control of blood glucose levels remained stable, in both groups, throughout the study. The mean blood pressure was stable in the enalapril group (initial group mean, 99 +/- 2.1 mm Hg; fifth-year mean, 100 +/- 3.2 mm Hg) and increased in the placebo group from an initial mean value of 97 +/- 3.2 mm Hg to 102 +/- 3.4 mm Hg at the end of the study period (P = 0.082).. In normotensive patients with diabetes mellitus type II, the institution of angiotensin-converting enzyme inhibition during early stages of diabetic nephropathy results in long-term stabilization of plasma creatinine levels and of the degree of urinary loss of albumin. These effects are probably independent of the antihypertensive action of these agents.

Topics: Adult; Albuminuria; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Humans; Kidney Function Tests; Male; Middle Aged; Nifedipine; Prospective Studies; Time Factors

1. Some non-insulin-dependent (type II) diabetic patients show albuminuria without arterial hypertension. In these patients, angiotensin-converting enzyme inhibitors reduce urinary albumin excretion without producing any changes in systemic blood pressure and renal haemodynamics. However, up to now it has not been clear whether these favourable renal effects are specifically related to angiotensin-converting enzyme inhibition or not. 2. Twelve type II diabetic outpatients with persistent macroalbuminuria (greater than 300 mg/daily on at least three consecutive occasions), without any other signs of renal disease and whose blood pressure was persistently below 140/90 mmHg, were studied. 3. In a randomized sequence and in a double-blind fashion, after a 2-month run-in period, patients were allocated to receive 5 mg of enalapril or 50 mg of atenolol daily for the next 6 months. At the end of this first period and after 6 months on placebo in a cross-over fashion, active treatment was replicated. Blood pressure and urinary albumin excretion were measured every 2 months, whereas the other variables studied were determined at the end of each period. 4. Kidney function and blood pressure did not change significantly, whereas albuminuria decreased significantly, after both of the drugs. 5. These data suggest that the inhibition of tissue angiotensin formation and the consequent reduction in glomerular permeability, rather than changes in renal and systemic haemodynamics, are the common mechanisms by which both enalapril and atenolol decreased albuminuria in our patients.

Topics: Adult; Aged; Albuminuria; Atenolol; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Humans; Kidney; Male; Middle Aged

To compare the efficacy, safety, and tolerance of enalapril and nifedipine in hypertensive patients with non-insulin dependent diabetes.. One year double blind follow up of patients randomly allocated to either enalapril or nifedipine with matching placebos for the alternative drug.. Metabolic Investigation Unit, Hong Kong.. 102 patients were randomised: 52 to nifedipine and 50 to enalapril. At baseline 44 patients had normoalbuminuria, 36 microalbuminuria, and 22 macroalbuminuria.. Blood pressure, albuminuria, and parameters of renal function and glycaemic control.. In patients who completed one year's treatment the median dose required by the nifedipine group (n = 49) was 60 mg/day; seven (14%) required additional diuretics. Of 41 patients given enalapril, 37 required the maximum dose (40 mg/day) and 27 (76%) required diuretics. At one year mean arterial blood pressures were similar in both groups. Albuminuria fell by 54% in the enalapril group and 11% in the nifedipine group (p = 0.006). Fractional albumin clearance ratio fell by 47% in the enalapril group and increased by 3% in the nifedipine group (p = 0.009). Creatinine clearance fell similarly in both groups but plasma creatinine concentration was increased by 20% in the enalapril group versus 8% in the nifedipine group (p = 0.001).. Patients taking enalapril often required diuretics to control blood pressure. Enalapril reduced proteinuria significantly more than nifedipine in the microalbuminuric and macroalbuminuric patients but increased plasma creatinine concentrations. Longer follow up is required to clarify the importance of enalapril's antiproteinuric effect.

Topics: Albuminuria; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Kidney; Male; Nifedipine

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

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

Lipid peroxides and fluorescent serum proteins, possible markers of free radical activity, are increased in diabetic patients, particularly those with angiopathy. Captopril, an angiotensin converting enzyme (ACE) inhibitor, scavenges free radicals in vitro independently of ACE inhibition. This is probably due to the presence of a sulphydryl group which is not present in other ACE inhibitor drugs. We have compared the effects of captopril and enalapril on free radical activity in thirty-two diabetic subjects with hypertension (BP greater than 160/95 mmHg). After a three week run-in period on no antihypertensive therapy, patients were randomly allocated to receive captopril or enalapril, the dose titrated according to BP response. After three months, BP was well controlled in both groups and glycaemic control unchanged. Both drugs were associated with a reduction of fluorescent IgG (captopril:Baseline [BL] 0.564 vs. 12 weeks [w] 0.428, P less than 0.05, enalapril:BL 0.603 vs. 12w 0.422 P less than 0.05) and thiobarbituric acid reactive material (captopril:BL 2.35 nmol MDA vs. 12w 1.46 nmol, P less than 0.05, enalapril:BL 2.44 nmol vs. 12w 1.72 nmol, P less than 0.01). In contrast to in vitro studies, there was no significant difference between the drugs when used in therapeutic doses, questioning a hypothesised advantage of captopril over enalapril.

Topics: Adult; Aged; Blood Proteins; Captopril; Diabetes Mellitus, Type 2; Enalapril; Female; Free Radical Scavengers; Free Radicals; Humans; Hypertension; Lipid Peroxides; Male; Middle Aged; Thiobarbiturates

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Enalapril; Glycated Hemoglobin; Humans; Hypertension; Insulin; Lipids; Middle Aged; Nifedipine

Long-term glycaemic control measured by glycosylated haemoglobin concentration was compared in hypertensive NIDD's taking placebo, alpha-blockers, beta-blockers (alone and in combination) and an ACE inhibitor (enalapril) each for 4 months. Alpha-blockade caused no deterioration in long-term glycaemic control in NIDD's. Beta-blockers caused a deterioration in glycaemic control in NIDD's (with some adverse effects on lipid profile). This was especially apparent with the lipophilic beta-blocker P. Concurrent use of an alpha-blocker with a beta-blocker prevents the deterioration due to beta-blockade. The ACE inhibitor, enalapril caused an improvement in long-term glycaemic control without alteration of lipid control in NIDD's.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Insulin; Lipids; Male; Middle Aged; Prospective Studies

The efficacy and tolerability of lisinopril administered once daily were evaluated in a 12-week open study of 60 elderly patients aged between 65 and 85 years (mean 75 years) with essential hypertension. Mean sitting blood pressure was reduced from 190/106 +/- 6.3/1.3mm Hg (mean +/- SEM) at entry to 162/89 +/- 5.5/0.9 mm Hg after 12 weeks of treatment (p less than 0.001). There was no significant alteration in heart rate, and no occurrence of postural hypotension. The median daily dose of lisinopril was 20mg (range 5 to 40 mg) and only 4 patients required the addition of a diuretic. Mean glomerular filtration rate (GFR) at entry was 61.6 +/- 3.4 ml/min and was unchanged after 12 weeks of therapy. 25 patients continued to receive treatment for 1 year, and 20 of these completed 2 years of treatment. Control of blood pressure was maintained, and heart rate, biochemical parameters and GFR remained unaltered throughout the study. Renal function was preserved and renal blood flow, measured in a group of 14 patients, was significantly increased (p less than 0.025) at the end of the first year after treatment with lisinopril. Thus, in the elderly, lisinopril was well tolerated and highly effective in lowering blood pressure, and renal function was maintained.

Topics: Age Factors; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Lisinopril; Male

Eighteen patients with non-insulin dependent diabetes mellitus (NIDDM), hypertension and nephropathy were randomized to receive captopril or enalapril for 6 months. Two patients with serum creatinine of greater than 400 mumol/l had to be excluded from the study because of rapidly deteriorating renal function after starting treatment. Of the remaining patients, 7 received captopril and 9 received enalapril. Blood pressure control was achieved in about 50% of patients with either drug alone. Serum creatinine and creatinine clearance were unchanged in both groups but there was a greater tendency for the former to increase in patients with higher pretreatment values. Proteinuria was reduced at 1 month only in the enalapril group which also showed a significant elevation of serum potassium after treatment. Captopril and enalapril have only a modest antihypertensive action in patients with NIDDM and nephropathy. Their use in patients with renal insufficiency must be balanced against the risk of further aggravating the deterioration of renal function.

Topics: Blood Pressure; Captopril; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Seven of eight hypertensive Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria completed a randomised crossover trial to compare the renal effects of angiotensin converting enzyme inhibitor (enalapril) and calcium antagonist (nicardipine). Four-week fixed oral maintenance dosages of enalapril (10-20 mg/day) and nicardipine (60-120 mg/day) significantly (p less than 0.05) lowered the systolic and diastolic blood pressures without altering renal blood flow, glomerular filtration rate and filtration fraction. Both drugs significantly reduced (p less than 0.05) urinary albumin excretion rate and fractional clearance of albumin to similar extents. Total renal vascular resistance decreased significantly by nicardipine (p less than 0.05) and non-significantly by enalapril. Plasma osmotic pressure, plasma aldosterone concentration, total serum protein concentration, serum electrolytes and HbA1c remained unchanged by these drugs, whereas plasma renin activity was significantly higher (p less than 0.05) in the enalapril than in the control and nicardipine phases. These results suggest that both drugs have similar renal function preserving effects with a concomitant hypotensive action in hypertensive Type 2 diabetic patients with microalbuminuria, and that the angiotensin converting enzyme inhibitor may not have advantageous renal effects when compared to the calcium antagonist and vice versa. Both drugs might be useful for treatment of high blood pressure in hypertensive diabetic patients, if long-term studies of these drugs can be shown to benefit the patients over other conventional antihypertensive therapies.

Topics: Aged; Albuminuria; Blood Pressure; Blood Proteins; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nicardipine; Random Allocation; Renal Circulation; Vascular Resistance

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

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

Two-thirds of patients with type 2 diabetes mellitus have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. This study investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were dosed orally with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by high performance liquid chromatography and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the K

Topics: Animals; Antiporters; Diabetes Mellitus, Type 2; Enalapril; Kidney; Metformin; Organic Cation Transport Proteins; Organic Cation Transporter 2; Rats; Rats, Wistar

Neurodegenerative processes with type 2 diabetes mellitus in particular aggravate the course of the disease, change the usual life rhythm, and are a considerable part of high disability and lethality rates.. The aim of the study was to examine enalapril effect on protein peroxide oxidation, activity of proteolysis and fibrinolysis enzymes and morphological state of the cerebral cortex and hippocampus under conditions of neurodegeneration in case of experimental type 2 diabetes mellitus.. Changes in the content of protein peroxide oxidation products activity of proteolysis and fibrinolysis enzymes in the cerebral cortex and hippocampus are examined under enalapril effect (1 mg/kg) in nonlinear laboratory albino male rats with neurodegeneration under conditions of type 2 diabetes mellitus simulated by streptozotocin and high-fat diet.. After introduction of enalapril during 14 days for rats with type 2 diabetes mellitus the content of proteins of a neutral and main character, activity of proteolysis and fibrinolysis enzymes in the cerebral cortex and hippocampus decreases, which is indicative of reduced protein peroxide oxidation, intensified under conditions of diabetic neurodegeneration. Morphological picture of the cerebral cortex and hippocampus is characterized by a decreased amount of cells with karyopyknosis and increased relative density of the tigroid substance staining of neurons and lack of denudation signs of the vessels, which is indicative of a positive rebuilding of the neuron structure.. The conducted study demonstrates a protective effect of enalapril in case of central neurodegeneration caused by type 2 diabetes mellitus, one of the mechanisms of which is decrease of protein peroxide oxidation in the cerebral cortex and hippocampus inhibiting the processes of nerve cells destruction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Type 2; Enalapril; Oxidative Stress; Rats; Streptozocin

Diabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase-2 inhibitor against diabetic nephropathy.. Sixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8 weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B. Obese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB-treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP-1 (CCR2) level and renal infiltration of CD-68 positive cells. PTUPB and enalapril significantly reduced urinary MCP-1 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.. Overall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Kidney; Rats

Angiotensin-1 converting enzyme inhibitors (ACEIs) improve insulin sensitivity. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are anti-diabetic drugs with several cardio-renal effects. Both ACE and DPP-4 share common features. Thus, we tested if they could be inhibited by one inhibitor. First, in silico screening was used to investigate the ability of different DPP-4 inhibitors or ACEIs to interact with DPP-4 and ACE. The results of screening were then extrapolated into animal study. Fifty Sprague Dawley rats were randomly assigned into 5 groups treated with vehicle, captopril, enalapril, linagliptin or sitagliptin. Both low and high doses of each drug were tested. Baseline blood samples and samples at days 1, 8, 10, 14 were used to measure plasma DPP-4 and ACE activities and angiotensin II levels. Active glucagon-like peptide-1 (GLP-1) levels were measured after oral glucose challenge. All tested DPP-4 inhibitors could interact with ACE at a relatively reasonable binding energy while most of the ACEIs only interacted with DPP-4 at a predicted high inhibition constant. In rats, high dose of sitagliptin was able to inhibit ACE activity and reduce angiotensin II levels while linagliptin had only a mild effect. ACEIs did not significantly affect DPP-4 activity or prevent GLP-1 degradation. It seems that some DPP-4 inhibitors could inhibit ACE and this could partially explain the cardio-renal effects of these drugs. Further studies are required to determine if such inhibition could take place in clinical settings.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enalapril; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Linagliptin; Peptidyl-Dipeptidase A; Protein Binding; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.. We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome-the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.. RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA. These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fatty Liver; Glucose Tolerance Test; Hypertension; Insulin Resistance; Kidney Glomerulus; Liver Cirrhosis; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Rats; Rats, Zucker

This study investigated the efficacy of monotherapy versus combination of menhaden oil, α-lipoic acid, and enalapril on corneal sensation and morphometry and other neuropathy-related endpoints in a rat model of type 2 diabetes.. Male Sprague-Dawley rats (aged 12 weeks) were fed a high-fat diet for 8 weeks followed by 30 mg/kg streptozotocin. After 16 weeks of hyperglycemia, 12-week treatments consisting of menhaden oil, α-lipoic acid, enalapril, or their combination were initiated. Before and after treatments, we performed analyses of multiple neural and vascular endpoints including corneal sensitivity, corneal nerve density, vascular reactivity of epineurial arterioles, motor and sensory nerve conduction velocity, intraepidermal nerve fiber density, and thermal nociception.. Before treatment, all the neural and vascular endpoints in diabetic rats were impaired. Treating diabetic rats with monotherapy was effective in improving neural and vascular deficits with menhaden oil being most efficacious. However, the combination therapy provided the greatest benefit and improved/reversed all nerve and vascular deficits. The effect of combination therapy on corneal relative sensitivity and structure (in mm/mm), primary endpoints for this study, for control, diabetic, and diabetic treated rats was 4.2 ± 1.4 and 7.5 ± 0.5, 12.1 ± 1.3* and 3.8 ± 0.2*, and 6.6 ± 2.3 and 7.3 ± 0.5, respectively (*P < 0.05 compared with control rats; P < 0.05 compared with diabetic rats).. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

Topics: Adiponectin; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Cornea; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, High-Fat; Drug Therapy, Combination; Enalapril; Fish Oils; Hypesthesia; Lipids; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Streptozocin; Thiobarbituric Acid Reactive Substances; Thioctic Acid; Trigeminal Nerve Diseases

The antihypertensive effect of indapamide has never been clearly understood, particularly in hypertensive patients with diabetes mellitus. A total of 565 patients were randomly selected to receive either indapamide 1.5 mg or enalapril 10 mg daily for 12 months. Brachial blood pressure (BP) and plasma and urinary electrolytes were measured at baseline and at the end of follow-up. Sodium and potassium levels and excretion rates were measured in overnight urine collections. After 12 months' treatment, similar significant reductions were observed in systolic and diastolic BP and pulse pressure levels in both treatment arms (P < .001). However, age, body mass index, diabetes duration, and plasma sodium reductions were shown to be major, independent factors influencing BP reduction with indapamide, but not with enalapril. Regression coefficients were positive for age and plasma sodium reductions (P ≤ .009) but negative for body mass index and diabetes duration (P ≤ .008). Similar findings were observed for pulse pressure. These results were more notable in elderly patients, did not differ regardless of whether BP reduction was measured in absolute or percent values, and were associated with increased sodium and potassium excretion rates.Indapamide is more effective than enalapril at reducing BP in elderly diabetic hypertensives with marked sodium retention.

Topics: Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Natriuresis

We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Obesity Agents; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Enalapril; Fish Oils; Hypoglycemic Agents; Male; Neuralgia; Non-alcoholic Fatty Liver Disease; Obesity; Rats, Sprague-Dawley; Streptozocin; Weight Loss

We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

Topics: Animals; Cornea; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Fish Oils; Glucose Tolerance Test; Male; Neural Conduction; Rats, Sprague-Dawley; Sciatic Nerve; Streptozocin; Thioctic Acid; Vasodilation

Differences in clinical effectiveness between angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in the primary treatment of hypertension are unknown. The aim of this retrospective cohort study was to assess the prevention of type 2 diabetes and cardiovascular disease (CVD) in patients treated with ARBs or ACEis. Patients initiated on enalapril or candesartan treatment in 71 Swedish primary care centers between 1999 and 2007 were included. Medical records data were extracted and linked with nationwide hospital discharge and cause of death registers. The 11,725 patients initiated on enalapril and 4265 on candesartan had similar baseline characteristics. During a mean follow-up of 1.84 years, 36,482 patient-years, the risk of new diabetes onset was lower in the candesartan group (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69-0.96, P=0.01) compared with the enalapril group. No difference between the groups was observed in CVD risk (HR 0.99, 95% CI 0.87-1.13, P=0.86). More patients discontinued treatment in the enalapril group (38.1%) vs the candesartan group (27.2%). In a clinical setting, patients initiated on candesartan treatment had a lower risk of new-onset type 2 diabetes and lower rates of drug discontinuation compared with patients initiated on enalapril. No differences in CVD risk were observed.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Primary Health Care; Retrospective Studies; Risk Factors; Sweden; Tetrazoles; Time Factors; Treatment Outcome

Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear.. This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8).. Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well.. Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enalapril; Glucose; Hypoglycemic Agents; Kidney; Kidney Glomerulus; Linagliptin; Male; Mice; Mice, Inbred Strains; Renin-Angiotensin System

The attempts to develop new treatments for acute ischemic stroke have been fraught with costly and spectacularly disappointing failures. Repurposing of safe, older drugs provides a lower risk alternative. Vascular protection is a novel strategy for improving stroke outcome. Promising targets for vascular protection after stroke have been identified, and several of these targets can be approached with "repurposed" old drugs, including statins, angiotensin receptor blockers (ARBs), and minocycline. We tested the vascular protection (ability to reduce hemorrhagic transformation) of three marketed drugs (candesartan, minocycline, and atorvastatin) in the experimental stroke model using three different rat strains [Wistar, spontaneously hypertensive rats (SHR) and type 2 diabetic Goto-Kakizaki (GK) rats]. All agents decreased the infarct size, improved the neurological outcome and decreased bleeding. Mechanisms identified include inhibition of MMP-9, activation of Akt, and increased expression of proangiogenic growth factors. Premorbid vascular damage (presence of either diabetes or hypertension) increased the likelihood of vascular injury after ischemia and reperfusion and improved the response to vascular protection.

Topics: Animals; Anticholesteremic Agents; Antihypertensive Agents; Atorvastatin; Benzimidazoles; Biphenyl Compounds; Brain Infarction; Diabetes Mellitus, Type 2; Disease Models, Animal; Enalapril; Enzyme-Linked Immunosorbent Assay; Functional Laterality; Hemoglobins; Hemorrhage; Heptanoic Acids; Male; Matrix Metalloproteinase 9; Pyrroles; Rats; Rats, Inbred SHR; Rats, Wistar; Reperfusion; Stroke; Tetrazoles; Vascular System Injuries

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Drug Therapy, Combination; Enalapril; Heart Rate; Hemodynamics; Humans; Metabolic Syndrome; Models, Biological; Peptidyl-Dipeptidase A; Pyrazines; Sitagliptin Phosphate; Triazoles

Recent data suggest that aldosterone antagonists have beneficial effects on diabetic nephropathy. In this study, we investigated the dose-dependent effect of eplerenone and a combined treatment with eplerenone and enalapril compared with each drug alone on renal function in type II diabetic rats. To further explore the molecular mechanism of action of combination therapy, we also performed in vitro study.. The animals were divided into six groups as follows: normal control Long-Evans Tokushima Otsuka (LETO) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, OLETF rats treated with low dose of eplerenone (50 mg/kg/day), OLETF rats treated with high dose of eplerenone (200 mg/kg/day), OLETF rats treated with enalapril (10 mg/kg/day) and OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and enalapril 10 mg/kg/day) for 6 months.. Treatment of OLETF rats had no significant effect on body weight, kidney weight and blood glucose levels. However, urinary albumin excretion, glomerular filtration rate and glomerulosclerosis were significantly improved in the enalapril group and improvement was observed in a dose-dependent manner in the eplerenone groups; the most dramatic decreases were observed in the combination group. In accordance with these findings, renal expressions of TGF-beta1, type IV collagen and PAI-1 were also markedly decreased in the treatment groups, with the combined treatment providing the most significant level of improvement. In cultured mesangial cells, combined treatment resulted in an additive decrease in TGF-beta1, PAI-1 and collagen gene expressions and protein production induced by high glucose and aldosterone stimulation.. Aldosterone receptor antagonism provided additional benefits beyond blockade of the renin-angiotensin system in type II diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Primers; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Eplerenone; Extracellular Matrix Proteins; Gene Expression; Glomerular Filtration Rate; In Vitro Techniques; Male; Mesangial Cells; Mineralocorticoid Receptor Antagonists; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred OLETF; Renin-Angiotensin System; Spironolactone; Transforming Growth Factor beta; Transforming Growth Factor beta1

A 48-year-old woman was hospitalized with the diagnosis of hepatitis. She presented with symptoms of jaundice, headache, elevated bilirubin, and elevated hepatic enzymes. She related a recent episode of a bronchial infection that was treated during the previous eight days with paracetamol (500mg, 2 doses only), chlorpheniramine, betamethasone and clindamycin. After an initial clinical and laboratorial improvement, she began to complain of pruritus of the palms and soles. Thereafter, vesicles evolving to blisters developed and a deterioration of her general health ensued. Serologies for hepatitis A, B, and C viruses were negative. Intrahepatic cholestasis and Stevens Johnson Syndrome (SJS) were the final diagnosis. The association of the Stevens Johnson Syndrome and intrahepatic cholestasis simultaneously, related to adverse drug reactions, is very rare. The drugs reportedly involved are mainly antibiotics, such as ampicillin, vancomycin, amoxicillin/clavulinic acid and erythromycin. Other drugs involved are non-steroidal anti-inflamatory drugs, such as mefenamic acid, ibuprofen, and sulindac. The reactions can be minor or severe and can even cause death, an outcome that has been reported in patients of all races and ethnic groups, but appears to be more rare in patients of Latin origin. We present a discussion of this case and review the main characteristics of the Stevens Johnson Syndrome.

Topics: Acetaminophen; Betamethasone; Bronchitis; Chlorpheniramine; Cholestasis, Intrahepatic; Clindamycin; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enalapril; Female; Foot Dermatoses; Hand Dermatoses; Humans; Insulin; Methylprednisolone; Middle Aged; Mucositis; Stevens-Johnson Syndrome

The study was designed to evaluate effect of enalapril and telmisartan on hemodynamic characteristics and diastolic function (DF) of left ventricle (LV) in patients with type 2 diabetes and arterial hypertension (AH). It included 64 patients aged 54.3 +/- 5.2 years. Those in group 1 (n = 31) were given enalapril (enap), patients of group 2 (n = 33) were treated with telmisartan (micardis). Examination included 24 hour AP monitoring, Holter ECG monitoring, and echocardiography. Compensation of metabolic disorders was evaluated from fasting and postprandial blood glucose and HbAc1 levels. Impaired LV DF was the main feature of affected myocardium in patients with DM2 and elevated AP in the absence of contractility disturbance. Enalapril therapy ensured the desired level of systolic and diastolic AP in 77 and 64.5% of the patients respectively in association with a decreased number of non-dippers and night-peakers in 45.4% of the observations in the absence of changes in HbAc1 level and LV DF. Treatment with telmisartan ensured within 24 weeks efficacious control of systolic AP and normalization of its daily profile in 87.5% patients with pathological circadian rhythm, besides improvement of carbohydrate metabolism and LV DF.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Glucose; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Diastole; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Myocardial Contraction; Telmisartan; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left

Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats, a model of the metabolic syndrome, and Zucker Diabetic Fatty (ZDF) rats, a model of type 2 diabetes. Because of their lipid lowering action and antioxidant activity, we predicted that treatment with Rosuvastatin, an HMG-CoA reductase inhibitor (statin) or Enalapril, an angiotensin converting enzyme (ACE) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes.. 20-week-old Zucker obese and 16-week-old ZDF rats were treated with Rosuvastatin (25 mg/kg/day) or Enalapril (20 mg/kg/day) for 12 weeks. We examined metabolic parameters, indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries (75-175 microm intraluminal diameter) from lean, Zucker obese and ZDF rats (untreated and treated).. Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats. Both drugs improved metabolic parameters, oxidative stress, and vascular dysfunction in Zucker obese rats, however, only partial improvement was observed in ZDF rats, suggesting more aggressive treatment is needed when hyperglycemia is involved.. Vascular dysfunction is improved when Zucker obese and, to a lesser degree, when ZDF rats were treated with Rosuvastatin or Enalapril.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Cholesterol; Coronary Vessels; Diabetes Mellitus, Type 2; Enalapril; Endothelium, Vascular; Fatty Acids; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mesenteric Arteries; Metabolic Syndrome; Oxidative Stress; Pyrimidines; Rats; Rats, Zucker; Rosuvastatin Calcium; Sulfonamides; Triglycerides

To evaluate the effects of angiotensin-converting enzyme inhibitors (ACE-I) in retarding progression of severe non-proliferative diabetic retinopathy (NPDR) in normotensive type 2 diabetic patients.. This was a retrospective case control study of 128 patients with normotensive type 2 diabetes with lower than +1 dipstick proteinuria and severe NPDR who were classified into either an ACE-I treated group (Enalapril maleate 10 mg, n=12 , Ramipril 5 mg, n=17) or an ACE-I untreated group (n=99). Medical records were reviewed for endpoints of (a) occurrence of proliferative diabetic retinopathy (PDR) or macular edema (ME) for which laser phototherapy was necessary or (b) development of proteinuria of higher than +1 level requiring medication of ACE-I.. From the total of 128 patients, there were 29 ACE-I treated patients and 99 ACE-I untreated patients. There were no differences in the average age, duration of diabetes, body mass indices, blood pressure and levels of hyperglycemia or HbA1C between the two groups. Blood pressure and HbA1C levels in both groups remained unchanged during the study. The mean follow-up period was 41.6 months. In the ACE-I group, 6 patients progressed to PDR, 5 to ME and 6 developed proteinuria of greater than +1 over the follow-up period. In the control group, 30 patients progressed to PDR, 6 to ME and 9 developed proteinuria of greater than +1 over the follow-up period.. Small doses of ACE-I did not yield any beneficial effects in retarding the progression of severe NPDR.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Progression; Dose-Response Relationship, Drug; Enalapril; Female; Fundus Oculi; Humans; Male; Middle Aged; Ramipril; Retrospective Studies; Severity of Illness Index; Treatment Failure

Progression of renal disease and cardiovascular complications in type II diabetes mellitus have been shown to correlate with control of blood glucose, lipids, blood pressure, and smoking. These factors, however, do not appear to totally explain these diabetic complications. Renal disease and cardiovascular complications in type II diabetes are associated with vascular abnormalities and fibrosis, both of which may occur with impaired fibrinolysis. A cross-sectional study was therefore performed in 107 type II diabetic patients recruited from the Denver Metropolitan Area to examine the effect of impaired fibrinolysis, as assessed by the ratio of plasminogen activator inhibitor (PAI-1) to tissue-type plasminogen activator (t-PA). With urinary albumin excretion (UAE) as a risk factor for both renal disease progression and cardiovascular complications, the patients were analyzed with respect to UAE less than and greater than 1 gm/day. The age, blood glucose, hemoglobin A1C, duration of diabetes, lipids, body mass index, and smoking were no different between the groups. As expected, the group with greater UAE had worse renal function, the serum creatinine (1.98 +/- 0.24 vs 1.21 +/- 0.05 mg/dl, P < 0.001) and creatinine clearance (55.5 +/- 6.0 vs 76.8 +/- 2.7 ml/min, P < 0.001) were significantly different. The type II diabetic patients with greater UAE exhibited significantly higher PAI-1/t-PA (2.43 +/- 0.26 vs 1.85 +/- 0.07, P < 0.03). The past history of cardiac complications was also higher (87.5 vs 72.3%, P < 0.07) in the diabetic patients with more impaired fibrinolysis and greater UAE. Thus a prospective, randomized clinical trial in type II diabetes with PAI-1 inhibitors is needed.

Topics: Aged; Albuminuria; Antihypertensive Agents; Atenolol; Cardiovascular Diseases; Cohort Studies; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enalapril; Fibrinolysis; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Plasminogen Activator Inhibitor 1; Risk Factors; Time Factors; Tissue Plasminogen Activator

The accumulation of advanced glycation end products (AGE) is a key factor in diabetic nephropathy (DN). Pyridoxamine inhibits AGE formation and protects against type I DN. Herein we tested: (1) whether C57BL6 db/db mice as a model of established type II DN resembled patients treated with drugs which inhibit angiotensin II action; (2) whether pyridoxamine was effective as a single therapy; and (3) whether pyridoxamine would add to the benefit of angiotensin-converting enzyme inhibition (ACEi) by enalapril. In first set of experiments mice were treated with ACEi (benazepril) and an angiotensin II receptor blocker (valsartan) combination for 16 weeks after the onset of diabetes. In second group, mice with established DN were treated with pyridoxamine for 8 weeks. In a third set, mice with established DN were treated with pyridoxamine and enalapril combination for 16 weeks. Benazepril and valsartan combination partially prevented the development and progression of DN. Pyridoxamine treatment, as single therapy, decreased the progression of albuminuria and glomerular lesions. The combination of pyridoxamine with enalapril reduced both mortality and the progression of DN. In conclusion, (1) C57 BL6 db/db mice are a model of progressive type II DN; (2) The combination of pyridoxamine with enalapril decreased progression of type 2 DN and overall mortality. Thus, pyridoxamine could be a valuable adjunct to the current treatment of established type II DN.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Enalapril; Female; Glycation End Products, Advanced; Mice; Mice, Inbred C57BL; Mice, Obese; Pyridoxamine; Tetrazoles; Valine; Valsartan; Vitamin B Complex

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Prospective Studies; Randomized Controlled Trials as Topic; Telmisartan; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Telmisartan; Therapeutic Equivalency

There is experimental evidence of an interaction between the angiotensin system and lipid metabolism. The aim of this study was to evaluate whether a block of the angiotensin system achieved both by ACE inhibition and angiotensin II-AT1 receptor blockade could affect the plasma lipid profile and, if so, what relationship exists between these possible changes and glucose metabolism and blood pressure. In 50 patients with type 2 diabetes and hypertension, treated with diabetes drugs and enalapril, we evaluated the glycemic and lipid profile together with the HOMA insulin-resistance index, blood pressure and microalbuminuria at baseline and 3 months after the addition of valsartan. At the second evaluation, blood pressure was reduced as expected, whereas the glycemic profile, the HOMA index, and the body mass index were unchanged. Total cholesterol, LDL-c, and apoprotein B were reduced during combination therapy (P = 0.003, P = 0.001, and P = 0.004, respectively), plasma HDL-c was slightly though significantly increased (P = 0.024), whereas apoprotein A and triglyceride levels did not change. After adjustment for the insulin resistance index and for blood pressure, the reduction of LDL-c and apoprotein B and the increase in HDL-c remained significant. The variation in lipid profile was not related to the changes in blood pressure. Moreover, the addition of valsartan to enalapril was associated with a reduction in microalbuminuria, which remained significant after adjustment for LDL-c or blood pressure changes. Thus, the greater degree of renin-angiotensin system blockade or specific pharmacodynamic effects of valsartan could account for the changes in plasma lipid profile observed in this study.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enalapril; Humans; Hypertension; Lipids; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

To study the plasma angiotensin II (Ang II) levels and the expressions of angiotensin II1 receptor (AT1) in blood vessels and kidneys in diabetic and high fat diet rats, and the effects of enalapril on plasma Ang II levels and the expressions of AT1 in blood vessels and kidneys in diabetic rats.. The plasma Ang II level was assayed with 125I-Ang II radioimmunoassay, and the expression of AT1 in blood vessel and kidney was analyzed with immunohistochemical technique.. The plasma Ang II level was significantly higher in type 2 diabetic rats (241 +/- 49) pg x mL(-1) than that in the control (71 +/- 22) pg x mL , high fat diet group (151 +/- 29) pg x mL(-1) (P < 0.01) , and enalapril-treated groups (136 +/- 25) pg x mL(-1) (P < 0.05). The plasma Ang II levels in high fat diet and in enalapril-treated groups were also significantly higher than that in control group ( P < 0.01 ). With immunohistochemical technique, it was found that the expression of AT1 in endothelial cells of blood vessels, vascular smooth muscle cells, and kidneys in diabetic group increased. The expression of AT1 in endothelial cells of blood vessels, vascular smooth muscle cells, and kidney in enalapril-treated group was similar to that in control group.. The plasma Ang II levels and the expression of AT1 in type 2 diabetic and high fat diet rats increased. Enalapril was shown to decrease the plasma Ang II level and downregulate the expression of AT1 in blood vessels and kidneys in type 2 diabetic rats.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Vessels; Diabetes Mellitus, Type 2; Dietary Fats; Enalapril; Endothelial Cells; Kidney; Male; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies

The renin-angiotensin system plays an important role in the pathogenesis of diabetes-induced vascular and renal complications. Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase.. To compare the effectiveness of vasopeptidase inhibition and ACE inhibition in preventing hypertension, endothelial dysfunction and diabetic nephropathy in spontaneously diabetic Goto-Kakizaki (GK) rats.. Eight-week-old GK rats received omapatrilat (40 mg/kg) or enalapril (30 mg/kg) for 12 weeks, either during a normal-sodium or high-sodium diet (7% w/w). Blood pressure, arterial functions and renal morphology were determined.. Blood pressure and albuminuria were increased in GK rats compared to non-diabetic Wistar controls. Endothelium-dependent vascular relaxation in response to acetylcholine (ACh) and endothelium-independent vascular relaxation in response to sodium nitroprusside (SNP) were impaired in GK rats. Experiments with N-nitro-L-arginine methyl ester (L-NAME), diclofenac, and L-NAME + diclofenac suggested that cyclooxygenase and endothelium-derived hyperpolarizing factor components of endothelium-dependent vascular relaxation were also impaired. A high-sodium diet aggravated hypertension and diabetes-induced vascular and renal complications. Omapatrilat and enalapril normalized blood pressure and albuminuria during the normal-sodium diet, and effectively ameliorated diabetes-induced renal complications also during the high-sodium diet. However, omapatrilat improved endothelium-dependent relaxation to ACh to a greater extent (85 +/- 5%) than enalapril (68 +/- 6%, P < 0.05). Diclofenac pre-incubation eliminated this difference between omapatrilat and enalapril in ACh-induced vascular relaxation, suggesting that it was mediated, at least in part, via the cyclooxygenase pathway.. Despite comparable blood pressure-lowering and renoprotective properties, omapatrilat may be more effective in preventing vascular dysfunction during diabetes compared to enalapril in GK rats.

Topics: Acetylcholine; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Diabetes Mellitus, Type 2; Diclofenac; Enalapril; Endothelium, Vascular; Kidney; Male; Metalloproteases; Neprilysin; NG-Nitroarginine Methyl Ester; Nitroprusside; Pyridines; Rats; Rats, Inbred Strains; Rats, Wistar; Sodium, Dietary; Thiazepines; Vasodilator Agents

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Diabetes Mellitus, Type 2; Echocardiography; Enalapril; Fibrosis; Heart; Insulin; Male; Metalloendopeptidases; Myocardium; Natriuretic Peptide, Brain; Organ Size; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary; Thiazepines

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

Pathological changes in glomerular structure are typically associated with the progression of diabetic nephropathy. The involvement of angiotensin II (AII) in pathogenesis of diabetic nephropathy has been extensively studied and the therapeutic advantages associated with blockade of renin-angiotensin system (RAS), primarily with angiotensin converting enzyme (ACE) inhibitors, has been well-documented. We studied the effect of RAS blockade with an AII receptor antagonist (losartan) vs. an ACE inhibitor (enalapril) on glomerular lesions in KKAy mice, a model of type 2 diabetes mellitus. Losartan was administered at 3 and 10 mg/kg/day and enalapril at 3 mg/kg/day for 14 weeks in the drinking water. The doses of losartan at 10 mg/kg/day was expected to be equivalent to 3 mg/kg/day of enalapril when considering clinical doses for lowering blood pressure. The dose of 3 mg/kg/day of losartan was selected to compare the efficacy at equivalent dose of enalapril. Histologic observation demonstrated suppression of glomerular mesangial expansion and glomerulosclerosis with exudative lesion in the 10 mg/kg/day losartan group when compared to the untreated diabetic controls. A lesser degree of glomerulosclerosis was also observed with losartan and enalapril treatment at 3 mg/kg/day. Ultrastructural examination of renal glomeruli from the high dose losartan group revealed a decreased degree of effacement and/or irregular arrangement of glomerular podocytic foot process. The beneficial effect of RAS inhibition with the AII receptor antagonist losartan on diabetic glomerular lesions was clearly demonstrated in this study. These findings, therefore, provide mechanistic explanation for the clinical utility of losartan for use in the treatment of diabetic nephropathy in man.

Topics: Administration, Oral; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Kidney; Kidney Glomerulus; Losartan; Male; Mice; Mice, Inbred Strains; Mice, Obese; Organ Size; Receptor, Angiotensin, Type 1; Water Supply

The renoprotection achieved by angiotensin II blockade in the treatment of diabetic nephropathy is well established in both the clinical and the experimental settings. In contrast, the therapeutic efficacy of calcium channel blockers (CCBs) in the treatment of diabetic nephropathy still remains controversial.. In the present study, we compared the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a dihydropyridine CCB, nilvadipine, on nephropathy in the db/db mouse, a rodent model of type 2 diabetes. Male db/db mice were divided into the following three groups at the age of 11 weeks, when treatment was started: vehicle, enalapril (10 mg/kg per day), and nilvadipine (10 mg/kg per day). Blood pressure, urine, and blood chemistry were monitored at the age of 17 and 27 weeks, and kidney samples were obtained at 29 weeks. Morphological changes were analyzed on periodic acid-Schiff-stained sections. Lipid peroxidation in kidney homogenates was measured.. Blood pressure remained normal and was similar in the three groups until 27 weeks. Blood glucose exceeded 300 mg/dl throughout the study in all groups. Reduction of microalbuminuria at 27 weeks, compared to the vehicle group, was 37% and 52% in the enalapril- and nilvadipine-treated groups, respectively. Increased lipid peroxidation was suppressed by 15% and 83% in the enalapril- and nilvadipine-treated groups, respectively. Glomerular hypertrophy, assessed by cross-sectional glomerular area, was significantly suppressed in the nilvadipine group, but not in the enalapril group, compared to the vehicle group.. Nilvadipine shows a stronger renoprotective effect than enalapril in the db/db mouse, independent of the blood-pressure-lowering effect. An antioxidative effect, indicated by the reduction in lipid peroxidation, may partly contribute to the renoprotection conferred by nilvadipine.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Glomerular Mesangium; Hypertrophy; Kidney Function Tests; Lipid Peroxidation; Male; Malondialdehyde; Mice; Nifedipine; Organ Size

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

We have investigated the protective effect of YM598, a selective endothelin type A receptor antagonist, against an endothelin-1-induced proliferation of rat mesangial cells and renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598, but not K-8794, a selective endothelin type B receptor antagonist, inhibited the endothelin-1-induced proliferation of cultured mesangial cells derived from intact Wistar rats in a concentration-dependent manner. YM598 (0.1 or 1 mg/kg), enalapril (5 mg/kg), an angiotensin- converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male OLETF rats for 32 weeks. YM598 blunted the development of albuminuria in a dose-dependent manner. A higher dose of YM598 reduced albuminuria comparable with enalapril. Urinary endothelin-1 excretion was greater in the diabetic rats than in the control rats, and was not substantially influenced by the agents. Enalapril, but not YM598, mildly lowered the blood pressure in the diabetic rats, indicating that blood pressure reduction is not involved in the major mechanism of the renoprotective effect of YM598 in OLETF rats. These data suggest that endothelin is involved in the progression of diabetic nephropathy in OLETF rats, and an endothelin type A antagonist is promising for the treatment of diabetic nephropathy.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enalapril; Endothelin A Receptor Antagonists; Endothelin-1; Hyperplasia; Male; Mesangial Cells; Pyrimidines; Rats; Rats, Inbred OLETF; Rats, Wistar; Receptor, Endothelin A; Sulfonamides

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Diabetes Mellitus, Type 2; Enalapril; Evidence-Based Medicine; Humans; Hypertension; Treatment Outcome

The study covered 72 patients with non-insulin-dependent diabetes mellitus (NIDDM) whose mean age was 54.2 +/- 0.8 years, duration of the disease 8.6 +/- 3.6 years. They had also mild or moderate arterial hypertension mean duration of which was 12.4 +/- 4.3 years. The examination of the patients consisted of 24-h arterial pressure (AP) monitoring, Holter ECG monitoring, cardiointervalography. For eight weeks 19 patients received enalapril (5-20 mg/day), 14 patients were given felodipin (5-10 mg/day) and 15 patients were treated with valsartan (80-160 mg/day). Enhanced activity of the sympathetic nervous system in hypertensive subjects with NIDDM raises daily average values of systolic and diastolic AP, variability and speed of AP morning rise. In NIDDM patients with moderate arterial hypertension vegetative regulation of AP was more stressed than in mild hypertension. Optimal medication of NIDDM patients' arterial hypertension may consist of ACE inhibitors and antagonists of angiotensin II receptors. These drug lower stress of the sympathetic nervous system and thus promote normalization of daily profile of AP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Circadian Rhythm; Diabetes Mellitus, Type 2; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Tetrazoles; Valine; Valsartan

The French experts present at the Eutherapy Symposium held in Prague confirmed the importance of left ventricular hypertrophy (LVH) and microalbuminuria as major independent risk factors for cardiovascular disease. Factors that must be considered for the treatment of hypertension in patients, particularly with type 2 diabetes. Professor J.M. Mallion stressed the contribution of thiazide and thiazide-like diruetics as indapamid, especially the 1.5 mg SR formulation. Professor F. Forette and Doctor O. Hanon recalled that the HYVET study is expected to confirm the beneficial effect of this same treatment on morbidity and mortality in very elderly patients. Professor O. Dubourg recalled the beneficial effect of indapamid SR on LVH demonstrated in the LIVE study. Likewise, Professor M. Marre emphasized its important impact on microalbuminuria as shown in the NESTOR study.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzothiadiazines; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Echocardiography; Electrocardiography; Enalapril; Humans; Hypertension; Hypertrophy, Left Ventricular; Indapamide; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Prognosis; Randomized Controlled Trials as Topic; Risk Factors; Sodium Chloride Symporter Inhibitors; Time Factors

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

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

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Industry; Enalapril; Humans; Irbesartan; Losartan; Research Design; Tetrazoles

To evaluate effects of enalapril (ednit) therapy on activity and reactivity of renin-angiotensin-aldosteron system (RAAS) and renal function.. Ednit was given in a dose 5-10 mg/day to 30 patients with mild or moderate arterial hypertension (AH) in combination with moderate or severe non-insulin-dependent diabetes mellitus (NIDDM) in compensation or subcompensation of carbohydrate metabolism.. Ednit lowered blood pressure after 6-7 days of treatment. Normal blood pressure was achieved on the treatment week 4-6. Antihypertensive effect of ednit resulted from a significant reduction in a total peripheral vascular resistance under unchanged cardiac output. Adequate hypoglycemic and antihypertensive therapy normalized carbohydrate metabolism. Renal elimination of nitrogen did not change much. Glomerular filtration rate in patients with hyper- and hypofiltration returned to normal. Proteinuria reduced, microalbuminuria was not registered. RAAS activity normalized.. Ednit has both high antihypertensive activity and marked renoprotective effect with minor influence on carbohydrate metabolism in AH patients with NIDDM.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Carbohydrate Metabolism; Cardiac Output; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Hypoglycemic Agents; Renin-Angiotensin System; Treatment Outcome; Vascular Resistance

The inhibitors of the angiotensin-converting-enzyme (ACEI) are considered as the best pharmacological class for the treatment of patients with diabetic nephropathy. Independently of lowering the arterial blood pressure they reduce the proteinuria and slow the evolution of the renal failure. Calcium-channels blockers not belonging to the dehydropyridine-type (verapamil-diltiazem) possess some of these features, too, contrarily to the rest of calcium-antagonists (nifedipine-like). Two clinical studies dealing with type-II diabetic-patients whose nephropathy was complicated by a nephrotic syndrome and a rapid progressive renal failure showed that the combination of verapamil with an ACEI, further dietetic measures (protein restriction, saltless diet), permitted a significant decrement of the proteinuria as well as a stabilisation of the kidney function. This effect could not be shown under treatment with only ACEI. Thus the proteinuria-inhibiting and kidney-protecting effects of the combination of theses two substances-groups should be known when the physician is confronted at this clinical situation that determines the prognostic of the kidney function in such a dramatic way and short laps of time.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Humans; Indoles; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome; Verapamil

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Enalapril; Follow-Up Studies; Heart Failure; Humans; Hypertension; Myocardial Infarction; Nisoldipine

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

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

1. The influence of angiotensin-converting enzyme (ACE) inhibitor is investigated in enalapril on renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneously non-insulin-dependent diabetes (NIDDM). 2. Enalapril (5 mg/kg) or vehicle was administered once daily by gastric gavage to 22-week-old male OLETF rats for 32 weeks. Blood pressure, albuminuria, creatinine clearance, plasma glucose, serum insulin and lipids were determined before and during the treatment. Renal haemodynamics was examined at the end of the treatment. 3. Enalapril lowered blood pressure mildly but significantly. In the vehicle-treated rats, urinary albumin excretion increased from 0.75 +/- 0.16 mg/mg creatinine (Cr) to 8.65 +/- 0.78 mg/mg Cr. Enalapril significantly blunted the development of albuminuria from 0.66 +/- 0.12 mg/mg Cr to 5.19 +/- 0.67 mg/mg Cr (P < 0.008) without significant influence on creatinine clearances. Enalapril also significantly blunted the rise in serum cholesterol and triglyceride prior to the development of massive albuminuria. Enalapril did not affect bodyweight, plasma glucose or insulin levels. Renal haemodynamics assessed by inulin and p-aminohippuric acid clearances were similar in both groups at the end of the treatment. 4. These results reconfirmed that the ACE inhibitor has protective effects on nephropathy in NIDDM. Massive albuminuria was preceded by increase in serum lipids in OLETF rats, which supports the view that hyperlipidaemia exacerbates glomerular injury in chronic renal disease. Enalapril attenuated the rise in serum lipids, suggesting that the beneficial effects of the compound on renal injury in OLETF rats might also be mediated through the action of affecting serum lipids.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Progression; Enalapril; Glucose Tolerance Test; Hyperlipidemias; Kidney; Kidney Function Tests; Lipids; Male; Rats; Rats, Long-Evans

To study a hypotensive effect of berlipril, an ACE inhibitor, using 24-h BP monitoring in patients with non-insulin-dependent diabetes mellitus (NIDDM) combined with stable mild or moderate arterial hypertension (AH).. 22 NIDDM patients with mild or moderate AH were treated with berlipril. 24-h monitoring of BP was made in all the patients before and 3 months after the treatment.. A stable hypotensive effect of berlipril was achieved at its therapeutic dose 1.5 tablets a day once a day or divided into two doses a day. On treatment week 3-4 a hypotensive effect of berlipril enhanced in 5 patients. This may be due to ACE inhibitors action on the tissue component of the reninangiotensin system.. Berlipril produces a high hypotensive effect and brings about a positive response of insulin-resistance in NIDDM associated with mild and moderate AH.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Diabetes Mellitus, Type 2; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

To study metabolic effects of berlipril-5 (enalapril) in patients with non-insulin-dependent diabetes mellitus (NIDDM) and arterial hypertension (AH).. 24 patients with NIDDM and AH were divided into three groups by the level of basal C-peptide: > 2 ng/ml (group 1), 2-4 ng/ml (group 2) and < 4 ng/ml (group 3).. A correlation was found between the level of basal C-peptide and duration of AH (r = 0.7) and NIDDM (r = -0.47), between the level of triglycerides (TG) and glycolized hemoglobin Hb A1c (r = 0.48). Berlipril treatment reduced basal C-peptide level in groups 2 and 3 by 20.65 +/- 1.95% and elevated it in group 1 by 16.4 +/- 1.5%. Fasting glucose levels lowered by 9.2 +/- 1.95% indicating better sensitivity of the liver to insulin. Blood glucose levels 2 hours after meal fell by 8.3 +/- 0.95% (p < 0.05) and Hb A1c by 8.14 +/- 1.25% showing indirectly diminishing insulin-resistance at the level of peripheral tissues. TG and VLDLP significantly declined.. Inhibitors of angiotensin converting enzyme (enalapril, in particular) produce a positive effect on carbohydrate and lipid metabolism in patients with NIDDM and AH.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Insulin Resistance; Lipoproteins, VLDL; Male; Middle Aged; Treatment Outcome; Triglycerides

To determine whether each of glycemic control (GC), low protein diet (LPD) or administration of angiotensin converting enzyme inhibitor (ACEI) has beneficial effects on diabetic nephropathy through the different mechanisms, changes in charge and size selectivity of glomerulus and renal hemodynamics were analyzed in microalbuminuric type 2 diabetic patients after additive combination therapy (first period: GC only, second period: GC-LPD, third period: GC+LPD+ACEI). To detect improvement of the impairments of glomerular charge selectivity and size selectivity, changes in the ratio of the renal clearance of two plasma proteins with similar molecular radii and different isoelectric points (pIs) (ceruloplasmin and IgG: CRL/IgG) and changes in the ratio of the renal clearance of two plasma proteins with similar pIs and different molecular radii (alpha2-macroglobulin and albumin: alpha2/Alb) were examined before and after each therapy. Creatinine clearance decreased significantly in the first and third periods although slight but not significant decrease was detected in the second period. Filtration fraction was significantly decreased only in the third period. Although renal clearances of Alb, IgG and CRL were decreased in periods of all three therapies, that of alpha2-macroglobulin with a large molecular radius was decreased significantly only after the third therapy. Neither CRL/IgG nor alpha2/Alb changed during these three therapies. These findings suggest that each of three short-term therapies consisting of GC, GC+LPD and GC+LPD+ACEI, reduced proteinuria in microalbuminuric type 2 diabetic patients not through the improvement of renal size and charge selectivities, but through improvement of renal hemodynamics.

Topics: Adult; Aged; Albuminuria; alpha-Macroglobulins; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Ceruloplasmin; Combined Modality Therapy; Comorbidity; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, Protein-Restricted; Enalapril; Female; Humans; Hypertension; Hypoglycemic Agents; Immunoglobulin G; Insulin; Kidney Glomerulus; Lipids; Male; Metabolic Clearance Rate; Middle Aged; Renal Circulation; Serum Albumin; Sulfonylurea Compounds; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Myocardial Infarction; Nisoldipine

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Insulin; Myocardial Infarction; Nisoldipine

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Myocardial Infarction; Nisoldipine

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Myocardial Infarction; Nisoldipine

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors

Recognition that non-insulin-dependent diabetes mellitus (NIDDM) is a leading cause of end-stage renal disease (ESRD), and a focus of recent therapeutic and genetic studies on the renin system have rekindled interest in mechanisms by which angiotensin converting enzyme (ACE) inhibitors influence the diabetic kidney. We evaluated the renal hemodynamic status of 19 hypertensive patients with NIDDM under controlled sodium balance, low (10 mmol/day for 5 to 7 days) or high (200 mmol/day for 5 to 7 days). The renal plasma flow (RPF) response to ACE inhibition and to angiotensin II (Ang II) infusion was measured as para-aminohippurate (PAH) clearance before and during enalapril administration (10 mg b.i.d. for 3 days). Our premise was that if renal vasodilation induced by ACEI involves kinins, prostaglandins, and/or nitric oxide, vasoconstrictor responses to Ang II would be blunted. Conversely, if the dominant ACE inhibitor action were a reduction in Ang II formation, the consequence would be up-regulation and an enhanced vasoconstrictor response to exogenous Ang II. RPF in NIDDM on a high-salt diet was lower than in age-matched controls (477 +/- 25 vs. 551 +/- 25 ml/min/1.73 m2; P = 0.02). Enalapril increased RPF in NIDDM to 511 +/- 29 ml/min/1.73 m2 (P < 0.05) and enhanced renal vasoconstrictor responses to Ang II infusion, from -68 +/- 9 to -106 +/- 18 ml/min/1.73 m2 (P = 0.03). Baseline plasma renin activity (PRA) and plasma aldosterone significantly exceeded matched normotensive controls (1.1 +/- 0.5 vs. 0.3 +/- 0.1 ng AI/ml/hr and 10 +/- 0.9 vs. 4.1 +/- 0.5 ng/dl, P < 0.01, respectively). Conversely all measures in studies on a low-salt diet were normal. Our findings indicate that: (1) NIDDM with hypertension is associated with reduced RPF when dietary salt intake is high, (2) reduced Ang II formation is the dominant mechanism of ACEI-induced renal vasodilation in hypertensives with NIDDM; and (3) the sustained renal hemodynamic responses to ACE inhibition despite high-salt balance, and the increased PRA suggest an autonomous renin-angiotensin system suppressed subnormally by a high salt diet in patients with NIDDM despite greater volume expansion.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diet, Sodium-Restricted; Enalapril; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renal Circulation; Renin; Renin-Angiotensin System

A 71 year old hypertensive, non insulin-dependent diabetic patient with moderate renal insufficiency taking 500 mg/d of metformin and 5 mg/d of enalapril, developed metabolic acidosis characterized by fairly elevated anion gap, hyperchloremia, severe hyperkaliemia, normal plasma level of 3-hydroxybutyric acid, absence of ketonuria and high plasma level of lactic acid. This biochemical feature allowed us to ascribe the pathogenesis of metabolic acidosis, both to the increased plasma level of lactic acid and to the type IV renal tubular acidosis syndrome, the precipitating factor being an infection of urinary tract (as we assumed on the basis of the urine culture). The patient was dehydrated and lethargic; the ECG revealed the presence of nonparoxysmal junctional tachycardia. The clinical evolution was favorable under the treatment with an infusion of isotonic saline solutions, mild alkalinizing solutions, low-dose regular insulin and antibiotics. It is likely that metformin and enalapril, regularly taken by this nephropathic patient, could have played an iatrogenic role, even if the doses were low. This case highlights the importance of complying with the contraindications of these drugs, to avoid the rare but reported life-threatening complications of metformin administration.

Topics: Acidosis; Aged; Antihypertensive Agents; Chlorides; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Hypoglycemic Agents; Lactic Acid; Metformin

Topics: Antihypertensive Agents; Captopril; Dental Calculus; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Male; Middle Aged; Molar; Risk Assessment; Toothbrushing

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enalapril; Humans; Kidney Failure, Chronic

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

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

Topics: Diabetes Mellitus, Type 2; Drug Interactions; Enalapril; Female; Glyburide; Humans; Hypertension; Hypoglycemia; Male; Middle Aged

There are conflicting reports about the effects of ACE inhibitors (ACEI) on insulin sensitivity and glycaemic control. Most studies have used a standard high dose of an ACEI but there have been no studies reported to establish whether any changes in glycaemic control or insulin sensitivity associated with ACEI are dose-related.. To examine the effect of increasing doses of enalapril on insulin sensitivity in normotensive non-insulin dependent diabetic subjects.. The effects of increasing doses of enalapril on insulin sensitivity in ten normotensive non-insulin dependent diabetic subjects were measured, using the hyperinsulinaemic isoglycaemic clamp technique. Following a baseline study, enalapril was commenced at 5 mg daily and increased to 10 mg daily then 20 mg daily at 14 day intervals. Repeat studies were undertaken after 14 days at each dosage.. There was a significant dose-related reduction of systolic blood pressure with enalapril. In contrast enalapril at 5-20 mg daily produced no significant changes in insulin mediated glucose uptake (M-value) or insulin sensitivity index (ISI).. These findings indicate that in this insulin resistant population of normotensive non-insulin dependent diabetics, angiotensin converting enzyme inhibition with enalapril has no significant effect on insulin mediated glucose uptake.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enalapril; Female; Glucose Clamp Technique; Humans; Insulin Resistance; Male; Middle Aged

The respective effects of 6 month's administration of beta-blockers (atenolol, metoprolol, carteolol and arotinolol), calcium-channel blockers (nicardipine, diltiazem) and angiotensin converting enzyme inhibitor (enalapril) on hemoglobin A1c (HbA1c) levels were evaluated in hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM), using a retrospective method. NIDDM patients with stable HbA1c and body weight were selected for this study. The following results were obtained. (1) The administration of nicardipine or beta-blockers significantly elevated HbA1c levels. (2) The administration of diltiazem or enalapril did not have any influence on HbA1c levels. These findings suggest that not only beta-blocker but nicardipine (dihydropyridine type calcium-channel blocker) may cause deterioration in glucose metabolism in NIDDM patients.

Topics: Adult; Aged; Atenolol; Carteolol; Diabetes Mellitus, Type 2; Diltiazem; Enalapril; Female; Glucose; Glycated Hemoglobin; Humans; Hypertension; Male; Metoprolol; Middle Aged; Nicardipine; Propanolamines

A 66-year-old hypertensive diabetic patient with latent hypoaldosteronism and mild renal failure was treated by adding enalapril, an angiotensin converting enzyme inhibitor, to the furosemide and nifedipine regimen because of an insufficient antihypertensive response for 1 month. Seven days after enalapril addition, the blood pressure was significantly reduced, but frank hyperkalemia occurred with a marked rise in BUN and a slight increase in serum creatinine. Plasma renin activity (PRA) and plasma aldosterone (PA) values remained low before and during enalapril therapy. Transient treatment with sodium polystyrene sulfate after enalapril withdrawal improved the hyperkalemia and renal function, but PRA and PA levels were low. PA and its precursor steroids also responded poorly to graded angiotensin II infusion and rapid ACTH injection. Latent hypoaldosteronism probably predisposed this patient to frank hyperkalemia with progressive dehydration and slightly reduced renal function during antihypertensive therapy.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Furosemide; Humans; Hyperaldosteronism; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Male; Nifedipine

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

Acute effects of 20 mg oral enalapril (E), and angiotensin-converting enzyme inhibitor, on renal function and the renin-angiotensin-aldosterone system were investigated in 13 patients with type II diabetes mellitus (8 female, 5 male) and 10 hypertensive controls using a radionuclide method. Plasma glucose control was evaluated with fructosamine (F) determinations. After intravenous administration of 370 MBq 99mTc-DTPA, sequential images were recorded. Glomerular filtration rate (GFR), perfusion index (PI), time to maximum activity and reno index values of the kidneys were calculated. Two days later, renal scintigraphy was repeated after oral administration of E. Plasma levels of renin, angiotensin II and aldosterone were analyzed using RIA. Basal GFR values (mean: 92.6 ml/min) correlated with F (r = 0.364; p < 0.05). In the diabetic group, 5 patients had a decrease in GFR and an increase in PI after oral E. The mean percent change of GFR was 12 +/- 32 for patients and 20 +/- 12 for controls, respectively. Percent change of GFR had a slightly negative correlation with F values (r = -0.51; p < 0.05) and with PI (r = -0.65; p < 0.001). The patients with good metabolic control had an increase in GFR and a decrease in PI indicating an increase in renal blood flow and glomerular filtration. In patients with proteinuria and poorly controlled diabetes, in response to E-induced efferent arteriolar dilation, there is a decrease in GFR and an increase in PI which indicates a fall in filtration and renal blood flow. This glomerular hemodynamic pathology precedes morphological changes due to diabetes.

Topics: Adult; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Radioisotope Renography; Renal Circulation; Renin-Angiotensin System

We selected 15 hypertensive non insulin-dependent diabetics in reasonable metabolic control, treated for 6 months with enalapril 20 mg/die. The results showed a significant reduction of mean arterial blood pressure and triglycerides without interference on the metabolic control.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Drug Evaluation; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Triglycerides

The effect of enalapril, an angiotensin converting enzyme inhibitor, on glucose tolerance and serum insulin response to a glucose load has been evaluated in 8 non-obese patients (3 women and 5 men) with untreated essential hypertension (WHO Stage I or II) and without insulin resistance. Following a 2-month run-in control period, each patient received oral enalapril 10 mg once daily for 6 months, and an intravenous glucose tolerance test (IVGTT) was performed at the end of the run-in control and active treatment periods. Treatment with enalapril significantly lowered both the systolic and diastolic blood pressures. The response of plasma glucose to the IVGTT, glucose disappearance rate (k-value) and area under the serum insulin concentration time curve were comparable between the two phases. The results suggest that long-term treatment with enalapril has no effect on glucose tolerance in non-obese, non-insulin-resistant patients with mild-to-moderate essential hypertension.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Enalapril; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Japan; Male; Middle Aged; Time Factors

The pressor responsiveness to noradrenaline was assessed before and after four weeks of treatment with enalapril (20 mg/day) in eight mild-to-moderate essential hypertensives, in eight normotensive type II diabetics and in eight mild-to-moderate hypertensive type II diabetic patients. The ACE inhibitor interfered to the same extent with the renin-angiotensin system and did not alter noradrenaline kinetics in the three groups of patients, but significantly reduced the arterial responsiveness only in non-diabetic subjects. It is suggested that factors, such as an exaggerated sodium retention, might determine the lack of effect of enalapril in diabetic patients.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Arteries; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Renin-Angiotensin System

Topics: Aged; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Hypoglycemia; Insulin Resistance; Male

This study was designed to characterize the nocturnal fall of blood pressure (NFBP) of elderly hypertensive patients (EH), with or without cerebrovascular disease or diabetes mellitus, as measured by automated blood pressure (BP) monitoring. Systolic and diastolic BP and heart rate was measured every 15 minutes in 133 hospitalized patients with nearly similar schedules and diets. The patients were divided into five groups: I, normotensive elderly patients over age 65: II, EH without cardiovascular diseases, controlled without medication: III, EH with cerebral infarction, chronic stage: IV, EH with noninsulin-dependent diabetes mellitus: and V, hypertensives under age 65, without cardiovascular diseases. A significant NFBP was observed in the patients of groups I and V, a significant but smaller NFBP in the hypertensives of groups II and IV, and no NFBP in the patients of group III. Administration of the antihypertensive drugs, enalapril and nifedipine, tended to augment the NFBP. These preliminary observations showed that NFBP did occur in elderly hypertensives but the fall was smaller than that observed in younger hypertensives or elderly normotensives. Although the ambulatory BP measurements were useful in the overall clinical evaluation of elderly patients, NFBP in elderly patients was affected by hypertensive drugs and therefore NFBP should be interpreted with caution.

Topics: Aged; Blood Pressure; Blood Pressure Determination; Cerebral Infarction; Circadian Rhythm; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Monitoring, Physiologic; Nifedipine

The effect of treatment with enalapril (10 days at 10 mg/d followed by 4 weeks at 20 mg/d) on forearm hemodynamics was assessed in eight normotensive patients and eight patients with hypertension affected by Type II diabetes as well as in eight patients with essential hypertension and normal glucose tolerance. The ACE inhibitor decreased regional vascular resistances and increased the maximum arteriolar-vasodilating capacity and venous distensibility in the three groups of patients. Thus, this study shows that ACE inhibition by enalapril improves regional hemodynamics in patients with Type II diabetes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Female; Forearm; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Vascular Resistance

The aim of this study was to compare the clinical effects of calcium-entry blocker Nifedipine and ACE-inhibitor Enalapril in hypertensive patients with glucose intolerance that have lower plasma renin activity. A blood sample for basal PRA was obtained from 21 subjects; then, 11 patients received Nifedipine (20 mg. b.i.d.) and 10 Enalapril (20 mg. q.d.). The extent of blood pressure fall after 12 weeks of treatment was inversely related to basal PRA levels in Nifedipine treated group only; however, the hypotensive effect of both drugs was comparable.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Renin; Sodium

Topics: Captopril; Diabetes Mellitus, Type 2; Enalapril; Glyburide; Humans; Hypertension; Hypoglycemia; Male; Middle Aged

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

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

The antihypertensive efficacy of enalapril and its effects on renal function and glucose homeostasis were investigated in 9 hypertensive patients with non-insulin-dependent diabetes mellitus. Enalapril therapy produced a significant fall in blood pressure (BP) (p less than 0.05) and a significant increase in renal blood flow (p less than 0.05) without a change in glomerular filtration rate. Furthermore, fasting plasma glucose was significantly reduced (p less than 0.01). Similarly, M value, as an index of plasma glucose control in diabetes, was significantly reduced from 19.6 to 10.1 (p less than 0.01). These findings suggested that the angiotensin-converting enzyme inhibitor enalapril was effective in reducing BP and improving renal function, and might improve glucose homeostasis in hypertensive diabetics.

Topics: Aged; Aldosterone; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Female; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension; Kidney; Male; Middle Aged; Renin; Vascular Resistance

A 63-year-old white male with a 25-year history of hypertension experienced the onset of intermittent diplopia and gait disturbance 24 hours after a change in antihypertensive medication from atenolol 50 mg/d to enalapril 5 mg bid. Three weeks later, the patient was admitted with a worsening of symptoms. Cerebral arteriography revealed significant bilateral vertebral artery stenosis. Symptoms continued to progress in the hospital, and at the time of posterior circulation revascularization the patient had a persistent bilateral internuclear ophthalmoplegia and right ptosis. The need for a neurovascular workup and adjustment of therapy in patients with antihypertensive-associated cerebral ischemia is discussed.

Topics: Antihypertensive Agents; Atenolol; Diabetes Mellitus, Type 2; Enalapril; Humans; Male; Middle Aged; Vertebrobasilar Insufficiency

The effects of enalapril treatment on blood glucose, insulin, and C-peptide levels and effects on the renin-angiotensin aldosterone system were studied in 22 hypertensive patients with non-insulin-dependent diabetes. After a 4-wk run-in period during which all previous antihypertensive drugs were discontinued, treatment was commenced with one daily dose of 10 mg enalapril. The dose was adjusted upward at 3-wk intervals to a maximum of 40 mg daily. In 3 subjects, addition of a thiazide diuretic was required after 9 wk of treatment. At completion of run-in and after 9 and 13 wk of treatment, subjects had blood samples drawn after fasting and 2 h after a standardized 1.6-mJ mixed meal. Mean fasting blood glucose at the end of the run-in period was 8.3 +/- 0.5 mM and at study completion was 7.3 +/- 0.4 mM. Mean postprandial blood glucose was 10.8 +/- 1.0 mM before treatment and 9.8 +/- 0.7 mM at study completion. The changes in fasting and postprandial blood glucose levels were not significant (P = .06 and P = .15, respectively). There was no significant change in glycosylated hemoglobin levels. Fasting and meal-stimulated insulin and C-peptide levels were not altered by enalapril treatment. Treatment was associated with a sustained reduction in plasma angiotensin-converting enzyme activity, an increase in plasma renin activity, reduced plasma aldosterone levels, and significant reductions in supine, seated, and standing arterial blood pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Heart Rate; Humans; Hypertension; Insulin; Kallikreins; Renin; Renin-Angiotensin System

The purpose of this study was to evaluate the effects of the ACE inhibitor enalapril (E) on blood pressure and metabolic control in 15 hypertensive patients with non-insulin-dependent diabetes mellitus. When the treatment goal was not reached with enalapril alone, hydrochlorothiazide (HCTZ) was added. A diastolic blood pressure (DBP) below 90 mmHg was achieved in seven patients with enalapril alone (47%), and in an additional four (27%) with concomitant hydrochlorothiazide. No significant adverse effects of enalapril occurred and all patients completed the study. Monotherapy with enalapril did not affect metabolic control or renal function. Addition of HCTZ to E did not consistently result in further lowering of blood pressure and caused deterioration of both the degree of metabolic control and renal function. We, therefore, conclude that monotherapy with enalapril can be a safe and satisfactory treatment for hypertensive patients with NIDDM. Caution is needed, however, when HCTZ is added, since this may adversely affect metabolic control and renal function whereas the effect on blood pressure may be variable.

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Female; Glycated Hemoglobin; Humans; Hydrochlorothiazide; Hypertension; Insulin; Male; Middle Aged

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypotension

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

Nine patients with non-insulin-dependent diabetes mellitus (NIDDM) and ten non-diabetic patients with mild hypertension were treated with enalapril 20 mg daily. None had overt nephropathy, though 4 diabetic subjects had microalbuminuria. Subjects with the highest baseline albumin excretion rates (AER) showed the greatest fall on therapy. Metabolic control of diabetes did not deteriorate. Enalapril had no significant effect on AER in NIDDM patients with AER below 20 micrograms/minute or in the non-diabetic group.

Topics: Adult; Aged; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Diabetes mellitus is frequently accompanied by specific abnormalities of the renin-angiotensin system, but it is not known whether these alterations modify the response to converting enzyme inhibition. To evaluate this possibility, 129 patients with severe chronic heart failure were treated with captopril or enalapril for one to three months, while doses of digoxin and diuretics were kept constant; 35 patients had diabetes mellitus. Prior to therapy, diabetic patients had lower plasma renin activity (3.4 +/- 0.5 versus 7.0 +/- 1.1 ng/ml/hour) than did nondiabetic control subjects (p less than 0.05); yet the initial hemodynamic response to captopril was similar in both groups. Plasma renin activity predicted the hypotensive response to the first dose of captopril in nondiabetic control subjects (r = 0.70, p less than 0.001) but not in diabetic patients (r = 0.29). During long-term treatment with captopril or enalapril, both diabetic and nondiabetic patients had similar increases in cardiac index and decreases in mean arterial pressure and systemic vascular resistance. Diabetic patients, however, showed larger reductions in left ventricular filling pressure (-13.8 versus -9.1 mm Hg, p less than 0.02) and mean right atrial pressure (-6.2 versus -3.9 mm Hg, p less than 0.05) than did nondiabetic subjects; this was accompanied by a notable decline in body weight in diabetic patients only. Renal function remained unaltered during converting enzyme inhibition in nondiabetic patients, but deteriorated significantly in diabetic patients, as reflected by a marked increase in serum creatinine concentration (1.7 +/- 0.1 to 2.1 +/- 0.1 mg/dl, p less than 0.001). In conclusion, despite lower pretreatment plasma renin activity, diabetic patients with severe chronic heart failure demonstrated improvement during long-term converting enzyme inhibition to a degree similar to (if not greater than) that seen in nondiabetic control subjects, but were more susceptible to the development of functional renal insufficiency than their nondiabetic counterparts. These differences are explicable by abnormalities of renin/aldosterone synthesis and angiotensin-mediated vasoregulation that are known to be present in the diabetic state.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 2; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Kidney; Male; Middle Aged; Renin-Angiotensin System

The treatment of arterial hypertension in diabetic patients still raises numerous problems. In this type of patients, the most commonly prescribed drugs (beta-blockers, diuretics, antihypertensive agents acting on the central nervous system) have troublesome and potentially detrimental effects (e.g. effects on lipids). The new categories of antihypertensive drugs recently introduced (angiotensin-converting enzyme inhibitors, calcium antagonists) are likely to be most useful in these patients. In an open trial in non-insulin-dependent diabetics with arterial hypertension followed-up for 1 year, enalapril administered alone has proved effective and devoid of clinical and biochemical side-effects. If these results are confirmed, angiotensin-converting enzyme inhibitors will rank high as first-choice treatment of arterial hypertension in diabetics.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Captopril; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Enalapril; Humans; Hypertension; Obesity; Vasodilator Agents