enalapril and Hypertension--Renal

There is now abundant evidence that treatment with angiotensin-converting enzyme inhibitors (ACE-I) ameliorates the progression of chronic renal disease. Attention has therefore focused on the role of the renin angiotensin-aldosterone (RAA) system in mediating the development of progressive glomerulosclerosis and angiotensin II (Ang II) has been implicated in several processes thought to be important in the pathogenesis of this entity. Conversely, ACE is also known to catalyse the breakdown of bradykinin. Thus, ACE-I treatment results in elevated bradykinin levels which may cause selective efferent arteriolar dilatation, suggesting an alternative explanation for the beneficial effects of this class of drugs in chronic renal disease. The development of specific angiotensin type 1 receptor antagonists (AT1RA) has provided a means of testing the relative importance of these two mechanisms. In addition, AT1RAs differ from ACE-I in their effect on the RAA system in other aspects which may represent therapeutic advantages. This paper reviews studies which have compared ACE-I and AT1RAs in several rat models of chronic renal disease. Most have found similar beneficial effects including amelioration of proteinuria and glomerulosclerosis, which suggests that the effects of ACE-I are due to a reduction in Ang II activity and not due to increased levels of bradykinin. One long-term study has suggested greater renal protection with candesartan than with enalapril. However, conclusions as regards the relative efficacy of these two groups of agents in ameliorating the progression of chronic renal disease await the results of further long-term studies.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Chronic Disease; Disease Models, Animal; Enalapril; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Peptidyl-Dipeptidase A; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Treatment Outcome

Renal glycosuria associated with the use of angiotensin-converting enzyme inhibitors has been previously reported in two patients. A third patient was studied who developed isolated glycosuria associated with lisinopril therapy. As in the two previously described patients, this patient had a normal serum glucose level, underlying hypertension, and onset of glycosuria between 2 and 16 weeks after initiation of therapy with an angiotensin-converting enzyme inhibitor. The patient had renal artery stenosis with elevated renin levels. Age, time until resolution of glycosuria, and a rise in serum creatinine level did not have a consistent relationship with glycosuria associated with angiotensin-converting enzyme inhibitor therapy. Since glycosuria was the only defect noted, without evidence of any other urinary solutes, angiotensin-converting enzyme inhibitors may exert an effect on the glucose-specific proximal tubule transport system.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glycosuria, Renal; Humans; Hypertension, Renal; Lisinopril; Male

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalapril; Humans; Hypertension, Renal; Hypertension, Renovascular; Kidney Failure, Chronic; Product Surveillance, Postmarketing; Renal Circulation

Reduction in functioning nephron number leads to progressive renal disease. A haemodynamic basis for this process has been suggested by studies of partially nephrectomized rats. In this model compensatory hyperfiltration in the remnant nephrons due to increases in the glomerular capillary hydraulic pressure (-PGC) and plasma flow rate is associated with eventual glomerular sclerosis. Therapeutic attenuation of these haemodynamic adaptations protects against glomerular injury. One such therapy is angiotensin converting enzyme (ACE) inhibition, which lowers systemic blood pressure and -PGC and prevents sclerosis in rats with renal ablation, as well as in the hyperfiltering kidneys of normotensive rats with diabetes mellitus. Control of -PGC with ACE inhibitor is also protective even when therapy is delayed until systemic hypertension and glomerular injury are established. In contrast, the control of systemic hypertension but not -PGC affords no protection in remnant kidney rats. Thus, control of glomerular hypertension slows the progression of renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Nephrectomy; Rats

Male Munich-Wistar rats were studied 18 weeks after 1 2/3 nephrectomy. One group received no therapy. A second group received the angiotensin converting enzyme (ACE) inhibitor enalapril, starting 1 week after ablation. Two additional groups received no therapy during the first 8 weeks, and then received ACE inhibitor or a low (12%) protein diet. Early ACE inhibitor therapy resulted in control of systemic and glomerular hypertension (HTN), and a striking limitation of proteinuria and glomerular sclerosis. During the first 8 weeks untreated rats developed severe systemic HTN and increasing proteinuria. After 8 weeks proteinuria increased further in untreated rats, and widespread sclerosis resulted. Late ACE inhibition reversed systemic HTN. Both late ACE inhibition and late protein restriction reversed glomerular HTN and prevented further increases in proteinuria and sclerosis. Thus, control of glomerular HTN can stabilize renal injury even when therapy is delayed until hypertension and glomerular injury are established.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Dietary Proteins; Enalapril; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Male; Nephrectomy; Rats

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

Enalapril, an orally-active, long-acting, nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor, is extensively hydrolysed in vivo to enalaprilat, its bioactive form. Bioactivation probably occurs in the liver. Metabolism beyond activation to enalaprilat is not observed in man. Administration with food does not affect the bioavailability of enalapril; excretion of enalapril and enalaprilat is primarily renal. Peak serum enalaprilat concentrations are reached 4 hours post-dose, and the profile is polyphasic with a prolonged terminal half-life (greater than 30 hours) due to the binding of enalaprilat to ACE. Steady-state is achieved by the fourth daily dose, with no evidence of accumulation. The effective accumulation half-life following multiple dosing is 11 hours. Higher serum concentrations and delayed urinary excretion occur in patients with severe renal insufficiency. Enalapril reduces blood pressure in hypertensive patients by decreasing systemic vascular resistance. The blood pressure reduction is not accompanied by an increase in heart rate. Furthermore, cardiac output is slightly increased and cardiovascular reflexes are not impaired. Once- and twice-daily dosage regimens reduce blood pressure to a similar extent. Enalapril increases renal blood flow and decreases renal vascular resistance. Enalapril also augments the glomerular filtration rate in patients with a glomerular filtration rate less than 80 ml/min. Enalapril reduces left ventricular mass, and does not affect cardiac function or myocardial perfusion during exercise. There is no rebound hypertension after enalapril therapy is stopped. Enalapril does not produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. When combined with hydrochlorothiazide, enalapril attenuates the undesirable diuretic-induced metabolic changes. Therapeutic doses of enalapril do not affect serum prolactin and plasma cortisol in healthy volunteers or T3, rT3, T4 and TSH in hypertensive patients. Enalapril has natriuretic and uricosuric properties. The antihypertensive effect of enalapril is potentiated by hydrochlorothiazide, timolol and methyldopa, but unaffected by indomethacin and sulindac. No interactions occur between enalapril and frusemide, hydrochlorothiazide, digoxin and warfarin. The bioavailability of enalapril is slightly reduced when propranolol is coadministered, but this does not appear to be of any clinical significance. Enalapril increases cardiac output and stroke volum

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Interactions; Enalapril; Heart Failure; Humans; Hypertension, Renal; Kinetics; Renal Circulation; Time Factors

Angiotensin converting enzyme inhibitors are effective therapy in hypertension. They are particularly useful in severe drug resistant or accelerated hypertension, in renal hypertension and in hypertensive heart failure. Although their exact mode of action has not been determined it is a consequence of the inhibition of angiotensin converting enzyme. They offer distinct advantages over conventional drugs in the treatment of high blood pressure particularly as they have no central or autonomic side effects and as a consequence the patients feel well. There is no postural effect on blood pressure and patients retain their normal cardiovascular reflex mechanisms and sexual function. They are particularly useful when combined with diuretics or salt restriction as not only do they have additive hypotensive effects but angiotensin converting enzyme inhibitors prevent the secondary hyperaldosteronism and hypokalemia associated with diuretic administration. Lastly, unlike many other forms of treatment for hypertension, renal blood flow and renal function tend to be maintained with converting enzyme inhibitors. Their overall role in the management of hypertension has yet to be determined, and the ultimate incidence of adverse effects after prolonged therapy is not yet known. They are however, an exciting new development in the treatment of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Dipeptides; Drug Interactions; Enalapril; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Kinetics; Proline

Among the many generic classes of drugs currently being used for the treatment of hypertension, few, following long-term therapy, improve or correct the underlying renal function and hemodynamic abnormalities encountered in patients with sustained hypertension. This review focuses on the renal effects of the angiotensin converting enzyme inhibitors captopril and enalapril. Each drug is discussed in terms of its short- and long-term effects on the renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion, and body fluid composition. Data are presented that demonstrate that enalapril, used alone or in combination with diuretic therapy, has the unique ability to control hypertension, to improve glomerular filtration rate and effective renal plasma/renal blood flow, and to decrease renal vascular resistance, without producing adverse effects on salt and water excretion or body fluid composition. If the safety of enalapril is confirmed in long-term studies, the drug will clearly assume a prominent role as either first- or second-step (in combination with a diuretic) therapy in the treatment of hypertension.

Topics: Body Fluids; Captopril; Dipeptides; Drug Evaluation; Enalapril; Glomerular Filtration Rate; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Potassium; Proline; Renin-Angiotensin System; Sodium; Teprotide

We conducted a randomized, open-label trial to determine which of the antihypertensive drugs was most beneficial for CKD patients with hypertension in spite of treatment with an angiotensin receptor blocker (ARB).. Patients 20-75 years of age who had CKD according to the definition in the K/DOQI Guidelines and hypertension (systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥80 mmHg) with the usual dose of an ARB were randomly assigned to receive losartan 50 mg plus 5 mg of the calcium channel blocker amlodipine (CCB group, n = 37), 5 mg of the angiotensin-converting enzyme inhibitor enalapril (ACEI group, n = 36), or 12.5 mg of the thiazide diuretic hydrochlorothiazide (HCTZ group, n = 36). The primary endpoints were changes in blood pressure (BP), ratio of urinary excretion of protein to creatinine (UPCR), tolerability, and eGFR during the 12-month treatment period compared with control period.. There were no significant differences in BP and tolerability between the three groups. The percentage changes in UPCR at 12 months after start of the combination therapy were significantly different in the HCTZ group (-26.3 ± 11.1 %, mean ± SE) and CCB group (+46.7 ± 33.6 %, p < 0.05), while eGFR was significantly lower in the HCTZ group than in the ACEI group or CCB group at 4 months but not at 12 months.. Addition of diuretics, CCB, or ACEI to ARB was equally effective for the control of hypertension in CKD, while, in terms of urinary excretion of protein, diuretics may be better than CCB.

Topics: Adult; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension, Renal; Losartan; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Young Adult

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

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

Adiponectin is an adipose tissue-specific protein with antiatherogenic and insulin-sensitizing properties. In patients with essential hypertension, plasma adiponectin concentrations are lower than in healthy subjects. Antihypertensive drugs do not uniformly influence components of the metabolic syndrome. Therefore, the aim of this study was to evaluate the influence of 6 months' monotherapy with different antihypertensive drugs on plasma adiponectin concentration in essential hypertension patients.. Forty essential hypertension patients were randomized to receive enalapril, metoprolol, amlodipine or indapamide. Plasma concentrations of adiponectin, insulin, glucose and body fat content were estimated twice: before and after 6 months of antihypertensive monotherapy.. Plasma adiponectin concentration did not change significantly after enalapril (11.5 +/- 4.8 vs. 11.1 +/- 4.1 mg/l), metoprolol (10.2 +/- 4.2 vs. 9.8 +/- 4.5 mg/l), and amlodipine (9.0 +/- 6.0 vs. 8.5 +/- 5.4 mg/l) treatment. However, a significant decrease of plasma adiponectin concentration (from 11.6 +/- 4.6 to 10.2 +/- 4.2 mg/l, p = 0.047) was observed in patients treated with indapamide. Additionally in these patients, a significant increase of the HOMA-IR index was found (p = 0.021).. Treatment with indapamide was followed by a significant decrease of plasma adiponectin concentration. This may participate in the pathogenesis of carbohydrate metabolism disturbances often found in patients treated with thiazide-type diuretics.

Topics: Adiponectin; Adult; Amlodipine; Antihypertensive Agents; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension, Renal; Indapamide; Insulin Resistance; Lipids; Male; Metoprolol; Middle Aged

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

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

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

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

Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for the treatment of hypertension in patients with non-diabetic nephropathies. However, not every trial has reported better results with ACE inhibitors (ACE-I) than with other drugs. This study investigates whether the acute and chronic effects of ACE inhibition on renal and glomerular haemodynamics are similar in glomerular and interstitial nephropathies.. We studied 20 hypertensive patients, on their usual diet, with mild-to-moderate chronic renal failure secondary to non-diabetic nephropathy. After a three-week wash out period, we determined plasma clearances of para-amino-hippurate and inulin before, and after acute oral administration of either enalapril or ramipril. This same test was carried out after one and two years of treatment with the same drug.. Acute ACE inhibition causes a decrease of renal perfusion, glomerular filtration and pressure with an increase of afferent resistances. Long-term ACE inhibition is associated only with a decrease in renal perfusion, with a non-significant tendency to higher filtration fraction and lower afferent resistances. All the renal haemodynamic modifications mentioned above are present only in patients with glomerular diseases.. Renal and glomerular haemodynamic responses are not similar after acute and chronic ACE inhibition. Only patients with glomerular diseases show acute or long-term responses to ACE inhibition.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension, Renal; Inulin; Kidney Failure, Chronic; Kidney Function Tests; Kidney Glomerulus; Male; Middle Aged; Nephritis, Interstitial; p-Aminohippuric Acid; Ramipril; Renal Circulation

Treatment of hypertension in patients with chronic renal failure has been shown to postpone the decline in renal function. Treatment with an ACE inhibitor has been shown to be superior to conventional antihypertensive treatment, but it is not known how an ACE inhibitor compares to treatment with a calcium channel blocker or to treatment with a combination of these drugs. The aim of the study was to evaluate the rate of decline in GFR in patients with chronic renal failure and hypertension treated with isradipine and spirapril as monotherapy and in combination.. Sixty patients with chronic renal failure and hypertension were enrolled in the study. After enrollment, patients were followed prospectively for 6 months in the outpatient clinic on their usual antihypertensive medication, and then randomized to a double-blinded comparison of either spirapril 6 mg daily, isradipine 5 mg daily or spirapril 3 mg and isradipine 2.5 mg daily. After randomization, patients were followed for 21 months or until the need for dialysis. Every 3 months before and 3.5 months after randomization the glomerular filtration rate was measured by 51Cr-EDTA clearance and the effective renal plasma flow evaluated using the renal clearance of paraaminohippuric acid.. Blood pressure and the decline in glomerular filtration rate did not differ between the groups before randomization. After randomization, the mean decline in the glomerular filtration rate was -0.32 ml/(min x month x 1.73 m2) in the spirapril group, -0.58 ml/(min x month x 1.73 m2) in the isradipine group and -0.14 ml/(min x month x 1.73 m2) in the combination group (p = 0.38). Twelve patients, 4 in each group, reached end-stage renal failure. No significant difference was found with respect to diastolic (p = 0.10) or systolic blood pressure (p = 0.08) during the treatment period, but a trend towards a better blood pressure control in the combination group was present. During treatment, the rate of decline in renal plasma flow did not differ significantly between the groups (p = 0.09), neither did the changes in filtration fraction (FF) (p = 0.58) nor the mean FF (p = 0.22) during the treatment.. Our study indicated differences between the 3 treatment modalities in favor of combined therapy with respect to both the rate of decline in GFR and blood pressure control, but the differences where insignificant. Thus, the treatments might differ, but we were unable to confirm this because of large variation in GFR and small sample size.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Isradipine; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Plasma Flow, Effective

Renal artery stenosis is among the most common curable causes of hypertension. The definitive diagnosis is made by renal angiography, an invasive and costly procedure. The prevalence of renal artery stenosis is less than 1% in non-selected hypertensive patients but is higher when hypertension is resistant to drugs.. To study the usefulness of standardised two-drug regimens for identifying drug-resistant hypertension as a predictor of renal artery stenosis.. Prospective cohort study carried out in 26 hospitals in The Netherlands.. Patients had been referred for analysis of possible secondary hypertension or because hypertension was difficult to treat. Patients < or =40 years of age were assigned to either amlodipine 10 mg or enalapril 20 mg, and patients >40 years to either amlodipine 10 mg combined with atenolol 50 mg or to enalapril 20 mg combined with hydrochlorothiazide 25 mg. Renal angiography was performed: (1) if hypertension was drug-resistant, ie if diastolic pressure remained > or =95 mm Hg at three visits 1-3 weeks apart or an extra drug was required, and/or (2) if serum creatinine rose by > or =20 micromol/L (> or =0.23 mg/dL) during ACE inhibitor treatment.. Of the 1106 patients with complete follow-up, 1022 had been assigned to either the amlodipine- or enalapril-based regimens, 772 by randomisation. Drug-resistant hypertension, as defined above, was identified in 41% of the patients, and 20% of these had renal artery stenosis. Renal function impairment was observed in 8% of the patients on ACE inhibitor, and this was associated with a 46% prevalence of renal artery stenosis. In the randomised patients, the prevalence of renal artery stenosis did not differ between the amlodipine- and enalapril-based regimens.. In the diagnostic work-up for renovascular hypertension the use of standardised medication regimens of maximally two drugs, to identify patients with drug-resistant hypertension, is a rational first step to increase the a priori chance of renal artery stenosis. Amlodipine- or enalapril-based regimens are equally effective for this purpose.

Topics: Adolescent; Adult; Aged; Amlodipine; Antihypertensive Agents; Atenolol; Blood Pressure; Cohort Studies; Drug Resistance; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension, Renal; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Radiography; Renal Artery; Renal Artery Obstruction

Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.. Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.. Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.. Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cross-Sectional Studies; Enalapril; Enalaprilat; Female; Genotype; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

The effect on renal function and efficacy of the angiotensin II AT1-receptor blocker (ARB), telmisartan, were compared with those of the angiotensin-converting enzyme inhibitor, enalapril, for the treatment of mild-to-moderate hypertension (diastolic blood pressure [DBP] 95-114 mmHg) in the presence of moderate renal failure (creatinine clearance [Ccr] 30-80 ml/minute). The study was multicentre, double-blind, double-dummy and active-controlled in design, with patients randomised in a 2:1 ratio to receive telmisartanor enalapril. After a two-week placebo run-in period, the 71 eligible patients received either telmisartan, 40 mg, orenalapril, 10 mg, once-daily for four weeks. Thereafter, doses were titrated to telmisartan 80 mg or enalapril 20 mg once-daily if supine trough DBP was still > or =90 mmHg. After a further four weeks, dose titration was again performed, as required, to telmisartan, 80 mg,or enalapril, 20 mg, or frusemide was given in addition if the double dose was already being administered. Mean Ccr decreases of 4.6% for telmisartan and 2.8% forenalapril were not clinically significant. Adverse events occurred in 12 (26.7%) telmisartan-treated patients and in 12 (46.2%) patients receiving enalapril. The mean reduction in supine trough DBP from baseline to the last available value was 12.5 mmHg for telmisartan,compared with 11.9 mmHg for enalapril. A full (reduction of >or=10 mmHg) or partial (reduction of 7-9 mmHg) response occurred in 78% of telmisartanpatients and 65% of enalapril patients. In the enalapril group, 43% of patients required frusemide, compared with 29% of those in the telmisartan group. In conclusion, telmisartan lacks detrimental effect on renal function, is effective in the treatment of mild-to-moderate hypertension in patients with moderate renal failure,and is comparable to enalapril.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Furosemide; Humans; Hypertension, Renal; Male; Middle Aged; Renal Insufficiency; Telmisartan; Treatment Outcome

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

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

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

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

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

Normal blood pressure is a good marker of graft survival after renal transplantation, and effective antihypertensive treatment reduces the progression of graft damage. We conducted a long-term follow-up study of 88 hypertensive renal transplant recipients, all of whom were taking sustained cyclosporine A (CsA) immunosuppression. The patients were treated for at least three years, and initially received 240 mg/day of verapamil (N = 24, group I), 5 mg/day of enalapril (N = 24, group II) or 1 mg/day of doxazosin (N = 40, group III). Baseline creatinine did not differ in the three groups, but proteinuria was higher in the enalapril group (7 patients had proteinuria > 1.5 g/day). Treatment was withdrawn in 5 patients in the verapamil group, 5 in the enalapril group and 2 in the doxazosin group due to drug-related side effects. Blood pressure (BP) control at three years was equivalent in the three groups (systolic BP, group I 157 +/- 12; group II 149 +/- 19; group III 154 +/- 21; diastolic BP, group I 90 +/- 8.7, group II 84 +/- 9.8, group III 90.5 +/- 16; mean BP, group I 113 +/- 7, group II 106 +/- 10, group III 106 +/- 29). Two patients in group I, 3 in group II and 15 in group III required additional antihypertensive drugs. CsA levels increased in the verapamil-treated patients, allowing for an early decrease in CsA doses (1 year doses, 3.3 +/- 1 mg/kg body wt/day in group I, 4.3 +/- 1.6 in group II, 3.7 +/- 1.6 in group III). Six cardiovascular events occurred, 3 in group I, 1 in group II, and 2 in group III patients. One patient died in the enalapril group and another in the doxazosin group. Eight verapamil-treated patients, 8 enalapril-treated patients and 4 doxazosin-treated patients lost their grafts due to biopsy-proven chronic transplant nephropathy. In conclusion, the three antihypertensive agents are effective in reducing blood pressure, with no clear advantage of one above any other. Verapamil allows the CsA dose to be reduced, thus decreasing the cost of immunosupression. Enalapril can be a more effective antiproteinuric agent, but hyperkalemia or impaired allograft function may occur in patients with non-optimal allograft function. Doxazosin offers an excellent safety and efficacy profile, and when not efficient by itself in controlling blood pressure, is an ideal concomitant agent in hypertensive renal transplant patients.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Doxazosin; Enalapril; Female; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Hypertension, Renal; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Postoperative Complications; Verapamil

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

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

To determine plasma renin activity (PRA), angiotensin I (Ang I), and aldosterone (ALDO) values in clinically normal cats and hypertensive cats with renal disease, and the relation of renin-angiotensin-aldosterone activation in response to treatment with beta-blockers or angiotensin-converting enzyme inhibitors.. 5 normotensive healthy control cats and 12 Untreated hypertensive cats with chronic renal disease.. Untreated hypertensive cats received either propanolol (n = 6) or enalapril (n = 6) as initial antihypertensive treatment. PRA and baseline plasma Ang I and ALDO concentrations were measured prior to treatment. The difference in Ang I values at 2 hours (Ang I generated) and at time 0 (baseline Ang I) was divided by 2 to give the PRA value. Values for PRA, Ang I, and ALDO were obtained from 5 clinically normal, normotensive cats, and compared with those of hypertensive cats.. Mean +/- SD PRA and baseline Ang I concentration were not significantly different between normotensive and hypertensive cats. Mean ALDO concentration was significantly (P = 0.0235) higher in hypertensive cats with renal disease (186.18 +/- 145.15 pg/ml), compared with that in normotensive controls (51.1 +/- 16.76 pg/ml). Eight hypertensive cats with ALDO concentration > 2 SD above the mean concentration in control cats had low (n = 3), normal (n = 4), or high (n = 1) PRA, suggesting variable activation of the renin-angiotensin-aldosterone axis in the hypertensive state. Overall, enalapril was effective long-term monotherapy in only 1 of 6 cats, and propranolol was ineffective as long-term monotherapy.. Evaluation of the renin-angiotensin-aldosterone system in cats with hypertension associated with renal disease may lead to greater understanding of the pathophysiologic mechanisms of this disorder. In addition, identification of biochemical markers in hypertensive cats may permit selection of appropriate antihypertensive drugs. Propranolol and enalapril were ineffective antihypertensive agents in most cats of this study.

Topics: Adrenergic beta-Antagonists; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cat Diseases; Cats; Dose-Response Relationship, Drug; Enalapril; Female; Hypertension, Renal; Kidney Failure, Chronic; Male; Propranolol; Radioimmunoassay; Renin; Renin-Angiotensin System

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

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

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

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

Hypertension is one of the most important accelerating factors for progression of nephropathies. Its prevalence is about 35% in patients with nephropathies, even in minor or medium severe functional impairment. This is evidence that it is essential to select an optimal therapeutic regimen as soon as possible. A group of 38 patients (14 hypertensive patients) with a minor or medium severe functional impairment were included in a controlled trial. The patients were served a low-protein diet--0.6-0.7 g/kg/day and 2-10mg enalapril/day divided into two doses. The amount of enalapril depended on the blood pressure and enalapril was given also to normotensive patients. The investigation lasted 8 months. In the course of 8 months the authors did not reveal progression of the renal disease, as apparent from results of assessment of the creatinine level and clearance, assessment of uric acid and urea. The authors did not find deterioration of metabolic acidosis, nor of nephrogenic anaemia. Hypertensive patients had a tendency to deteriorating of insulin sensitivity while in normotensive patients a decline of triacylglycerols, VLDL and rise of HDL was recorded. The total cholesterol and LDL cholesterol level did not change. The authors conclude that the combination of a low-protein diet with ACEI in hypertensive and normotensive patients with mild to medium severe functional disorders inhibits the progression of nephropathies, but in hypertensive patients it does not prevent deterioration of insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Female; Glucose Tolerance Test; Humans; Hypertension, Renal; Insulin Resistance; Male; Middle Aged

Hypertension and end-stage renal disease (ESRD) are major causes of morbidity and mortality in the United States, especially among African Americans. The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study evaluated the feasibility of conducting a long-term clinical trial to compare the effects of two levels of blood pressure control and three different antihypertensive drug regimens on the rate of decline in glomerular filtration rate (GFR) in African Americans with clinically diagnosed hypertensive renal disease. African American men and women aged 18-70 years with a GFR of 25-70 ml/min/ 1.73m2 and hypertension were randomized in a 3 x 2 factorial design to initial treatment with either an angiotensin-converting enzyme inhibitor (enalapril), a calcium channel blocker (amlodipine), or a beta blocker (atenolol) and to a mean arterial blood pressure (goal MAP) of either 102-107 mm Hg or < or = 92 mm Hg. Furosemide, doxazosin, clonidine, hydralazine, and minoxidil were added sequentially until goal MAP was achieved. To compare the pathologic diagnosis with the clinical diagnosis of renal disease, study participants without contraindication were also asked to undergo a renal biopsy. The goals of the AASK Pilot Study were to evaluate recruitment techniques, adherence to prescribed antihypertensive drug regimens, ability of the antihypertensive regimens to achieve blood pressure goals, rates of participation in scheduled clinic visits and procedures, and variability of GFR measurements. A further goal was to obtain renal biopsy data in at least 75% of the randomized study participants. Compared to the ESRD patient population whose renal disease is caused by hypertension, women were underrepresented in the AASK Pilot Study. AASK Pilot Study participants had higher unemployment rates and lower income levels than African Americans in the general U.S. population.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Atenolol; Black or African American; Blood Pressure; Drug Evaluation; Enalapril; Female; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Multicenter Studies as Topic; Patient Compliance; Patient Selection; Pilot Projects; Quality Control; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Sample Size

The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study evaluated the feasibility of carrying out a randomized, multicenter, 7-year clinical trial to determine the effects of two goal levels of blood pressure control and three antihypertensive drug regimens on decline in glomerular filtration rate in African Americans with clinically diagnosed hypertensive nephrosclerosis. Participants were randomized to either a usual mean arterial blood pressure (MAP) goal group (102-107 mm Hg) or a low-MAP goal group (< or = 92 mm Hg) and to a drug regimen (initial therapy with either atenolol, amlodipine, or enalapril). Quality of life was assessed by the Medical Outcomes Short-Form 36 (MOS SF-36) at baseline and the last follow-up visit for 84 of the 94 participants of the AASK Pilot Study. Symptoms were assessed at baseline and throughout the course of therapy by participant self-report. Mean SF-36 scores increased significantly on physical functioning (9.2), role limitations (physical) (19.0), social functioning (9.0), and vitality dimensions (5.6) from baseline to the last follow-up visit in the usual MAP goal group. Scores for the eight health dimensions assessed by the MOS SF-36 did not change significantly during the same time period either in the low-MAP goal group or in any of the drug regimens. The mean score for general health perception was significantly lower at the last follow-up visit in the enalapril drug regimen (49.9) compared to drug regimens with atenolol (65.4) or amlodipine (63.9). Physical functioning, role limitations (emotional), social functioning, mental health, vitality, and general health perception scores were negatively correlated with self-reported symptoms during treatment. We conclude that selected dimensions of quality of life improved during the AASK Pilot Study only in participants randomized to the usual MAP goal group. Significant differences between MAP goal groups and drug regimens at the end of follow-up were observed for only a few health dimensions.

Topics: Adult; Aged; Amlodipine; Analysis of Variance; Antihypertensive Agents; Atenolol; Black or African American; Blood Pressure; Enalapril; Female; Humans; Hypertension, Renal; Male; Middle Aged; Multivariate Analysis; Pilot Projects; Prospective Studies; Quality of Life; Research Design

Topics: Adolescent; Adult; Child; Drug Administration Schedule; Enalapril; Fish Oils; Glomerulonephritis, IGA; Humans; Hypertension, Renal; Prednisone; Prospective Studies

Treatment of hypertension with an angiotensin converting enzyme inhibitor (ACEI) may be associated with a decrease in haemoglobin concentration especially in patients with renal insufficiency. This open study in 19 patients with a variety of renal diseases with complicating hypertension investigated the effects of the ACEI, enalapril, on haemoglobin and plasma erythropoietin (EPO) concentrations. Blood samples were obtained at baseline and 2, 60 and 120 days after starting treatment with enalapril. By day 60 there was a significant decrease in mean haemoglobin concentration (mean decrease 7.4 g/l) that was sustained until day 120. Apart from a small, but significant, reduction by day 2, mean plasma EPO concentration remained constant throughout the study. The magnitude of the decrease in haemoglobin concentration was, however, significantly correlated with the baseline plasma creatinine concentration and creatinine clearance. These results suggested that the degree of renal insufficiency was important in determining the haematological response to ACE inhibition. While the mechanism of these changes remains unclear, our findings suggest that inhibition of the renin-angiotensin system, rather than decreasing EPO production, may reduce the erythropoietic activity of the hormone.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalapril; Erythropoietin; Female; Hemoglobins; Humans; Hypertension, Renal; Kidney; Male; Middle Aged; Polycythemia

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Ramipril; Renal Circulation; Renal Plasma Flow; Time Factors

A multicenter, double-blind, placebo-controlled, randomized trial of fish oil in proteinuric patients with IgA nephropathy is being conducted by the Mayo Nephrology Collaborative Group. We completed enrollment of 106 patients into the trial in December 1991. The treatment period is for two years. Hypertension is being managed in all patients with enalapril maleate (Vasotec). We evaluated the associations between a variety of clinical and renal morphologic features and renal function at the entry of all enrolled patients. Among 78 males and 28 females [age(mean +/- SD) 36 +/- 14 years], older age at treatment randomization, hypertension, at disease discovery as well as at study entry, increased fractional excretion of albumin, increased serum triglyceride levels, and more severe tubulointerstitial, vascular, and combined glomerular and tubulointerstitial histologic lesions were all univariately associated (p < or = 0.01) with poorer renal function measured by reciprocal serum creatinine and creatinine clearance levels. In a multiple regression analysis used to predict baseline reciprocal creatinine, the best final model (R2 = 0.48) included male sex (p < .001), hypertension at treatment randomization (p = .001), decreased peripheral blood erythrocytes (p = .001), increased tubulointerstitial score (p = .004), and increased fractional excretion of albumin (p = .025) as independent predictors of decreased kidney function. These associations are similar to those seen in the high-risk subset of patients with IgA nephropathy who develop end-stage renal disease. In the eventual outcome analysis of the clinical trial, we will examine the effects of treatment on the two potentially modifiable risk factors, hypertension and proteinuria, on renal function.

Topics: Adult; Biopsy; Double-Blind Method; Enalapril; Female; Fish Oils; Glomerulonephritis, IGA; Humans; Hypertension, Renal; Kidney; Male; Regression Analysis; Risk Factors

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

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

Twenty-four-hour "ambulatory blood pressure monitoring" (ABPM) was performed during the day at every 30 min and during the night at every 60 min in 38 persons admitted to the hospital. The subjects were divided into four groups: Group 1. healthy subjects (11); Group 2. essential hypertensive patients (7) before and during enalapril treatment; Group 3. patients with essential hypertension (10) treated with different antihypertensive drugs and Group 4. renal patients treated as in Group 3. Normal circadian rhythm was found in the healthy subjects and in the patients with essential hypertension, but no rhythm could be demonstrated in the renal patients. The high blood pressure decreased in response to enalapril in 7 patients without any decrease in the circadian rhythm. It was concluded that antihypertensive therapy does not abolish the circadian rhythm if there is any--and does not restore if it is lacking. The chances of the diagnostic use of circadian blood pressure rhythm are not impaired by the antihypertensive treatment.

Topics: Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Enalapril; Humans; Hypertension; Hypertension, Renal

The comparative effects of enalapril (E) and nifedipine (N) on renal hemodynamics were assessed in twenty-two moderately hypertensive, cadaveric renal transplant patients who were maintaining stable renal function. Fourteen patients were on cyclosporin (CSA) and eight were receiving azathioprine with prednisolone (AZA). In each patient effective renal plasma flow (ERPF) was determined four times, first baseline, second with E, third as another baseline after a washout period, and fourth with N; and renal vascular resistance (RVR) was derived in each. ERPF and RVR were significantly compromised in the CSA group (202 +/- 55 ml/min and 65 +/- 18 mmHg/ml/min) compared to the AZA group (302 +/- 99 and 43 +/- 15 respectively). During E therapy, RVR further increased in the CSA group to 82 +/- 37 while it decreased in the AZA group to 31 +/- 7 (both changes were significant when compared to their respective baseline values). N, on the other hand, only significantly lowered RVR in the AZA group. Furthermore, two patients, one from each group, developed acute reversible renal failure shortly after E therapy. However, both agents were effective in lowering blood pressure to a comparable degree in both groups. In conclusion, our data showed a somewhat less favourable renal hemodynamic response to short-term enalapril therapy in hypertensive renal transplant patients maintained on CSA. However, the significance of such hemodynamic changes for long-term renal function remains uncertain.

Topics: Adult; Azathioprine; Cyclosporine; Enalapril; Female; Humans; Hypertension, Renal; Kidney Transplantation; Male; Middle Aged; Nifedipine; Prospective Studies; Renal Circulation

In a half-year open clinical study the authors investigated the antihypertensive action of enalapril--an inhibitor of the angiotensin converting enzyme--and its action on renal functions in a group of 11 patients with nephrogenic hypertension. In seven patients monotherapy, using a mean dose of 12 mg, was sufficiently effective. In the remaining four patients treatment was combined with diuretics. It was revealed: that: 1. a significant drop of systolic and diastolic pressure occurred with a concurrent decline of the total peripheral vascular resistance, 2. a slight (statistically not significant) reduction of the glomerular filtration as well as quantitative proteinuria with a decline of glomerular hypertension. 3. In this group of patients without left ventricular hypertrophy no signs of regression of its mass were present. 4. Even in patients with nephrogenic disease no negative effect on the lipid, carbohydrate and purine metabolism was observed. The subjective tolerance of the preparation was very satisfactory.

Topics: Adult; Enalapril; Female; Hemodynamics; Humans; Hypertension, Renal; Male; Middle Aged

Angiotensin II has many actions in the kidney, including regulation and distribution of renal circulation and glomerular filtration, as well as effects on mesangial contraction and on the filtration coefficient. The reduction in circulating and intrarenal angiotensin II by angiotensin converting enzyme (ACE) inhibitors in essential hypertension is associated with a significant increase in renal blood flow and a decrease in filtration fraction, without changes in glomerular filtration rate. In addition, administration of ACE inhibitors can reduce proximal sodium reabsorption via changes in peritubular hydrostatic and oncotic forces resulting from the fall in postglomerular capillary resistance. In severe hypertension the state of the renal vasculature does not allow ACE inhibition to induce similar haemodynamic changes and, therefore, it cannot contribute to renal sodium handling that requires the recruitment of alternate mechanisms. In spite of this, ACE inhibitors may exert a protective effect on the renal function of patients with severe hypertension as well as in those with renal impairment, by lowering systemic and, probably, intraglomerular pressure, reducing proteinuria and slowing the progression of renal failure.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cilazapril; Enalapril; Female; Humans; Hypertension; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Pyridazines; Renal Circulation

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

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

The long-term effects of converting enzyme inhibitors and calcium channel blockers on proteinuria and the progression of renal disease in patients with hypertension and chronic renal insufficiency are not well established. We have studied the long-term effects of treating hypertension with an angiotensin-converting enzyme inhibitor, enalapril, and a calcium channel blocker, nicardipine, on urinary albumin excretion (UAE) and on renal function in 16 patients with hypertension and chronic renal insufficiency (creatinine clearance ranging between 17 and 62 ml/min). After 1 year of treatment, these agents caused a similar decrease in blood pressure. Only enalapril, however, caused a significant decrease in UAE (from 641 +/- 98 to 292 +/- 47 mg/24 h, p less than 0.01), whereas UAE did not change in the group treated with nicardipine (675 +/- 78 vs. 601 +/- 75 mg/24 h). Creatinine clearance at the beginning of the study was similar in the group treated with enalapril and in the group treated with nicardipine (35 +/- 3.6 vs. 40 +/- 4.1 ml/min). After 1 year of follow-up, creatinine clearance remained unchanged in both groups of patients. These studies demonstrate that both enalapril and nicardipine can effectively reduce blood pressure in patients with hypertension and chronic renal insufficiency. Enalapril but not nicardipine, however, appears to reduce urinary albumin excretion in these patients. Whether the reduction in UAE has any significant impact on the progression of renal disease remains to be established.

Topics: Albuminuria; Enalapril; Female; Follow-Up Studies; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Nicardipine; Time Factors

Angiotensin converting enzyme (ACE) inhibitors has been suggested to halt the progression of chronic renal failure. As the initial step of a controlled trial of this hypothesis, it was investigated whether start of enalapril in patients with severe chronic nephropathy might cause a critical fall in their renal function. Thirty-one patients were studied, 26 on chronic antihypertensive treatment with drugs other than ACE inhibitors and 5 untreated normotensive. 51Cr-EDTA plasma clearance and renal technetium-99m dimercaptosuccinic acid (99mTc-DMSA) scintigraphy were made before and 24 h after start of enalapril, mean dose 9 mg. Blood pressure fell from median 148/88 to 119/78 mmHg (p less than 0.01). Glomerular filtration rate (GFR) fell from median 14 to 12 ml/min/1.73 m2 (p less than 0.01). The median change in GFR was -14% (range -44% to +10%). The split renal function was unchanged and the scintigrams showed no intrarenal activity defects. In conclusion, enalapril caused a fall in GFR, which was clinically acceptable in most of the patients.

Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Diabetic Nephropathies; Enalapril; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Polycystic Kidney Diseases; Succimer

Seven patients with glomerular proteinuria and hypertension (six with biopsy confirmation of glomerulonephritis, one with proteinuria after unilateral nephrectomy) were randomly given, for 14 days each, a calcium antagonist and then a conversion enzyme inhibitor, or vice versa, following a 14-day pause of all medication. Fractional albuminuria rose significantly during administration of calcium antagonists (P less than 0.05), while it decreased significantly during administration of converting enzyme inhibitor (P less than 0.05). The explanation for this finding may be that calcium antagonists raise glomerular capillary pressure by dilating the afferent arterioles, while converting enzyme inhibitors predominantly cause dilatation of the efferent arterioles.

Topics: Adult; Albuminuria; Calcium Channel Blockers; Enalapril; Hemodynamics; Humans; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Nifedipine

Topics: Acute Kidney Injury; Antihypertensive Agents; Biopsy; Child; Diagnosis, Differential; Enalapril; Follow-Up Studies; Hemolytic-Uremic Syndrome; Humans; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney; Propranolol; Purpura, Thrombotic Thrombocytopenic; Radionuclide Imaging; Renal Dialysis; Severity of Illness Index; Technetium Tc 99m Dimercaptosuccinic Acid; Time Factors; Treatment Outcome

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

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

This study assessed whether the Rho kinase signaling pathway contributes to androgenic amplification of angiotensin II (Ang II) induced pressor and renal constrictor responses.. Mean arterial pressure (MAP) responses to angiotensin II receptor 1 (AT1) inhibition were measured in conscious male New Zealand genetically hypertensive rats (NZGH) subjected to sham operation, castration or castration+testosterone replacement. MAP and renal vascular resistance (RVR) responses to Ang II were recorded with and without a Rho kinase inhibitor, fasudil, in anesthetized NZGH. Western blot was used to analyze target protein expression in the kidney.. MAP responses to AT1 receptor inhibition and exogenous Ang II were attenuated in castrated NZGH. The increase in RVR (mm Hg/ml/min/g kidney) at the maximum dose of Ang II was significantly lower in castrated NZGH than in sham operated NZGH. Testosterone replacement restored RVR responses to Ang II in castrated rats. Fasudil treatment reduced both MAP and RVR responses to Ang II in each group. In addition, the differential MAP and RVR responses to Ang II amongst the three groups were significantly attenuated by Rho kinase inhibition. Western blot showed that Rho kinase protein expression was reduced by castration, while testosterone replacement restored the Rho kinase protein levels in castrated rats. The phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a downstream target of Rho kinase, was also increased by androgens.. Collectively, these results indicate that androgens potentiate Ang II-induced renal vascular responses, an effect mediated at least partly via up-regulation of the Rho kinase signaling pathway.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blotting, Western; Carrier Proteins; Enalapril; Enzyme Activation; Hypertension, Renal; Intracellular Signaling Peptides and Proteins; Kidney; Male; Orchiectomy; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Serine-Threonine Kinases; Rats; Rats, Mutant Strains; Renal Veins; rho-Associated Kinases; Signal Transduction; Testosterone; Vascular Resistance

Hypertension plays a major role in the progression of both experimental and clinical chronic renal disease. However, the pathogenesis of the more slowly developing glomerulosclerosis that is seen even in the absence of overt hypertension, both in renal mass reduction models and in humans with chronic renal disease, remains controversial.. The relationship of such glomerulosclerosis to the ambient blood pressure profiles was examined in the normotensive approximately 5/6 surgical excision rat remnant kidney model. Blood pressure was radiotelemetrically monitored at 10-minute intervals for 15 to 16 weeks ( approximately 15,000 blood pressure readings) in untreated rats (N= 13), or those treated with enalapril (N= 8), amlodipine (N= 9), or a combination of hydralazine, reserpine, and hydrochlorothiazide (N= 10).. Even in these normotensive rats (systolic blood pressure <140 mm Hg), % glomerulosclerosis was significantly correlated with the overall average systolic blood pressure (r= 0.62, P < 0.0001; N= 40). However, much stronger correlations were observed between glomerulosclerosis and the % systolic blood pressure readings >150 mm Hg (r= 0.77, P < 0.0001) and the standard deviation of the average systolic blood pressure (r= 0.87, P < 0.0001).. These data indicate that pressure dependent injury mechanisms continue to contribute to glomerular injury even within the "normotensive" blood pressure range in rats with reduced renal mass. This most likely represents the consequence of the impairment of protective renal autoregulation and enhanced glomerular transmission of the blood pressure fluctuations into the hypertensive range characteristic of the conscious state in both experimental animals and in humans. Such pathophysiology supports the need for more aggressive and around-the-clock blood pressure control in chronic renal disease.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Enalapril; Glomerulosclerosis, Focal Segmental; Hydralazine; Hydrochlorothiazide; Hypertension, Renal; Male; Monitoring, Physiologic; Nephrectomy; Rats; Rats, Sprague-Dawley; Reserpine; Telemetry

Stage IV hypertensive retinopathies in children have been described, but their incidence appears to be rare. Most etiologies are nephropathies. The authors present a clinical case of malignant high blood pressure in a young girl whose ophthalmological tests detected an unusual nephropathy, the Ask-Upmark kidney, illustrating the importance of determining high blood pressure chronicity and using Kirkendall's classification. Systematic fluorescein angiography and NMR on atypical subjects prevents the diagnosis of Leber neuroretinis, the main differential diagnosis. Early treatment of high blood pressure can avoid complications such as macular exudes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Child; Diagnosis, Differential; Enalapril; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Hypertension, Malignant; Hypertension, Renal; Kidney; Optic Atrophy, Hereditary, Leber; Retinal Diseases; Retinitis; Time Factors; Visual Acuity

To elucidate the mechanisms responsible for the adverse renal effects induced by dual blockade of the renin-angiotensin system (RAS) and the role of salt therein.. The effects of enalapril, losartan and their combination on blood pressure, renal haemodynamics, renal function and RAS were investigated over a wide range of doses in spontaneously hypertensive rats fed either a low-sodium or a high-sodium diet.. In rats fed the low-sodium diet, the losartan-enalapril combination induced the same dose-dependent haemodynamic and hormonal changes as did three- to 10-fold greater doses of enalapril or losartan alone. When a strong decrease (> 50%) in blood pressure was achieved (with 10 mg/kg enalapril plus 10 mg/kg losartan, 100 mg/kg enalapril or 100 mg/kg losartan), a massive renal vasoplegia occurred and renal insufficiency developed. In addition, because of the huge release of renin, angiotensinogen concentrations were reduced, leading to a decrease in intrarenal angiotensins. In rats fed the high-sodium diet, those treated with the enalapril 30 mg/kg plus losartan 30 mg/kg combination, despite complete functional RAS blockade, exhibited smaller decreases in blood pressure and renal resistance, lesser release of renin and angiotensinogen consumption, and a normal renal function. These effects were similar to those produced by 100 mg/kg of enalapril or losartan in rats fed the high-salt diet, or by 10 mg/kg of enalapril or of losartan in rats fed the low-salt diet.. Dual RAS blockade could be either beneficial, when sodium intake is unrestricted, or dangerous, when sodium intake is restricted.

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Consciousness; Drug Therapy, Combination; Enalapril; Hypertension, Renal; Kidney; Losartan; Male; Rats; Rats, Inbred SHR; Renal Circulation; Renin-Angiotensin System; Sodium Chloride, Dietary

To compare 2 techniques of inducing combined renal insufficiency and systemic hypertension in cats.. 22 cats 6 to 12 months of age.. Cats were randomly assigned to 1 of 3 groups. Control (C) group cats had 2 intact kidneys, remnant kidney (RK) group cats underwent unilateral partial renal infarction and contralateral nephrectomy, and remnant-wrap (W) group cats underwent unilateral partial renal infarction and partial abtation and wrapping of the contralateral kidney. Systemic arterial blood pressure (BP) was measured continuously by use of implanted radiotelemetric devices. Renal function was assessed via determination of glomerular filtration rate, measurement of serum creatinine and BUN concentrations, and determination of urine protein-to-creatinine ratio (UP/C). Serum aldosterone concentration and plasma renin activity were measured on day 75.. Systolic BP was significantly higher in groups RK and W than in group C, and systolic BP was significantly higher in group W than in group RK. Serum aldosterone concentration and plasma renin activity were significantly higher in group W, compared with groups C and RK. Glomerular filtration rate was significantly lower in groups RK and W, compared with group C. Histologic indices of renal injury and UP/C were significantly higher in group W, compared with groups C and RK.. Hypertensive renal insufficiency in group W was characterized by marked sustained systemic hypertension, decreased renal function, proteinuria, activation of the renin-angiotensin-aldosterone axis, and renal structural injury. Results support the hypothesis that marked systemic hypertension, activation of the renin-angiotensin-aldosterone axis, and proteinuria may damage the kidney of cats with preexisting renal insufficiency.

Topics: Amlodipine; Analysis of Variance; Animals; Blood Pressure; Blood Pressure Determination; Cat Diseases; Cats; Diltiazem; Enalapril; Heart Rate; Hypertension, Renal; Infarction; Kidney; Ligation; Losartan; Nephrectomy; Renal Insufficiency; Telemetry; Time Factors

The effect of angiotensin-converting enzyme (ACE) inhibitor enalapril (EPL) (2 and 4 mg/kg), angiotensin (AT) II receptor antagonist losartan (LRN) (5 and 10 mg/kg), and anxiolytic drug diazepam (DZP) (0.5 mg/kg) on anxiety parameters were evaluated in experimentally induced renal hypertensive rats (RHR). Renal hypertension was induced in Wistar strain male albino rats weighing 200-250 g by following the method of Goldblatt. The animals having systolic blood pressure more than 180-210 mm Hg were subjected to open-field exploratory behaviour, elevated plus maze behaviour, and social interaction tests of anxiety. The RHR showed hyperactivity in open-field behaviour and anxiogenicity in elevated plus maze and social interaction tests. Losartan (5 and 10 mg/kg) and DZP (0.5 mg/kg) significantly attenuated the hyperactivity and anxiogenic behaviour in experimentally induced hypertensive rats and induced anxiolysis in normotensive rats (NTR). Enalapril reversed the hypertension-induced alteration only at higher dose (4 mg/kg) and failed to show any effect in NTR. It can be concluded that renin angiotensin aldosterone system (RAAS) has a significant role on behaviour, and LRN has shown better effect in reversing the hyperactivity and anxiogenicity in the experimentally induced hypertensive rats, indicating a possible role of AT receptor in the mediation of anxiolysis.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Anxiety Agents; Antihypertensive Agents; Anxiety; Blood Pressure; Diazepam; Enalapril; Exploratory Behavior; Hypertension, Renal; Losartan; Male; Rats; Rats, Wistar; Social Behavior

Recent studies indicate that the coexistence of hypertension and glucose intolerance leads to impairment in saline volume-induced diuresis and natriuresis. Furthermore, taurine and enalapril affect renal function and blood pressure (BP). Therefore, we tested the hypothesis that therapy combining taurine and enalapril would confer greater antihypertensive activity and responsiveness to saline volume loading in the hypertensive glucose-intolerant (HGI) rat than either agent alone.. Hypertensive (H) and HGI rats were treated from 6 weeks to 6 months with tap water containing no addition, taurine (0.25%), enalapril (15 mg/kg/day), or the taurine-enalapril combination. Hemodynamic and renal responses to an intravenous isotonic saline volume load were then determined in the conscious animal.. The vehicle-treated HGI rats displayed reduced saline volume-induced diuresis and natriuresis relative to their H counterparts. Although none of the three drug regimens affected BP, they were similarly effective in increasing the renal excretory responses to saline volume loading and in eliminating differences that existed between the untreated H and HGI groups. Although reduced tubular reabsorption activity contributed to the taurine- and enalapril-mediated augmentation in renal excretory function, enalapril also enhanced glomerular function. The augmentation in the glomerular filtration rate was greatest in the HGI rat treated with the combination of taurine and enalapril. Furthermore, all three drug regimens significantly reduced protein excretion in both H and HGI rats.. Despite exerting no influence on BP, all three drug regimens were renoprotective, as indicated by the drug-mediated improvement in kidney function of the HGI rat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Antihypertensive Agents; Body Weight; Diabetes Mellitus, Experimental; Enalapril; Glomerular Filtration Rate; Glucose Intolerance; Glucose Tolerance Test; Hemodynamics; Hypertension; Hypertension, Renal; Kidney; Kidney Function Tests; Male; Organ Size; Rats; Rats, Inbred WKY; Sodium; Taurine

Vasopeptidase inhibitors are a new class of compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase. This study determined whether treatment with the vasopeptidase inhibitor omapatrilat (OMA) produced different effects on renal and cardiovascular structure compared with inhibition of ACE by enalapril (ENP) in rats with two-kidney, one clip hypertension (2K1C).. Hypertensive 2K1C rats were randomized into four groups and studied for another 8 weeks: no treatment, OMA, ENP or ENP combined with the diuretic hydrochlorothiazide (ENP + HCTZ). Albuminuria, vascular and renal histology as well as glomerular expression of transforming growth factor-beta (TGF-beta) were determined at the end of the experiment.. OMA decreased blood pressure slightly better than ENP. However, combination of ENP with a diuretic lowered blood pressure equally effective as OMA. OMA was numerically more efficient in reducing cardiovascular and renal hypertensive changes compared with ENP. In contrast, the combination of ENP + HCTZ was as efficient as OMA. However, OMA lowered overexpression of TGF-beta in the non-clipped kidney better than ENP or ENP +HCTZ. Antihypertensive therapy surprisingly decreased renal function as shown by increased plasma creatinine and urea and decreased creatinine clearance.. OMA is marginally more potent compared with ENP alone in lowering blood pressure and preventing cardiovascular and renal injury. This effect may be due to slightly better blood pressure reduction because addition of HCTZ enhances the cardio- and nephroprotective capacity of ENP. In contrast, OMA reduces TGF-beta overexpression in the non-clipped kidney better than ENP or ENP + HCTZ. Therefore, vasopeptidase inhibition is not superior to ACE inhibition in the prevention of cardiovascular and renal damage Goldblatt hypertension.

Topics: Analysis of Variance; Animals; Biopsy, Needle; Blotting, Western; Disease Models, Animal; Enalapril; Enzyme-Linked Immunosorbent Assay; Hypertension, Renal; Immunohistochemistry; Male; Organ Size; Probability; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Inbred Strains; Reference Values; Renal Circulation; Survival Rate; Thiazepines

ACE inhibitors (ACEIs) and angiotensin II type 1 (AT(1)) receptor blockers are effective in reducing left ventricular mass in hypertension and heart failure. However, the ability of these drugs to reverse excessive myocyte lengthening and transverse growth in heart failure is unknown.. L-158,809 (an AT(1) blocker; AT(1)), enalapril (an ACEI), and hydralazine (a vasodilator) were administered to spontaneously hypertensive heart failure rats between 6 and 10 months of age (early treatment) and between 18 and 22 months of age (late treatment). After 4 months of treatment, hemodynamics and chamber dimensions were collected before left ventricular myocyte isolation and subsequent analysis of myocyte shape. Each drug reduced systolic blood pressures to normal values. In the early and late studies, the ACEI reduced myocyte volume. Myocyte length was also reduced in the late study. However, the AT(1) was most effective in reversing myocyte dimensions to near-normal values in both studies. Hydralazine was ineffective in reducing cell size but arrested progression of myocyte lengthening in the late study. Changes in myocyte shape reflected alterations in chamber dimensions and wall thickness.. Reversal of myocyte hypertrophy was produced in hypertensive/heart failure rats with an AT(1). The ACEI was effective but to a lesser extent. Results indicate that it is possible to significantly reverse myocyte remodeling pharmacologically even if therapy is initiated near the onset of failure. Further work is needed to determine whether similar results can be obtained in humans.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Echocardiography; Enalapril; Female; Heart Failure; Hypertension, Renal; Imidazoles; Muscle Fibers, Skeletal; Myocardium; Organ Size; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Tetrazoles; Ventricular Remodeling

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

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

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

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

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cerebrovascular Circulation; Enalapril; Homeostasis; Hypertension; Hypertension, Renal; Rats; Rats, Inbred SHR

Hypertension and renal injury in experimental polycystic kidney disease.. Hypertension accelerates renal failure in autosomal dominant polycystic kidney disease (ADPKD), and evidence suggests a role for the renin-angiotensin system (RAS) in the functional and structural changes. To explore the hypothesis that RAS adaptations contribute to disease progression, we examined RAS activity and the long-term consequences of antihypertensive drugs, which suppress (enalapril) or stimulate (hydralazine) the RAS, in experimental polycystic kidney disease.. Studies were conducted in male heterozygous cystic Han:SPRD rats (Cy/+) and in unaffected littermates (controls). In protocol 1, either angiotensin II (Ang II), enalaprilat, or saline vehicle was acutely infused into cystic and control rats, which were aged 10 to 12 weeks. The mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured at baseline and after an infusion of test substances. In protocol 2, cystic rats received chronic therapy with either enalapril, hydralazine, or no therapy for 10 to 12 weeks of age and then underwent renal function and RAS studies. In protocol 3, similar cohorts were followed for 40 weeks to assess the effects of therapy on blood pressure, proteinuria, serum creatinine, RAS parameters, and renal morphology.. In protocol 1, cystic rats had massive kidneys, slightly elevated blood pressure, and profound renal vasoconstriction and reduced GFR. Ang II induced similar changes in MAP and renal function in control and cystic rats. Enalaprilat induced little effect on MAP but more striking increases in GFR and RPF in cystic rats. In protocol 2, at 10 weeks of age, enalapril was superior in preserving renal function, but neither drug limited the expansion of the tubulointerstitium. In protocol 3, at 40 weeks of age, both drugs ameliorated the increase in serum creatinine, although only enalapril reduced proteinuria and kidney size.. In polycystic rats, acute RAS suppression markedly ameliorates renal dysfunction. However, although chronic enalapril and hydralazine protect against the loss of renal function, only enalapril limits renal growth and proteinuria, and neither significantly limits tubulointerstitial fibrosis. The long-term studies give clear support to the importance of blood pressure control, per se, but only partial support to the importance of the particular agent used. As in clinical studies, angiotensin-converting enzyme inhibition may be less beneficial in ADPKD than in renal diseases characterized by predominant glomerular injury.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Enalapril; Fibrosis; Hydralazine; Hypertension, Renal; Kidney Glomerulus; Male; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Vasoconstrictor Agents

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

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

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

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

The antihypertensive activity and pharmacokinetics of KD3-671 (previously named KT3-671), a nonpeptide AT1-receptor antagonist, were investigated in renal hypertensive dogs with normal or high plasma renin activity (PRA). A single administration of KD3-671 at 3 and 10 mg/kg, p.o., to the hypertensive dogs with high PRA dose-dependently reduced mean blood pressure (MBP), which was not correlated with plasma KD3-671 concentration. Significant increases in PRA and plasma angiotensin (Ang) II occurred 2 h after KD3-671 dosing. Enalapril at 3 mg/kg, p.o., also reduced MBP. Neither KD3-671 nor enalapril affected heart rate. When given orally once a day for 29 days to the hypertensive dogs with normal PRA, KD3-671 at 3 and 10 mg/kg/day dose-dependently reduced MBP, which was smaller than that in the dogs with high PRA. This was the case for enalapril. The hypotension induced by the first dose of KD3-671 or enalapril was consistently observed after doses 8, 15, 22, and 29. After cessation of repeated dosing, no rebound phenomenon in MBP was observed. Pharmacokinetic parameters of KD3-671 were not influenced by repeated dosing. KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that KD3-671 may be useful for the treatment of hypertension.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Dogs; Enalapril; Hypertension, Renal; Imidazoles; Male; Renin; Tetrazoles

The antihypertensive effects of valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl¿ valine, CAS 137862-53-4, CGP 48933), an angiotensin II type 1 receptor antagonist, were examined in hypertensive rats and dogs. In normotensive rats and deoxycorticosterone acetate (DOCA)/salt hypertensive rats, valsartan had no effect on blood pressure. Single oral administrations of valsartan at doses of 3-30 mg/kg reduced blood pressure dose-dependently in renal (2 kidney 1 clip, 2K1C) hypertensive and spontaneously hypertensive rats (SHR). Repeated oral administrations of valsartan to these hypertensive rats controlled blood pressure throughout a treatment period of 4 weeks, and showed no rebound phenomenon following drug withdrawal. This drug at 30 mg/kg p.o. decreased blood pressure in renal (2K1C) hypertensive dogs by single and repeated administrations. The extent and duration of the hypotensive action of valsartan were similar to those of enalapril. Valsartan would thus appear as useful as enalapril.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Dogs; Enalapril; Heart Rate; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Tetrazoles; Valine; Valsartan

Surgical ablation of renal mass leads to a reduction in kidney function and commonly to the development of hypertension and chronic renal failure (CRF) in rats. The objective of this study was to determine whether endothelin (ET)-1 is involved in the maintenance of the hypertension that accompanies loss of renal mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a selective, orally active ET(A) receptor antagonist, in a group of rats made hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[-1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4 micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6 reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days resulted in a sustained reduction in BP. Sham-operated rats also showed a slight hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma creatinine, urinary protein excretion, and creatinine clearance were not altered by PD 155080 administration in RRM or sham rats. In a third experiment, we investigated the contribution of the renin-angiotensin system to BP control in RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment days, and this antihypertensive effect was not altered by coadministration of the angiotensin-converting enzyme inhibitor enalapril in the drinking water (508 micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in established RRM hypertension through activation of the ET(A) receptor subtype, (2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism is not opposed by the renin-angiotensin system.

Topics: Animals; Blood Pressure; Dioxoles; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypertension, Renal; Infusions, Intravenous; Kidney Failure, Chronic; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renin-Angiotensin System

We have previously shown that idiopathic focal segmental glomerulosclerosis (FSGS) is the most common non-proliferative primary glomerulopathy in adult African Americans. In this report we present our experience with treated FSGS in 15 such patients followed over five years. They were all treated with prednisone 60 mg daily for three months, followed by a slow tapering. In addition, two patients later had cyclophosphamide, and five had enalapril. At entry hypertension was present in 73% of the patients, nephrotic syndrome in 87%, and elevated serum creatinine (> or = 1.4 mg/dl) in 40%. Five of the 15 patients (33%) developed end-stage renal failure (ESRF), one of them having a "malignant" course after the advent of pregnancy. Two patients (13%) have chronic renal insufficiency (CRI; serum creatinine > 2.5 mg/dl); three (20%) have mild renal insufficiency (serum creatinine 1.4-2.5 mg/dl), and five patients (33%) have normal renal function. The cumulative renal survival was 93% at five years, but only 26% at eight years. At last follow-up all the ten patients who did not develop ESRF were in partial remission (urinary protein of 1.3 g/day +/- 1.21), but 4 of the 5 patients who did not develop ESRF had no prolonged partial remission of nephrotic syndrome. Neither the initial clinical parameters not the use of enalapril correlated with the renal outcome (univariate analysis). However, 4 of the 5 patients who developed ESRF had elevated serum creatinine at entry, versus only 2 of the 10 not developing ESRF (p = 0.09 by two-sided, and 0.045 by one-sided Fisher's exact test). We conclude that the short-term renal outcome in nephrotic adult African Americans with treated FSGS is comparable to that of the non-African Americans, but their long-term prognosis may be poorer. Patients developing ESRF were more likely to present with elevated serum creatinine. Enalapril did not seem to modify the course of renal disease, but its utility and that of other ACE inhibitors in the treatment of FSGS must await prospective randomized studies.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Cyclophosphamide; Disease Progression; Enalapril; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Prednisone; Prognosis; Time Factors

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.

Topics: Administration, Oral; Angiotensin I; Angiotensin II; Angiotensin III; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Enalapril; Enzyme Activation; Hypertension, Renal; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Artery; Surgical Instruments; Tetrazoles; Vasoconstrictor Agents

The effects of TCV-116, a new non-peptide angiotensin II receptor antagonist, on systemic and renal hemodynamics were studied in conscious normotensive and renal hypertensive (2-kidney, 1-clip Gold-blatt type) dogs. When orally administered at 0.03 to 1.0 mg/kg, TCV-116 inhibited the pressor response to angiotensin II in conscious normotensive dogs in a dose-dependent fashion. The IC50 and IC100 values were 0.06 mg/kg and 0.86 mg/kg, respectively. TCV-116 at doses of 0.3 mg/kg and 1.0 mg/kg dose-dependently and persistently decreased systolic and diastolic blood pressure in both dogs with acute renal (hyperreninemic) and those with chronic renal (normoreninemic) hypertension. Even a high dose of TCV-116 (10 mg/kg, p.o.) increased effective renal plasma flow without affecting blood pressure or glomerular filtration rate in normotensive dogs. Furthermore, even at this high dose, TCV-116 did not reduce effective renal plasma flow or glomerular filtration rate in dogs with renal hypertension despite marked reduction in systemic blood pressure. The angiotensin converting enzyme inhibitor enalapril (10 mg/kg, p.o.) had renal hemodynamic effects similar to those of TCV-116. These findings indicate that TCV-116 has potent hypotensive effects not only in dogs with acute renal hypertension but also in those with chronic renal hypertension, but does not appear to adversely affect renal hemodynamics.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dogs; Dose-Response Relationship, Drug; Enalapril; Heart Rate; Hemodynamics; Hypertension, Renal; Kidney Function Tests; Male; Renal Circulation; Renin; Tetrazoles

Hypertensive mechanisms are postulated to play a major role in the progressive glomerulosclerosis (GS) after renal mass reduction. But, in contrast to converting enzyme inhibitors, BP reduction by calcium channel blockers, has not provided consistent protection. Radiotelemetric BP monitoring for 7 wk was used to compare nifedipine (N) and enalapril (E) in the rat approximately 5/6 renal ablation model. After the first week, rats received N, E, or no treatment (C). The overall averaged systolic BP in C (173 +/- 7 mmHg) was reduced by both E and N (P < 0.001), but E was more effective (113 +/- 2 vs. 134 +/- 3 mmHg, P < 0.01). GS was prevented by E (2 +/- 1 vs. 26 +/- 5% in C) but not by N (25 +/- 6%). GS correlated well with the overall averaged BP in individual animals of all groups, but the slope of the relationship was significantly steeper in N compared with C+E rats (P < 0.02), suggesting greater pressure transmission to the glomeruli and GS for any given BP. Since autoregulatory mechanisms provide the primary protection against pressure transmission, renal autoregulation was examined at 3 wk in additional rats. Autoregulation was impaired in C rats, was not additionally altered by E, but was completely abolished by N. These data demonstrate the importance of autoregulatory mechanisms in the pathogenesis of hypertensive injury and suggest that calcium channel blockers which adversely affect pressure transmission may not provide protection despite significant BP reduction.

Topics: Animals; Enalapril; Feedback; Hypertension, Renal; Infarction; Kidney; Male; Nephrectomy; Nifedipine; Rats; Rats, Sprague-Dawley

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

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

Inhibitors of angiotensin converting enzyme (ACE) are suspected of inducing angioedemas in up to 0.2% of all patients. These angioedemas are mainly localized in the upper airways and therefore can cause severe airway obstruction and even death due to suffocation. We report the case of a 64-year-old man, who underwent emergency tracheotomy because of severe angioedema of the larynx, which was refractory to pharmacological treatment. We conclude that patients with ACE inhibitor-induced angioedemas should be observed by monitoring in an intensive care unit to ensure the possibility of early intubation, because conventional antiallergic-antiedematous therapy by histamine-receptor antagonists and corticosteroids is an insufficient, unreliable form of therapy in severe cases. Especially otolaryngologists should know about this uncommon potentially life-threatening side-effect of ACE inhibitors.

Topics: Angioedema; Clemastine; Clonidine; Combined Modality Therapy; Drug Hypersensitivity; Emergencies; Enalapril; Humans; Hypertension, Renal; Laryngeal Edema; Male; Middle Aged; Prednisolone; Ranitidine; Tracheotomy

The angiotensin II (Ang II) type 1 receptor (AT1) mediates all known physiological effects of ANG II, whereas functions of the type 2 (AT2) receptor are not clear. Should undesirable AT2 effects be identified, it may be advantageous to combine antagonism of AT1 and AT2 receptors. XR510 was shown to inhibit the specific binding of [125I]Sar1,Ile8-Ang II for AT1 and AT2 subtype binding sites in rat adrenal membranes with IC50 of 0.26 and 0.28 nM, respectively, and in human tissues with subnanomolar binding affinity. In isolated rabbit aorta, XR510 exerted insurmountable Ang II antagonism with a Kb value of 4 nM. In conscious renal hypertensive rats, XR510 decreased blood pressure (BP) with intravenous (i.v.) and oral (p.o.) ED30 of 0.08 and 0.27 mg/kg, respectively. In spontaneously hypertensive rats (SHR), repeated daily oral dosing of XR510, losartan, and enalapril at 30 mg/kg/day decreased BP similarly. In conscious furosemide-treated dogs, XR510, given either intravenously or orally, decreased BP. These results suggest that XR510 is an orally active and selective Ang II receptor antagonist with equal binding affinities for AT1 and AT2 receptor binding sites.

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Administration, Oral; Adrenal Glands; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Binding, Competitive; Biphenyl Compounds; Blood Pressure; Decerebrate State; Dogs; Enalapril; Female; Guinea Pigs; Humans; Hypertension, Renal; Imidazoles; Injections, Intravenous; Losartan; Male; Rabbits; Radioligand Assay; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Tetrazoles

The efficacy of SR 47436 (BMS-186295), 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)- biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, a non-peptide angiotensin AT1 receptor antagonist, was characterized in various conscious hypertensive rat models. In spontaneously hypertensive rats, single intravenous or oral doses of SR 47436 induced mild to modest antihypertensive effects. No tolerance of the antihypertensive effect was observed when the oral treatment was extended to 15 days. SR 47436 was highly effective to lower blood pressure in high renin-dependent hypertensive models such as two-kidney, one-clip renal hypertensive rats and renal artery-ligated hypertensive rats. In this last model, intravenous or oral administration of the angiotensin II antagonist produced a dose-dependent decrease in blood pressure. When injected after the maximal effective dose, enalapril did not induce any further decrease in blood pressure. Furthermore, the antihypertensive effect elicited after a single oral dose (10 mg/kg) was long-lasting (at least 24 h). The simultaneous blunting effect of the angiotensin II-induced blood pressure increase indicated clearly that the antihypertensive effect was due to the blockade of vascular angiotensin AT1 receptors. As expected, the angiotensin AT1 receptor antagonist did not show any efficacy in deoxycorticosterone acetate hypertensive rats, with a suppressed renin-angiotensin system. In genetic and renal hypertensive rats, the antihypertensive effect induced after acute dosing of SR 47436 was similar to that observed after losartan and enalapril. A reflex tachycardia accompanied the antihypertensive effect only after intravenous treatment with either SR 47436 or losartan. These results show that this angiotensin II antagonist, SR 47436, is an effective and long-lasting antihypertensive agent in rats.

Topics: Administration, Oral; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Enalapril; Hypertension, Renal; Imidazoles; Injections, Intravenous; Irbesartan; Losartan; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Tachycardia; Tetrazoles

Our previous studies showed that imidapril prevented the occurrence of cerebral stroke and ameliorated biochemical parameter changes of renal dysfunction at a dose that did not inhibit the progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). To confirm these findings, a histopathological investigation was conducted on the kidney of salt-loaded (from 11 to 16 weeks of age) SHRSP, which was the subject of the preceding study. Their brains and hearts were also examined. Histopathologically, renal lesions such as fibrinoid necrosis and proliferative arteritis of small calibration arteries, necrotizing glomerulitis and tubular degeneration, and cerebral hemorrhage and slight cardial hypertrophy were observed in salt-loaded control SHRSP. The occurrence of these lesions were prevented in a dose-dependent manner by the administration of imidapril (1 and 2 mg/kg/day). Especially, the preventive effects on the renal lesions were apparently noted. Enalapril also prevented these renal lesions, but its preventive effects were weaker than those of imidapril at the same dose (2 mg/kg/day). It became evident from the results of the present and previous studies that imidapril reduced renal biochemical and histopathological injuries.

Topics: Animals; Antihypertensive Agents; Autopsy; Basilar Artery; Brain; Cerebrovascular Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart; Hypertension, Renal; Imidazoles; Imidazolidines; Kidney; Kidney Function Tests; Kidney Glomerulus; Male; Microscopy, Fluorescence; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary

1. We used the kinin antagonist HOE 140 to investigate the role of endogenous kinins in the acute antihypertensive effect of the angiotensin converting enzyme inhibitor enalapril in chronic and acute renal hypertensive rats. 2. In normotensive rats, treatment with HOE 140 (33 micrograms/kg, sc) caused a complete blockade of the depressor effect of bradykinin (100 ng, ia) without affecting the depressor effect of sodium nitroprusside (1 microgram, i.v.) or the basal blood pressure. 3. HOE 140 treatment (33 micrograms/kg, sc, plus 330 ng/min, i.v.) did not affect basal blood pressure of chronic (6-7 weeks) one-kidney, one clip and two-kidney, one clip hypertensive rats and in rats with acute hypertension, elicited by unclamping the renal pedicle that had been occluded for 5 h, but HOE 140 completely blocked the hypotensive response to bradykinin (100 ng, ia) during the 60-min period after enalapril administration (2 mg/kg, i.v.). 4. Acutely hypertensive rats treated or not with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) presented a similar fall in blood pressure after enalapril (165 +/- 5 to 137 +/- 6 mmHg and 166 +/- 5 to 136 +/- 6 mmHg, respectively). 5. Untreated two-kidney, one clip hypertensive rats presented a rapid and sustained fall in blood pressure after enalapril (177 +/- 4 to 148 +/- 4 mmHg) that did not differ from the HOE 140-treated (33 micrograms/kg, sc, plus 330 ng/min, i.v.) group (177 +/- 6 to 154 +/- 4 mmHg). 6. One-kidney, one clip hypertensive rats treated with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) showed a significantly smaller fall in blood pressure after enalapril (204 +/- 7 to 179 +/- 9 mmHg) compared to the untreated rats (197 +/- 7 to 149 +/- 2 mmHg). 7. These results indicate that kinin potentiation plays an important role in the antihypertensive effect of acutely administered angiotensin converting enzyme inhibitor in the one-kidney, one clip model of hypertension.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Enalapril; Hypertension, Renal; Kinins; Male; Rats; Rats, Wistar; Time Factors

The goal of the present study was to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) and a long-acting calcium antagonist (Ro 40-5967) on cardiac remodeling secondary to renovascular hypertension. For this purpose, two kidney-one clip (2K-1C) hypertensive rats, 6 weeks after renal artery clipping, were either untreated or treated for 5 weeks with equihypotensive doses of enalapril (3 mg/kg/day) and Ro 40-5967 (30 mg/kg/day). At the end of the treatment period, cardiac weight, maximum coronary blood flow ([MCBF], measured in isolated perfused hearts), and interstitial and perivascular collagen volume fraction (measured by morphometry) were evaluated in all rats. Both drugs similarly decreased arterial blood pressure (ABP) for 24 h. Enalapril was more effective than Ro 40-5967 in inducing regression of cardiac hypertrophy. MCBF was decreased in untreated hypertensive rats and was increased to the same extent by both treatments, although not normalized. Interstitial cardiac collagen content after 11 weeks of hypertension was not increased in untreated hypertensive rats. In contrast, the collagen volume fraction measured in the perivascular area was increased in untreated hypertensive rats and this increase was not significantly suppressed by either enalapril or Ro 40-5967. These results show that cardiac hypertrophy, decrease in MCBF and increase in myocardial collagen content, do not evolve in parallel in 2K-1C hypertensive rats. Two antihypertensive treatments, enalapril and Ro 40-5967, increased MCBF to the same extent but had different effects on cardiac hypertrophy despite having equal antihypertensive efficacy.

Topics: Animals; Benzimidazoles; Calcium Channel Blockers; Coronary Circulation; Enalapril; Heart; Heart Rate; Hypertension, Renal; Male; Mibefradil; Organ Size; Rats; Rats, Wistar; Renin-Angiotensin System; Tetrahydronaphthalenes

Radiation of the kidney often leads to renal failure. The contribution of arterial hypertension to the development of this complication is unclear. The aim of this study was to determine the renal effects of antihypertensive therapy in 1- and 2-kidney rat models of radiation nephritis. Five groups of Long Evans rats had X-irradiation of the left kidney. In groups 1 and 2, the right kidney was left undisturbed (2-kidney model). The rats in group 3, 4 and 5 underwent right nephrectomy 21 days before radiation (1-kidney model). Groups 1 and 3 received no drug treatment and served as controls for each model. Groups 2 and 4 had enalapril 50 mg/l in drinking water and group 5 hydrochlorothiazide (HCT) 200 mg/l, also in drinking water. Blood pressure increased significantly in both control groups and remained normal throughout the study in all treated groups. At the end of the study, mean urinary protein excretion was lower in the two enalapril-treated groups but not in HCT-treated animals. Groups 1 and 2 (2-kidney models) showed similar increments in plasma creatinine (PCreat), and, in both groups, the creatinine clearance (CCreat) dropped to the same extent. Among nephrectomized animals (1-kidney model), PCreat was lower and CCreat higher in the enalapril-treated group. Consistent with these findings, glomerular sclerosis was less severe in both enalapril-treated groups. We conclude that, in radiation nephritis, lowering blood pressure with enalapril exerts a beneficial effect on renal function and structure, whereas a similar reduction in blood pressure induced by HCT does not.

Topics: Animals; Blood Pressure; Enalapril; Hydrochlorothiazide; Hypertension, Renal; Nephrectomy; Nephritis; Radiation Injuries, Experimental; Rats; Time Factors

The antihypertensive activity of quinapril was examined in normotensive and various hypertensive animal models. In 2-kidney, 1-clip renal hypertensive rats (2K-RHR), quinapril (0.1 to 1.0 mg/kg, p.o.) had a dose-related and sustained antihypertensive action, which was as potent as that of enalapril and approximately 40 times stronger than that of captopril. Heart rate was not changed by these doses of quinapril. In spontaneously hypertensive rats (SHR) and 1-kidney, 1-clip renal hypertensive rats, quinapril as well as enalapril dose-dependently produced a significant fall in blood pressure. The relative potency and duration of the effect of quinapril was the same as that of enalapril in these models. Quinapril at 30 mg/kg, p.o. lowered blood pressure and increased heart rate in normotensive rats. In contrast, quinapril and enalapril failed to reduce blood pressure in DOCA/salt hypertensive rats. In the repeated dose study, no development of tolerance was observed during the administration period in 2K RHR and SHR. The antihypertensive effects in 2K RHR was greater than those in SHR. Quinapril was more potent and long-lasting than enalapril in 2K RHR and SHR. From these results, quinapril is expected to be useful for the clinical treatment of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart Rate; Hypertension; Hypertension, Renal; Isoquinolines; Male; Quinapril; Rats; Rats, Inbred SHR; Rats, Wistar; Tetrahydroisoquinolines

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

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

Angiotensin converting enzyme inhibitors (ACEI) are believed to protect remnant kidney, but all previous studies used the ligation model which causes severe hypertension, and very few have compared drugs in rats having similar control of blood pressure (BP). We compared rats with uremia obtained by 70% excision of total renal mass, a model which causes mild, late hypertension. Study I compared the effects of enalapril (E), cicletanine (C) and placebo (P) in uremic (U) rats fed a 0.50% (normal-high) Na diet. Study II compared the effects of E, C, P, and guanfacine (G) in U rats fed a diet restricted to 0.25% Na (normal-low). In study I, UP rats developed progressive hypertension (140, 146, 160 and 166 mm Hg at 3, 6, 9 and 12 weeks), proteinuria (240 mg/day at 9 and 12 weeks) which were not affected by E or C. The occurrence of end-stage renal disease (ESRD) led to the sacrifice of all rats after three months. All three groups had similar severe renal lesions (over 25% sclerosed glomeruli in 5 of 10 UP, 9 of 14 UE, 7 of 14 UC rats, with huge cystic tubular dilatations). In study II, rats could be sacrificed later (6 months) and had evidence of less severe renal disease. All the drugs tested prevented hypertension throughout the study (P less than 0.001), with lowest values in UE rats. E and G, but not C, reduced proteinuria. Renal damage was reduced with E and G, but not with C, despite similar BP in C and G rats. Thus, in contrast with what was obtained in the ligation model, ACEI affected neither the BP nor the renal lesions of rats made uremic by renal excision and fed a 0.50% Na diet. Moderate Na restriction improved the consequences of nephron loss and restored the anti-hypertensive effect of drugs. However, these drugs had a different effect on renal preservation: it was dramatic with E, good with G, and undetectable with C.

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Diuretics; Enalapril; Hypertension, Renal; Kidney; Male; Nephrectomy; Pyridines; Rats; Rats, Wistar; Sodium, Dietary; Uremia

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Drug Synergism; Enalapril; Humans; Hypertension, Renal; Male; Nephrosclerosis

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

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

Topics: Diabetic Nephropathies; Enalapril; Humans; Hypertension, Renal; Metoprolol

The effect of beta-blocking agents and enalapril as antihypertensive drugs has been compared in 47 patients with IgA nephropathy. The deterioration rate was calculated from the regression line of 51Cr-EDTA clearance and expressed in ml/min/year. The annual loss in glomerular filtration rate (GFR) was greater in patients treated with different beta-blocking agents (-4.9 +/- 6.8 ml/min/year) compared to patients treated with Enalapril (1.7 +/- 7.4 ml/min/year), in spite of the fact that these patients had a lower initial GFR. Nine patients were initially treated with beta-blocking agents (-9.5 +/- 9.3 ml/min/year) and then with an angiotensin-converting enzyme inhibitor (5.5 +/- 11.2 ml/min/year). Angiotensin-converting enzyme inhibitors should therefore be preferred in the treatment of hypertension in IgA nephropathy.

Topics: Adrenergic beta-Antagonists; Adult; Enalapril; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Hypertension, Renal; Male; Middle Aged

The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Desoxycorticosterone; Dipeptides; Enalapril; Hemodynamics; Hypertension; Hypertension, Renal; Injections, Intravenous; Male; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred WKY

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

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

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

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

1. The population pharmacokinetics of lisinopril were investigated using data collected from two multicentre trials of lisinopril in the treatment of hypertension in elderly patients (n = 40) and patients with renal disease (n = 20). 2. Lisinopril was started at doses of 2.5-5 mg daily and increased at 2-4 weekly intervals as required for control of blood pressure. Steady-state concentration-time profiles were measured after at least 2 weeks at a constant dose. 3. All concentration-time data were analysed simultaneously using the program NONMEM and the influence of clinical factors on clearance/F and volume of distribution/F was tested. 4. Clearance was significantly influenced by creatinine concentration, age, weight and cardiac failure. No clinical features tested were found to influence volume of distribution. 5. The influence of renal function and cardiac failure on lisinopril clearance has been confirmed using a population pharmacokinetic analysis technique.

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Weight; Creatinine; Enalapril; Half-Life; Heart Failure; Humans; Hypertension; Hypertension, Renal; Lisinopril

Blood pressure responses to the angiotensin-converting enzyme (ACE) inhibitor enalapril were investigated in rats with salt-dependent hypertension. In both one- and two-kidney deoxycorticosterone (DOC)-NaCl hypertension, enalapril (50 mg/kg p.o.) caused a similar, slight blood pressure fall, which passed off with continuation of the treatment. Changes in the salt concentration of the drinking fluid (from 1% NaCl to 0.2% NaCl in the one-kidney rats and from 1% NaCl to 2% NaCl in those with intact kidneys) did not alter the depressor effect of enalapril. Plasma renin activity in all DOC-NaCl hypertensive groups was negligible. Our results indicate that in DOC-NaCl hypertensive rats, the presence of intact kidneys vs. one kidney has no influence on the blood pressure response to ACE inhibition. The blood pressure-lowering effect of enalapril may result from local converting enzyme inhibition in tissues.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Drinking; Enalapril; Hypertension, Renal; Male; Rats; Rats, Inbred Strains; Renin; Sodium Chloride; Time Factors

Atrial natriuretic peptide (ANP, 2 micrograms/min) was infused intravenously into rabbits four weeks after renal wrap or sham operation. Mean arterial pressure (MAP) averaged 132 +/- 4 mmHg in the renal wrapped rabbits and 89 +/- 3 mmHg in the sham rabbits, and glomerular filtration rate (GFR) was significantly lower in the hypertensive rabbits (6.2 +/- 1.0 ml/min) than in sham rabbits (8.9 +/- 0.7 ml/min). In sham rabbits, ANP caused a significant diuresis, natriuresis and increase in GFR. Enalapril pretreatment blunted these responses. In the hypertensive rabbits, ANP reduced mean arterial pressure but did not cause significant diuresis or natriuresis or change in GFR. Enalapril pretreatment did not significantly alter this response to ANP. In separate experiments, nitroprusside was infused to lower arterial pressure in hypertensive rabbits by a similar amount to that achieved with ANP and this reduced GFR, sodium and urine excretion rates. Thus ANP maintained GFR and sodium excretion in hypertensive rabbits compared to an equihypotensive dose of nitroprusside. In summary, ANP did not cause natriuresis or diuresis in renal wrapped kidneys at a dose which was effective in normal kidneys, but did maintain GFR, sodium and water excretion rates, compared to an equally hypotensive dose of nitroprusside.

Topics: Animals; Atrial Natriuretic Factor; Consciousness; Enalapril; Glomerular Filtration Rate; Hypertension, Renal; Kidney; Male; Nitroprusside; Rabbits; Renin

We have developed marmoset models for the in vivo evaluation of primate-specific inhibitors of human renin. After acute intravenous administration to normotensive sodium-depleted marmosets, renin inhibitors of different structural types induced a maximum hypotensive response of a magnitude similar to that induced after angiotensin converting enzyme (ACE) inhibition. The response was prevented by pretreatment with an ACE inhibitor. A close relationship between the inhibition of plasma renin activity (PRA) and the fall in blood pressure was observed with most of the inhibitors. CGP 29,287, a synthetic renin inhibitor, and R-3-36-16, a monoclonal antibody, both induced a selective increase in renal blood flow similar to that induced by an ACE inhibitor. A sustained reduction in blood pressure was observed during continuous administration of CGP 29,287 or R-3-36-16 over 14 days, despite an increase in immunoreactive renin and an apparent recovery of PRA. A similar blood pressure fall and an increase in plasma renin was observed during continuous administration of an ACE inhibitor. The renin inhibitor CGP 29,287 also lowered blood pressure after acute administration to hypertensive marmosets with normal PRA. Our studies demonstrate that renin inhibitors have similar haemodynamic effects to ACE inhibitors, and indicate that they may have a similar antihypertensive efficacy.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Callithrix; Disease Models, Animal; Enalapril; Female; Hypertension, Renal; Kidney; Male; Oligopeptides; Regional Blood Flow; Renin; Sodium

Renal effects of enalapril maleate in ten hypertensive patients with glomerulonephritis were evaluated after 1 and 16 weeks of therapy. Systemic blood pressure decreased, glomerular filtration rate was not significantly changed, and sodium fractional excretion and renal plasma flow increased, whereas renal vascular resistances and filtration fraction decreased acutely at the end of the study. Proteinuria diminished, but no variations in qualitative pattern were observed. ACE inhibitors, promoting efferent rather than afferent arteriolar vasodilatation and reduction of glomerular permeability coefficient, may reduce glomerular capillary hypertension and the development of proteinuria.

Topics: Blood Pressure; Enalapril; Glomerular Filtration Rate; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Hypertension, Renal; Kidney Function Tests; Renal Circulation; Sodium; Vascular Resistance

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

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

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

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

The aim of the study was to evaluate the long term antihypertensive effect of nicardipine in hypertensive patients with chronic renal disease. Eight patients (creatinine clearance ranging from 51 to 78 ml/min/1.73 m2) received nicardipine (20 mg t.i.d.). Four weeks later, patients with diastolic blood pressure greater than or equal to 90 mmHg in recumbent position, were given enalapril (10 mg/day) as well. Blood pressure control was achieved in 3 patients treated with nicardipine alone and in 5 patients on a combined nicardipine-enalapril regimen, and it was maintained throughout the whole trial period (52 weeks). In two cases serum creatinine rose from 2.3 to 3.3 and from 1.4 to 2.2 respectively. However, the slope of the creatinine ratio, plotted against time, showed a significant reduction in renal function loss as compared to expected values. In conclusion, nicardipine, alone or in combination with enalapril, is an effective and well tolerated drug for use in treatment of hypertension secondary to chronic renal disease.

Topics: Adult; Drug Evaluation; Drug Therapy, Combination; Enalapril; Female; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Hypertension, Renal; Male; Middle Aged; Nicardipine; Polyarteritis Nodosa

The antihypertensive activity of a new angiotensin converting enzyme (ACE) inhibitor, CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl] amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was examined in normotensive rats and various hypertensive animal models. In spontaneously hypertensive rats, CV-5975 (1 to 10 mg/kg, p.o.) had a dose-related, sustained antihypertensive action, which was more potent and longer than that of enalapril. The potency and duration of action of CV-5975 was intensified when it was administered repeatedly or combined with hydrochlorothiazide. CV-5975 (1 mg/kg, p.o.) inhibited the ACE activity of plasma and tissues; inhibition on the ACE activity of the aorta, kidney, and brain was marked when CV-5975 was administered repeatedly. In 2-kidney, 1 clip hypertensive rats (1 to 10 mg/kg, p.o.) and dogs (0.3 and 1 mg/kg, p.o.), CV-5975 had a marked, sustained antihypertensive action, which was more marked than that of enalapril. In normotensive rats (10 mg/kg), 1-kidney, 1 clip hypertensive rats (3 and 10 mg/kg), and hyporeninemic DOCA/salt hypertensive rats (1 to 10 mg/kg/day), CV-5975 administered orally once or repeatedly reduced blood pressure, whereas enalapril did not. These results indicate that CV-5975 is a potent and long-lasting antihypertensive agent, the action of which is mediated primarily by inhibiting ACE activity and partly by some unknown mechanisms.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dogs; Enalapril; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renin; Species Specificity; Thiazepines

The synthesis of a new class of potential angiotensin converting enzyme (ACE) inhibitors, analogs of enalapril, is reported. In these molecules the C-terminal amino acidic sequence Ala-Pro of enalapril was replaced by the sequence Pro-Pro. The compounds were tested both in vitro and in vivo. They showed no in vivo activity but only a week in vitro inhibitory activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Chemical Phenomena; Chemistry; Differential Thermal Analysis; Enalapril; Hypertension, Renal; In Vitro Techniques; Rats; Rats, Inbred Strains

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

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

The effect of strict blood pressure control on progression of renal disease in patients with essential hypertension has not been well defined. We have followed prospectively for three years 23 patients with essential hypertension. Blood pressure was well controlled on either enalapril or enalapril-hydrochlorothiazide therapy. Yearly assessment of renal function revealed no change in glomerular filtration rate as assessed by creatinine or inulin clearance, and a sustained 17% increase in effective renal plasma flow. In patients with moderately impaired renal function (inulin clearance less than or equal to 1.33 mL/s [80 mL/min]), there was a first-year 50% increase in inulin clearance, and a 33% increase in inulin clearance at year three. In these patients, there was a 39% first-year increase in effective renal plasma flow, which was sustained at year three. Filtration fraction and urinary protein excretion were unchanged. These results suggest that long-term blood pressure control with the angiotensin-converting enzyme inhibitor enalapril or enalapril-hydrochlorothiazide is associated with preservation and/or improvement in renal function.

Topics: Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Prospective Studies; Time Factors

Lisinopril is a new, long-acting, nonsulfhydryl angiotension-converting enzyme (ACE) inhibitor that is excreted unchanged by the kidney. The antihypertensive efficacy and safety profiles of lisinopril were assessed in 24 patients (15 men, 9 women; mean age 52.3 years; range 21-75 years) with hypertension associated with impaired renal function (glomerular filtration rate GFR 60 ml/min or less), in an open study of 12 weeks' duration. Previous antihypertensive drugs were discontinued at entry into the study. Lisinopril was given orally once daily; the starting dose was 2.5 mg in patients with a GFR of less than 30 ml/min, and 5 mg in all other patients. The dosage of lisinopril was titrated upward to 40 mg daily according to BP response. A diuretic could then be added if hypertension was inadequately controlled. Twenty-three patients completed the study. Mean sitting BP was reduced from 177 +/- 21.2/106 +/- 9.1 mm Hg (mean +/- SD) at entry to the study to 145 +/- 21.4/88 +/- 8.3 mm Hg after 12 weeks of treatment (p less than 0.001). The median dose of lisinopril used was 10 mg (range 2.5-40 mg) and only 4 patients had a diuretic added to the lisinopril. Overall GFR was unchanged during the study: mean baseline value was 37 +/- 16.4 ml/min (range 10-60 ml/min) at the beginning of the study and 40 +/- 21.0 ml/min at the end. As in a previous pharmacokinetic study in similar patients, a tendency toward drug accumulation was noted only in those patients with the most severe renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Drug Administration Schedule; Drug Evaluation; Enalapril; Female; Hemodynamics; Humans; Hypertension, Renal; Kidney Function Tests; Lisinopril; Male; Middle Aged

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

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

We report our experience with a converting-enzyme inhibitor, enalapril, as antihypertensive agent in eighteen patients with hypertension after renal transplantation. Renal function was prospectively followed up. Six patients demonstrated an acute renal failure episode (defined by a 25% increase of serum creatinine during enalapril therapy). Renal failure was always reversible with interruption or dosage reduction of the drug. We recommend to start therapy with low dose and to closely monitor renal function.

Topics: Adult; Combined Modality Therapy; Enalapril; Female; Humans; Hypertension, Renal; Kidney; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications

The acute and chronic antihypertensive and renal effects of the angiotensin converting enzyme inhibitor, enalapril, were studied prospectively in ten hypertensive renal transplant recipients. Acute administration of enalapril produced a significant decrement in both systolic and diastolic blood pressure but had no significant effect on glomerular filtration rate or effective renal plasma flow. The antihypertensive effect of enalapril was enhanced by gradually increasing the dose of the drug or by addition of a diuretic during six to eight weeks of chronic therapy. During chronic enalapril therapy, four patients developed renal insufficiency that reversed after discontinuation of the drug. In three of these four cases, overt renal insufficiency was associated temporally with the addition of a diuretic. Digital angiography revealed unequivocal transplant renal-artery stenosis in three of the four patients with renal insufficiency; the fourth patient had diffuse narrowing of the transplant renal artery without a discrete stenosis. It is concluded that enalapril alone or in combination with a diuretic is effective in lowering blood pressure in patients with post-transplant hypertension. The development of renal insufficiency during enalapril therapy may be exacerbated by concomitant diuretic therapy and should raise the suspicion of underlying transplant renal-artery stenosis. The acute blood pressure or renal response to a small dose of enalapril does not reliably predict the development of renal insufficiency during treatment with larger doses of the drug.

Topics: Enalapril; Humans; Hypertension, Renal; Kidney; Kidney Transplantation; Postoperative Complications

Micropuncture and morphological studies were performed in three protocols assessing the renal hemodynamic and structural effects of angiotensin I-converting enzyme inhibitors (CEIs) in the progression of glomerular injury. In protocol I, rats were subjected to 5/6 renal ablation and received no therapy, enalapril (CEI), or triple-drug therapy (TRX) for 12 weeks. Control of systemic and glomerular hypertension with CEI resulted in prevention of glomerular capillary hypertension and protection against glomerular injury. Despite equivalent control of systemic BP, failure of TRX to control glomerular hypertension was associated with no protection against eventual proteinuria and glomerular sclerosis, values for these indexes being as abnormal as in rats receiving no therapy. In protocol II, rats were again subjected to 5/6 renal ablation and followed for 18 weeks. Early institution of CEI soon after ablation again prevented systemic and glomerular hypertension and largely limited glomerular injury. In a third group, enalapril therapy was delayed for 8 weeks after ablation until hypertension and proteinuria were established. Late institution of CEI resulted in prompt reduction in systemic and glomerular capillary hypertension and stabilization of glomerular disease. In protocol III, CEI was administered to normotensive, moderately hyperglycemic diabetic rats. A modest, 20-mm Hg reduction in systemic arterial pressure was associated with the normalization of glomerular capillary pressure and a striking reduction in the development of albuminuria and glomerular injury. These studies suggest that CEI effectively prevent glomerular capillary hypertension and thereby afford protection against glomerular injury in diverse models of progressive renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Male; Rats; Renal Circulation; Renin-Angiotensin System

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

A patient with scleroderma renal crisis is described. At presentation he had severe hypertension, deteriorating renal function, microangiopathic haemolytic anaemia, and elevated levels of renin, aldosterone and noradrenaline. Enalapril controlled blood pressure, stabilized renal function, lowered aldosterone and noradrenaline levels, and improved peripheral circulation. It appears that converting-enzyme inhibitors can favourably alter the outlook of this otherwise fatal disorder.

Topics: Acute Kidney Injury; Enalapril; Humans; Hypertension, Renal; Male; Middle Aged; Scleroderma, Systemic

Thirteen patients were entered into a protocol to assess the safety and efficacy of enalapril (MK 421), 5 to 20 mg b.i.d., and hydrochlorothiazide, 50 to 100 mg daily, for the treatment of renovascular hypertension. Specifically monitored were the effects of therapy on blood pressure and pulse, renal function, and the renin-angiotensin-aldosterone axis. Enalapril and hydrochlorothiazide therapy produced excellent control of blood pressure with no adverse side effects. After approximately 8 weeks of therapy, renal vascular resistance was decreased and no adverse effects on glomerular filtration rate or renal blood flow were noted, except in one patient with a functional unilateral stenotic kidney. Patients receiving enalapril and hydrochlorothiazide showed stimulation of plasma renin activity and suppression of plasma angiotensin II, although the initial degree of suppression was not sustained in all patients during prolonged therapy. Although plasma aldosterone concentration was initially suppressed, the degree of suppression was not sustained. Nine patients have been followed for an additional 6 months; none have experienced further progression of renal disease, as assessed by repeated measurements of glomerular filtration and effective renal plasma flow. These results suggest that combined enalapril and hydrochlorothiazide therapy is safe and effective in the medical management of renovascular hypertension and that blood pressure control may be achieved in the absence of sustained interruption of the renin-angiotensin-aldosterone system.

Topics: Angiography; Blood Pressure; Creatinine; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hydrochlorothiazide; Hypertension, Renal; Inulin; Male; Middle Aged; p-Aminohippuric Acid; Posture; Renal Circulation; Renin; Renin-Angiotensin System

Topics: Enalapril; Humans; Hyperkalemia; Hypertension, Renal; Kidney Failure, Chronic

Two groups of adult male Munich-Wistar rats and a third group of nondiabetic age-matched and weight-matched normal control rats underwent micropuncture study 1 mo, and morphologic studies 14 mo, after induction of streptozotocin diabetes or sham treatment. All animals were fed standard rat chow. Diabetic rats received daily ultralente insulin to maintain stable moderate hyperglycemia (approximately 350 mg/dl). In addition, one group of diabetic rats was treated with the angiotensin I converting enzyme inhibitor, enalapril, 15 mg/liter of drinking water. Average kidney weight, whole kidney and single-nephron glomerular filtration rate, and glomerular plasma flow rate were elevated to similar values in both groups of diabetic rats, relative to normal control rats. Non-enalapril-treated diabetic rats exhibited significant elevations in mean glomerular capillary hydraulic pressure and transcapillary hydraulic pressure gradient, compared with the other groups studied, and only this group eventually developed marked and progressive albuminuria. Likewise, histological examination of the kidneys at 14 mo disclosed a high incidence of glomerular structural abnormalities only in non-enalapril-treated diabetic rats. These findings indicate that prevention of glomerular capillary hypertension in rats with diabetes mellitus effectively protects against the subsequent development of glomerular structural injury and proteinuria. This protection is afforded despite pronounced hyperglycemia and elevated levels of glucosylated hemoglobin, further supporting our view that hemodynamic rather than metabolic factors predominate in the pathogenesis of diabetic glomerulopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Glycated Hemoglobin; Hemodynamics; Hypertension, Renal; Kidney; Kidney Glomerulus; Male; Microcirculation; Rats; Regional Blood Flow; Time Factors

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

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

The possible role of the renin-angiotensin system in the maintenance of hypertension in two-kidney, one clip hypertensive rats was studied. Plasma renin activity rose rapidly and markedly in association with the elevation of blood pressure and then decreased gradually, although blood pressure remained high. Renin activity in the lung, aorta, and mesenteric artery also increased with the development of hypertension and then decreased in a way similar to that of plasma renin activity at the chronic stage of hypertension. Plasma angiotensin converting enzyme activity did not change significantly until 16 weeks after unilateral renal artery clipping, whereas vascular angiotensin converting enzyme activity significantly increased at the chronic, but not the acute, stage of hypertension. In chronically renal hypertensive rats, 1-sarcosine, 8-isoleucine angiotensin II or enalapril, an angiotensin converting enzyme inhibitor, lowered the blood pressure and enalapril also lowered the angiotensin converting enzyme activity of vascular tissues. The constrictor effect of angiotensin I was greater in isolated arteries from chronically hypertensive rats than in those from age-matched normotensive rats. These results suggest that the vascular renin-angiotensin system plays an important role in the maintenance of two-kidney, one clip hypertension. Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle.

Topics: Angiotensin II; Angiotensins; Animals; Aorta; Arteries; Enalapril; Hypertension, Renal; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Vasoconstriction

Topics: Captopril; Cough; Enalapril; Female; Humans; Hypertension, Renal; Middle Aged

Topics: Adult; Enalapril; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

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

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

Topics: Adolescent; Captopril; Cardiovascular Diseases; Child; Child, Preschool; Enalapril; Endocrine System Diseases; Humans; Hypertension, Renal; Infant; Infant, Newborn; Renin-Angiotensin System

Streptozotocin-diabetic rats kept moderately hyperglycaemic by daily injections of ultralente insulin for 4-6 weeks (group DM) demonstrated a higher glomerular transcapillary hydraulic pressure gradient (delta P), glomerular plasma flow rate and single-nephron glomerular filtration rate (GFR) than was observed in age- and weight-matched non-diabetic controls (group C). This rise in delta P was prevented by therapy with the angiotensin I converting enzyme inhibitor enalapril (15 mg/l drinking water, group DM + E) even though glomerular hyperperfusion and hyperfiltration persisted. Fourteen months after induction of diabetes, animals in group DM displayed high levels of albuminuria and an increased incidence of focal glomerular sclerosis; treatment with enalapril maintained these parameters at levels which did not differ from those observed in group C. We conclude that prevention of glomerular capillary hypertension with enalapril therapy obviates functional and structural glomerular injury in experimental diabetes mellitus.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Enalapril; Hypertension, Renal; Male; Rats

A series of non-sulfhydryl modified dipeptides related to CI-906, CI-907, and enalapril was prepared in which various isosteric moieties (O, S, SO, SO2) have been substituted for the amino group and in which the proline residue has been replaced with various hydrophobic amino acids. The compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme and in vivo for antihypertensive activity. Compound 7c, the most potent member of this series, had an in vitro IC50 of 1.4 X 10(-8) M and showed modest oral antihypertensive activity at 30 mg/kg in conscious, two kidney, one clip Goldblatt hypertensive rats. Structure-activity relationships are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chemical Phenomena; Chemistry; Dipeptides; Enalapril; Guinea Pigs; Hypertension, Renal; Indoles; Isoquinolines; Quinapril; Rats; Structure-Activity Relationship; Tetrahydroisoquinolines

This pilot study was undertaken to examine the safety and efficacy of enalapril in the treatment of hypertension associated with impaired renal function. Forty-one patients with glomerular filtration rate (GFR) < or = 50 ml/min received enalapril for up 12 weeks. Blood pressure, renal function, biochemistry and haematology were monitored weekly for 4 weeks and then monthly. Blood pressure was effectively reduced within 4 weeks; this reduction was maintained for at least 12 weeks. Renal function remained stable and there was no significant sustained alteration in any biochemical or haematological parameter. Requirement for additional antihypertensive drugs was reduced during enalapril therapy. These data suggest that enalapril may have a useful role in the management of hypertension associated with renal impairment.

Topics: Adult; Aged; Aged, 80 and over; Enalapril; Female; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Pilot Projects

Thirty-four ACE inhibitors were evaluated to determine the concentration giving 50% inhibition of purified rabbit lung ACE (IC50 microM) using benzyloxycarboxyl-p-NO2-Phe-His-Leu as substrate, to determine the oral dose causing a lowering in blood pressure of 30 mm Hg (ED30 mumol/kg) in acute aortic coarctate (AAC) rats, and to determine inhibition of plasma ACE (PACE) activity in mice after oral dosing. Mouse PACE activity was determined with 14C-Hip-His-Leu as substrate one hour after oral dosing of 3 animals/group with 5 or 50 mumol ACE inhibitor per kg. Data from mice were expressed as percent of control group PACE activity. Least squares regression analysis showed the IC50 data to be poorly correlated with either rat data or mouse PACE data at 50 mumol/kg p.o. However, correlation was significant between log rat ED30 and mouse PACE at 5 (p less than 0.001, r = 0.570) and 50 (p less than 0.025, r = 0.387) mumol/kg p.o. Thus, the simple mouse plasma ACE determination after a dose of 5 mumol/kg is a convenient supplement to the AAC rat model for showing oral activity of ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Captopril; Dipeptides; Enalapril; Hypertension, Renal; Lung; Male; Mice; Peptidyl-Dipeptidase A; Rabbits; Rats

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

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

In the single dose study, the aortic blood pressure in conscious normotensive rats, 2-kidney, 1-clip renal hypertensive rats (2K-RHR), 1-kidney, 1-clip renal hypertensive rats (1K-RHR) or DOCA hypertensive rats was measured for 24 hr after the oral administration of angiotensin converting enzyme (ACE) inhibitors such as MK-421 or captopril. MK-421 at 3 mg/kg and captopril at 10 mg/kg markedly lowered the blood pressure of 2K-RHR. MK-421 at 10 mg/kg and captopril at 30 mg/kg only modestly lowered the blood pressure of 1K-RHR. In contrast, both ACE inhibitors failed to reduce blood pressure in DOCA and normotensive rats. In the repeated dose study, the systolic blood pressures in normotensive rats, 2K-RHR or spontaneously hypertensive rats (SHR) were measured twice a week for 3 weeks treatment of either MK-421 at 3 mg/kg or captopril at 10 mg/kg. Both ACE inhibitors produced significant antihypertensive effects in these model rats, and the effects were sustained throughout the treatment period. The antihypertensive effects in 2K-RHR were greater than those in SHR and normotensive rats. These results indicate that MK-421 and captopril cause the most significant antihypertensive effect in 2K-RHR in which the renin-angiotensin system played a dominant role in blood pressure regulation. The antihypertensive effect of MK-421 was approximately 3 times as potent as that of captopril in these hypertensive models.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Captopril; Desoxycorticosterone; Enalapril; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains

The angiotensin converting enzyme (ACE) activity in tissues and plasma renin activity (PRA) were measured in 2-kidney, 1-clip renal hypertensive rats (2K-RHR) and normotensive rats after a single and 3-weeks oral administrations of ACE inhibitors such as MK-421 and captopril. In the single dose study, MK-421 (1 and 3 mg/kg) and captopril (3 and 10 mg/kg) inhibited the ACE activities in kidney, aorta and plasma in a dose-dependent fashion. The inhibition of ACE activity in kidney or aorta was observed for a longer time than that in plasma. PRA took a time course reversal to that of plasma ACE activity. In the 3-weeks repeated dose study, the ACE activity in kidney and aorta was strongly inhibited after the administration of each ACE inhibitor, while there was no significant change in lung ACE activity at any time point examined. The plasma ACE activity markedly elevated after the administration of each agent. PRA significantly increased after the administration of either agent, while the plasma angiotensin II level was significantly inhibited. These results indicate that the inhibition of the ACE activity in blood vessel or kidney correlate well with the antihypertensive activity in 2K-RHR after a single and repeated administration of both ACE inhibitors, but not well with the inhibition of plasma ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Captopril; Enalapril; Hypertension, Renal; Kidney; Lung; Male; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dipeptides; Drug Interactions; Enalapril; Humans; Hypertension; Hypertension, Renal

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Dipeptides; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Enalapril; Female; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Indoles; Isoquinolines; Kinetics; Male; Quinapril; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Tetrahydroisoquinolines

Topics: 3-Mercaptopropionic Acid; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Dipeptides; Drug Evaluation, Preclinical; Enalapril; Female; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred Strains; Thiazolidines

The responses to 48 h of renal artery stenosis were compared in uninephrectomized, chronically-instrumented dogs with or without inhibition of angiotensin II (AII) formation by enalapril. Mean arterial pressure rose by an average of 29.9 mmHg (s.e.m. 3.5) in untreated dogs and by 14.5 mmHg (s.e.m. 2.8) in enalapril-treated dogs over the two days of stenosis. Renal artery stenosis reduced glomerular filtration rate (GFR) by 49% (s.e.m. 9) in untreated dogs and by 86% (s.e.m. 8) in enalapril-treated dogs. Compared to untreated dogs, enalapril-treated dogs also had lower renal artery pressure distal to the stenosis, drank less water and had larger rises in plasma K+ following renal artery stenosis. There were no differences in renal blood flow or urinary Na+ excretion in the two groups of dogs. Thus blockade of AII production did not prevent hypertension occurring in response to renal artery stenosis, but the rise in blood pressure was only about half that which occurred in normal dogs and GFR was much more severely reduced.

Topics: Angiotensin II; Animals; Blood Pressure; Body Water; Dipeptides; Dogs; Enalapril; Glomerular Filtration Rate; Heart Rate; Hypertension, Renal; Male; Renal Artery Obstruction; Renin; Sodium; Time Factors

The mechanism of action of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure remains unclear, but the weight of available data favour peripheral blockade of the formation of angiotensin II (AII). Previous work in rats has shown that the prodrug ACE inhibitor, enalapril (MK-421), lowered blood pressure most effectively when PRA was elevated [sodium deficiency, two-kidney, one figure 8 hypertension, diuretic-treated spontaneously hypertensive rats (SHR)]. In sodium-deficient rats, the enalapril-sensitive component of the blood pressure was greatly reduced after salt loading, and nephrectomy blocked the antihypertensive response to enalapril in SHR. In the present study, further support that the mechanism of action of enalapril involves a reduction in AII has been obtained from rats made hypertensive by continuous intravenous (i.v.) AII infusion for 10 days. Enalapril administered for seven days did not significantly lower blood pressure, suggesting that there were no important non-angiotensin mechanisms (such as bradykinin potentiation) involved in its action. From earlier studies in SHR, the time course for blockade of angiotensin I (AI) pressor responses and the blood pressure reduction did not correspond, suggesting a tissue site of action. In the present studies in adult SHR, a central site of action was ruled out since the parent inhibitor, enalaprilic acid (MK-422), injected into the brain ventricles did not acutely reduce blood pressure. An interaction of enalaprilic acid with the sympathetic nervous system was evaluated in dogs in which adrenergic activity was enhanced as a result of diuretic-induced renin release. Enlaprilic acid did not alter the enhanced hindquarter vasoconstrictor responses to sympathetic nerve stimulation. Enalapril increased renal blood flow, glomerular filtration rate and sodium excretion. The mechanism of the natriuresis in dogs probably involves several mechanisms including a decrease in aldosterone biosynthesis, changes in renal function (glomerular filtration rate and renal blood flow) and possibly blockade of a direct tubular effect of AII on sodium reabsorption. Enalaprlic acid was also studied in a closed chest dog model of acute left ventricular (LV) failure caused by embolization via the left main coronary artery with 50 microns plastic microspheres. Enalaprilic acid at 100 micrograms/kg i.v. reduced preload, afterload and improved LV performance without changing the heart rate. In conclusion, en

Topics: Adrenalectomy; Angiotensin II; Animals; Blood Pressure; Captopril; Dogs; Enalapril; Female; Heart Failure; Heart Ventricles; Hindlimb; Hypertension; Hypertension, Renal; Kidney; Male; Muscles; Rats; Rats, Inbred SHR; Renin; Sodium; Vasoconstriction

1 The effect of the angiotensin converting enzyme inhibitor, MK 421 (N-((S)-1-(ethoxycarbonyl)-3-phenylpropyl)L-Ala-L-Pro), on the blood pressure of two-kidney Goldblatt hypertensive rats has been investigated in relation to he initial plasma renin activity (PRA) and the initial blood pressure of the individual animals. 2 Blood pressure was monitored by an indirect tail-cuff method at 1, 3, 6 and 24 h after dosing. MK 421 produced a fall in blood pressure in the majority of animals, but the extent of this reduction varied considerably between individuals. 3 The change in blood pressure showed a significant correlation with both the initial PRA and the initial blood pressures of the animals. However, only a modest correlation was found between the initial PRA and the degree of hypertension. 4 MK 421 (10 mg/kg, orally) produced a mean blood pressure change which was statistically significant (P less than 0.001) at all times tested. 5 It is concluded that the degree of antihypertensive activity of MK 421 is related to the degree of activity of the renin-angiotensin system which, in this model at least, is reflected by the PRA.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Dipeptides; Enalapril; Hypertension; Hypertension, Renal; Male; Rats; Renin; Renin-Angiotensin System

Enalapril maleate (MK421), a new inhibitor of angiotensin converting enzyme, in single daily doses of 1.25-40 mg was assessed in five patients with hypertension and renal artery stenosis. Only small falls in plasma angiotensin II concentrations were seen at doses less than 10 mg; even with 10 and 20 mg, angiotensin II concentrations had risen again 24 hours from the last dose. During long-term treatment with 10-40 mg daily all patients achieved good blood-pressure control. No significant changes of body sodium or potassium values were seen. The drug was well tolerated with no serious side effects. These findings are evidence of the efficacy and acceptability of enalapril in the medical management of hypertension with renal artery stenosis.

Topics: Adult; Angiotensin II; Antihypertensive Agents; Dipeptides; Enalapril; Enzyme Inhibitors; Female; Humans; Hypertension, Renal; Hypertension, Renovascular; Male; Middle Aged; Renal Artery Obstruction; Renin-Angiotensin System

The exact mechanism of action of angiotensin converting enzyme (ACE) inhibitors in reducing blood pressure is not known, although inhibition of angiotensin II formation is the generally accepted mechanism. Experiments were performed in two models of experimental hypertension to determine whether or not inhibition of the pressor response to angiotensin I, 300 ng/kg i.v., would correlate with the antihypertensive response to single oral doses of N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-Ala-L-Pro (MK-421), a new ACE inhibitor. Captopril, given as a single oral dose, was studied in spontaneously hypertensive rats (SHR) for comparative purposes. In SHR, MK-421 at 0.1-3 mg/kg p.o. and captopril at 0.1-3 mg/kg p.o. were approximately equipotent with regard to inhibiting the pressor response to angiotensin I (relative potency=1.7; 95% C.I.=0.7-4.5). The magnitude of ACE inhibition and onset of action were similar with both agents, but MK-421 had a longer duration of action. The decrement in systolic pressure following each ACE inhibitor consisted of an initial decrease in blood pressure corresponding to the maximal inhibition of angiotensin I pressor response and a secondary fall in blood pressure which was evident 5-6 h after treatment. At this time, the inhibition of the pressor response to angiotensin I was minimal. Thus, the time course for blockade of angiotensin I and the blood pressure reduction did not correspond. The dose-response regression lines for the antihypertensive effect of each inhibitor, unlike those for ACE inhibition, were flat. The potency ratio computed on the basis of the maximum fall in blood pressure over 6 h revealed that MK-421 was 11.5 times (P less than 0.05) more potent thant captopril. In 2-kidney Grollman renal hypertensive rats (RHR), MK-421 at 0.3-10 mg/kg p.o. inhibited the pressor response to angiotensin I by 65-95%, but produced significant decrements in blood pressure only at 10 mg/kg p.o. The finding that MK-421 was more potent than captopril in lowering blood pressure in SHR, yet equally active in its ability to block angiotensin I pressor responses, suggests that a mechanism(s) other than inhibition of plasma ACE is involved in the decrease in blood pressure was not reduced. However, a higher dose which produced a similar degree of blockade was associated with a significant decrease in blood pressure.

Topics: Angiotensin I; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Dipeptides; Enalapril; Hypertension; Hypertension, Renal; Oligopeptides; Proline; Rats; Rats, Inbred Strains; Teprotide

Topics: Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dipeptides; Disease Models, Animal; Dogs; Drug Therapy, Combination; Enalapril; Female; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Male; Nephrectomy; Rats; Renin