enalapril and Body-Weight

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectively in 110 hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24-h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose-dependent manner. During a 2-week, double-blind, randomized, dose-response period, patients were stratified by weight (< 50 kg or > or = 50 kg), then assigned to one of three dosing groups: low(0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight-adjusted basis. On completion of the dose-response phase of the study, patients entered a 2-week, double-blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose-response relationship for enalapril had a negative slope and was linear over the chosen dosing range, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug orplacebo confirmed the antihypertensive effectiveness of enalapril in the middle- and high-dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well-tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing > 50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose-dependent fashion, with larger doses resulting in a greater reduction.

Topics: Adolescent; Antihypertensive Agents; Blood Pressure; Body Weight; Child; Dose-Response Relationship, Drug; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male

Arthritis and hypertension are frequent comorbidities in the elderly hypertensive population. Nonsteroidal anti-inflammatory drugs are often used to relieve pain in arthritic patients but a side effect is sodium retention and consequent elevation of blood pressure (BP). The effect of dihydropyridine calcium blocking drugs is relatively independent of sodium intake, whereas the angiotensin-converting enzyme (ACE) inhibitors' effects can be blunted by a high-sodium diet. This study compared the effects of indomethacin with placebo in elderly patients with essential hypertension who had been controlled with amlodipine or enalapril. Indomethacin 50 mg twice daily or placebo was administered for 3 weeks in a double-blind crossover study to patients controlled with amlodipine or enalapril. The response was assessed by ambulatory BP measurement. Indomethacin raised BP and lowered pulse rates in patients taking enalapril but had little effect in patients receiving amlodipine. The difference caused by indomethacin between the two groups was 10.1/4.9 mm Hg increase in BP and a 5.6 beats/min fall in pulse in people taking enalapril. Addition of indomethacin to patients taking either drug caused a rise in weight and a fall in plasma renin. It is postulated that the effect is due to inhibition of prostaglandin synthesis, which causes sodium retention. In patients taking amlodipine, the fall in plasma renin ameliorates the effect of sodium retention on BP. In patients taking enalapril, plasma renin falls but this is not translated into an effect because of the blockage of converting enzyme. Thus, the full effect of sodium retention on BP is expressed. In patients treated with indomethacin, fewer patients may respond to ACE inhibitors. However, the major problem is the patient who intermittently takes indomethacin or other nonsteroidal anti-inflammatory drugs, which, if a person is treated by an ACE inhibitor causes BP to go out of control. In such patients amlodipine would appear to be a preferred choice to enalapril.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Amlodipine; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Double-Blind Method; Drug Interactions; Dyspepsia; Enalapril; Female; Humans; Hypertension; Indomethacin; Male; Middle Aged; Nausea; Pain; Renin

Enalapril treatment (20 mg every 12 hours) of 24 patients with essential hypertension and left ventricular (LV) hypertrophy established normal blood pressures after 8 weeks, and after 5 years, it had reduced LV mass index by 39% (from 148+/-34 to 90+/-16 g/m(2)) and had normalized LV structure and function and QT dispersion. Stepwise reduction of the enalapril dosage from 40 to 30, 20, 10, and 5 mg/d during the eighth year caused no significant change in blood pressure, LV structure, LV systolic function, or QT dispersion, which all likewise remained unaltered during an additional 2-year period of the 5-mg/d regimen. We conclude that for hypertensive patients in whom prolonged treatment with high doses of enalapril has normalized blood pressure, LV structure, LV function, and QT dispersion, the dose may be reduced as much as 8-fold without detriment to cardiovascular control. The use of smaller doses is evidently advantageous from the point of view of health costs.

Topics: Adult; Antihypertensive Agents; Body Weight; Circadian Rhythm; Drug Administration Schedule; Enalapril; Exercise Test; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Male; Middle Aged; Potassium; Stroke Volume; Treatment Outcome; Ventricular Function, Left

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

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

A double-blind, randomized, parallel-group study was performed to compare the efficacy and tolerability of captopril-thiazide and enalapril-thiazide combinations. After a 3-week placebo run-in period, 47 Black patients with mild to moderate essential hypertension (mean 24-hour diastolic blood pressure (BP) > 90 mmHg and < 115 mmHg) were randomized to receive 1 of 2 combination tablets: captopril 50 mg plus hydrochlorothiazide 25 mg (CAP, n = 24) or enalapril 20 mg plus hydrochlorothiazide 12.5 mg (COR, n = 23) once daily. After 12 weeks of active treatment the mean 24-hour ambulatory BP was reduced from 152 +/- 11/99 +/- 6 to 133 +/- 13/86 +/- 7 mmHg (p < 0.005) in the CAP group and 157 +/- 15/100 +/- 6 to 141 +/- 18/90 +/- 12 in the COR group (p < 0.005). Target BP (24-hour diastolic BP < 90 mmHg) was achieved in 75% (18/24) of patients on CAP and 48% (11/23) on COR (p = n.s.). 24-hour BP load fell significantly with both CAP (from 69% to 34%, p < 0.001) and COR (from 67% to 37%, p < 0.001). Left ventricular mass index decreased by 7% with CAP and 11% with COR. Cardiac index and fractional shortening remained essentially unchanged in both groups. Both treatments were well tolerated and overall incidence of side effects was very low. It is concluded that both CAP and COR are effective, safe first-line antihypertensive choices in Black patients with mild to moderate hypertension with the former showing a trend towards greater efficacy than the latter.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzothiadiazines; Black People; Blood Pressure; Body Weight; Captopril; Diuretics; Double-Blind Method; Drug Combinations; Echocardiography; Echocardiography, Doppler; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Sodium Chloride Symporter Inhibitors; Time Factors; Ventricular Function, Left

The above study was performed as a single blind trial in 70 elderly patients (average age 66 years) who were randomized into two groups of 36 and 34 subjects respectively. After clinical and laboratory evaluation without treatment for at least two weeks, the two groups were treated with enalapril 5-10 or 20 mg daily plus doxazosin at the dosage of 1-2-4- or 8 mg daily; they were observed for 24 weeks. During the trial, pressure values, both systolic and diastolic, were seen to diminish significantly in both groups. This effect was accompanied by minor, usually transient side effects. At echocardiography at the end of the treatment period, doxazosin was found to reduce some volumetric cardiac parameters, thus showing to be apt to counteract left ventricular hypertrophy. These findings go to counteract left ventricular hypertrophy. These findings go to show that alpha-1 inhibitors are a valid alternative in the "first step" of antihypertensive therapy, especially in patients at risk for cardiovascular complications.

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Body Weight; Dose-Response Relationship, Drug; Doxazosin; Echocardiography; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Sex Factors

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

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

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

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

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

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

The antihypertensive effect and tolerance of the combined low doses of felodipine and enalapril (5 + 5 mg daily) were compared with those of either drug at a higher dose level (10 mg daily). Our double-blind, three-way crossover study (balanced Latin square design) involved 36 elderly subjects (mean age 67 +/- 6 years) with essential hypertension. After a 4-week placebo run-in phase the subjects were randomized to the active treatment periods, starting with 5 mg felodipine plus 5 mg enalapril, 5 mg felodipine, or 5 mg enalapril daily for the first 4 weeks. The doses in the felodipine and enalapril periods were then doubled for another 2 weeks. All medication was given once daily in the morning, and blood pressure was measured 24 h after a previous dose. The supine blood pressure for subjects given placebo was 178/101 mm Hg. After 6 weeks' treatment systolic and diastolic supine blood pressures were significantly lower with 5 mg felodipine plus 5 mg enalapril (154/85 mg Hg) than with 10 mg felodipine (159/88 mm Hg) or with 10 mg enalapril (162/91 mm Hg), and the diastolic blood pressure was significantly lower with felodipine than with enalapril. At the end of the felodipine plus enalapril, felodipine, and enalapril treatment periods, 75, 69, and 56% of the subjects, respectively, had a supine diastolic blood pressure 90 mm Hg or less. The combination was tolerated better than either monotherapy. The most commonly reported adverse event was swollen ankles, which occurred in one, nine, and five subjects during felodipine plus enalapril, felodipine, and enalapril treatment, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aging; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Enalapril; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Pulse

In order to study the influence of angiotensin converting enzyme (ACE) inhibition on the progression of chronic nephropathy, 70 patients with a median glomerular filtration rate (GFR) of 15 (range, 6 to 54) mL/min/1.73 m2 were randomized in an open study to basic treatment with enalapril or conventional antihypertensive treatment. The patients were followed for at least 2 years or until they needed dialysis. The groups were comparable with respect to age and sex distribution, etiology of renal diseases, initial levels of renal function and arterial blood pressure (BP), and protein intake. The therapeutic goal was a BP of 120 to 140/80 to 90 mm Hg. The GFR, estimated by the plasma clearance of 51Cr-EDTA, was measured every third month, and the individual rate of progression was calculated as the slope of the GFR v time plot. In the enalapril group, the median decline in GFR was -0.20 (range, +0.18 to -7.11) mL/min/1.73 m2/month and in the control group it was -0.31 (+0.01 to -1.97) mL/min/1.73 m2/month (P less than .05). There was no significant difference in blood pressure or plasma lipid levels between the groups. Thus, the progression of moderate to severe chronic nephropathy was slower on a basic treatment with enalapril as compared to conventional antihypertensive therapy.

Topics: Adolescent; Adult; Aged; Albuminuria; Antihypertensive Agents; Bicarbonates; Blood Pressure; Body Weight; Enalapril; Hemoglobins; Humans; Kidney Failure, Chronic; Middle Aged; Potassium; Urea

To elucidate the effect of natriuretic and antinatriuretic factors on the excretion of an intravenous sodium load, we observed the natriuretic responses of 12 patients with essential hypertension (EHT) and 7 age- and sex-matched normotensive (NT) subjects following the intravenous administration of 1500 mL of normal saline over a 3 h period. After saline infusion, both groups showed increases in urinary sodium excretion (UNaV). The increases in glomerular filtration rate (GFR), atrial natriuretic peptide (ANP) and urinary dopamine excretion (UDAV) and the suppression of plasma renin activity (PRA) were similar in both groups. However, no significant change in blood pressure (BP) was seen in either group. Since significant negative linear correlations between the basal level of PRA and percent change in UNaV or GFR were seen only in EHT, we observed the influence of suppressing the renin-angiotensin system with a converting enzyme inhibitor. After a 7 day treatment with enalapril, GFR and UNaV in EHT after saline infusion were comparable to data obtained in the absence of enalapril, despite a reduction in preexpansion BP. Furthermore, a significant positive correlation between the basal BP and the percent increase in UNaV was seen among EHT after enalapril treatment. These results suggest that the state of the renin-angiotensin system is important in renal sodium excretion in EHT.

Topics: Adult; Aging; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatine; Dopamine; Enalapril; Female; Glomerular Filtration Rate; Hematocrit; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Natriuresis; Norepinephrine; Prostaglandins; Regional Blood Flow; Renin; Renin-Angiotensin System; Sodium Chloride; Water-Electrolyte Balance

Twenty-four patients (one female, 23 male) with mild to moderate heart failure were randomly and double-blindly assigned to an oral treatment with 5 mg enalapril twice daily or 5 mg pimobendan (UDCG 115) twice daily. After the first tablet intake, blood pressure and heart rate were measured for 6 h. Therapy continued over 6 months. Systolic arterial blood pressure dropped from 126 +/- 20 mmHg to 111 +/- 14 mmHg (P less than 0.05) after the first enalapril tablet and from 123 +/- 16 mmHg to 112 +/- 13 mmHg (P less than 0.05) after the first pimobendan tablet. After 6 months, no important changes in blood pressure were observed in the pimobendan group and only a minor decrease in the enalapril group. There was no significant change in heart rate either after the first dose or after long-term therapy with either medication. After 6 months, cardiac index increased from 2.73 +/- 0.75 l.min-1.m-2 to 3.38 +/- 0.69 l.min-1.m-2 (P less than 0.01) after pimobendam, but did not change after enalapril (2.95 +/- 0.75 l.min-1.m-2 to 2.96 +/- 0.89 l.min-1.m-2, NS). Pulmonary capillary wedge pressure decreased during pimobendan long-term therapy from 16 +/- 8 mmHg to 14 +/- 8 mmHg (NS) and during enalapril from 21 +/- 7 to 14 +/- 7 mmHg (P less than 0.01). Exercise capacity increased in the pimobendan group from 17.2 +/- 5.4 kJ to 23.0 +/- 9.6 kJ (P less than 0.05), and in the enalapril group from 20.4 +/- 11.9 kJ to 24.8 +/- 18.5 kJ (NS) during long-term therapy over 6 months. Plasma renin activity increased from 0.96 to 3.6 ng.ml-1.h-1 (P less than 0.05) during enalapril long-term therapy, but remained unchanged (1.38 vs. 1.32 ng.ml-1.h-1, NS) during pimobendan. The new inotrope, pimobendan, exerted favourable long-term effects without haemodynamic or humoral signs of tolerance development.

Topics: Aged; Body Weight; Creatinine; Double-Blind Method; Enalapril; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Potassium; Pyridazines; Renin

During the course of a long-term, prospective, randomized study in 77 hypertensive nephrosclerosis patients, five patients developed evidence suggestive of renal artery stenosis. However, arteriography demonstrated patent renal arteries. The evidence suggestive of renal artery stenosis was: (1) converting-enzyme inhibitor (CEI)-induced renal dysfunction including marked and reversible increases in serum creatinine and urea concentrations, (2) minoxidil-induced hyperreninemia despite beta-adrenoceptor blockade and volume expansion, and (3) minoxidil-induced salt and water retention with diuretic resistant edema. Thus, the renal dysfunction induced by CEI in these patients with patent renal arteries is similar to the alterations occurring in patients having bilateral renal artery stenosis. The diuretic resistant edema and the beta-adrenoceptor blocker resistant high renin release are also functional alterations of renal artery stenosis. We suspect that the long-standing and usually severe hypertension in these patients has caused sufficient arteriolar hypertrophy or sclerosis to interfere with renal blood flow and to induce these functional lesions of renal artery stenosis. With widespread use of the new CEI agents in patients with renal disease, this syndrome suggestive of renal artery stenosis may be encountered in as many as 10% of hypertensive nephrosclerosis patients during long-term treatment with converting-enzyme inhibitors.

Topics: Angiography; Blood Pressure; Body Weight; Creatinine; Double-Blind Method; Enalapril; Humans; Hydralazine; Hypertension; Minoxidil; Nephrosclerosis; Prospective Studies; Random Allocation; Renal Artery; Renal Artery Obstruction; Renin; Syndrome

About one third of patients receiving dialysis for end stage renal failure have chronic fluid overload despite advice to restrict their oral fluid intake. To investigate the potential of an angiotensin converting enzyme inhibitor in reducing the urge to drink and consequent gain in weight, a double blind, placebo controlled crossover trial of enalapril was conducted in 25 patients receiving dialysis who had fluid overload. The trial comprised a baseline period of four weeks; two periods of treatment, each of four weeks, during which patients received either placebo or enalapril 5 mg twice each week; and a follow up period of four weeks. Five patients withdrew from the trial, one because of an adverse drug reaction to enalapril. A range of biochemical and behavioural variables was measured during the baseline period, at the completion of periods 1 and 2, and during follow up. These variables included gain in weight between dialysis sessions; blood pressure; plasma concentrations of sodium, angiotensin II, and vasopressin; plasma renin and angiotensin converting enzyme activities; osmolality; and estimations of thirst, intake of fluid, and control of drinking. Enalapril caused a significant reduction in gain in weight between dialysis sessions, thirst, and oral intake of fluid in parallel with significantly increased renin activity, significantly decreased angiotensin converting enzyme activity, and decreased concentrations of angiotensin II. Gain in weight and angiotensin converting enzyme activity returned to baseline values once patients stopped taking enalapril. These results suggest that enalapril may act on the renin-angiotensin system and reduce intake of fluid by inhibiting angiotensin converting enzyme.

Topics: Blood Pressure; Body Weight; Clinical Trials as Topic; Double-Blind Method; Drinking Behavior; Enalapril; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Random Allocation; Renal Dialysis; Thirst

Angiotensin-converting enzyme inhibitors are effective vasodilators in the treatment of congestive heart failure. Enalapril, a new angiotensin-converting enzyme inhibitor, or placebo, in addition to digoxin and diuretic drugs, were given to 17 patients with chronic congestive heart failure who were followed up for 12 weeks. In random double-blind fashion, nine patients received enalapril and eight received placebo. Cardiac dimensions and function improved slightly but insignificantly in both groups. Treadmill exercise duration increased from a mean value (+/- standard deviation) of 9.1 +/- 3.2 to 12.0 +/- 3.5 minutes during enalapril administration (p less than 0.025) and was unchanged during placebo administration (10.1 +/- 3.7 versus 11.1 +/- 5.2 minutes). Maximal oxygen consumption also increased during enalapril therapy (15.8 +/- 3.4 to 18.4 +/- 4.4 ml/min per kg, p less than 0.05) and remained unchanged during placebo treatment (16.0 +/- 6.4 versus 17.0 +/- 4.6 ml/min per kg). Clinical functional class (Yale scale) improved 3.1 +/- 1.9 points (p less than 0.01) during enalapril treatment but not during placebo treatment (0.8 +/- 3.5 points, no significant difference). No significant side effects were observed. Thus, enalapril appears to be a clinically effective and useful new angiotensin-converting enzyme inhibitor for the management of chronic congestive heart failure.

Topics: Adult; Aged; Body Weight; Dipeptides; Double-Blind Method; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Oligopeptides; Physical Exertion; Renin; Teprotide

The effects of enalapril on clinical well-being, treadmill exercise performance, haemodynamic measurements, hormone levels, and plasma biochemistry in patients with moderate heart failure, were assessed in a 12-week placebo-controlled, double-blind study. Maintenance frusemide and digoxin treatment was continued throughout the study. Compared with placebo, enalapril treatment improved clinical status and increased exercise capacity. The most obvious haemodynamic change was a fall in pulmonary artery wedge pressure and pulmonary artery pressure. Enalapril-induced increases in left-ventricular ejection fraction and cardiac index, and falls in systemic arterial pressure, were small. Of the hormone indices measured, plasma renin activity rose 4-fold, angiotensin II and aldosterone fell slightly, and plasma catecholamines were unaltered by enalapril. Plasma potassium increased on average by 0.3 mmol/L during enalapril therapy. No adverse clinical or biochemical effects were observed. Enalapril has a sustained beneficial action in patients with moderate heart failure.

Topics: Adult; Aged; Antihypertensive Agents; Body Weight; Catecholamines; Clinical Trials as Topic; Double-Blind Method; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Physical Exertion; Random Allocation; Time Factors

We report the first comparative study on enalapril maleate, a new angiotensin converting enzyme inhibitor, in patients with uncomplicated mild to moderate essential hypertension. Fifty-four patients were randomly assigned to treatment with enalapril or propranolol for 16 weeks following a placebo run-in-phase. The study was double-blind. Enalapril and propranolol both reduced blood pressure, though the changes were significantly treated with enalapril were normotensive at the end of the study. Enalapril treatment was associated with a significant reduction in weight. Both drugs raised plasma potassium and urea. No haematological abnormalities occurred with enalapril and there were no reports of rash, taste disturbance or proteinuria. At the end of the trial the mean daily dose of enalapril was 20 mg and that of propranolol was 180 mg.

Topics: Adult; Blood Pressure; Body Weight; Dipeptides; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Propranolol; Pulse; Random Allocation

Escape from the sodium-retaining action of mineralocorticoids coincides with the suppression of plasma renin and angiotensin II levels. The purpose of this study was to evaluate whether blockade of the renin system accelerates this escape. Eight male normotensive volunteers, aged 24--33 yr, were maintained during two subsequent periods of 12 days each, separated by 3--4 weeks, on a constant intake of sodium and potassium of 140 mmol/day. During both periods, fludrocortisone acetate (0.2 mg) was administered orally three times a day on days 4--12. In addition, on days 3--12, either a converting enzyme inhibitor (MK 421;20 mg orally, twice daily) or a placebo was added in double blind fashion and randomized sequence. During both periods, blood pressures were similar; they tended to increase slightly toward day 12. The weight increase did not differ between the two periods. With MK 421, angiotension II levels were significantly lower than with placebo on days 3--6 (P less than 0.001). On the same days, PRA was increased due to converting enzyme blockade. Despite the significantly different angiotensin II levels on days 3--6, daily urinary sodium excretion on all individual days as well as cumulative sodium balance were the same during both periods. Therefore, we could find no evidence in man that suppression of circulating angiotensin II levels is causally related to escape from mineralocorticoid excess.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Body Weight; Creatinine; Dipeptides; Enalapril; Fludrocortisone; Humans; Male; Natriuresis; Osmolar Concentration; Potassium; Renin

Solanum sisymbriifolium Lam., is used in Paraguayan folk medicine claiming antihypertensive and diuretic properties.. This study aimed to determine the influence of chronic oral administration of the crude root extract and saponins obtained from S. sisymbriifolium Lam., on the blood pressure of male and female rats with hypertension induced by L-NAME, and its consequences on diuresis, the body weight, blood glucose, and level of serum parameters of liver and kidney functionality.. Wistar rats were randomly divided into seven male, and seven female groups (8 animals each), which received as 6-week pretreatment, 0.9% saline solution (two groups; 0.1mL/10 g of b.w.), L-arginine (100.0 mg/kg/day), enalapril (15.0 mg/kg/day), crude extract (CESs 100.0 mg/kg/day), and saponin purified fraction (1.0, and 10.0 mg/kg/day), and treated with L-NAME (20 mg/kg/day/i.p.) twice, 1, and 6 h after pre-treatment. The animals' body weight, glycemia, and blood pressure were recorded weekly, while serum, hepatic, renal, and histological parameters were analyzed at the end of 6-week of treatment.. A protective effect of CESs (100.0 mg/kg/day), and saponins (1.0, and 10.0 mg/kg/day) against hypertension induced by L-NAME was verified in the systolic, diastolic, and mean blood pressure values, which were significantly lower than the positive L-NAME-hypertensive control group (male and female) at the end of the 6-week treatment. Also, pretreatment with enalapril (15.0 mg/kg/day) induced an efficient protective activity, which validates the method used. Likewise, the volume of urine, creatinine, uric acid, urea, and electrolyte excretion was enhanced at the end of 6-week of treatment in concordance with the reduction in serum level of the same parameters, compatible with the improvement of the diuretic activity. The glycemia, body weight, heart rate, and functional hepato-renal parameters were not modified after a 6-week of treatment, in comparison to the control group, indicating relatively acceptable harmless properties of CESs and saponins. Interestingly, the HDL level in females was increased in contrast to male rats by chronic saponins treatment when compared with the negative control group.. It can be concluded that either the increment in blood pressure (systolic, diastolic, and median) or cardiorenal remodeling effects in male and female rats submitted to L-NAME-induced hypertensive condition, were prevented and well-preserved without a significant variation during a period of 6-week of pretreatment with CESs and saponins pretreatments. Likewise, an important diuretic effect was revealed after this period of treatment.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diuretics; Enalapril; Female; Hypertension; Male; NG-Nitroarginine Methyl Ester; Plant Extracts; Rats; Rats, Wistar; Saponins; Solanum

The role of the renin-angiotensin system (RAS), oxidative stress, and inflammation on the development of obesity and its comorbidities has been extensively addressed. Euterpe oleracea Mart. (açaí) seed extract (ASE), with antioxidant and anti-inflammatory properties and capable to modulate plasma renin levels, has been evidenced as a potential regulator of body mass. We hypothesized that the supplementation with ASE might exert beneficial effects on obesity-related white adipose tissue changes and metabolic disorders by interfering with the local adipose tissue overexpression of RAS, inflammation, and oxidative stress in C57BL/6 mice fed a high-fat (HF) diet. The animals were fed a standard diet (10% fat, control), 60% fat (HF), HF + ASE (300 mg/kg per day) and HF + ENA (enalapril, 30 mg/kg per day) for 12 weeks. ASE and ENA prevented weight gain and adiposity, adipocyte hypertrophy, dyslipidemia, and insulin resistance. In adipose tissue, ASE increased the insulin receptor expression and reduced renin and AT1 receptor expression, which was associated with decreased plasma levels of renin and angiotensin II. Differently, ENA increased the expression of angiotensin-conversing enzyme 2, AT2, B2, and Mas receptors in adipose tissue. Also, ASE but not ENA decreased malondialdehyde and 8-isoprostane levels in adipose tissue. Finally, ASE and ENA reduced the adipose tissue inflammatory markers tumor necrosis factor alpha and interleukin 6. These results demonstrate that ASE prevented the adipocyte hypertrophy, obesity, hyperlipidemia, hyperglycemia, and insulin resistance in HF diet-fed mice. The downregulation of RAS in adipose tissue, reducing oxidative stress and inflammation, may contribute to the prevention of obesity-related disorders.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, White; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Diet, High-Fat; Eating; Enalapril; Energy Intake; Euterpe; Inflammation; Insulin; Lipids; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Plant Extracts; Renin-Angiotensin System; Seeds

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8-10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18-20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Diltiazem; Disease Progression; Enalapril; Gene Expression Regulation; Heart; Kidney; Male; Organ Size; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Regional Blood Flow; Renal Insufficiency, Chronic

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function.

Topics: Adaptation, Physiological; Animals; Body Weight; Cell Cycle; Enalapril; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Male; Organ Size; Podocytes; Random Allocation; Rats, Inbred F344; Stress, Physiological; Transcriptome

Lipogenesis is a process that involves the fatty acids synthesis. Resveratrol and enalapril have been studied for their beneficial physiological properties on the glucose and lipid metabolism.. The aim of the present study was to evaluate the oral administration of resveratrol and enalapril effects on glucose and lipid metabolism, evaluating the white pad lipogenesis genes expression in mice.. Swiss male mice were divided into four groups and treated for eight weeks as follows: Standard diet ad libitum (G1); Standard diet + Resveratrol (G2); Standard diet + Enalapril (G3); Standard diet + Resveratrol + Enalapril (G4), where resveratrol was administered with the food and enalapril with the water. Body weight, lipid profile, adiposity, glycemic parameters and epididymal adipocytes area were assessed. The expression levels of FAS, ACC, PPARγ and SREBP-1c were assessed by RT-PCR.. The main findings showed an improvement in the insulin sensitivity and glucose tolerance in the group G2 as compared to G1. Similar results were found for the fasting glucose levels. Decreased triglycerides were observed in the animals treated with resveratrol and enalapril, along with decreased weight of the epididymal adipose tissue in the animals of the G2 group. A mild reduction in the group G4 as compared to the group G1 was observed. Decreased mRNA expression of FAS, ACC and PPARγ in the G4 group when compared to the G1 group were observed.. In conclusion the resveratrol and enalapril association improved the glucose and lipid profiles by modulating the expression of some lipogenesis genes, which are critical regulators of metabolic homeostasis.

Topics: Adipocytes; Adipogenesis; Adipose Tissue, White; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Enalapril; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; Male; Mice; Resveratrol; Stilbenes

Obesity-related kidney disease should be prevented or retarded. We aimed to investigate whether early treatment with enalapril ameliorates later renal injury induced by early postnatal overnutrition. Three or ten male pups per mother were assigned to either the Obese or Lean group during the first 21 days of life. These pups were treated with enalapril (Obese enalapril, OE; Lean enalapril, LE) or vehicle (Obese control, OC; Lean control, LC) for 15-28 days. Body weight, blood pressure (BP), and renal alterations were determined at 3 months. Enalapril decreased body weight only in the Lean group at 3 months (P < 0.05). Systemic BP levels were higher in the LE, OC, and OE groups than in the LC group at 3 months (P < 0.05). Fewer glomeruli per section area were found in the LE, OC, and OE groups than in the LC group and in the OE group than in the OC group (P < 0.05). The LE and OE groups had higher index scores of glomerulosclerosis and tubulointerstitial fibrosis than the controls (P < 0.05). LE pups showed increased intrarenal angiotensin II receptor type (AT)2 and matrix metalloproteinase (MMP)-9 and decreased renin and tissue inhibitor of MMP (TIMP)-1 expression than the LC rats (P < 0.05). OE pups showed increased intrarenal AT2 and decreased AT1 and TIMP-1 expression than the OC rats (P < 0.05). In conclusion, early treatment with enalapril can induce detrimental renal effects in later life and may not be renoprotective in programmed obese adult rats. J. Cell. Physiol. 232: 447-455, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Apoptosis; Blood Pressure; Body Weight; Cell Proliferation; Enalapril; Female; Kidney; Male; Obesity; Organ Size; Rats, Sprague-Dawley; Thinness

To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS).. 6 healthy Beagles.. 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7.. High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C.. In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Body Weight; Dogs; Enalapril; Female; Furosemide; Heart Rate; Male; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Time Factors

Combination therapy can play a significant role in the amelioration of several toxic effects of lead (Pb) and recovery from associated cardiovascular changes.. To investigate the effects of combination therapy on the cardiovascular effects of perinatal lead exposure in young and adult rats Methods: Female Wistar rats received drinking water with or without 500 ppm of Pb during pregnancy and lactation. Twenty-two- and 70-day-old rat offspring who were or were not exposed to Pb in the perinatal period received meso-dimercaptosuccinic acid (DMSA), L-arginine, or enalapril and a combination of these compounds for 30 additional days. Noradrenaline response curves were plotted for intact and denuded aortas from 23-, 52-, 70-, and 100-day-old rats stratified by perinatal Pb exposure (exposed/unexposed) and treatment received (treated/untreated).. Systolic blood pressure was evaluated and shown to be higher in the 23-, 52-, 70-, and 100-day age groups with Pb exposure than in the corresponding control age groups: 117.8 ± 3.9*, 135.2 ± 1.3*, 139.6 ± 1.6*, and 131.7 ± 2.8*, respectively and 107.1 ± 1.8, 118.8 ± 2.1, 126.1 ± 1.1, and 120.5 ± 2.2, respectively (p < 0.05). Increased reactivity to noradrenaline was observed in intact, but not denuded, aortas from 52-, 70-, and 100-day-old exposed rats, and the maximum responses (g of tension) in the respective Pb-exposed and control age groups were as follows: 3.43 ± 0.16*, 4.32 ± 0.18*, and 4.21 ± 0.23*, respectively and 2.38 ± 0.33, 3.37 ± 0.13, and 3.22 ± 0.21, respectively (p < 0.05).. All treatments reversed the changes in vascular reactivity to noradrenaline in rats perinatally exposed to Pb. The combination therapy resulted in an earlier restoration of blood pressure in Pb-exposed rats compared with the monotherapies, except for enalapril therapy in young rats. These findings represent a new approach to the development of therapeutic protocols for the treatment of Pb-induced hypertension.

Topics: Age Factors; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Body Weight; Cardiovascular System; Chelating Agents; Combined Modality Therapy; Enalapril; Female; Hypertension; Lactation; Lead; Lead Poisoning; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Wistar; Succimer; Time Factors; Treatment Outcome

Cadmium is a highly toxic metal that is present in phosphate fertilizers, and the incidence of cadmium poisoning in the general population has increased, mainly due to cigarette smoking. Once absorbed, cadmium accumulates in the tissues, causing harmful effects including high blood pressure, endothelial damage and oxidative stress. Oxidative stress is known to efficiently produce oxidized low-density lipoprotein and consequently atherosclerosis, mainly in the aorta. However, the mechanisms through which endothelial damage is induced by cadmium have not been elucidated. Thus, the aim of this study was to investigate the effects of this metal in the isolated aorta and the possible role of oxidative stress. Rats received 100 mg.L(-1) cadmium chloride (CdCl2) in the drinking water or distilled water alone for four weeks. The pressor effect of cadmium was followed throughout the exposure period by tail plethysmography. At the end of the fourth week, the blood cadmium content was established, and the vascular reactivity of the isolated aorta to phenylephrine, acetylcholine and sodium nitroprusside was analyzed in the context of endothelium denudation and incubation with L-NAME, apocynin, losartan, enalapril, superoxide dismutase (SOD) or catalase. We observed an increased response to phenylephrine in cadmium-treated rats. This increase was abolished by catalase and SOD incubation. Apocynin treatment reduced the phenylephrine response in both treatment groups, but its effect was greater in cadmium-treated rats, and NOX2 expression was greater in the cadmium group. These results suggested that cadmium in blood concentrations similar to those found in occupationally exposed populations is able to stimulate NOX2 expression, contributing to oxidative stress and reducing NO bioavailability, despite enhanced eNOS expression. These findings suggest that cadmium exposure promotes endothelial damage that might contribute to inflammation, vascular injury and the development of atherosclerosis.

Topics: Acetophenones; Acetylcholine; Animals; Aorta; Blood Pressure; Body Weight; Cadmium; Catalase; Densitometry; Enalapril; Endothelium, Vascular; In Vitro Techniques; Losartan; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Nitroprusside; Oxidative Stress; Phenylephrine; Rats; Superoxide Dismutase; Systole

Activation of renin-angiotensin system has been linked to cardiovascular and autonomic dysfunctions in diabetes. Experiments were performed to investigate the effects of angiotensin-converting enzyme inhibitor (ACEI), enalapril, on cardiac and autonomic functions in diabetic rats. Diabetes was induced by streptozotocin (50 mg/kg), and rats were treated with enalapril (1 mg · kg(-1) · d(-1)). After 30 days, evaluations were performed in control, diabetic, and enalapril-treated groups. Cardiac function was evaluated by echocardiography and through cannulation of the left ventricle (at baseline and in response to volume overload). Heart rate and systolic blood pressure variabilities were evaluated in the time and frequency domains. Streptozotocin rats had left ventricular systolic and diastolic dysfunctions, expressed by reduced ejection fraction and increased isovolumic relaxation time. The ACEI prevented these changes, improved diastolic cardiac responses to volume overload and total power of heart rate variability, reduced the ACE1 activity and protein expression and cardiac angiotensin (Ang) II levels, and increased angiotensin-converting enzyme 2 activity, despite unchanged blood pressure. Correlations were obtained between Ang II content with systolic and diastolic functions and heart rate variability. These findings provide evidence that the low-dose ACEI prevents autonomic and cardiac dysfunctions induced by diabetes without changing blood pressure and associated with reduced cardiac Ang II and increased angiotensin-converting enzyme 2 activity.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Autonomic Nervous System; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Electrocardiography; Enalapril; Heart; Heart Rate; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin-Angiotensin System; Ventricular Function, Left

High Na(+) intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na(+) overload-programmed alterations in Na(+) transporters and the renin/angiotensin system (RAS) were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney.. Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l), an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na(+)+K(+))ATPase expression and activity. Ouabain-insensitive Na(+)-ATPase activity remained unchanged but its response to angiotensin II (Ang II) was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS), macrophage infiltration and collagen deposition markedly increased, and AT(2) receptor expression decreased while AT(1) expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na(+)+K(+))ATPase, partially recovered the response of Na(+)-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na(+) or not. In addition, treatment with enalapril per se reduced AT(2) receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na(+)-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS.. Maternal Na(+) overload programmed alterations in renal Na(+) transporters and in its regulation, as well as severe structural lesions in adult offspring. Enalapril was beneficial predominantly through its influence on Na(+) pumping activities in adult offspring. However, side effects including down-regulation of PKA, PKC and AT(2) receptors and increased TBARS could impair renal function in later life.

Topics: Adenosine Triphosphatases; Aging; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Transport; Blood Pressure; Body Weight; Cation Transport Proteins; Creatinine; Cyclic AMP-Dependent Protein Kinases; Enalapril; Female; Gene Expression Regulation; Kidney Tubules, Proximal; Lipid Peroxidation; Macrophages; Male; Parturition; Pregnancy; Protein Kinase C; Rats; Receptors, Angiotensin; Renin-Angiotensin System; Signal Transduction; Sodium; Sodium-Potassium-Exchanging ATPase; Thiobarbituric Acid Reactive Substances; Water; Weaning

The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.

Topics: Adiposity; Aging; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Composition; Body Temperature; Body Weight; Eating; Enalapril; Insulin; Losartan; Magnetic Resonance Spectroscopy; Male; Mitochondria, Muscle; Motor Activity; Muscle Strength; Muscle, Skeletal; Rats; Rats, Inbred F344

Neuroglucopenia induced by 2-deoxy-D-glucose (2DG) activates hypothalamic glucoreceptors leading to increased hepatic glucose production and insulin inhibition. This response is similar to what is observed with intravenous injection of angiotensin II (Ang II). However, the involvement of an angiotensin-converting enzyme inhibitor on neuroglucopenia has not been investigated. The aim of this study was to determine the effects of chronic enalapril treatment on plasma glucose, insulin and lipid levels in response to neuroglucopenia. Male Holtzman rats (120-170 g) were chronically treated with enalapril (10 mg/kg per day) in the drinking water for two weeks. On the day of experiment the animals received an i.v. enalapril final dose one hour before the neuroglucopenic stress by 2DG infusion (500 mg/kg), and blood samples were drawn before and 5, 10, 20, 30 and 60 minutes following infusion. The hyperglycaemic response to 2DG was not significantly changed by enalapril treatment. The enalapril-treated group exhibited a peak of plasma insulin higher than controls. Plasma triglyceride showed a significant increase only in the enalapril group after neuroglucopenic stress (p < 0.05).These data show that chronic enalapril treatment changes insulin and triglyceride responses to neuroglucopenia, suggesting an effect on glucose-induced insulin secretion and the storage of triglycerides.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Cholesterol; Deoxyglucose; Drinking Behavior; Enalapril; Glucose; Insulin; Male; Neurons; Peptidyl-Dipeptidase A; Rats; Stress, Physiological; Time Factors; Triglycerides; Weight Gain

Respiratory function is the main cause of mortality in patients with Duchenne muscular dystrophy (DMD). Elevated levels of TGF-β play a key role in the pathophysiology of DMD. To determine whether therapeutic attenuation of TGF-β signaling improves respiratory function, mdx mice were treated from 2 weeks of age to 2 months or 9 months of age with either 1D11 (a neutralizing antibody to all three isoforms of TGF-β), losartan (an angiotensin receptor antagonist), or a combination of the two agents. Respiratory function was measured in nonanesthetized mice by plethysmography. The 9-month-old mdx mice had elevated Penh values and decreased breathing frequency, due primarily to decreased inspiratory flow rate. All treatments normalized Penh values and increased peak inspiratory flow, leading to decreased inspiration times and breathing frequency. Additionally, forelimb grip strength was improved after 1D11 treatment at both 2 and 9 months of age, whereas, losartan improved grip strength only at 2 months. Decreased serum creatine kinase levels (significant improvement for all groups), increased diaphragm muscle fiber density, and decreased hydroxyproline levels (significant improvement for 1D11 only) also suggested improved muscle function after treatment. For all endpoints, 1D11 was equivalent or superior to losartan; coadministration of the two agents was not superior to 1D11 alone. In conclusion, TGF-β antagonism may be a useful therapeutic approach for treating DMD patients.

Topics: Animals; Biomarkers; Body Weight; Cell Adhesion Molecules; Creatine Kinase; Diaphragm; Dose-Response Relationship, Drug; Enalapril; Gene Expression Regulation; Hand Strength; Hydroxyproline; Inflammation; Losartan; Mice; Mice, Inbred mdx; Muscle Fibers, Skeletal; Myogenin; Organ Size; Respiration; Respiratory Function Tests; RNA, Messenger; Transforming Growth Factor beta

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Humans; Hypoglycemic Agents; Kidney; Liver; Male; Metabolic Syndrome; Myocardium; Obesity; PPAR gamma; Rats; Rosiglitazone; Thiazolidinediones

Female growth-restricted offspring are normotensive in adulthood. However, ovariectomy induces a marked increase in mean arterial pressure (MAP) that is abolished by renin angiotensin system (RAS) blockade, suggesting RAS involvement in the etiology of hypertension induced by ovariectomy in adult female growth-restricted offspring. Blockade of the RAS also abolishes hypertension in adult male growth-restricted offspring. Moreover, sensitivity to acute ANG II is enhanced in male growth-restricted offspring. Thus, we hypothesized that an enhanced sensitivity to acute ANG II may contribute to hypertension induced by ovariectomy in female growth-restricted offspring. Female offspring were subjected to ovariectomy (OVX) or sham ovariectomy (intact) at 10 wk of age. Cardio-renal hemodynamic parameters were determined before and after an acute infusion of ANG II (100 ng·kg(-1)·min(-1) for 30 min) at 16 wk of age in female offspring pretreated with enalapril (40 mg·kg(-1)·day(-1) for 7 days). Acute ANG II induced a significant increase in MAP in intact growth-restricted offspring (155 ± 2 mmHg, P < 0.05) relative to intact control (145 ± 4 mmHg). Ovariectomy augmented the pressor response to ANG II in growth-restricted offspring (163 ± 2 mmHg, P < 0.05), with no effect in control (142 ± 2 mmHg). Acute pressor responses to phenylephrine did not differ in growth-restricted offspring relative to control, intact, or ovariectomized. Furthermore, renal hemodynamic responses to acute ANG II were significantly enhanced only in ovariectomized female growth-restricted offspring. Thus, these data suggest that enhanced responsiveness to acute ANG II is programmed by intrauterine growth restriction and that sensitivity to acute ANG II is modulated by ovarian hormones in female growth-restricted offspring.

Topics: Angiotensin II; Animals; Animals, Newborn; Antihypertensive Agents; Blood Pressure; Body Weight; Enalapril; Female; Fetal Growth Retardation; Male; Models, Animal; Ovariectomy; Phenylephrine; Pregnancy; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Sex Characteristics; Vasoconstrictor Agents

The androgen nandrolone decanoate (ND) is known to cause cardiovascular abnormalities, such as attenuation of the Bezold-Jarisch Reflex (BJR), cardiac hypertrophy, and elevation of mean arterial pressure (MAP). Futhermore, a relationship between androgens and the renin-angiotensin system (RAS) has been reported. The purpose of this study was to evaluate the influence of RAS on the BJR, cardiac and prostatic hypertrophy, and MAP evoked by ND. For this, male Wistar rats were treated with ND (10 mg·(kg body mass)(-1) for 8 weeks; DECA), or vehicle (control animals; CON), or enalapril (10 mg·(kg body mass)(-1), daily; CONE), or ND and enalapril (10 mg ND + 10 mg enalapril per kilogram of body mass; DECAE). After 8 weeks of treatment, the BJR was evaluated by bradycardia and hypotensive responses that were elicited by serotonin administration (2-32 µg·(kg body mass)(-1)). MAP was assessed; cardiac and prostate hypertrophy were determined by the ratio of the tissue mass:body mass, and by histological analysis of the heart. Animals from the DECA group showed prostatic and cardiac hypertrophy, elevation in mean arterial pressure, and an impairment of BJR. Co-treatment with enalapril inhibited these changes. The data from the present study suggest that RAS has an impact on BJR attenuation, cardiac and prostatic hypertrophy, and the elevation in MAP evoked by ND.

Topics: Anabolic Agents; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradycardia; Cardiomegaly; Enalapril; Heart Rate; Male; Nandrolone; Nandrolone Decanoate; Prostatic Hyperplasia; Rats, Wistar; Renin-Angiotensin System

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

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

The gain of the volume-sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. Rats (SHR or Wistar-Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE (-41 +/- 8%) compared with WKY rats (-44 +/- 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 +/- 5, 133 +/- 6 and 160 +/- 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 +/- 0.14 vs 1.98 +/- 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 +/- 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 +/- 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.

Topics: Animals; Antihypertensive Agents; Baroreflex; Body Weight; Cardiomegaly; Enalapril; Heart; Hemodynamics; Hydralazine; Hypertension; Kidney; Lung; Male; Pressoreceptors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke Volume; Sympathetic Nervous System

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

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

Obesity is considered a worldwide public health problem showing an increased prevalence in developing countries, with urgent need for new and more efficient drugs and therapies. Enalapril, an angiotensin-I converting enzyme inhibitor (ACEi), is classically used in anti-hypertensive therapies, however, earlier publications have shown that this drug could also have significant impact on body weight in rats as well as in humans, besides reducing blood pressure. The effect of this drug in the white adipose tissue has been neglected for long time, even considering that most components of the renin-angiotensin and kallikrein-kinin system are expressed in this tissue. Furthermore, the adipose tissue is considered today as one of the most important sites for endocrine/inflammatory regulation of appetite and energy output and AngII has been linked to the metabolism in this tissue. Therefore, we analyzed the influence of chronic enalapril treatment in normotensive rats at earlier ages, evaluating body weight, energy homeostasis, lipid profile and serum levels of the hormones leptin and insulin, in the presence of a standard or a palatable hyperlipidic diet regimen for one month. Our results show that enalapril treatment is able to reduce body fat on both diets, without alteration in serum lipid profile. Furthermore, animals receiving enalapril showed reduction in food intake, leptin level and energy intake. In summary, these findings show for the first time that the ACEi enalapril reduces body fat in young normotensive rats and highlights a novel target to treat obesity and associated diseases.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Composition; Body Weight; Enalapril; Energy Intake; Leptin; Lipids; Rats; Rats, Wistar

Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to examine the developmental origins of adult disease. In this model only male IUGR offspring remain hypertensive in adulthood, revealing sex-specific differences. The purpose of this study was to determine whether testosterone with participation of the renin-angiotensin system (RAS) contributes to hypertension in adult male IUGR offspring. At 16 wk of age a significant increase in testosterone (346 +/- 34 vs. 189 +/- 12 ng/dl, P < 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 +/- 1 vs. 125 +/- 1 mmHg, P < 0.05, IUGR vs. control, respectively). Gonadectomy (CTX) at 10 wk of age significantly reduced MAP by 16 wk of age in IUGR offspring (124 +/- 2 mmHg, P < 0.05 vs. intact IUGR) but had no effect in control (125 +/- 2 mmHg). A significant decrease in MAP in intact IUGR (111 +/- 3 mmHg, P < 0.05 vs. untreated intact IUGR) and castrated IUGR (110 +/- 4 mmHg, P < 0.05 vs. untreated CTX IUGR) after treatment with enalapril for 2 wk suggests a role for RAS involvement. However, the decrease in blood pressure in response to enalapril was greater in intact IUGR (Delta36 +/- 1 mmHg, P < 0.05) compared with CTX IUGR (Delta15 +/- 2 mmHg), indicating an enhanced response to RAS blockade in the presence of testosterone. Thus these results suggest that testosterone plays a role in modulating hypertension in adult male IUGR offspring with participation of the RAS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Birth Weight; Blood Pressure; Body Weight; Enalapril; Female; Fetal Growth Retardation; Hypertension; Male; Orchiectomy; Placenta; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renin; Renin-Angiotensin System; Sex Characteristics; Telemetry; Testosterone

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

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

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg x kg(-1) x day(-1); Enal), or a NO synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg x kg(-1) x day(-1)), or both (Enal+L-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by L-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. L-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by L-NAME cotreatment. In Enal, kidney mitochondria H(2)O(2) production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by L-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Availability; Blood Pressure; Body Weight; Drug Interactions; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Enalapril; Enzyme Inhibitors; Hydrogen Peroxide; Ion Channels; Kidney; Male; Membrane Potentials; Mitochondria; Mitochondrial Proteins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type I; Organ Size; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Uncoupling Protein 2

Experimental studies indicate that angiotensin II (ANG II) through its type 1 receptor (AT(1)) promotes cardiovascular hypertrophy and fibrosis. Therefore, the aim of this study was to analyze whether chronic long-term inhibition of the renin-angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system of the normal rat. The main objective was to compare two strategies of ANG II blockade: a converting enzyme inhibitor (CEI) and an AT(1) receptor blocker (AT(1)RB). A control group remained untreated; treatment was initiated 2 wk after weaning. A CEI, enalapril (10 mg.kg(-1).day(-1)), or an AT(1)RB, losartan (30 mg.kg(-1).day(-1)), was used to inhibit the RAS. Systolic blood pressure, body weight, and water and food intake were recorded over the whole experimental period. Heart, aorta, and mesenteric artery weight as well as histological analysis of cardiovascular structure were performed at 6 and 18 mo. Twenty animals in each of the three experimental groups were allowed to die spontaneously. The results demonstrated a significant protective effect on the function and structure of the cardiovascular system in all treated animals. Changes observed at 18 mo of age in the hearts and aortas were quite significant, but each treatment completely abolished this deterioration. The similarity between the results detected with either enalapril or losartan treatment clearly indicates that most of the effects are exerted through AT(1) receptors. An outstanding finding was the significant and similar prolongation of life span in both groups of treated animals compared with untreated control animals.

Topics: Aging; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Cardiovascular System; Enalapril; Losartan; Male; Myocardium; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Renin-Angiotensin System

Males develop higher blood pressure than do females. This study tested the hypothesis that androgens enhance responsiveness to ANG II during the development of hypertension in New Zealand genetically hypertensive (NZGH) rats. Male NZGH rats were obtained at 5 wk of age and subjected to sham operation (Sham) or castration (Cas) then studied at three age groups: 6-7, 11-12, and 16-17 wk. Mean arterial blood pressure (MAP), heart rate (HR), and renal blood flow (RBF) measurements were recorded under Inactin anesthesia. These variables were measured after enalapril (1 mg/kg) treatment and during intravenous ANG II infusion (20, 40, and 80 ng/kg/min). Plasma testosterone was measured by ELISA. Angiotensin type 1 (AT1) receptor expression was assessed by Western blot analysis and RT-PCR. ANG II-induced MAP responses were significantly attenuated in Cas NZGH rats. At the highest ANG II dose, MAP increased by 40+/-4% in Sham vs. 22+/-1% in Cas NZGH rats of 16-17 wk of age. Similarly, renal vascular resistance (RVR) responses to ANG II were reduced by castration (209+/-20% in Sham vs. 168+/-10% in Cas NZGH rats at 16-17 wk of age). Castration also reduced MAP recorded in conscious NZGH rats of this age group. Testosterone replacement restored baseline MAP and the pressor and RVR responses to ANG II. Castration reduced testosterone concentrations markedly. Testosterone treatment restored these concentrations. Neither castration nor castration+testosterone treatment affected AT1 receptor mRNA or protein expression. Collectively, these data suggest that androgens modulate renal and systemic vascular responsiveness to ANG II, which may contribute to androgen-induced facilitation of NZGH rat hypertension.

Topics: Age Factors; Androgens; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Enalapril; Gene Expression; Heart Rate; Hypertension; Kidney; Male; Orchiectomy; Organ Size; Rats; Rats, Inbred Strains; Receptor, Angiotensin, Type 1; Renal Artery; Renal Circulation; Testosterone

Spontaneously hypertensive rats (SHRs) exhibit endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance may contribute to hypertension by causing imbalanced regulation of endothelial-derived vasodilators (e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1 [ET-1]). Treatment of SHRs with rosiglitazone (insulin sensitizer) and/or enalapril (ACE inhibitor) may simultaneously improve hypertension, insulin resistance, and endothelial dysfunction by rebalancing insulin-stimulated production of vasoactive mediators. When compared with WKY control rats, 12-week-old vehicle-treated SHRs were hypertensive, overweight, and insulin resistant, with elevated fasting levels of insulin and ET-1 and reduced serum adiponectin levels. In mesenteric vascular beds (MVBs) isolated from vehicle-treated SHRs and preconstricted with norepinephrine (NE) ex vivo, vasodilator responses to insulin were significantly impaired, whereas the ability of insulin to oppose vasoconstrictor actions of NE was absent (versus WKY controls). Three-week treatment of SHRs with rosiglitazone and/or enalapril significantly reduced blood pressure, insulin resistance, fasting insulin, and ET-1 levels and increased adiponectin levels to values comparable with those observed in vehicle-treated WKY controls. By restoring phosphatidylinositol 3-kinase-dependent effects, rosiglitazone and/or enalapril therapy of SHRs also significantly improved vasodilator responses to insulin in MVB preconstricted with NE ex vivo. Taken together, our data provide strong support for the existence of reciprocal relationships between endothelial dysfunction and insulin resistance that may be relevant for developing novel therapeutic strategies for the metabolic syndrome.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Enalapril; Hypertension; Insulin; Insulin Resistance; Rats; Rats, Inbred SHR; Reference Values; Rosiglitazone; Thiazolidinediones; Vasoconstriction; Vasodilation

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

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

Adult hypertension in the rat can be programmed experimentally by changes in intrauterine environment. The offspring typically do not become hypertensive until 6 to 8 wk of age, and recent evidence suggests that renal dysfunction may participate in the pathogenesis. The present study was based on the hypothesis that the window for programming extends to the postnatal period in the rat. Adult hypertension was induced by maternal low-protein diet during the second half of gestation. After being weaned at 3 wk, the offspring were exposed to one of the following regimens for the subsequent 3 wk: 1) low-Na diet, 2) standard Na diet, 3) high-Na diet, and 4) standard Na diet with enalapril. The pups were followed for 10 wk after discontinuation of the treatments. The brief exposure to low-Na diet or enalapril totally prevented the development of hypertension and the effect lasted throughout the observation period. The development of hyperreninemia, present in the standard Na group at 16 wk of age, was abolished in the low-Na and enalapril groups. Conversely, 3-wk exposure to high-Na diet increased the severity of the later hypertension and did not prevent the hyperreninemia. The findings suggest that there is a period of susceptibility during which prenatally programmed hypertension can be modulated postnatally, possibly coinciding with a critical stage in renal maturation.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Enalapril; Female; Hypertension; Kidney; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Sodium

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

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

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

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

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

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

1. Inhibition of the renin-angiotensin system (RAS) during kidney development produces chronic alterations in renal morphology and function that have been characterized in detail in adult animals. The aim of the present study was to determine the consequences of neonatal angiotensin-converting enzyme (ACE) inhibition on renal haemodynamics and function in rats at a much earlier age, namely 3-4 weeks. 2. Male Wistar pups received daily intraperitoneal injections of enalapril (10 mg/kg) or isotonic saline from birth until 24-28 days of age, when renal haemodynamics and function were assessed using clearance techniques under pentobarbital anaesthesia. 3. Enalapril-treated rats showed significant reductions in glomerular filtration rate (GFR; -44 +/- 6%; P < 0.05), effective renal plasma flow (ERPF; -33 +/- 6%; P < 0.05) and filtration fraction (-16 +/- 3%; P < 0.05) compared with saline-treated controls. Although mean arterial pressure tended to be lower in enalapril-treated rats, this group demonstrated a significant increase in renal vascular resistance compared with control rats (RVR; 46 +/- 6 vs 32 +/- 3 mmHg/mL per.min per g.kidney weight, respectively; P < 0.05). In enalapril-treated rats, urine osmolality was reduced (-59 +/- 5%; P < 0.05) and urine flow rate and fractional urinary excretion rates of sodium and potassium were markedly elevated compared with controls (P < 0.05). Enalapril-treated rats showed severe renal histological abnormalities, including wall thickening of cortical arterioles, papillary atrophy and tubulointerstitial alterations, mimicking those described previously in similarly treated rats examined in adulthood. 4. In conclusion, neonatal ACE inhibition in rats induces pronounced alterations in renal haemodynamics and function, characterized by reductions in ERPF and GFR, increased RVR and impaired tubular sodium and water reabsorption, which are evident at weaning.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Body Weight; Enalapril; Female; Glomerular Filtration Rate; Kidney; Kidney Tubules; Male; Natriuresis; Organ Size; Potassium; Rats; Rats, Wistar; Renal Circulation; Renal Plasma Flow, Effective; Sodium; Weaning

Stereological structural alterations of the heart and kidney were studied in four groups (n=5) of spontaneously hypertensive rats (SHRs) treated for 30 days: (i) control, (ii) NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthesis inhibitor] alone, (iii) enalapril alone and (iv) L-NAME plus enalapril. Blood pressure (BP) was elevated significantly in NO-deficient SHRs (rats receiving L-NAME) or significantly lower in enalapril-treated SHRs. Co-administration of L-NAME and enalapril caused a 20% decrease in BP compared with untreated SHRs. NO-deficient SHRs had a decrease in body mass, but this loss of body mass was prevented efficiently in the enalapril-treated group. Enalapril treatment decreased the left ventricular (LV) mass index in SHRs, even in animals with NO synthesis blocked. NO deficiency in SHRs caused a larger decrease in the number of LV cardiomyocyte nuclei, which had a negative correlation with both LV mass index and BP. The volume-weighted glomerular volume (VWGV) separated the SHRs into two groupings: (i) control and NO-deficient SHRs, and (ii) enalapril- and L-NAME plus enalapril-treated SHRs. There was a significant difference between these two groupings, with VWGV being more than 15% smaller in the latter compared with the former grouping. The present findings reinforce the evidence that enalapril efficiently treats genetic hypertension, and demonstrate that this effect is observed even when NO synthesis is inhibited. Enalapril administration also decreases cardiac and renal structural damage caused by genetic hypertension, as well as by the interaction between genetic hypertension and NO deficiency.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cell Count; Enalapril; Hypertension; Kidney Glomerulus; Male; Myocytes, Cardiac; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Inbred SHR

Cardiovascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus (DM). Strategies that interrupt the renin-angiotensin system have been shown to reduce the ensuing threatening risk factors. The present study was carried out to investigate the effect of subchronic administration of enalapril on the aortic reactivity of streptozotocin (STZ)-diabetic rats. For this purpose, STZ-diabetic rats received enalapril (10 and 20 mg/kg ip) daily for 2 months. Contractile responses to phenylephrine (PE) and relaxation responses to acetylcholine (Ach) and isosorbide dinitrate (ISD) were obtained from aortic rings. Concentration-response curves from enalapril-treated diabetic (ED) rats to PE were attenuated as compared to vehicle-treated diabetics (VD), especially at a dose of 20 mg/kg for enalapril. In addition, endothelium-dependent relaxation responses induced by Ach was significantly higher in ED rats as compared to diabetic ones. The endothelium-independent relaxation responses for ISD were also found not to be significantly different among the groups. Therefore, subchronic treatment of diabetic rats with enalapril in a dose-dependent manner could prevent the functional changes in vascular reactivity in diabetic rats.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enalapril; Endothelium, Vascular; In Vitro Techniques; Isosorbide Dinitrate; Male; Muscle, Smooth, Vascular; Phenylephrine; Rats; Rats, Wistar; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

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

Smooth muscle cell (SMC) apoptosis occurs at the onset of enalapril-induced regression of aortic hypertrophy in SHR. A potential mechanism is the correction of endothelial dysfunction (ED) leading to reduced production of reactive oxygen species and enhanced bioavailability of nitric oxide (NO), a potent apoptosis inducer. Stimulants of NO include the precursor L-arginine and the NO synthase cofactor tetrahydrobiopterin (BH(4)), which correct ED in several models. The objective was to examine the relationships between ED and the cell growth/death balance during vascular remodeling induced by enalapril in SHR. SHR, 10-week-old, received enalapril (ENA: 30 mg x kg(-1) x day(-1) p.o.) for 1 or 2 weeks, or a co-treatment of L-arginine (2.0 g x kg(-1) x day(-1) p.o.) and BH(4) (5.4 mg x kg(-1) x day(-1) i.p. twice daily) administered alone (group: LB) or in combination with enalapril (ENA+LB) for 1 week. Controls received vehicle. After 1 week, ED was completely corrected with LB but not affected significantly by ENA, whereas both treatments failed to induce SMC apoptosis or aortic remodeling. The correction of ED and the induction of SMC apoptosis (3.3-fold increase in TUNEL labeling) required 2 weeks of ENA treatment. The combination of LB with ENA for 1 week, however, was additive for the reduction of SMC proliferation, and synergistic for the induction of apoptosis and regression of vascular hypertrophy. These interactions were independent of blood pressure regulation. Our results suggest that the correction of ED is not sufficient to induce SMC apoptosis and vascular remodeling, although it facilitates these responses during enalapril treatment.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Apoptosis; Arginine; Biopterins; Blood Pressure; Body Weight; DNA Fragmentation; Drug Synergism; Enalapril; Endothelium, Vascular; In Situ Nick-End Labeling; Male; Muscle, Smooth, Vascular; Nitric Oxide; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Vasodilator Agents

Angiotensin-converting enzyme inhibitors reduce the blood pressure (BP) and inhibit the generation of the angiotensin II from the inactive angiotensin I. Ten 28-week-old spontaneously hypertensive rats (SHRs) had their ovaries bilaterally removed and five rats were left intact and studied for 7 additional weeks: intact group, ovariectomized group (ovx SHRs) and ovariectomized + enalapril group (ovx + en). BP was higher in ovx SHRs and lower in treated ovx SHRs. Left ventricular (LV) mass index was greater in untreated ovx SHRs and smaller in ovx + en group. The LV cardiomyocyte (cmy) mean cross-sectional area, measured by stereology, was greater in ovx SHRs and smaller in both intact and ovx + en SHRs. Ovx significantly decreased the density of intramyocardial blood vessels (ive), but administration of enalapril was able to restore the density of the ive to that seen in intact group. The worst ive:cmy ratio was found in untreated ovx SHRs, the intact group showed a 90% greater ratio, and the treated ovx group showed a 150% greater ratio than the untreated ovx group. In conclusion, ovariectomy, in SHRs, causes cardiac hypertrophy and an unfavourable myocardial remodelling. Of the spectrum of changes seen, the major effect of enalapril appears to be mediated via an increase in the density of ive.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiomegaly; Enalapril; Estradiol; Female; Heart; Heart Ventricles; Hypertension; Myocytes, Cardiac; Ovariectomy; Rats; Rats, Inbred SHR

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

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

To clarify the precise mechanisms involved in the reduced coronary flow reserve in hypertension, we compared the effects of the angiotensin II type 1 (AT1) receptor antagonist FK-739 with those of the angiotensin-converting enzyme (ACE) inhibitor enalapril for 6 weeks on the smooth muscle (SM) cell phenotype in intramyocardial arteries from male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Compared with WKY, SHR showed a significant increase in left ventricular (LV) hypertrophy and fibrosis, blood pressure (BP), and vascular remodeling of the intramyocardial arteries, and a significant decrease in endothelial NO synthase and the contractile-type myosin heavy chain isoform SM2 of the intramyocardial arteries as well as calponin 1 and GATA-6. In the hearts of SHR, both drugs equivalently and significantly reduced BP, which was still significantly higher than that in the WKY groups, and also reduced LV hypertrophy and fibrosis, whereas endothelial NO synthase was significantly restored. Although both drugs showed little effect on the vascular remodeling of the intramyocardial arteries in the SHR hearts, FK-739, but not enalapril, significantly restored SM2 and GATA-6 in the SHR hearts to the same levels as those of the vehicle WKY group. The effects of the two drugs on these indices were not observed in the three WKY hearts. Thus, the AT1 receptor antagonist may modulate the SM cell phenotype toward the contractile-type more effectively than the ACE inhibitor before the morphological changes occur in the intramyocardial arteries of the SHR hearts.

Topics: Actins; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Calcium-Binding Proteins; Calponins; Coronary Vessels; DNA-Binding Proteins; Enalapril; GATA6 Transcription Factor; Heart Rate; Hypertension; Imidazoles; Immunoblotting; Male; Microfilament Proteins; Muscle, Smooth, Vascular; Myosin Heavy Chains; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transcription Factors

Chronic angiotensin I-converting enzyme inhibition can be associated with aldosterone escape. We investigated the effects of enalapril, spironolactone, and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters to determine whether these drugs could exert additive effects. Cardiomyopathic hamsters, Bio TO-2 dilated strain, were orally treated with enalapril (20 mg. kg. day ) and/or spironolactone (20 mg. kg. day ) according to a 2 x 2 factorial design from 120 days of age. Animals were investigated at 180 (10 animals per group) and 240 (16 animals per group) days of age. Compared with corresponding untreated groups, enalapril significantly decreased mean blood pressure (-18%); enalapril and spironolactone significantly increased cardiac output (+28%, +11%) and femoral blood flow (+10%, +12%) and significantly decreased systemic (-38%, -17%) and femoral (-26%, -13%) vascular resistances. Enalapril and spironolactone significantly decreased left ventricle cavity area (-21%, -26%) and left (-34%, -47%) and right (-37%, -48%) ventricle collagen density. Spironolactone significantly increased left ventricle wall thickness (+4%). There were significant enalapril x spironolactone interactions for most variables (compared with control group, +52%, +36%, +45% for cardiac output; +26%, +28%, +26% for femoral blood flow; -50%, -30%, -45% for systemic vascular resistance; -33%, -20%, -35% for femoral vascular resistance; -27%, -31%, -40% for left ventricle cavity area; and -46%, -58%, -60% for left and -39%, -50%, -66% for right ventricle collagen density in enalapril, spironolactone, and enalapril + spironolactone groups, respectively). In cardiomyopathic hamsters, enalapril and spironolactone in combination did not improve hemodynamics more than enalapril alone but induced stronger effects than each drug alone on cardiac remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cardiomyopathy, Dilated; Cricetinae; Drug Therapy, Combination; Enalapril; Hemodynamics; Mineralocorticoid Receptor Antagonists; Organ Size; Spironolactone; Ventricular Remodeling

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

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

Recent experimental studies in chronic kidney disease have suggested that sympathicolytic drugs, similar to angiotensin II antagonism, limit renal fibrosis independent of blood pressure control. Using the model of acute and normotensive anti-thy1 glomerulonephritis, we analysed the action of beta-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-beta.. One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the beta-blockers metoprolol or nebivolol (0.1-fold, one-fold, 10-fold and 20-fold of the known blood pressure dose) until day 6 and the 20-fold dose until day 12. Additional animals were treated with a high dose of the angiotensin-converting enzyme inhibitor enalapril. At the end of each experiment, blood pressure and heart rate were recorded, glomerular matrix expansion was scored histologically, and protein expression of TGF-beta(1), fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli.. Metoprolol and nebivolol reduced heart rate in a dose-dependent manner. Blood pressure was normal in untreated animals and not significantly affected by either treatment. Compared with untreated nephritic rats, TGF-beta(1) overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-beta(1) levels were significantly reduced by enalapril both 6 and 12 days after disease induction (-52 and -63%, respectively). The changes in glomerular matrix score, fibronectin and plasminogen activator inhibitor-1 production closely followed expression of TGF-beta(1).. In a model of acute and normotensive glomerular fibrosis, beta-adrenergic antagonism does not reduce TGF-beta overexpression, suggesting that its pressure-independent antifibrotic action may be limited to chronic renal diseases. The beneficial effect of angiotensin II inhibition even on acute matrix expansion may be a relevant mechanism as to the explanation of its superiority in treating fibrotic renal diseases.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzopyrans; Biomarkers; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Enalapril; Ethanolamines; Fibrosis; Glomerulonephritis; Heart Rate; Isoantibodies; Male; Metoprolol; Nebivolol; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1

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

The present study evaluated the importance of ovarian functions and the renin-angiotensin system in the progression of the right ventricular (RV) hypertrophy. Female Sprague-Dawley rats were bilaterally ovariectomized (Ovx) and injected with monocrotaline (MCT, 60 mg/kg, sc). Four weeks after MCT-treatment, only the male and Ovx female rats showed marked RV hypertrophy. The hypertrophied RV of the male-MCT and Ovx-MCT rats exhibited remarkably elevated renin mRNA levels. Gene expression levels of angiotensinogen, TGF-beta1, and endothelin-1 in the hypertrophied RV also increased, but to the less degree than did the renin mRNA. To investigate beneficial effects of estrogen or enalapril on progression of the pulmonary hypertension and RV hypertrophy, histological changes of the lung and heart were examined. Sham-MCT female rats showed histological changes indicating pulmonary hypertension without RV hypertrophy. In contrast, Ovx-MCT rats showed marked RV hypertrophy with pathological changes, denoting severe pulmonary and myocardial injuries. Estrogen-or enalapril-treated Ovx-MCT rats did not show RV hypertrophy, and showed remarkably ameliorated ultrastructural changes in the lung and RV. These results from this rat model suggest that both estrogen and inhibition of the renin-angiotensin system have protective functions against the development of the pulmonary hypertension and cardiac remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Body Weight; Densitometry; Disease Progression; Enalapril; Endothelin-1; Estrogens; Female; Hypertrophy, Right Ventricular; Male; Microscopy, Electron; Monocrotaline; Ovariectomy; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sex Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart; Heart Ventricles; Kidney; Losartan; Matrix Metalloproteinases; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

It is well established that angiotensin-converting enzyme (ACE) inhibitors (ACEI) reduce blood pressure (BP) and hypertrophy of the left ventricle and vessels. The aim of our study was to compare chemically different ACEIs regarding their ability to modulate left ventricular and media hypertrophy, ACE activity and plasma endothelin-1 concentrations in spontaneously hypertensive rats (SHRs).. After establishing equi-effective dose regimes, SHRs were treated (3 months) with captopril, enalapril, fosinopril or ramipril (2 x 25, 10, 20 or 1 mg/kg per day or corresponding 1% doses for studying blood pressure-independent effects).. Systolic blood pressure was reduced in SHRs receiving high doses of captopril, enalapril, fosinopril or ramipril (-61, -54, -35 and -47 mmHg), whereas low doses were ineffective. Left ventricular weight was decreased in animals treated with high doses (captopril/enalapril/fosinopril/ramipril: -17/-19/-17/-19%), but not low doses of agents. Media thickness of thoracal aorta was reduced by administering high doses (captopril/enalapril/fosinopril/ramipril: -31/-32/-27/-26%) and low doses (-16/-22/-22/-19%) of agents. ACE activity was reduced in heart, aorta and kidney of rats treated with high and low doses of all ACE inhibitors, whereby high doses showed more pronounced effects. Plasma endothelin-1 concentrations were not altered. A blood-pressure-ineffective treatment with an AT -antagonist revealed similar effects on cardiovascular hypertrophy.. ACEIs reduce cardiovascular hypertrophy uniformly via an AT -receptor- mediated mechanism, reinforcing the opinion that ACEI effects are indeed class effects. The significance of local renin-angiotensin systems was confirmed by antihypertrophic effects in the aorta that were apparent in the absence of any blood pressure reduction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Captopril; Circadian Rhythm; Dose-Response Relationship, Drug; Enalapril; Endothelin-1; Fosinopril; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred SHR

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

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

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

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

The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor-alpha (TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 +/- 2.5 mmHg (P < 0.05) vs. 15.2 +/- 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NF-kappaB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 +/- 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly (P < 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NF-kappaB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bleomycin; Body Weight; Cardiac Output; Collagen Type I; Disease Models, Animal; Enalapril; Female; Gene Expression; Hemodynamics; Hypertension, Pulmonary; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Pneumonia; Pulmonary Circulation; Receptors, Tumor Necrosis Factor; RNA, Messenger; Specific Pathogen-Free Organisms; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Effects of the angiotensin II type 1 (AT1) receptor antagonist valsartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril were studied in streptozotocine (STZ)-induced diabetes in rats on the basis of microalbuminuria (Ma) and renal morphology. Five groups of Wistar rats were used, one group was the non-diabetic control, one group consisted of untreated STZ-diabetics and 3 groups of STZ-diabetics were treated with either enalapril and/or valsartan for 30 days. Blood glucose (BG) and Ma levels, body and kidney weight and glomerular size were measured. Immunohistochemical staining with an anti-transforming growth factor-beta1 (TGF-beta1) antibody was performed as well. In STZ-diabetics, BG and Ma levels were significantly increased when compared with the non-diabetic group. Although Ma levels in the valsartan-treated group was found to be higher than those in the non-diabetics group after 15 days of treatment, in all treated diabetic groups Ma levels were significantly decreased as compared with STZ-diabetics at the end of the experiment. Thickening of the glomerular and tubular basement membranes, increased mesangial matrix and glomerular size were found in the untreated diabetic group. All these changes were less in the treated groups. A significant increase in TGF-beta1 immunoreactivity was found in glomeruli of untreated STZ-diabetics as compared with non-diabetics. Again, TGF-beta1 expression was decreased in the treated groups as compared with untreated STZ-diabetics. We conclude that valsartan and enalapril have renoprotective effects in diabetic nephropathy. A combined therapy has an advantage because lower dosages of these drugs can be used. Their beneficial effects are related to a blockade of the renin-angiotensin system (RAS) and a decrease in TGF-beta1 expression in glomeruli.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Female; Immunoenzyme Techniques; Immunohistochemistry; Kidney; Organ Size; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Tetrazoles; Transforming Growth Factor beta; Valine; Valsartan

It is not clear whether some pathological changes in hypertension are directly pressure-dependent, or hormonally induced, or both. The aortic arch has apparently never before been studied for those changes. The aim of this study was to compare the effects of controlling angiotensin II (Ang II) and/or blood pressure (BP), directly at the inception of hypertension, on the aortic arch, the left ventricle of the heart (LV), and the kidneys of spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto (WKY) rats. An angiotensin-converting enzyme inhibitor (ACEI, enalapril) and a calcium-channel blocker (nifedipine) were used for 21 weeks. After treatment, rats were assessed for arterial plasma renin activity (PRA). The LV, aortic arch, and kidneys were then excised for the determination of organ and tissue weight in some of the animals, while in others the aortic arch was fixed in situ and processed for microscopic analysis. Both enalapril and nifedipine levelled BP in the SHRs to almost normal values. Enalapril was able to prevent the increase in LV and kidney weights (p=0.04 wet, p<0.001 dry; p<0.001 wet and dry, respectively) and the increase in the weight of the aortic arch and in the thickness of its media (p<0.001 wet and dry; p<0.001, respectively) seen in untreated SHRs. This was associated with a larger lumen diameter (p<0.001) and a lower media to lumen ratio (p=0.01). In contrast, nifedipine did not prevent any of the changes described. Neither nifedipine nor enalapril treatment had any effects on PRA in either rat strain. Our results support previous observations that BP is not the only factor causing some of the pathological changes in hypertension; tissue Ang II level may also play a major role.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Calcium Channel Blockers; Enalapril; Heart Ventricles; Hypertension; Kidney; Male; Nifedipine; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin

Fifty mature male rats were separated into groups of ten rats each (control, L-NAME, spironolactone, enalapril and verapamil). On the 41st day of experimentation, animals were anesthetized, weighed and sacrificed. The tail blood pressure (TBP) was 76% higher in L-NAME group than in the control group. Spironolactone, enalapril and verapamil were efficient in reducing TBP in those respective groups of rats (spironolactone was less efficient in reducing TBP). The heart mass/body mass ratio (HBR) increased 24% in L-NAME group and spironolactone group. No differences in HBR were found when control animals and animals treated with enalapril and verapamil were compared. Heart volume (HV) was greater in L-NAME group than other groups, but it was not different comparing the L-NAME and the spironolactone groups. The left ventricle was responsible for the changes in the HV. The relationship between the HV and the body mass (BM) was not significant in the groups L-NAME and spironolactone. However, this relationship was significant and allometric in control, enalapril and verapamil groups. In control group, HV had a positive allometric tendency against the BM, but in the enalapril and verapamil groups this tendency was allometrically negative. Cardiac hypertrophy in rats under inhibition of NO synthesis was prevented by treatment with enalapril and verapamil more efficiently than spironolactone.

Topics: Animals; Antihypertensive Agents; Body Weight; Enalapril; Heart; Heart Ventricles; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ Size; Rats; Rats, Wistar; Regression Analysis; Spironolactone; Verapamil

We examined the influence of chronic antihypertensive treatment on the central pressor response in SHR. Adult male SHR were divided into 5 groups, i.e., those receiving 1) enalapril (Enal: 25 mg/kg/day in drinking water, n=12); 2) losartan (Los: 40 mg/kg/day, n=11); 3) candesartan (Cand: 4 mg/kg/day, n=12); 4) hydralazine+hydrochlorothiazide (H&H: 50+7.5 mg/kg/day, n=9); 5) vehicle (. n=9). At 4 weeks of treatment, hypertonic saline (0.25, 0.5 M) was intracerebroventricularly (i.c.v.) injected into conscious rats. Plasma catecholamines were measured before and after i.c.v. injection. On completion of the experiment, heart weight was measured, and angiotensin-converting enzyme (ACE) activity of the cerebrum was determined. All antihypertensive drugs elicited comparable reductions in systolic blood pressure, while heart rate was significantly higher in the H&H group than in the other groups during treatment. Pressor response to i.c.v. hypertonic saline (0.5 M) was significantly smaller in the Enal (12 +/- 3 mmHg) and Cand (11 +/- 2 mmHg) groups than in the Los (22 +/- 2 mmHg), H&H (16 +/- 2 mmHg), and CONTROL (29 +/- 5 mmHg) groups. Plasma catecholamines did not differ among the groups. Heart weight was lowest in the Enal group, followed by the Los and Cand groups. ACE activity of the cerebrum was significantly decreased in the Enal group. The results suggest that chronic treatment with various antihypertensive drugs differentially alters the central pressor response in SHR, and enalapril and candesartan are effective in attenuating this response.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Brain; Enalapril; Epinephrine; Heart Rate; Hydralazine; Hydrochlorothiazide; Hypertension; Injections, Intraventricular; Losartan; Male; Norepinephrine; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Saline Solution, Hypertonic; Tetrazoles

Activation of the renal transforming growth factor beta (TGF-beta) axis has been suggested to play a part in the development of diabetic nephropathy by a direct stimulatory effect of hyperglycaemia or through the activation of the renin-angiotensin system. Our aim was to evaluate the involvement of the renin-angiotensin system by examining the effects of ACE-inhibition on intrarenal changes in all three TGF-beta isoforms and receptors in experimental diabetes in vivo.. Immunocytochemistry, western blotting and ribonuclease protection assays were carried out for each TGF-beta isoform and receptor on kidney from non-diabetic and streptozotocin-diabetic rats after treatment with the ACE inhibitor, enalapril, for 30 days.. Enalapril partially prevented the renal hypertrophy and fully prevented the increase in urinary albumin excretion rate in diabetic animals. The glomerular TGF-beta Type II Receptor mRNA and protein concentrations increased over 30 days in untreated diabetic animals compared with non-diabetic controls, while enalapril-treated diabetic animals showed a normalisation of TGF-beta Type II Receptor mRNA and protein.. The ACE-inhibition had pronounced inhibitory effects on the increased expression of the glomerular TGF-beta Type II Receptor in the diabetic kidney required for intracellular signalling through this growth factor axis. This suggests a new mechanism of action of the ACE-inhibition in regulating the development of diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Female; Gene Expression; Hypertrophy; Kidney; Kidney Glomerulus; Organ Size; Peptide Fragments; Procollagen; Rats; Rats, Wistar; Receptors, Transforming Growth Factor beta; RNA, Messenger

We evaluated the effects of chronic oral administration of an angiotensin II type 1 (AT1)-receptor antagonist YM358 and an angiotensin converting enzyme inhibitor enalapril on hemodynamics and cardiac hypertrophy in rats with volume overload-induced heart failure. We assessed changes of cardiac hemodynamics and cardiac hypertrophy at 2 and 4 weeks after administration of YM358 (3, 30 mg/kg per day) or enalapril (30 mg/kg per day) in abdominal aortocaval shunt rats. YM358 (30 mg/kg) attenuated increases of left ventricle (LV)/body weight (BW), left atrium (LA)/BW, right ventricle (RV)/BW and heart/BW ratios, but did not affect cardiac hemodynamics in shunt rats. Enalapril also reduced the increased LV/BW and heart/BW ratios together with significant reductions of systolic blood pressure, left ventricular systolic pressure and the first derivative of left ventricular pressure. These data suggest that the effects on attenuation of the development of cardiac hypertrophy are not different for YM358 and enalapril, although the effects on cardiac hemodynamics are different for the same dosages. The attenuating action of YM358 on cardiac hypertrophy was independent of the action on hemodynamics and indicated the direct action of the AT1 receptor on the heart.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Abdominal; Azoles; Biphenyl Compounds; Body Weight; Cardiac Output, Low; Cardiomegaly; Coronary Circulation; Enalapril; Heart; Male; Organ Size; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Time Factors

1. We have evaluated the effects of the angiotensin-converting enzyme inhibitor enalapril on renal function and oxidative status in the kidney of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous onset of type 2 diabetes mellitus. 2. Enalapril (5 mg/kg) or vehicle (distilled water) was given once daily by gavage to 22-week-old male OLETF rats for 32 weeks. Long-Evans Tokushima Otsuka (LETO) rats, the control animals for OLETF rats, received vehicle alone (n = 10 in each group). 3. Enalapril attenuated the rise in blood pressure mildly, but significantly. Enalapril significantly blunted the development of proteinuria without a significant effect on creatinine clearance. At the end of the study period, the lipid peroxide content in the renal cortex was significantly increased in OLETF compared with LETO rats, in which enalapril had no effect on lipid peroxide content. Enalapril enhanced the activity of catalase in the renal cortex of OLETF rats, but had no effect on the activity of either superoxide dismutase or glutathione peroxidase. 4. These results suggest that oxidative stress may be involved in the development of nephropathy in type 2 diabetes. Enalapril exhibited renoprotective effects without changing lipid peroxides in the kidney, suggesting that the beneficial effects of the compound on diabetic renal damage in OLETF rats may not be mediated through an anti-oxidative action.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Blood Glucose; Blood Pressure; Body Weight; Catalase; Diabetic Nephropathies; Enalapril; Glutathione Peroxidase; Kidney; Lipid Peroxidation; Male; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Superoxide Dismutase

Chronic inhibition of NO synthesis induces cardiac hypertrophy independent of systemic blood pressure (SBP) by increasing protein synthesis in vivo. We examined whether ACE inhibitors (ACEIs) enalapril and temocapril and angiotensin II type-I receptor antagonists (angiotensin receptor blockers [ARBs]) losartan and CS-866 can block cardiac hypertrophy and whether changes in activation of 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated protein kinase (ERK) are involved. The following 13 groups were studied: untreated Wistar-Kyoto rats and rats treated with NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME), D-NAME (the inactive isomer of L-NAME), L-NAME plus hydralazine, L-NAME plus enalapril (3 mg. kg(-1). d(-1)) or temocapril (1 or 10 mg. kg(-1). d(-1)), L-NAME plus losartan (10 mg. kg(-1). d(-1)) or CS-866 (1 or 10 mg. kg(-1). d(-1)), L-NAME plus temocapril-CS866 in combination (1 or 10 mg. kg(-1). d(-1)), and L-NAME plus rapamycin (0.5 mg. kg(-1). d(-1)). After 8 weeks of each experiment, ratios of coronary wall to lumen (wall/lumen) and left ventricular weight to body weight (LVW/BW) were quantified. L-NAME increased SBP, wall/lumen, and LVW/BW compared with that of control. ACEIs, ARBs, and hydralazine equally canceled the increase in SBP induced by L-NAME. However, ACEIs and ARBs equally (but not hydralazine) attenuated increase in wall/lumen and LVW/BW induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in myocardium (2.2-fold and 1.8-fold versus control, respectively). ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase. Thus, ACEIs and ARBs modulate different intracellular signaling pathways, inhibiting p70S6K or ERK, respectively, to elicit equal reduction of cardiac hypertrophy induced by chronic inhibition of NO synthesis in vivo.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiomegaly; Coronary Vessels; Enalapril; Enzyme Inhibitors; Heart Rate; Heart Ventricles; Imidazoles; Losartan; Male; Mitogen-Activated Protein Kinases; Myocardium; Neutrophil Infiltration; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Olmesartan Medoxomil; Organ Size; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Ribosomal Protein S6 Kinases; Tetrazoles; Thiazepines

The purpose of this study was to examine the role of the renin-angiotensin system in mediating the hypertension in response to chronic reductions in uterine perfusion pressure (RUPP) in conscious chronically instrumented pregnant rats. Mean arterial pressure was significantly higher in pregnant rats with chronic RUPP (125+/-3.0 mm Hg, P<0.01, n=12) than in pregnant rats (100+/-2.3 mm Hg, n=17). Plasma renin activity in pregnant rats with chronic RUPP was 17.1+/-2.5 nmol angiotensin I. L(-1). h(-1) compared with 21.9+/-3.5 nmol angiotensin I. L(-1). h(-1) in pregnant rats. Chronic oral administration of a converting-enzyme inhibitor (enalapril, 250 mg/L for 6 days) decreased mean arterial pressure to a similar extent in pregnant rats with chronic RUPP (109+/-4.2 mm Hg, P<0.01, n=9) and in normal pregnant (81+/-1.8 mm Hg, P<0.01, n=9) rats. Blockade of the renin-angiotensin system, however, had no significant effect on the blood pressure response to chronic RUPP as differences were similar in control (Delta25 mm Hg) and converting-enzyme inhibitor-treated (Delta27 mm Hg) groups. These findings suggest that the renin-angiotensin system does not play a major role in mediating the hypertension produced by chronic RUPP in pregnant rats.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Blood Pressure; Body Weight; Enalapril; Female; Hypertension; Pregnancy; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Uterus

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating s

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Digoxin; Dihydropyridines; Enalapril; Heart; Hypertension; Losartan; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nifedipine; Organ Size; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium-Potassium-Exchanging ATPase; Tunica Media

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

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

Cyclosporine A causes hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). In the present study, arterial function was investigated using in vitro vascular preparations after long-term treatment with cyclosporine A. SHR received cyclosporine A (5 mg kg(-1) day(-1) s.c.) and high-Na(+) diet for 6 weeks during the developmental phase of hypertension. Part of the rats were treated concomitantly either with the angiotensin converting enzyme inhibitor enalapril (30 mg kg(-1) day(-1) p.o.) or with an angiotensin AT(1) receptor antagonist valsartan (3 or 30 mg kg(-1) day(-1) p.o.). In renal arteries, contractile responses to noradrenaline and angiotensin II, as well as relaxation responses to acetylcholine (endothelium-dependent) and to sodium nitroprusside (endothelium-independent), were severely impaired by cyclosporine A-treatment. There was also a trend for the dysfunction of the mesenteric arteries, but the impairment did not reach statistical difference. Enalapril and valsartan improved the impaired renal arterial functions. Cyclosporine A-induced hypertension and nephrotoxicity seem to be associated with renal arterial dysfunction in SHR on high-Na(+) diet. Antagonism of the renin-angiotensin system protects from vascular toxicity of cyclosporine A.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cyclosporine; Dose-Response Relationship, Drug; Enalapril; Hypertension; Male; Mesenteric Arteries; Nitroprusside; Norepinephrine; Rats; Rats, Inbred SHR; Renal Artery; Systole; Tetrazoles; Valine; Valsartan; Vasoconstriction; Vasodilation

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

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

We evaluated whether a novel dual inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), SA7060, (S)-2-[3-[(S)-2-(butoxycarbonyl)-2-hydroxyethyl]-3-isobutylureido] -3-(2-naphtyl) propionic acid, prevents deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related organ damage, such as cardiovascular hypertrophy, renal dysfunction and renal tissue injury in rats. The effectiveness was compared with candoxatril and enalapril, which are a selective NEP and ACE inhibitor, respectively. During DOCA-salt treatment for 4 weeks, the rats were given SA7060, candoxatril, enalapril or vehicle, once daily by gavage. The 4-weeks treatment with DOCA and salt produced progressive increases in systolic blood pressure. Daily administration of SA7060, candoxatril or enalapril significantly suppressed the development of hypertension induced by DOCA and salt, although the effect of enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated DOCA-salt rats, decreases in creatinine clearance and increases in urinary excretion of protein and blood urea nitrogen were observed. This functional damage was improved most efficiently by the treatment with SA7060. There were significant increases in urinary excretions of atrial natriuretic peptide and cyclic GMP in SA7060- or candoxatril-treated animals. Histopathological examination of the kidney in DOCA-salt rats revealed tubular, glomerular and vascular lesions, all of which were improved in animals given SA7060 or candoxatril. When the vascular hypertrophy of the aorta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with the sham rats. The development of vascular hypertrophy was suppressed by the treatment with SA7060, candoxatril or enalapril. Our findings indicate that SA7060 efficiently prevents DOCA-salt-induced hypertension and related tissue injury, mainly by inhibiting NEP. Thus, SA7060 may be useful for treatment of both renin-dependent and renin-independent hypertensive subjects, although further studies examining efficiency in a renin-dependent hypertensive model are needed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Cardiomegaly; Desoxycorticosterone; Enalapril; Heart; Hypertension; Hypertrophy; Indans; Kidney; Kidney Function Tests; Male; Naphthalenes; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Propionates; Rats; Rats, Sprague-Dawley; Urea

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

Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg. kg(-1). d(-1) enalapril (WKY-E group) or a combination of 50 mg. kg(-1). d(-1) hydralazine and 7.5 mg. kg(-1). d(-1) hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10(-)(5) mol/L ACh in the presence of norepinephrine: WKY-O, -14+/-2 mV; WKY-E, -22+/-3 mV; WKY-H, -15+/-2 mV; and WKY-Y, -28+/-0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45+/-6%; WKY-E, 63+/-8%; WKY-H, 43+/-4%; and WKY-Y, 72+/-4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K(+) channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system.

Topics: Acetylcholine; Administration, Oral; Aging; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Biological Factors; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Enalapril; Endothelium, Vascular; Heart Rate; Hydralazine; Hydrochlorothiazide; In Vitro Techniques; Male; Mesenteric Arteries; Nitric Oxide Synthase; Norepinephrine; Rats; Rats, Inbred WKY; Vasodilation

Previous studies have demonstrated in normal rats that chronic treatment, from weaning to 30 days, with either enalapril or losartan, induced significant changes in cardiovascular structure and function. The present study was performed to assess the effect of either enalapril or losartan on the structure and function of the heart and arteries given to normal rats from weaning until 6 months of age. Animals (n = 48) were divided into three groups: control, enalapril treated, and losartan treated; treated rats received 10 mg/kg/day of drug. Blood pressure, body weight, and water intake were recorded for that time period. DNA, cGMP, collagen, degree of fibrosis, and nitric oxide synthase-NADPH-diaphorase-dependent activity in the heart and arteries were determined. Only significant differences (P < .05) are reported. Blood pressure increased only in control rats (13 +/- 1 mm Hg), enalapril treatment enhanced water intake and reduced the rate of body growth (control, 672.9 +/- 15.4 g; losartan, 692.4 +/- 21.8 g; enalapril, 541.8 +/- 13.8 g). In the heart, DNA (control, 120 +/- 5; losartan, 99 +/- 4; enalapril, 93 +/- 6 microg/100 mg), collagen (control, 2.5 +/- 0.2; enalapril, 1.85 +/- 0.08 microg/100 mg), and fibrosis (control, 3.5 +/- 0.4%; losartan, 2.2 +/- 0.3%; enalapril, 2.1 +/- 0.4%) were reduced by treatment. In the aorta, cGMP (control, 0.15 +/- 0.01; losartan, 0.24 +/- 0.02 pmol/mg), and NADPH-diaphorase (control, 0.114 +/- 0.003; losartan, 0.148 +/- 0.006; enalapril, 0.169 +/- 0.003 as optical density) were enhanced. The enzyme was also higher in the aortic endothelium of treated animals (control, 0.193 +/- 0.010; losartan, 0.228 +/- 0.009; enalapril, 0.278 +/- 0.005). The lower rate of body weight increase, the enhanced water intake, and the reduced cardiac and left ventricular weight attributable to enalapril treatment do not seem to be related to inhibition of the renin-angiotensin system. On the other hand, renin-angiotensin system inhibition induces a protective effect on the heart and aorta through structural and functional changes. Most of this action seems to be exerted through angiotensin II type 1 receptors.

Topics: Angiotensin II; Animals; Aorta; Blood Pressure; Body Weight; Cardiovascular System; Collagen; Cyclic GMP; DNA; Drinking; Enalapril; Fibrosis; Losartan; Male; Myocardium; NADPH Dehydrogenase; Rats; Rats, Wistar; Reference Values; Systole; Time Factors

To determine whether effects of angiotensin converting enzyme (ACE) inhibitors on well-established pressure overload-induced cardiac hypertrophy and coronary remodeling depend upon normal plasma renin levels, the influence of enalapril on ventricular mass and coronary vascular resistance (CVR) was determined in a low-renin female rat model of chronic pressure overload, (deoxycorticosterone acetate hypertension, DOCA), and compared to its effect in a normal-renin model, (aortic construction, AC). Six weeks after experiment initiation, plasma renin activity of DOCA-treated rats was reduced to approximately 12% that of sham-treated and AC-treated groups. Enalapril was then added to the drinking water of half the animals in each group for two additional weeks. Comparing experimental groups to controls, this delayed enalapril treatment had 1) no effect on the elevated arterial pressures, 2) no effect on the elevated coronary resistance, and, in the DOCA group, 3) no effect on cardiac hypertrophy. However, this brief enalapril treatment reduced absolute and relative ventricular weights of AC rats. These data suggest that circulating renin is required for the anti-hypertrophic efficacy of late-onset brief treatment with enalapril. Since enalapril-induced reversal of cardiac hypertrophy in AC rats was not accompanied by reversal of coronary remodeling, growth signals other than angiotensin II may be involved in coronary remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Body Weight; Cardiomegaly; Coronary Circulation; Desoxycorticosterone; Enalapril; Female; Hypertension; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Vascular Resistance

We studied the effects of 10-week long enalapril and losartan treatments (4 and 15 mg kg(-1) day(-1), respectively) on mesenteric arterial function in vitro in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The relaxations of noradrenaline-precontracted rings to acetylcholine, nitroprusside and cromakalim were similar in WKY and enalapril- and losartan-treated SHR, and more pronounced than in untreated SHR. The responses to acetylcholine were attenuated by N(G)-nitro-L-arginine methyl ester in WKY and drug-treated SHR, but were completely inhibited in untreated SHR. When hyperpolarization of smooth muscle was prevented by KCl-induced precontractions, no differences were found in the relaxations to acetylcholine and nitroprusside between the groups, and the dilatations to cromakalim were abolished. Moreover, in noradrenaline-precontracted rings of drug-treated SHR, the addition of tetraethylammonium attenuated the nitric oxide synthase and cyclooxygenase-resistant relaxations to acetylcholine and abolished the enhanced dilatations to nitroprusside. In conclusion, since the enhancement of vasorelaxation in enalapril- and losartan-treated SHR was abolished by conditions preventing hyperpolarization, the improved vasodilatation following these therapies could be attributed to enhanced vasodilatation via K+ channels in this model of hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diclofenac; Enalapril; Endothelium; Enzyme Inhibitors; Heart Rate; Hypertension; In Vitro Techniques; Losartan; Male; Mesenteric Arteries; Muscle Contraction; Muscle Relaxation; NG-Nitroarginine Methyl Ester; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstrictor Agents; Vasodilation

TGR(mREN2)27 (TGR) rats are transgenic animals with an additional mouse renin gene, which leads to overactivity of the renin-angiotensin system. Adult TGR rats are characterized by fulminant hypertension, hypertensive end-organ damage, and an inverse circadian blood pressure pattern. To study the ontogenetic development of cardiovascular circadian rhythms, telemetric blood pressure transmitters were implanted in male Sprague-Dawley (SPRD, n = 5) and heterozygous, transgenic TGR rats before 5 weeks of age. The TGR received either drinking water or enalapril 10 mg/L in drinking water (n = 5 per group). Drug intake was measured throughout the study by computerized monitoring of drinking volume. Circadian patterns in blood pressure and heart rate were analyzed from 5 to 11 weeks of age. In the first week after transmitter implantation, blood pressure did not differ among SPRD, untreated, and enalapril-treated TGR rats. In parallel with the rise in blood pressure of untreated TGR rats, a continuous delay of the circadian acrophase (time of fitted blood pressure maximum) was observed, leading to a complete reversal of the rhythm in blood pressure at an age of 8 weeks. Enalapril reduced blood pressure at night, but was less effective during the day, presumably due to the drinking pattern of the animals, which ingested about 90% of their daily water intake during the nocturnal activity period. After discontinuation of treatment, blood pressure returned almost immediately to values found in untreated TGR rats. In conclusion, the inverse circadian blood pressure profile in TGR rats develops in parallel with the increase in blood pressure. Direct effects of the brain renin-angiotensin system may be involved in the disturbed circadian rhythmicity in TGR(mREN2)27 rats.

Topics: Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Pressure; Body Weight; Circadian Rhythm; Enalapril; Heart Rate; Heterozygote; Hypertension; Male; Mice; Motor Activity; Rats; Rats, Sprague-Dawley; Renin

Cyclosporine A (CsA)-induced hypertension has been shown to be dependent on the level of dietary salt. The present study assessed the role of the renin-angiotensin system in the development of CsA-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR) on a high-sodium diet. In addition, we examined whether ACE inhibition prevents the detrimental effects of CsA on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. Eight-week-old SHR were divided into three different groups (n = 8 in each group): (i) SHR control group receiving a high-sodium diet (Na 2.6% of the dry weight of the chow), (ii) CsA group (5 mg/kg s.c.) on a high-sodium diet and (iii) CsA + enalapril group (30 mg/kg p.o.) on a high-sodium diet. At the end of the six-week experimental period, systolic blood pressure in the CsA group was significantly higher compared to the control group (245+/-6 vs 208+/-9 mmHg, respectively, p < 0.05). Plasma renin activity was increased 20-fold by CsA treatment (p < 0.05 compared to controls). CsA increased serum creatinine by 22%, the 24-h urinary protein excretion by 190% and the 24-h urinary excretions of calcium, phosphorus and magnesium by 150%, 25% and 140%, respectively (p < 0.05 compared to controls). Histologically, the kidneys of CsA-treated SHR showed severe thickening of the media of the afferent arteriole and fibrinoid necrosis of the arteriolar wall. Interestingly, CsA induced vascular injury also in the small myocardial arteries. Enalapril treatment prevented CsA-induced hypertension and deterioration of kidney function as well as CsA-induced vascular injuries in the kidneys and myocardium. Enalapril also decreased left ventricular weight-to body weight ratio and prevented CsA-induced increases in urinary calcium and phosphorus excretions. Our findings indicate that CsA has a detrimental effect on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. ACE inhibition prevents the CsA-induced hypertension, nephrotoxicity and vascular injuries. Our findings thus suggest that increased activity of the renin-angiotensin system is involved in the pathogenesis of CsA-induced hypertension and nephrotoxicity in SHR on a high-sodium diet.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Creatinine; Cyclosporine; Enalapril; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Kidney; Potassium; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium, Dietary

Systemic arterial elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in myocardial infarction (MI). The cardiac effect of angiotensin-converting enzyme inhibitors (ACEIs) has been extensively studied, whereas their arterial effect has been poorly reported in MI. The aim of this work was to study the effect of prolonged ACEI enalapril treatment on systemic arterial structure and elastic properties in rats with MI. One week after the induction of an MI, 40 male Wistar rats received either no treatment (n = 20) or ACEI enalapril (2 mg/kg; n = 20) for 17 weeks. At the end of the treatment period, blood pressure, cardiac output, total peripheral resistance, systemic arterial compliance, characteristic impedance, and left ventricular power were measured in anesthetized rats. Then the rats were killed for infarct-size determination and aortic histomorphometric study. Infarct size, heart, and left and right ventricular weights were similar in the ACEI-treated and untreated infarcted rats. Prolonged ACEI enalapril treatment reduced blood pressure by 17% (p < 0.001), total peripheral resistance by 22% (p < 0.01), and characteristic impedance by 26% (p < 0.03), and increased systemic arterial compliance by 35% (p < 0.01), in comparison with untreated infarcted rats. Enalapril reduced aortic media wall thickness by 9% (p < 0.02) and increased elastin content by 22% (p < 0.03) and elastin-to-collagen content ratio by 42% (p < 0.01). Enalapril did not affect cardiac output and left ventricular power. Smooth muscle cell nuclei number and size and collagen content of aortic wall were similar in the ACEI-treated and untreated infarcted rats. These results indicate that long-term treatment with ACEI enalapril improves arterial elastic properties through structural modifications of arterial wall in rats with MI. This vascular effect may contribute to improve the left ventricular function and the coronary perfusion of infarcted myocardium, and added to the cardiac effect, may explain the prevention of left ventricular remodeling observed with ACEI in this model.

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Body Weight; Enalapril; Hemodynamics; Male; Myocardial Infarction; Organ Size; Rats; Rats, Wistar; Time Factors

To determine whether antihypertensive treatment could alter hypertension and age-related progressive impairment of coronary hemodynamics and cardiac fibrosis in aged spontaneously hypertensive rats (SHR).. Old SHR were given their respective therapy for 3 months. To differentiate between hypertension and age-related changes, a comparison was made between left and right ventricular indices since the right ventricle was not exposed to pressure overload.. Male, 65-week-old spontaneously SHR were divided into three groups and were given either vehicle, felodipine (30 mg/kg per day) or enalapril (30 mg/kg per day). After 12 weeks of the respective treatments, systemic and coronary hemodynamics (radionuclide-labelled microspheres), right and left ventricular and aortic mass indices, and right and left ventricular hydroxyproline concentrations (an estimate of collagen) were determined.. Arterial pressure and total peripheral resistance were reduced to the same extent in SHRs treated with either felodipine or enalapril; however, compared to the control rats, enalapril was more effective in reducing left ventricular and aortic mass indices. Both agents also improved coronary hemodynamics of both ventricles in aged SHR but enalapril was more effective as indicated by a greater increase in coronary flow reserve and a greater decrease in minimal coronary vascular resistance. Furthermore, enalapril but not felodipine reduced left ventricular hydroxyproline concentration; and right ventricular hydroxyproline concentration increased with felodipine but remained unchanged with enalapril.. Both enalapril and felodipine ameliorated adverse cardiovascular effects of hypertension in the aged SHRs within 12 weeks, as demonstrated by reduced arterial pressure, diminished left ventricular mass, and improved coronary hemodynamics. Enalapril also decreased aortic mass and left ventricular collagen concentration and appeared to be more effective in improving coronary hemodynamics than felodipine, possibly as a result, in part, of reduced myocardial fibrosis.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Calcium Channel Blockers; Cardiovascular System; Collagen; Enalapril; Endomyocardial Fibrosis; Felodipine; Hemodynamics; Hydroxyproline; Hypertension; Male; Myocardium; Rats; Rats, Inbred SHR

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

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

Imidapril, enalapril and quinapril were subcutaneously administered to aortic-banded rats by osmotic minipumps to compare the suppressive actions of these angiotensin converting enzyme (ACE) inhibitors on pressure-induced cardiac hypertrophy. Among the three drugs tested, imidapril was most potent for the prevention of cardiac hypertrophy, although equipotent hypotensive doses were used. Imidapril reduced both serum and cardiac ACE activities, while enalapril reduced only the former. Quinapril also reduced both, however, it was less potent at reducing the former compared to imidapril. Moreover, only imidapril significantly decreased left ventricular end diastolic pressure, which tended to be increased by aortic-banding. The lipophilicity of ACE inhibitors could not explain the more potent suppressive action of imidapril on cardiac hypertrophy because the lipophilicity of imidaprilat, an active metabolite of imidapril, was as low as an active metabolite of enalapril; i.e., much lower than an active metabolite of quinapril. The efficacy of ACE inhibitors on pressure-induced cardiac hypertrophy depends not only on an inhibitory effect on cardiac ACE activity, but also on other actions such as their effect on left ventricular end diastolic pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiomegaly; Diastole; Enalapril; Heart; Imidazoles; Imidazolidines; Isoquinolines; Quinapril; Rats; Tetrahydroisoquinolines; Ventricular Function, Left

We have recently reported that the cardiovascular responses to excitatory amino acids are augmented in the rostral ventrolateral medulla of spontaneously hypertensive rats (SHR). In the present study, we investigated whether the responsiveness to excitatory amino acids would be normalized by antihypertensive treatment. Thus we treated 4-week-old SHR and age-matched Wistar-Kyoto (WKY) rats with either enalapril (25 mg/kg per day in drinking water) or vehicle for 8 weeks. At 12 weeks of age, systolic blood pressure in the untreated SHR (248+/-9 mm Hg) was significantly (P<.01) higher than that in the enalapril-treated SHR (140+/-4 mm Hg), untreated WKY rats (148+/-4 mm Hg), and enalapril-treated WKY rats (117+/-1 mm Hg). The pressor responses to L-glutamate (2 nmol) microinjected into the rostral ventrolateral medulla were similar in enalapril-treated and untreated SHR (40+/-5 and 47+/-3 mm Hg, respectively, NS), and these responses were significantly greater than that seen in the untreated WKY rats (24+/-2 mm Hg, P<.01). On the other hand, the pressor response to either N-methyl-D-aspartate, an ionotropic glutamate receptor agonist, or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a metabotropic glutamate receptor agonist, in the enalapril-treated SHR was slightly but significantly smaller than that in the untreated SHR but was still markedly greater than those in untreated and enalapril-treated WKY rats. These results suggest that the augmented responsiveness to excitatory amino acids in the rostral ventrolateral medulla of SHR may be at least partly genetically determined and cannot be normalized by the treatment with enalapril.

Topics: Animals; Antihypertensive Agents; Baroreflex; Blood Pressure; Body Weight; Enalapril; Excitatory Amino Acid Agonists; Glutamic Acid; Heart Rate; Hypertension; Medulla Oblongata; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Glutamate

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

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

Spontaneous rupture of the internal elastic lamina (IEL) occurs in some arteries of the rat during growth and aging. Inbred, normotensive, Brown Norway (BN) rats are particularly susceptible to rupture of the IEL, especially in the abdominal aorta (AA). Preliminary experiments showed that different angiotensin-converting enzyme (ACE) inhibitors protect against rupture of the IEL in the BN rat to a greater extent than hydralazine, suggesting a role of the renin-angiotensin system (RAS) in this phenomenon. To explore this possibility, we have treated male BN rats from 4.5 to 14 weeks of age with either enalapril or losartan (both at 1, 3, and 10 mg x kg(-1) x d(-1)) or with the calcium antagonists mibefradil (at 3, 10, 30, and 45 mg x kg(-1) x d(-1)) and amlodipine (at 30 mg x kg(-1) x d(-1)). Systolic blood pressure (SBP) was measured weekly, and at the end of treatment we (1) recorded body and heart weights, (2) measured various parameters of the RAS in plasma, (3) quantified interruptions in the IEL on "en face" preparations of AA, and (4) quantified elastin, collagen, and cell proteins in the media of the thoracic aorta. Results showed that enalapril and losartan similarly decrease SBP and rupture of the IEL in the AA, suggesting that enalapril inhibits the latter via a decrease in the production of angiotensin II (Ang II) and not via another effect on ACE. The decrease in IEL rupture and in SBP, as well as the modifications in the parameters of the RAS, were all dose dependent. Mibefradil had little effect on the RAS and, at the highest doses, decreased SBP to an extent similar to that for enalapril at 3 mg x kg(-1) x d(-1) but did not significantly inhibit IEL rupture. Amlodipine decreased SBP, increased plasma renin concentration, and was without effect on IEL rupture. All treatments at the highest doses had a hypotrophic effect on the aortic media but differed in their effects on the heart, with enalapril and losartan decreasing and mibefradil and amlodipine increasing heart weight, suggesting that the inhibition of IEL rupture may be related to a cardiac hypotrophic effect. All these results, taken together, suggest that Ang II plays a role in the rupture of the IEL that is, in part, independent of SBP.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Rupture; Benzimidazoles; Blood Pressure; Body Weight; Calcium Channel Blockers; Collagen; Elastic Tissue; Elastin; Enalapril; Heart; Heart Rate; Losartan; Male; Mibefradil; Muscle, Smooth, Vascular; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred BN; Renin; Renin-Angiotensin System; Tetrahydronaphthalenes

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

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

This study examined the effects of long-term treatments with the angiotensin-converting enzyme inhibitor, enalapril, and the calcium antagonist, amlodipine, on the morphologic changes, progressive left ventricular dysfunction, and gene expression of the ryanodine receptor (RyR) and phospholamban (PLN) in dilated cardiomyopathy. From the ages of 5 through 20 weeks, dilated cardiomyopathic hamsters, BIO53.58 (BIO), and control hamsters, F1b, orally received either enalapril or amlodipine. Cardiac function was assessed by echocardiography. At the age of 20 weeks, the collagen volume fractions were analyzed by the stereologic method. RyR and PLN messenger RNAs (mRNAs) were examined by Northern blot in the amlodipine group. In BIO, the reduction of left ventricular percentage of fractional shortening was attenuated in the enalapril group (p < 0.05) and amlodipine group (p < 0.001), and the increase in the collagen volume fraction and the loss of myocytes were suppressed in the amlodipine group compared with the untreated group. RyR mRNA level decreased in BIO (p < 0.01) compared with F1b, but PLN mRNA level was unchanged. RyR and PLN mRNA levels were unaffected by the treatment with amlodipine. Enalapril and amlodipine prevent progressive remodeling and reduce cardiac dysfunction in BIO. Amlodipine prevents fibrosis and cell death without modifying RyR and PLN mRNA levels in BIO.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Calcium; Calcium Channel Blockers; Calcium-Binding Proteins; Cardiomyopathies; Cricetinae; Disease Models, Animal; Enalapril; Extracellular Matrix; Gene Expression; Heart; Male; Myocardium; Rats; Ryanodine Receptor Calcium Release Channel; Vasodilator Agents; Ventricular Function, Left

We studied the effects of long-term treatment with enalapril (5 mg/kg/day orally) on various biochemical and cardiovascular complications in streptozotocin (STZ) diabetic and deoxycorticosterone acetate (DOCA) hypertensive rats. Female Wistar rats made diabetic or hypertensive or both by streptozotocin (STZ; 45 mg/kg) or deoxycorticosterone acetate (DOCA; 10 mg/kg, p.o., daily) or both. Enalapril (5 mg/kg) was administered daily by the oral route for 6 weeks. At the end of 6 weeks, blood samples were taken to analyze glucose, insulin, and lipids. Blood pressure and heart rate were recorded by a noninvasive technique, and cardiac functions were recorded by Neely's working heart preparation. Injection of STZ produced severe glycosuria (>2%), hyperglycemia, hypoinsulinemia, and loss of body weight. It also produced hypercholesterolemia, hypertriglyceridemia, hypertension, bradycardia, and decreased left ventricular developed pressure (LVDP) and increase in angiotensin-converting enzyme (ACE) in left ventricular tissue. DOCA by itself did not produce any change in blood glucose but reduced serum insulin levels in nondiabetic animals. However, in the diabetic group, DOCA reduced blood sugar levels. Treatment with enalapril prevented an increase in the blood pressure and the heart weight. Decrease in the heart rate, reduction in LVDP, and increase in intracardiac activity were observed in diabetic rats; these were also prevented by enalapril treatment. Enalapril had no effect on plasma glucose and did not modify plasma insulin levels in diabetic animals. The effects of STZ and DOCA together were not additive on the investigated parameters, and enalapril was similarly efficient in diabetic and diabetic hypertensive animals.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Desoxycorticosterone; Diabetes Mellitus, Experimental; Enalapril; Female; Hypertension; Lipid Metabolism; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Streptozocin

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

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

Previous experiments showed that enalapril (EN) treatment as well as enalaprilic acid, when added to the perfusion bath, diminish the inotropic response of the papillary muscles to isoproterenol (ISO). The main objective of this study was to evaluate, in normal rats, the effect of EN on basal contractility and inotropic response to ISO on the whole perfused ventricles (Langendorff preparation). Blood pressure (BP), increase in body weight (IBW), ventricular weight/body weight ratio (R) and concentration of ventricular proteins and DNA were also analyzed. Five groups were studied: EN10: 5 mg/kg/day, 10 days; EN21(L): 5mg/kg/day, 21 days; EN21(H): 15 mg/kg/day, 21 days. C10 and C21 were untreated controls. Cardiac contractility was evaluated by the maximal developed pressure, maximal rate of rise of pressure and maximal velocity of relaxation; no changes were found due to EN treatments either on basal conditions or on ISO stimulation. Significant differences (p<0.05 vs C21) were: lower BP and R in EN21(L) and EN21(H), slower IBW in EN21(H), decreased ventricular DNA in EN21(H). In conclusion, daily treatment for ten or twenty one days with enalapril does not change either basal cardiac contractile performance or inotropic response to ISO in the Langendorff preparation. Longterm treatment with EN seems to modify nuclear processes involved in cardiomyocite DNA content.

Topics: Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Basal Metabolism; Blood Pressure; Body Weight; Enalapril; Heart; Heart Ventricles; Heart, Artificial; Isoproterenol; Male; Rats; Rats, Wistar; Reference Values; Renin

Overproduction of transforming growth factor-beta (TGF-beta) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease.. One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated.. Both enalapril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-beta expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-beta expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-beta expression.. The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulonephritis, Membranoproliferative; Kidney; Losartan; Male; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

The roles of elevated cell sodium concentrations and the angiotensin-aldosterone system (AAS) in the structural and functional adaptation of the distal tubule and collecting duct system to a chronic increase of sodium delivery were examined using electron microprobe and quantitative morphologic/stereologic analyses. Studies were performed on rats given the loop diuretic torasemide acutely (20 min) or chronically (12 days), either alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor, enalapril. In the sodium-absorbing cells of the distal tubule and cortical collecting duct-that is, in distal convoluted tubule (DCT), connecting tubule (CNT) and principal cells-an acute increase in sodium delivery caused a significant rise in intracellular sodium concentration and rubidium uptake, the latter an index of in vivo Na,K(Rb)-ATPase activity. The elevated cell sodium concentrations returned to, or close to, control values during chronic torasemide treatment. Intracellular rubidium concentrations, measured after a 30-second rubidium exposure, were not different from controls in DCT and CNT cells but were still higher in principal cells. Since, however, the distribution space for rubidium was significantly increased in chronic torasemide animals, rubidium uptake, and hence Na,K-ATPase activity, must have increased in proportion to cell volume in DCT and CNT cells, but more than proportionately in principal cells. When ACE was inhibited during chronic torasemide, the epithelial volume of DCT and cortical collecting duct (CCD) was increased mainly by lengthening and not, as was the case in rats given torasemide alone, by thickening of the tubule wall. Adaptation of the proximal tubule exclusively by lengthening was not affected by inhibition of the ACE. These data indicate that changes in cell ion composition may participate in initiating cell processes leading to adaptation of distal nephron segments to chronically increased salt delivery. Inhibition of the ACE reverses the torasemide-induced increase in apparent Na pump density in principal cells and seems to shift the relationship between hypertrophy and hyperplasia noted in DCT and CCD after chronic torasemide in favor of hyperplasia.

Topics: Aldosterone; Anesthesia; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Consciousness; Diuresis; Diuretics; Electrolytes; Enalapril; Hematocrit; Kidney Cortex; Kidney Function Tests; Kidney Tubules; Male; Rats; Rats, Wistar; Rubidium; Sodium; Sodium-Potassium-Exchanging ATPase; Sulfonamides; Torsemide; Urine; Vasoconstrictor Agents; Water-Electrolyte Balance

Recently, we reported that neonatal blockade of the renin-angiotensin system in the rat produces irreversible abnormalities in renal histology associated with increased diuresis. In the present study, we assessed the long-term consequences of neonatal angiotensin-converting enzyme inhibition on renal function. Rats were injected with 10 mg.kg-1.d-1 enalapril or vehicle from day 3 to day 24 after birth. Urine concentrating ability, renal function, and renal histology were assessed in 16-week-old rats. There was a twofold increase in diuresis and water intake in enalapril-treated rats throughout the study course. Urine osmolality after 24 hours of water deprivation was 1008 +/- 108 and 2549 +/- 48 mOsm.kg-1 (P < .05) in enalapril- and vehicle-treated rats, respectively. Glomerular filtration rate (0.54 +/- 0.03 versus 0.75 +/- 0.06 mL.min-1x100 g body wt-1, P < .05) and effective renal plasma flow (1.76 +/- 0.09 versus 2.19 +/- 0.14 mL.min-1x100 g body wt-1, P < .05) were reduced in neonatally enalapril-treated versus control rats. Absolute and fractional urinary sodium excretion values were elevated (P < .05) in enalapril-treated rats. Semiquantitative assessment of renal histology demonstrated statistically significant degrees of papillary atrophy, interstitial fibrosis and inflammation, tubular atrophy and dilatation, and focal glomerulosclerosis in neonatally enalapril-treated rats. In conclusion, neonatal angiotensin-converting enzyme inhibition in the rat produces irreversible alterations in renal function and morphology, demonstrating the importance of an intact renin-angiotensin system neonatally for normal renal development.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Body Weight; Diuresis; Enalapril; Glomerular Filtration Rate; Kidney; Male; Organ Size; Osmolar Concentration; Rats; Rats, Wistar; Renal Plasma Flow, Effective; Sodium

Chronic hypoxia induces pulmonary hypertension and right ventricular hypertrophy. These changes are completely reversible, except for persistent myocardial fibrosis. The aim of the present study was to determine whether treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can reduce the ventricular collagen content in animals recovering from chronic hypoxia. Adult male Wistar rats were exposed to intermittent high-altitude hypoxia simulated in a barochamber (7000 m, 8 hr/day, 5 days a week, 24 exposures), then transferred to normoxia and divided into two groups: (a) treated with enalapril (0.1 g/kg/day for 60 days) and (b) without treatment. The corresponding control groups were kept under normoxic conditions. Enalapril significantly decreased the heart rate, systemic arterial pressure, and absolute left and right ventricular weights in both hypoxic and control rats; on the other hand, the pulmonary blood pressure was unchanged. The content and concentration of collagen was reduced in both ventricles of enalapril-treated hypoxic and control animals by 10-26% compared with the corresponding untreated groups. These data suggest that the partial regression of cardiac fibrosis due to enalapril may be independent of the pressure load.

Topics: Altitude Sickness; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Enalapril; Hemodynamics; Hydroxyproline; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Myocardium; Organ Size; Pulmonary Fibrosis; Rats; Rats, Wistar

It is not yet known if the alterations in myocardial glucose metabolism and the exaggerated left ventricular dysfunction that occur during reperfusion in hypertrophied hearts are reversible. Thus, we studied isolated working hearts from aortic-banded (n = 29) and sham-operated control (n = 32) male Sprague-Dawley rats with or without enalapril maleate treatment (25.6 +/- 0.8 mg/kg per day, p.o.) to determine the effect of regression of cardiac hypertrophy on myocardial glucose metabolism and post-ischemic heart function. Hearts were perfused with buffer containing 1.2 mM palmitate, 11 mM [5-3H]/[U-14C]-glucose, 0.5 mM lactate and 100 microU/ml insulin. Glucose metabolism [rates of glycolysis (3H2O production) and rates of oxidation (14CO2 production) of exogenous glucose] and heart function (heart rate x peak systolic pressure) were measured during 30 min pre-ischemic perfusion and 60 min of reperfusion following 20 min of global, no-flow ischemia. Hearts from untreated aortic-banded rats were hypertrophied, being 27.6 +/- 1.8% larger than hearts from untreated control rats. Enalapril treatment caused regression of cardiac hypertrophy that normalized heart weight in aortic-banded rats. Rates of glycolysis of exogenous glucose in hearts from untreated aortic-banded rats were accelerated compared to rates in hearts from untreated control rats during pre-ischemic perfusion (4391 +/- 97 v 2652 +/- 69 nmol glucose/min per g dry wt, respectively, P < 0.05) and reperfusion (2402 +/- 58 v 1597 +/- 88 nmol glucose/min per g dry wt. respectively, P < 0.05). In contrast, rates of glycolysis of exogenous glucose in hearts from enalapril-treated aortic-banded rats were normalized before and after ischemia. Rates of glycolysis of exogenous glucose in hearts of control rats were not affected by enalapril treatment. Oxidation of exogenous glucose was not different among groups either before or after ischemia. Function of hearts from untreated aortic-banded rats at the end of reperfusion was significantly less than that of hearts from untreated control rats (23.9 +/- 2.6 v 32.2 +/- 0.7 mmHg x beats per min/1000, respectively, P < 0.05). As with myocardial glucose metabolism function of hearts from aortic-banded rats treated with enalapril was normalized during reperfusion. Thus, pharmacologically induced regression of pressure-overload cardiac hypertrophy normalizes glucose metabolism as well as left ventricular function during reperfusion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Enalapril; Glucose; Glycolysis; Hypertrophy, Left Ventricular; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Organ Size; Oxidation-Reduction; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

Valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl¿ valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist, or enalapril was administered to spontaneously hypertensive rats stroke-prone (SHR-SP) for 1 year from 8 weeks to 56 weeks of age under a normal diet without saline load. During 48 weeks, control rats showed increase in systolic blood pressure from 180 to 250 mmHg accompanying stroke-related behaviour, cardiac and aortic hypertrophy, hyperreactive contractility of mesenteric vascular beds, proteinuria, high water turnover and death. Valsartan at 3, 10 and 30 mg/kg/d p.o. and enalapril at 1 and 10 mg/kg/d p.o suppressed the increase in blood pressure dose-dependently. Systolic blood pressure was steadily controlled to around 180 mmHg at the highest dose of either drug throughout the study. In proportion to the antihypertensive action of the drugs, end-organ damage was prevented. During 1-year administration, effects of enalapril and valsartan were much the same, indicating the clinical usefulness of valsartan being comparable to enalapril.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; Body Weight; Cardiomegaly; Cerebrovascular Disorders; Enalapril; Heart Rate; Hypertension; Male; Mesentery; Muscle Contraction; Organ Size; Rats; Rats, Inbred SHR; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles; Valine; Valsartan

The hemodynamic effects of valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)bipheneoyl-4-yl]meth yl¿valine, CAS 137862-53-4, CGP 48933), a new angiotensin II type 1 receptor antagonist, on rats with myocardial infarction induced by coronary artery ligation was examined. Four weeks after ligation, mean blood pressure, left ventricular pressure and cardiac output decreased, while left ventricular end-diastolic pressure increased in control rats. Left ventricular end-diastolic pressure significantly decreased in rats treated with valsartan at 30 mg/kg/d p.o. for 4 weeks. Total systemic resistance remarkably decreased in those with enalapril 3 mg/kg/d p.o. and valsartan 30 mg/kg/d p.o. Valsartan and enalaprilat did not affect cardiac functions of isolated intact rat hearts before and after ischemia in Langendorff apparatus. In addition to hemodynamic effects observed in vivo, valsartan at 30 mg/kg p.o. significantly inhibited left ventricular hypertrophy. Valsartan would thus appear to be clinically useful for treating heart failure following myocardial infarction.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Enalapril; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Organ Size; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles; Valine; Valsartan; Vascular Resistance; Ventricular Function, Left

We administered angiotensin (Ang) II receptor type 1 (AT1) blockade (losartan; 10 or 40 mg/kg per day), type II receptor (AT2) blockades (PD123319; 100 mg/kg per day), or angiotensin-converting enzyme (ACE) inhibitor (enalapril; 30 mg/kg per day) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. At the end of the treatment, high doses of losartan and enalapril significantly reduced the arterial systolic blood pressure compared with the untreated SHR to the level of WKY rats. But low doses of losartan and PD123319 were without effect. High doses of losartan and enalapril also significantly reduced both the left ventricular (LV) weight and the ratio of LV to body weight compared with the untreated SHR, which were still larger than that of WKY rats. However, the collagen concentration of SHR treated with high doses of losartan or enalapril was completely reduced to the level of WKY rats. Using reverse transcription polymerase chain reaction, we examined the mRNA expression for ACE, AT1, and AT2 in experimental animals. The enhanced AT1 mRNA expression was significantly decreased in the SHR treated with a high dose of losartan or PD123319 compared with the untreated SHR. The level of ACE mRNA was also decreased in the SHR treated with a high dose of losartan or enalapril. The level of AT2 mRNA was not significantly different between the Wistar-Kyoto rats and the SHR; however, this expression was decreased significantly after the treatment with a high dose of losartan or PD123319. These results indicate that AT1 receptor and ACE, but not AT2 receptor, play a crucial role in the remodeling of matrix tissue but a smaller role in the development of the hypertrophy of LV myocyte in SHR and that the LV/body weight changes do not fully account for the complete suppression of hypertension.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cardiomegaly; Dose-Response Relationship, Drug; Down-Regulation; Enalapril; Imidazoles; Losartan; Male; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger

We investigated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor enalapril and low-salt intake on the survival rate of Dahl salt-sensitive rats fed a high-salt (6.0% NaCl) diet. The systolic blood pressure of the rats increased gradually from 5 weeks of age and reached >240 mm Hg at 12 weeks of age. At this point, a low-salt diet group received a placebo (group 1, n = 10), and the high-salt diet group was divided into three groups: those given a placebo with the high-salt diet (group 2, n = 15), those given a chow change from a high- to a low-salt diet with a placebo (group 3, n = 14) and those given enalapril (30 mg/kg/day p.o., group 4, n = 14). At 19 weeks of age, all rats in group 1 were alive, and the survival rate of group 2 was only 40% (P < .001 vs. group 1). The survival rates of both groups 3 and 4 were significantly better: 86% (P < .01 vs. group 2) and 93% (P < .01), respectively. This beneficial effect on mortality was accompanied by an amelioration of the elevated plasma creatinine and urea nitrogen levels and a decrease in the glomerular sclerosis lesion scores in both groups. These results suggested that a high-salt content diet and the renin-angiotensin system are deterioration factors in lethal renal damage and the limitation of the diet salt content and inhibition of the renin-angiotensin system are important to improve the survival rate in high-salt-loaded hypertensive Dahl salt-sensitive rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Enalapril; Heart Rate; Hypertension; Kidney; Male; Rats; Sodium Chloride, Dietary; Survival Rate

The renin-angiotensin system plays an important role in renal growth and development: exposure of the fetus or neonate to angiotensin-converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. This study was designed to investigate the effects of ACE inhibition in the neonatal rat on the expression of genes known to modulate renal cellular proliferation, cell interactions, and extracellular matrix. Newborn rat pups were treated with enalapril (30 mg/kg/d) or vehicle for 14 d, and kidneys were removed for Northern analysis of mRNA for transforming growth factor-beta1 (TGF-beta1), prepro epidermal growth factor (EGF), clusterin, and renin. Distribution of TGF-beta1, EGF, and clusterin was also determined by immunohistochemistry. Enalapril treatment resulted in 40% mortality by d 14, reduced body and kidney weight, decreased glomerular area, and caused tubular dilatation (p < 0.05 versus vehicle group). Enalapril decreased renal TGF-beta1 and EGF mRNA expression, and increased renal clusterin and renin expression (p < 0.05). Renal tubular immunoreactive EGF was decreased, and clusterin was increased by enalapril treatment. These results indicate that ACE inhibition in the developing kidney reduces the renal expression of critical growth factors, which may account for renal growth impairment. Clusterin expression may increase either due to blockade of tonic angiotensin-mediated inhibition, or as an adaptive response to renal ischemia.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Body Weight; Clusterin; Enalapril; Epidermal Growth Factor; Glycoproteins; Growth Substances; Kidney; Kidney Glomerulus; Kidney Tubules; Molecular Chaperones; Organ Size; Protein Precursors; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

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

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

High blood pressure results in cardiac hypertrophy and fibrosis, increased thickness and stiffness of large artery walls, and decreased renal function. The objective of our study was to assess the role of endothelin, angiotensin II, and high blood pressure in the end-organ damage observed in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 10 weeks with either a mixed endothelin-A and endothelin-B receptor antagonist, bosentan (100 mg/kg per day), an angiotensin-converting enzyme inhibitor, enalapril (10 mg/kg per day), or a long-acting calcium antagonist, mibefradil (20 mg/kg per day). A group of SHR was left untreated, and a group of normotensive Wistar rats was used as control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and fibrosis, aortic medial thickness, and extracellular matrix content were evaluated by quantitative morphometry. Proteinuria and urea and creatinine clearances were measured, and renal histopathology was assessed. SHR exhibited cardiac hypertrophy, perivascular fibrosis, and decreased maximal coronary blood flow. Aortic medial thickness was increased, whereas elastin density was decreased. Finally, SHR showed decreased urinary excretion and decreased urea and creatinine clearances. No renal histological lesions were observed. Although bosentan did not affect blood pressure, it normalized renal function and slightly decreased left ventricular hypertrophy and fibrosis. Enalapril and mibefradil were both effective in significantly decreasing blood pressure, left ventricular hypertrophy, and aortic medial thickness and improving coronary blood flow, but in contrast to bosentan, they did not improve creatinine clearance. We conclude that in SHR, high blood pressure plays a major role in end-organ damage and that endothelin may partly mediate renal dysfunction and cardiac remodeling independently of a direct hemodynamic effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Benzimidazoles; Body Weight; Bosentan; Calcium Channel Blockers; Cardiomegaly; Coronary Circulation; Enalapril; Endothelins; Fibrosis; Heart Ventricles; Hemodynamics; Hormones; Hypertension; Kidney; Mibefradil; Myocardium; Rats; Rats, Inbred SHR; Sulfonamides; Tetrahydronaphthalenes

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

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

This study characterizes the renin-angiotensin-aldosterone system during the normal menstrual cycle in the baboon. Ten animals received a daily dose of an ACE inhibitor or placebo in a randomized blind cross-over design. Data were obtained during the mid-follicular and early luteal phases of normal non-pregnant menstrual cycles. All examinations and blood collections were performed with ketamine sedation: 7-kg by im injection. Blood pressure was recorded by sphygmomanometer. Serum ACE activity was measured by spectrophotometry. Aldosterone (ALDO), angiotensin I (AI), and angiotensin II (AII) were measured by radioimmunoassay. Plasma renin activity (PRA) was measured by AI generation. The renin-angiotensin-aldosterone system was found to be activated in the follicular phase and suppressed during the luteal phase of the normal non-pregnant menstrual cycle in the baboon.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Electrolytes; Enalapril; Female; Lactation; Male; Menstrual Cycle; Papio; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

To study long-term effects of enalapril, an angiotensin-converting enzyme inhibitor, and hydralazine, an arteriodilator, on renin-angiotensin-aldosterone system and fluid balance before and after administration of furosemide.. 22 dogs with clinical signs of congestive heart failure (CHF) attributable to mitral regurgitation.. After initial examination, 12 dogs received enalapril and 10 received hydralazine. Dogs were re-examined 3 weeks and 6 months after initial examination. Furosemide was added after the 3-week examination, and at 6 months, dogs had received furosemide for at least 4 months.. Angiotensin II and aldosterone plasma concentrations were low before treatment, and only aldosterone became significantly decreased after enalapril monotherapy. Concentrations of both hormones and heart rate increased in dogs receiving hydralazine monotherapy, and fluid retention was evident. After long-term treatment with either of the 2 drugs together with furosemide, angiotensin II and aldosterone values increased in both groups. Natriuresis and kaliuresis developed in all dogs, with greatest effect in those receiving enalapril and furosemide. These dogs had decreased plasma sodium concentration, whereas potassium concentration was equally decreased in both groups. After 6 months, the enalapril group, but not the hydralazine group, had increased cardiac size. All dogs had moderate reduction of weight and were azotemic, although changes were more pronounced in those of the hydralazine group.. The 2 drugs have different effects on the renin-angiotensin-aldosterone system and fluid balance in dogs with CHF.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Dog Diseases; Dogs; Echocardiography; Enalapril; Female; Furosemide; Heart Failure; Heart Rate; Hydralazine; Male; Mitral Valve Insufficiency; Renin-Angiotensin System; Vasodilator Agents; Water-Electrolyte Balance

1. A comparison was made on the protective effects of the following: ME3221, a competitive angiotensin AT1 receptor antagonist; losartan, in which a major active metabolite is a non-competitive angiotensin AT1 receptor antagonist; and enalapril, an angiotensin-converting enzyme inhibitor, using the salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP received orally ME3221 (3 and 10 mg/kg per day), losartan (10 mg/kg per day) and enalapril (10 mg/kg per day) from the 6th to the 20th week of age. All the control rats showed rapid elevation of systolic blood pressure (SBP), accompanied by hypertensive complications, and died by 15 weeks of age. 3. ME3221, losartan and enalapril suppressed the elevation of SBP in the salt-loaded SHRSP to a comparable degree. ME3221 and losartan increased the survival rate to > 90%, and diminished hypertensive complications such as cerebral apoplexy (stroke), renal injury (increased proteinuria, and total N-acetyl-beta-D-glucosaminidase activity) and heart failure (cardiac hypertrophy and pleural effusion). 4. Competitive (ME3221) and non-competitive (losartan) angiotensin AT1 receptor antagonists showed comparable efficacy against the complications and mortality of the salt-loaded SHRSP; both were more potent than enalapril in the protective effect.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Body Weight; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Enalapril; Hypertension; Imidazoles; Losartan; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles

Losartan, a recently developed nonpeptide angiotensin II (AII) receptor antagonist, was orally administered for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus inoculation. The angiotensin-converting enzyme inhibitors (ACEI) captopril and enalapril were also administered in the same manner to compare the therapeutic effects of these three drugs on the degree of myocarditis, acute heart failure, and left ventricular (LV) hypertrophy. Heart weight and the heart weight/body weight ratio were reduced by losartan (60 mg/kg/day) and captopril (7.5 mg/kg/day), but not by enalapril (1 mg/kg/day). LV wall thickness and cavity dimension were decreased in the losartan and captopril groups. Captopril reduced both myocardial necrosis and inflammation, whereas enalapril reduced myocardial necrosis but not inflammation. However, none of the studied losartan doses (1.2, 12, 60 mg/kg/day) influenced myocardial necrosis and inflammation resulting from viral infection. Thus, specific blockade of AII is beneficial in congestive heart failure (CHF) and LV hypertrophy but is not effective in viral-evoked inflammation and injury.

Topics: Acute Disease; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Body Weight; Captopril; Cardiovirus Infections; Enalapril; Encephalomyocarditis virus; Female; Heart; Heart Failure; Hypertrophy, Left Ventricular; Imidazoles; Injections, Intraperitoneal; Losartan; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Organ Size; Random Allocation; Tetrazoles; Therapeutic Equivalency

The effects of chronic angiotensin II (Ang II) receptor blockade (losartan) or converting enzyme inhibition (enalapril) on blood pressure (BP), urinary albumin excretion (Ualb V), renal histology and the hemodynamic and excretory function of the clipped and nonclipped kidneys were studied in two-kidney, one-clip (2-K 1-C) rats. One day after clipping the right renal artery, male Wistar rats were divided into three groups receiving: (1) losartan, 20 mg/kg/day (N = 7), (2) enalapril, 20 mg/kg/day (N = 8), or (3) no treatment (controls, N = 9) for three weeks. Both losartan and enalapril treatments maintained conscious BP at comparably lowered levels compared to control animals (116 +/- 6 mm Hg and 113 +/- 2 mm Hg vs. 188 +/- 11 mm Hg, respectively, P < 0.01). Treatment also prevented the increase in Ualb V, observed for the untreated group, three weeks after clipping (1.7 +/- 0.5 and 0.7 +/- 0.1 mg/24 hr vs. 17.8 +/- 7 mg/24 hr, respectively, P < 0.01). After three weeks of treatment, acute study of renal function during pentobarbital anesthesia revealed higher values of GFR and RPF and lowered vascular resistance for nonclipped kidneys from the losartan and enalapril groups compared to the corresponding kidneys from control animals. Despite the lower BP of both treated groups, clipped kidney GFR and RPF were unchanged compared to the control group. Ualb V for nonclipped kidneys from untreated rats was approximately 5- to 10-fold higher than in the nonclipped kidneys from the treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Body Weight; Enalapril; Hemodynamics; Hypertension, Renovascular; Imidazoles; Kidney; Losartan; Male; Organ Size; Random Allocation; Rats; Rats, Wistar; Tetrazoles

We studied the long-term effects after withdrawal of enalapril, an angiotensin-converting enzyme inhibitor, on tail systolic pressure and cardiovascular structural properties in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Observations in control rats were from 4 to 35 weeks of age, whereas treated rats received enalapril from 4 to 20 weeks and were studied for a further 15 weeks. We measured blood pressure and the ratio of left ventricle weight to body weight and derived methoxamine log dose-perfusion pressure curves in the isolated hindquarter bed. From the changes in resistance properties we also estimated the changes in structure using a model developed previously. During therapy, blood pressure was depressed to a common value in both strains. After drug withdrawal, by age 35 weeks, previously treated SHR developed only mild hypertension, whereas blood pressure of WKY had recovered to the corresponding control level. At 21 weeks, soon after enalapril was stopped, left ventricular development was depressed in both strains; the depression was slightly greater in SHR, but that of vascular resistance was proportionately similar in each strain. Late cardiovascular development between 21 and 35 weeks was attenuated in the previously treated groups. For the left ventricle, it was similar in each strain, but for the vasculature, late development was relatively smaller in SHR than WKY. In the former, the pattern of development between 21 and 35 weeks was the same as in untreated controls and appeared to be mediated in response to the rise in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Enalapril; Hemodynamics; Hypertension; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Vascular Resistance

During the first 2 weeks of life the left ventricular free wall of the neonatal pig heart grows rapidly. The mass of the left ventricular free wall (LVFW) increased from 2.22 +/- 0.10 g to 9.62 +/- 1.01 g while the right ventricular free wall (RVFW) increased from 2.03 +/- 0.24 g to 3.56 +/- 0.41 g from birth to 14 days of age. During the same period, the cellular volume of myocytes from the LVFW increased from 1075 microns3 to 3688 microns3 while myocytes from the RVFW increased in volume from 1511 microns3 to 2454 microns3. The number of RVFW myocytes did not change during the first 2 weeks of life, while the number of LVFW myocytes increased 28%. Myocytes from both ventricles were approximately 90% mononuclear from birth to 4-5 days of age. By 14 days, 67% of LVFW myocytes and 53% of RVFW myocytes were multinucleated. When growth of the heart was restrained by treatment of the piglet with enalapril maleate, the LVFW mass was reduced by 24% over 2 weeks compared to hearts from untreated piglets and was accounted for by a reduction in myocyte volume. Enalapril treatment did not alter the number of myocytes in either the LVFW or RVFW as compared to hearts from untreated piglets. After 14 days of enalapril treatment, the percentage of multinucleated cells was reduced in the LVFW and unchanged in the RVFW as compared to hearts from untreated piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Animals, Newborn; Body Weight; Cardiomegaly; Enalapril; Heart; Heart Ventricles; Myocardium; Organ Size; Reference Values; Swine; Time Factors

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

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

Converting enzyme inhibitor treatment of congestive heart failure slows progression to failure and reduces mortality rate. It is known whether these benefits are due solely to improved hemodynamics or also to improved myocyte energetics. This study examines the effect of enalapril treatment on both isovolumic contractile performance and its biochemical correlate, flux through the creatine kinase (CK) system, in an animal model of severely failing myocardium.. Seven-month-old Syrian cardiomyopathic (TO-2 strain) and normal golden Syrian (FIB strain) hamsters were each randomly assigned to one of three groups supplied daily with either no, low (25 mg/kg body wt), or high (100 mg/kg body wt) doses of enalapril for 12 to 14 weeks. At 10 months of age, all substrates and products and flux through the CK reaction were measured in isolated perfused hearts by 31P magnetization transfer and chemical assay. Compared with normal hamsters, the myopathic hamsters exhibited significantly lower body weights and higher biventricular heart weights, which were partially reversed by drug treatment. The Langendorff-perfused hearts showed decreased isovolumic contractile performance with identical load conditions. This was partially reversed by drug treatment. In the failing hearts, the following substrate and product concentrations and enzyme activities were decreased compared with nonfailing hearts but were unchanged by drug treatment: ATP (-28%), phosphocreatine (-48%), free creatine (-64%), ADP (-51%), and CK (-34%, primarily MM isoenzyme). Flux through the CK reaction for the untreated cardiomyopathic hamster hearts was decreased by 67%, and this decrease was almost completely reversed by enalapril treatment. The increased CK flux is due to an increase in the rate constant for the reaction, since substrate concentrations are unchanged, and is not predicted by the rate equation. In enalapril-treated failing hearts, phosphoryl transfer via the CK reaction increased with contractile performance. This was not observed in the nonfailing hearts, in which energy reserve is adequate to support changes in contractile performance.. Decreased flux through CK reaction leads to decreased capacity for ATP synthesis and may contribute to decreased contractile performance in cardiomyopathic hamster hearts. Enalapril treatment results in increased phosphoryl transfer through the CK reaction in failing myocardium, and this increase is coupled to improved cardiac performance. Decreased CK flux in failing hearts is due to a combination of decreased Vmax and lower guanidino pool; this mechanism fails to explain changes in CK flux in enalapril-treated failing hearts.

Topics: Animals; Body Weight; Creatine Kinase; Cricetinae; Enalapril; Energy Metabolism; Heart Failure; In Vitro Techniques; Isoenzymes; Kinetics; Magnetic Resonance Spectroscopy; Male; Mesocricetus; Myocardial Contraction; Myocardium; Organ Size

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

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

The positioning of a nonocclusive silicone collar around the rabbit carotid artery results in the formation of a neointima under a morphologically continuous endothelium. We wished to determine whether oral treatment with angiotensin-converting enzyme (ACE) inhibitors prevents or retards intimal thickening and whether this is related to the blood pressure (BP) lowering effects of such drugs. Silicone collars were placed around the left carotid artery of 104 male New Zealand white rabbits for 14 days. The contralateral carotid artery was sham-operated. Three ACE inhibitors were administered from 7 days before collar placement until the end of the experiment: zabicipril (0, 0.03, 0.10, or 0.30 mg/kg/day), moexipril (0, 0.3, 1, or 3 mg/kg twice daily, b.i.d.), and enalapril (0 or 3 mg/kg/day). Each group consisted of 6-12 animals. BP and plasma ACE activity were measured in the nonanesthetized rabbits after 3-week treatment. To evaluate intimal thickening, we measured the cross-sectional area of intima and media. The positioning of the collar led to significant intimal thickening after 14 days. Although the ACE inhibitors decreased BP (zabicipril, 9, 16, 16%; moexipril, 10, 22, 31%; enalapril, 15%) and plasma ACE activity (zabicipril, 87, 88, 92%; moexipril, 79, 92, 93%; enalapril, 88%) significantly and dose dependently, they did not reduce intimal thickening or the cross-sectional area of the media. Angiotensin II does not play a dominant role in collar-induced intimal thickening in rabbits. Furthermore, reducing the BP of normotensive rabbits does not alter neointima formation in this model.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Carotid Arteries; Enalapril; Isoquinolines; Male; Peptidyl-Dipeptidase A; Rabbits; Silicones; Tetrahydroisoquinolines; Tunica Intima

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril (20 mg/kg per day in drinking fluids) from age 4-10 weeks; one group (GHex-enal) was then taken off enalapril and followed for 6 more weeks to see if the drug-induced changes in blood pressure (BP) and structure of mesenteric resistance arteries (MRA) were long lasting once the enalapril was withdrawn. Control groups consisted of untreated GH and their normotensive (N) control strain. 2. Tail-cuff BP in GH treated rats fell significantly to N BP levels during treatment. On cessation of treatment BP rose rapidly. At age 16 weeks BP, although at a hypertensive level (mean +/- s.e.m., GHex-enal, 210.8 +/- 4.7 mmHg), was still significantly below the GH controls (230 +/- 6.9, P < 0.05), but above the N control group (137 +/- 3, P < 0.001). 3. Left ventricular (LV) mass in GH rats was reduced by enalapril to that in N rats; at the end of the subsequent period without treatment it was still significantly lower than the GH control group, but also significantly above the N group (GHex-enal, 255 +/- 6; GH 306 +/- 11; N 179 +/- 3, mg/100 g bodyweight). 4. The large changes in media, lumen and media/lumen ratio seen after 6 weeks of treatment were not sustained over the subsequent non-treatment period. However, values in the GHex-enal group at 16 weeks were closer to those in the N16 control group. 5. The persisting effects on smooth muscle (SM) cell density and SM fraction of the media contributed to an increase in SM cell volume which was significantly greater than the N16 group (P < 0.01). The number of layers of SM in the media was less than in the GH16 control group and not different from the N16 controls. 6. In GH rats the effect of ACEI on PB, LV mass and MRA structure is relatively longlasting once treatment is withdrawn.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Enalapril; Hypertension; Hypertrophy, Left Ventricular; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Rats; Vascular Resistance

The renin-angiotensin system (RAS) has been proposed to play a major role in causing the heart to hypertrophy during pressure overload. We examined whether blockade of this system by the angiotensin-converting enzyme (ACE) inhibitors enalapril (0.5 to 20 mg/kg p.o.) or ramipril (1.0 mg/kg p.o.) or the angiotensin receptor (AT1) antagonist losartan (3.0 mg/kg p.o.) could prevent pressure overload-induced hypertrophy. Pressure overload was produced by abdominal aortic constriction in rats. Cardiac hypertrophy was assessed by an increase in the ratio of left ventricular (LV) weight to body weight and total protein content of the left ventricle. Treatment with enalapril or ramipril, initiated 3 weeks after aortic banding and continued for 3 more weeks, failed to prevent the progression or cause regression of cardiac hypertrophy. Treatment for 6 weeks with ramipril initiated immediately after aortic banding also failed to prevent cardiac hypertrophy. Losartan treatment initiated 3 weeks after aortic banding and continued for 3 more weeks resulted in a slight but significant reduction in the extent of cardiac hypertrophy (45.6% hypertrophy in controls and 35.6% hypertrophy in losartan-treated animals, p < 0.05, n = 11 and 10, respectively). Surgical removal of bands 3 weeks after placement reduced cardiac hypertrophy to a greater extent than that observed in losartan-treated animals. These results suggest that angiotensin may not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Biphenyl Compounds; Blood Pressure; Body Weight; Cardiomegaly; Enalapril; Heart Ventricles; Imidazoles; Losartan; Male; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Ventricular Function

The effects of a 3-month treatment period with the angiotensin-converting enzyme (ACE) inhibitors trandolapril (0.3 mg/kg/day, p.o.) and enalapril (10 mg/kg/day, p.o.) on hemodynamics, cardiac hypertrophy, and vascular structures were examined in old spontaneously hypertensive rats (SHRs) (24 months at the end of treatment) presenting with congestive heart failure. During the course of treatment, the mortality rate was lower in the two treated groups than in the control group. At the end of treatment, serum ACE activity was inhibited by 63 and 33% by trandolapril and enalapril, respectively, but the decrease in blood pressure they induced was not significant. The atrial natriuretic factor(ANF) plasma levels and cyclic GMP urine excretion were about 10-fold and 3-fold higher, respectively, in old SHRs than in old Wistar rats. These values were markedly decreased by both ACE inhibitors. The ventricular hypertrophy was greatly decreased by both compounds (-24% by trandolapril and -26% by enalapril). In the aorta, the media hypertrophy was significantly decreased and nuclear density increased to a similar extent by both ACE inhibitors. In the mesenteric artery, trandolapril treatment induced a complete regression of the media hypertrophy and a marked decrease in extracellular matrix surface. In addition, the collagen network appeared less dissociated in the treated animals. Similarly the nuclear density was increased and the surface of cell nuclei was decreased by trandolapril. Enalapril appeared much less potent on these parameters. These data demonstrate that treatment with trandolapril of aged SHRs presenting with heart failure results in an increase in survival of the animals and a marked regression of cardiac and vascular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Vessels; Body Weight; Cardiomegaly; Enalapril; Heart Failure; Hemodynamics; Hypertension; Indoles; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR

We recently demonstrated that glucocorticoid increases the number of angiotensin II type 1 (AT1) receptors and their gene expression in cultured vascular smooth muscle cells. To clarify whether this mechanism participates in glucocorticoid-induced hypertension, we investigated the effect of dexamethasone on the modulation of vascular AT1 receptor messenger RNA (mRNA) expression in rats.. The effects were studied of administering dexamethasone orally to rats at a dose of 0.1 mg/day on the modulation of the expression of vascular AT1 receptor mRNA and the blood pressure. The effects of enalapril maleate, an angiotensin converting enzyme inhibitor, were also evaluated.. The dexamethasone-treated rats showed a rise in systolic blood pressure beginning on day 3. On day 5 the blood pressure rose significantly. Before dexamethasone administration the vascular AT1 receptor mRNA was difficult to detect by Northern blot analysis. However, the level of vascular AT1A receptor mRNA began to increase on day 2, when the blood pressure was not yet elevated, and increased further on day 5. The concurrent administration of dexamethasone and enalapril maleate attenuated the elevation of blood pressure. However, as in the dexamethasone-treated rats, the level of AT1A receptor mRNA began to increase on day 2 and increased further on day 5. In rats treated with enalapril maleate alone, the AT1 receptor mRNA was difficult to detect during the experiment.. Glucocorticoid increased the amount of vascular AT1 receptor mRNA and contributed to the elevation of blood pressure.

Topics: Animals; Blood Pressure; Blood Vessels; Body Weight; Dexamethasone; Enalapril; Gene Expression; Hypertension; Male; Rats; Rats, Wistar; Receptors, Angiotensin; RNA, Messenger; Systole

The role of nonhemodynamic cardiac trophic mechanisms differs not only between different models of cardiac hypertrophy but also within the same model for development versus maintenance of cardiac hypertrophy. Our previous studies pointed to a major role for the renin-angiotensin system (RAS) as a cardiac trophic stimulus in the remodeling of the heart in response to volume overload by aortocaval shunt or minoxidil treatment.. In the present study, we evaluated the effects of blockade of the RAS by the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor blocker losartan on left ventricular (LV) and right ventricular mass and LV dilation in relation to changes in central hemodynamics during the maintenance of minoxidil and aortocaval shunt-induced cardiac hypertrophy. Both blockers similarly decreased LV end-diastolic pressure (LVEDP) and LV peak systolic pressure, whereas cardiac output remained unchanged in both models of volume overload. This suggests a major contribution of improved LV performance and decreased afterload to the decrease in cardiac preload by the two blockers rather than decreased venous return. Both blockers reversed LV hypertrophy in parallel to their effects on LVEDP in both models of volume overload. In minoxidil-treated rats, the extent of reversal in LV mass and dilation by the two blockers was similar to "spontaneous regression" after discontinuation of minoxidil treatment.. These results indicate that in contrast to the development phase of cardiac hypertrophy, the RAS does not contribute to the maintenance of volume overload-induced cardiac hypertrophy in these two models via direct cardiac trophic effects. The RAS, however, maintains cardiac hypertrophy indirectly by contributing to the persistence of high filling pressures.

Topics: Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Volume; Body Weight; Cardiomegaly; Coronary Circulation; Enalapril; Heart Ventricles; Hematocrit; Hemodynamics; Hyperemia; Imidazoles; Losartan; Male; Minoxidil; Myocardium; Organ Size; Rats; Rats, Wistar; Tetrazoles

We found that the administration of an angiotensin I-converting enzyme inhibitor and sodium chloride loading lessen the development of renal cystic disease induced by 2-amino-4-5-diphenylthiazole in rats. To determine whether similar effects could be observed in an autosomal dominant model of polycystic kidney disease, heterozygous cystic (Cy/+) and homozygous normal (+/+) Han:SPRD rats were divided into experimental groups at 3 weeks of age. The first study included four groups receiving enalapril (50 mg/L), losartan (400 mg/L), hydralazine (80 mg/L), or no drug in their drinking water. The second study included four groups fed a sodium-deficient diet or the same diet supplemented with 0.25%, 0.6%, or 3.3% sodium chloride. The Cy/+ rats receiving enalapril had lower kidney weights and histologic scores than those in the control group, and lower kidney weights, plasma creatinines, and histologic scores than those in the hydralazine group. The Cy/+ rats receiving losartan had lower plasma creatinines and histologic scores than those in the control and hydralazine treatment groups. A sodium-deficient diet markedly blunted the growth of the animals and the development of cystic disease. Increases in the sodium content of the diet in the other three groups were accompanied by higher relative kidney weights and histology scores, while the levels of plasma creatinine were not significantly different. Regression of the cystic disease was observed between 3 and 4 months of age. These results indicate that the development of autosomal dominant polycystic kidney disease in the rat can be modulated by pharmacologic and nutritional factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Body Weight; Creatinine; Enalapril; Female; Imidazoles; Losartan; Male; Polycystic Kidney Diseases; Rats; Rats, Sprague-Dawley; Renin; Sodium Chloride; Tetrazoles

Although angiotensin converting enzyme inhibitors and alpha 1-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an alpha 1-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128 +/- 1 mmHg) and doxazosin (132 +/- 2 mmHg) decreased mean blood pressure compared with control levels (148 +/- 1 mmHg) (P < .01). The glucose requirement for the clamp test during the administration of enalapril (25.8 +/- 0.5 mg/kg per minute) or doxazosin (28.6 +/- 0.7 mg/kg per minute) was higher than that of the control group (19.8 +/- 0.5 mg/kg per minute) (P < .05). Although Hoe 140 did not alter the glucose requirement of doxazosin (27.8 +/- 0.5 mg/kg per minute), it decreased that of enalapril (22.6 +/- 0.9 mg/kg per minute) (P < .05) without affecting the changes in mean blood pressure induced by enalapril. In addition, losartan decreased mean blood pressure but did not affect the glucose requirement. Thus, the improvement in insulin sensitivity produced by an angiotensin converting enzyme inhibitor is mostly dependent on kinins but not on angiotensin II antagonism, and an alpha 1-blocker improves insulin sensitivity irrespective of kinins.

Topics: Analysis of Variance; Angiotensin II; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Glucose; Blood Pressure; Body Weight; Bradykinin; Doxazosin; Enalapril; Glucose Clamp Technique; Hypertension; Imidazoles; Insulin; Kinins; Losartan; Male; Potassium; Rats; Rats, Inbred SHR; Sodium; Tetrazoles

To examine the regulation of angiotensin receptors in vascular smooth muscle cells, we studied the effects of antihypertensive drugs on angiotensin type 1A (AT1A) receptor gene expression in aortic smooth muscle cells (ASMCs) from spontaneously hypertensive rats (SHRs) using both ribonuclease protection assay and reverse-transcription polymerase chain reaction. An increase in AT1A receptor gene expression in ASMCs of SHRs was induced by treatment with an angiotensin converting enzyme inhibitor (enalapril) for 2 weeks and 4 weeks, but not by other types of antihypertensive drugs such as alpha-blocker (doxazosin), alpha, beta-blocker (arotinolol), Ca antagonist (nicardipine) or vascular smooth muscle relaxant (hydralazine). Since all antihypertensive drugs lowered the blood pressure of the rats almost equally, our results suggest that AT1A receptor gene expression in ASMCs of SHRs may be regulated by the vascular renin-angiotensin system.

Topics: Animals; Antihypertensive Agents; Aorta; Base Sequence; Blood Pressure; Body Weight; Enalapril; Gene Expression; Heart Rate; Hypertension; Male; Molecular Sequence Data; Muscle, Smooth, Vascular; Oligonucleotide Probes; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Ribonucleases; RNA, Messenger

Little is known about the effects of common antihypertensive drugs in obese, insulin-resistant females. Nine-month-old obese female SHHF/Mcc-fa(cp) rats that received either nifedipine, a calcium channel antagonist, or enalapril, an angiotensin-converting-enzyme inhibitor, for three months were compared with untreated SHHF/Mcc-fa(cp) rats (controls). After one month, nifedipine significantly decreased body weight in obese females compared to either enalapril or controls. After three months of treatment, total, abdominal, and subcutaneous fat masses were decreased in obese females given nifedipine compared to either enalapril or controls. Enalapril treatment was associated with a redistribution of fat mass from abdominal to subcutaneous depots. Nifedipine reduced plasma triglyceride and fasting glucose levels and improved insulin response to an oral glucose load in obese females, whereas enalapril did not appear to affect glycemic control. Systolic pressure was not significantly decreased until after two months of treatment with nifedipine or three months of treatment with enalapril in obese females and may have coincided with improvement in insulin-resistance. Similarly, plasma atrial natriuretic peptide concentrations were significantly lower in obese females given nifedipine. To determine how obese males responded to a calcium channel antagonist, six-month-old obese male SHHF/Mcc-fa(cp) rats were treated for three months with either nifedipine or placebo (controls). Nifedipine-treated obese males showed a mild but significant decrease in weight gain that was due to a decrease in fat deposition in both subcutaneous and abdominal depots and systolic blood pressure was significantly reduced after one month of treatment. Nifedipine did not affect other plasma biochemical parameters in obese males. In conclusion, nifedipine improved systolic pressure and glycemic control in obese female SHHF/Mcc-fa(cp) rats, effects that may be associated with a marked loss in body weight and fat mass and improved lipid metabolism. Nifedipine-treated obese males exhibited only a diminished weight gain that was not associated with changes in diabetic characteristics.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Composition; Body Constitution; Body Weight; Disease Models, Animal; Enalapril; Female; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Male; Nifedipine; Obesity; Placebos; Rats; Sex Factors; Systole; Time Factors; Vasodilator Agents

To test whether angiotensin-converting enzyme (ACE) inhibition may prevent myocardial damage and may affect coronary microvasculature in spontaneously hypertensive rats (SHR), young 5-week-old SHR were treated for 3 months with spirapril and changes in blood pressure (BP) were monitored. Untreated SHR were used as controls. The rats were killed; left ventricular (LV) shape, weight, and wall thickness were examined and the ventricular myocardium was analyzed morphometrically to determine the effect of the drug on the relative amount, number per unit area of myocardium, and average dimension of foci of myocardial scarring. Moreover, volume fraction, surface, numerical density, and diffusion distance for oxygen of the coronary capillaries were analyzed. BP remained 20-30% lower in treated SHR with respect to controls, and LV weight and thickness decreased 20 and 21%, respectively. The number and dimension of the foci of fibrosis were reduced, resulting in an overall 68% decrement in the amount of myocardial damage. Finally, a 28% increment in numerical density of capillary profiles associated with a 13% reduction in their cross-sectional area decreased the diffusion distance for oxygen from the capillary wall to the myocytes by 14% in treated SHR. Spirapril decreases BP and LV weight and thickness in the SHR model of hypertension and substantially improves coronary capillary microvasculature, decreasing hypertensive myocardial damage. These results may be attributed to inhibition of the systemic effects of angiotensin II (AII) as well as to a local protective action of the drug against possible intramyocardial AII production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Capillaries; Coronary Vessels; Enalapril; Fibrosis; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Rats; Rats, Inbred SHR

Structural alterations after myocardial infarction (MI) in rats are usually examined only after death of the experimental animal. Magnetic resonance imaging (MRI) allows repeated and noninvasive measurements of important structural [left ventricular (LV) mass, LV wall thickness, LV chamber radius] as well as function [LV end-systolic and LV end-diastolic volume, stroke volume (SV), ejection fraction (EF)] parameters for a prolonged period. We describe our experience in a series of experiments in rats. Three weeks after MI, infarct size (IS) was determined by MRI and the rats were divided into two groups with equal IS. Three weeks later, treatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (10 mg/kg in food) or placebo was started. In both groups, the first MRI scan taken before the treatment showed moderately dilated left ventricles and signs of impaired LV function, i.e., an increase in LV end-systolic and end-diastolic volume and decreased EF. After 3-week treatment, no significant differences with respect to heart structure and function were detected as compared with those of untreated animals. Prolonged treatment for 10 weeks with spirapril resulted in significant reduction of LV dilatation, LV mass, and LV end-systolic and end-diastolic volume, which was accompanied by improved EF. Hemodynamic examinations after treatment for 6 months showed, in contrast to control animals, no increase in right ventricular systolic pressure in animals receiving spirapril. Furthermore, histologic examination of perfusion-fixed hearts at the end of the study demonstrated more pronounced LV dilatation in control animals, thus confirming the in vivo MRI data. Delayed treatment with spirapril proved to have beneficial effects on structure and function of infarcted hearts within 10 weeks. Spirapril limited LV dilatation, reduced LV weight and LV end-systolic and end-diastolic volumes, and improved EF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Enalapril; Hemodynamics; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Myocardial Infarction; Peptidyl-Dipeptidase A; Perfusion; Rats; Rats, Wistar; Stroke Volume; Ventricular Function, Left

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

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

Five groups of 12 rats were subject to balloon lesion of the left carotid artery and neointimal thickening was measured histologically 2 weeks after injury. Rat groups received either spirapril (3, 10 or 30 mg/kg/day, administered throughout the study in the food), cilazapril (10 mg/kg/day) or placebo. Spirapril caused a dose-dependent inhibition of the neointimal thickening of the rat carotid artery. The degree of inhibition with 10 mg/kg/d spirapril and cilazapril was similar (-44% and -42% respectively). The carotid lumen area was measured in vivo by nuclear magnetic resonance (NMR) imaging both before and 2 weeks after balloon injury and also postmortem by histological techniques. Two weeks after injury, the lumen area of the left carotid artery was significantly reduced following balloon injury, as measured by both techniques. Treatment did not detectably modify this stenosis process despite the use of two independent methods for assessing lumen size, even though neointimal thickening was strongly attenuated by both angiotensin converting enzyme inhibitors. This dissociation between inhibition of neointimal lesion development and decrease of lumen size provides a new view of the role of angiotensin converting enzyme inhibitors in vascular damage situations. Our results suggest that the focus, particularly in clinical studies, on lumen size, may mean that potentially beneficial effects of these drugs on other parts of the vascular wall be overlooked.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Carotid Arteries; Carotid Artery Injuries; Catheterization; Cilazapril; Enalapril; Heart Rate; Histocytochemistry; Magnetic Resonance Imaging; Rats; Rats, Wistar; Tissue Fixation

To investigate the effects of angiotensin-converting enzyme (ACE) inhibitors on the cellular function and structure in a variety of organs during the aging process, one hundred CF1 mice were divided into four groups of 25 animals each. Groups A, B, and C received enalapril in drinking water from weaning until the age of 24 mo. Doses administered were (in mg/l): group A, 20; group B, 10; group C, 5. Group D is the control. Animals were killed, and morphometric studies were performed in heart, kidney, liver, and spleen. As a result, there was a decrease of renal and myocardial sclerosis and an increase in the number of mitochondria in heart and liver cells, which is associated with a significant increase in survival of animals receiving ACE inhibitors. These findings lead us to think that natural aging mechanisms have been altered in those animals.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Enalapril; Female; Heart; Kidney; Liver; Mice; Mice, Inbred Strains; Mitochondria; Myocardium; Organ Size; Spleen

The degree of cardiac hypertrophy is not only load dependent: Among other factors, the renin-angiotensin system may play a role in the regulation of cardiac myocyte growth.. To evaluate the role of the renin-angiotensin system in volume overload-induced cardiac hypertrophy, we assessed: 1) the time course of changes in cardiac hemodynamics, cardiac anatomy, and plasma and cardiac renin activity in response to volume overload induced by two sizes of abdominal aortocaval shunt and 2) the effects of chronic treatment with an angiotensin converting enzyme inhibitor (ACEI) versus an angiotensin II receptor blocker on hemodynamics and cardiac hypertrophy. Drug treatment started 3 days before shunt surgery. An increase in left ventricular end-diastolic pressure (LVEDP) and the development of right ventricular (RV) and left ventricular (LV) eccentric hypertrophy in response to volume overload occurred within the first week after induction of the shunt. Plasma renin activity (PRA) and cardiac renin activity peaked shortly after induction of the shunt. During the chronic phase, LVEDP and PRA decreased somewhat but remained significantly elevated up to 7 weeks after shunt surgery. Cardiac renin activity returned toward normal within 4 weeks after surgery. Treatment with the ACEI enalapril caused only a modest decrease in LV internal diameter but did not affect increases in LV and RV weights in response to volume overload despite a major decrease in LVEDP after chronic treatment. In contrast, treatment with the angiotensin II receptor blocker losartan, which had similar effects on cardiac and peripheral hemodynamics, prevented dilation of the LV after 7 days and attenuated the dilation of the LV after 28 days. Moreover, increases in LV and RV weights were significantly attenuated by losartan.. The development of volume overload-induced cardiac hypertrophy is associated with significant increases in PRA and cardiac renin activity shortly after induction of an aortocaval shunt. Whereas the two blockers of the renin-angiotensin system decreased LVEDP to a similar extent, only the angiotensin II receptor blocker blunted the hypertrophic response of the heart to volume overload, which is indicative for other than hemodynamic determinants of the cardiac hypertrophic response. One trophic factor may be cardiac angiotensin II generated via an angiotensin II-forming enzyme resistant to ACEI and possibly activated by cardiac volume overload.

Topics: Angiotensin II; Animals; Aorta; Arteriovenous Shunt, Surgical; Biphenyl Compounds; Body Weight; Cardiac Volume; Cardiomegaly; Enalapril; Hemodynamics; Imidazoles; Losartan; Male; Myocardium; Organ Size; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Tetrazoles; Venae Cavae

Effects of (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]- propionyl]-2-oxoimidazolidine-4-carboxylic acid hydrochloride (TA-6366) on morphological change and mechanical property related to sodium ion permeability in the aorta of spontaneously hypertensive rats (SHRs) were examined, as compared with those of enalapril and captopril. Ten-week oral administration of TA-6366 (1 and 5 mg/kg/d) from 4 weeks of age impeded aortic media-thickening together with a rise in blood pressure in SHRs. Concomitantly, aorta weights in both groups were markedly decreased. The higher dose of TA-6366 almost fully suppressed the accelerated tension development induced by K(+)-free medium and decreased total sodium ion content in the aorta. These vascular effects of TA-6366 was more prominent than those of enalapril and captopril at 5 mg/kg/d. The difference in potencies on the above vascular parameters between TA-6366 and these drugs seemed to be mainly related to the difference in their antihypertensive activities. These results suggest that TA-6366 has preventive effects against progression of vascular diseases, particularly atherosclerosis, accompanied with hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Captopril; Cardiomegaly; Dose-Response Relationship, Drug; Enalapril; Imidazoles; Imidazolidines; Male; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium

To test the hypothesis that effects of angiotensin converting enzyme (ACE) inhibitors upon resistance vessel structure are responsible for their ability to cause long-term reduction in blood pressure.. Stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats were treated with enalapril or hydralazine from 4 to 15 weeks of age. Effects upon tail-cuff blood pressure, left ventricular hypertrophy and structural indices of the superior mesenteric artery (SMA) and its resistance vessels were assessed at 11 weeks of treatment and up to 11 weeks post-treatment.. Left ventricular hypertrophy was assessed by left ventricular weight:body weight ratios. Evidence of vascular structural change was obtained from tissue weight:body weight ratios, levels of RNA, DNA and expression of alpha-actin and elastin messenger (m)RNA.. The effects of enalapril and hydralazine upon left ventricular hypertrophy in SHRSP were consistent with their respective effects upon blood pressure. Both drugs prevented the development of medial hypertrophy in SMA and resistance vessels. This was accompanied by substantial reductions in RNA:DNA ratios. Alpha-actin mRNA levels were not affected by either drug but elastin mRNA levels were reduced by both drugs. During the first 12 days post-treatment there was evidence of structural change in SMA accompanying the increases in blood pressure but importantly not in the resistance vessels.. The effects of enalapril upon left ventricular hypertrophy and mesenteric arterial hypertrophy are totally consistent with responses to blood pressure and the persistence of structural changes post-treatment does not underlie the ability of the ACE inhibitors to persistently suppress hypertension.

Topics: Animals; Blood Pressure; Body Weight; DNA; Elastin; Enalapril; Heart Ventricles; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Male; Mesenteric Artery, Superior; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Vascular Resistance

Using a spectral procedure, we studied the acute and chronic effects of enalapril and hydralazine on the variability of blood pressure (BP) and heart rate (HR) in conscious Wistar rats. In the acute protocol, rats received two injections 25 min apart (saline followed by enalaprilic acid or hydralazine hydrochloride). In the chronic protocol, animals received oral enalapril maleate, hydralazine hydrochloride, or distilled water. A 5-min recording session was initiated on day 12. Acute enalapril and hydralazine amplified the low-frequency (LF) component of the systolic BP (SBP) spectrum. Chronic enalapril reduced the variability of BP, as indicated by the lower variance in SBP distribution. Chronic enalapril preferentially reduced the amplitude of the 400-mHz oscillations of SBP. Acute administration of enalapril or hydralazine resulted in BP variability profiles, suggesting a reflexly mediated vascular sympathetic activation. In contrast, chronic angiotensin-converting enzyme (ACE) blockade with enalapril caused a significant decrease in the LF oscillations of BP. This could reflect a reduced sympathetic outflow to vascular smooth muscles.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Drinking Behavior; Enalapril; Heart Rate; Hydralazine; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Rats; Rats, Inbred Strains; Renin-Angiotensin System

There is evidence that cardiac hypertrophy in spontaneously hypertensive rats (SHR) occurs before the development of hypertension. 1,2-Diacylglycerol, which is thought to be a second messenger activating protein kinase C, is also produced in excess in SHR hearts at 4 weeks of age, before established hypertension. We determined myocardial 1,2-diacylglycerol content in SHR with and without prazosin and enalapril from 3 to 4 weeks of age. Hearts from untreated SHR had greater RNA and DNA synthesis and greater relative weights at 4 weeks of age than those from Wistar-Kyoto (WKY) rats. There was no difference in triglyceride content or phospholipid species between WKY rats and untreated SHR, except for a higher cholesterol content in SHR. Treatment of SHR with enalapril, but not prazosin, lowered not only 1,2-diacylglycerol content but also RNA synthesis to the levels of WKY rats. Moreover, fatty acids involved in 1,2-diacylglycerol were altered by enalapril despite the lack of a difference between WKY rats and untreated SHR. Prazosin did not have any effect on 1,2-diacylglycerol fatty acid composition. Enalapril may decrease cardiac hypertrophy in SHR by lowering myocardial 1,2-diacylglycerol production.

Topics: Animals; Body Weight; Cardiomegaly; Diglycerides; Enalapril; Heart Ventricles; Hypertension; Lipids; Male; Myocardium; Organ Size; Prazosin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA

Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.

Topics: Albuminuria; Animals; Blood Pressure; Body Weight; Cholesterol; Diet, Sodium-Restricted; Drug Resistance; Enalapril; Kidney Glomerulus; Lovastatin; Male; Punctures; Rats; Rats, Inbred Strains; Sodium Chloride; Triglycerides; Vascular Resistance

Enalapril (MK, 421), an angiotensin converting enzyme inhibitor, was tested for teratogenicity using Wistar rats. The drug was given by oral intubation, from 6-15 days of gestation, at the doses of 0, 3, 10 and 30 mg/kg/day. Reduction in body weight and food consumption were observed in the treated dams. However, food efficiency index, assessed at different periods of gestation was found to be unaffected. On day 20 of gestation, all the dams were sacrificed by cervical dislocation and sign of maternal toxicity, reproduction indices and fetal measures were recorded. The dams treated with enalapril at only the doses of 10 and 30 mg/kg, produced significant decrease in numbers of implants, litter size and incidence of reabsorbed fetuses, and also reduced neonatal growth. No such effects were observed at the lowest dose level (3 mg/kg) used. External, visceral and skeletal examinations of the fetuses of enalapril-treated dams showed several types of variations in all groups, but no consistent pattern were observed. However, a slight increase in skeletal variations was seen with the highest dose (30 mg/kg) group. The data of the present study under the conditions described herein and at the doses employed, revealed no evidence of teratogenesis, but numerous deleterious effects on the fetus were evident.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Body Weight; Drinking; Eating; Embryonic and Fetal Development; Enalapril; Female; Male; Pregnancy; Rats; Rats, Wistar

1. The effect of enalapril on handling of an Na load and on body Na during 96 h of zero Na intake was measured in hypertensive rats (GH and SHR) and their normotensive controls (N and WKY) by a whole body counting method. 2. Enalapril treatment led to a greater fall in body Na in the first 24 h after the Na load (as expected from the known effect of ACE inhibition on aldosterone production) and thus to a slightly faster excretion of an amount equivalent to the load. 3. Enalapril-treated rats were unable to maintain body Na on a zero Na intake. This was also expected from the known effect on aldosterone production, though other mechanisms are not excluded. The effect was more marked in the SHR and WKY than in GH and N but there was no significant difference in this effect between the hypertensives and their respective control strains.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Enalapril; Hypertension; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Sodium; Sodium Chloride

1. We have examined the baroreceptor-heart rate (HR) reflex in weight-matched conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats during development. 2. Graded steady-state changes in mean arterial pressure (MAP) and the corresponding HR responses before and after vagal blockade with methylatropine were fitted to an S-shaped logistic function. 3. At 6 weeks of age, SHR had a 17% higher MAP than WKY and an increased baroreflex gain (slope) compared with WKY due to an increased curvature of the MAP-HR relationship. The HR range (the difference between the upper and lower HR plateaus) was similar in the two strains at this time. 4. From 9-14 weeks of age, the baroreflex gain progressively increased in WKY and decreased in SHR due to corresponding alterations in HR range. 5. By 20 weeks the baroreflex gain was 23% lower in SHR than WKY due to a 37% lower HR range. 6. There were no differences between the two strains in the sympathetic component of the baroreflex at any age, suggesting that the changes to baroreflex properties were confined to the cardiac vagus. 7. Pretreatment with enalapril from 4-9 weeks reduced the hypertension of SHR at 14 and 20 weeks by 38% and abolished all baroreceptor-HR reflex differences between the two strains. 8. These studies suggest that the major alteration to the baroreceptor-heart rate reflex in the SHR during development was a reduction in the maximum vagal capacity to respond to changes in blood pressure. This effect developed after the onset of hypertension and was prevented by antihypertensive treatment early in life. The lack of effect on the cardiac sympathetic component suggests that altered arterial baroreceptor afferents are not unlikely to be responsible.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Enalapril; Heart Rate; Male; Pressoreceptors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reflex; Sympathetic Nervous System; Vagus Nerve

It is not clear whether regression of cardiac hypertrophy normalizes cardiac contractility. We studied the effect of enalapril treatment on the contractile response to beta-adrenergic stimulation with isoproterenol in renal hypertension. Male Wistar rats (n = 28) were divided into a clipped group (n = 14) and control group (n = 14). Three weeks after surgery, half of the animals from each group received for 21 days either enalapril (2.5 mg/kg) twice a day or vehicle by gastric intubation. Arterial pressure and body weight were measured twice a week. At the end of the experimental period, the hearts were excised, the ventricles were weighed, and the left ventricular papillary muscle was mounted in a bath. Myocardial contractility was characterized by the maximal developed tension, the maximal rate of rise of tension (+T), and the maximal velocity of relaxation (-T), which were measured at basal conditions and after cumulative doses of isoproterenol (10(-11) to 10(-4) M). The ratio of ventricular weight to body weight increased in hypertensive rats. Enalapril induced a decrease in arterial pressure and in the cardiac mass in both treated groups (p less than 0.05). The basal values of maximal developed tension, +T, and -T were similar in the four groups. The increment in +T and -T in response to isoproterenol (10(-4) M) was depressed in the hypertensive animals and in both treated groups (p less than 0.05). There was no significant difference in the +T/-T ratio or in the ED50 among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Cardiomegaly; Enalapril; Hypertension, Renovascular; Isoproterenol; Male; Muscle Relaxation; Myocardial Contraction; Papillary Muscles; Rats; Rats, Inbred Strains

To evaluate the role of glomerular hypertension, glomerular hypertrophy, glomerular lipid deposition, and plasma cholesterol levels in diabetic glomerulopathy, Munich-Wistar rats received streptozocin and daily insulin injections and were assigned to one of three groups: untreated diabetic (DMC), hydralazine-treated diabetic (DMH), and enalapril-treated diabetic (DME). Age-matched control rats were also studied. At 6-10 wk of diabetes, DMC rats showed marked elevations of glomerular pressure and glomerular filtration rate as well as slight glomerular enlargement and cholesterol elevation. DMH and DME rats exhibited arterial hypotension but no change in cholesterol or glomerular volume. Glomerular pressure was normalized by enalapril but not by hydralazine treatment. Additional rats were followed up to 12 mo of diabetes. Slight hypertension was seen in DMC rats, whereas sustained hypotension occurred in DMH and DME rats. Progressive albuminuria occurred in DMC and DMH but not in DME rats. At 12 mo, glomerular hypertension persisted in DMC and DMH rats but was still absent in DME rats. Cholesterol was elevated in DMC and slightly lower in DMH and DME rats. Glomeruli were equally enlarged in the diabetic groups. Glomerular sclerotic lesions and lipid deposits appeared in DMC and DMH but not in DME rats. These findings are consistent with the notion that glomerular hypertension may promote glomerular injury in experimental diabetes. Glomerular lipid deposition may also participate in this process, although a causal relationship was not demonstrated. Glomerular hypertrophy and cholesterol were unrelated to glomerular injury, although they may have exacerbated hemodynamically mediated damage.

Topics: Albuminuria; Analysis of Variance; Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Hydralazine; Hypertension; Kidney Glomerulus; Male; Rats; Rats, Inbred Strains; Reference Values; Renal Circulation; Vascular Resistance

We have investigated the effect of enalapril, an angiotensin converting-enzyme (ACE) inhibitor, on the accumulation of ventricular and vascular collagen and elastin in young, growing rats. Beginning at either 4 or 10 wk of age, male Wistar rats were treated with enalapril for 2 or 5 wk. Enalapril treatment had no significant effect on body weight and small, generally non-significant effects on systolic and diastolic blood pressures. In contrast, young enalapril-treated animals showed a marked decrease in accumulation of total elastin and collagen in both large (aorta, renal, and carotid) and smaller (superior and large mesenteric) arteries, as well as a large reduction in total collagen in both left and right ventricles. This effect also was present but less pronounced in rats treated with enalapril beginning at 10 wk of age. These data indicate that inhibition of ACE activity during a period of rapid growth significantly reduces accumulation of vascular and ventricular connective tissue and suggests that angiotensin II may be important in normal cardiovascular development and growth.

Topics: Aging; Animals; Blood Pressure; Body Weight; Cardiovascular System; Collagen; Elastin; Enalapril; Male; Organ Size; Rats; Rats, Inbred Strains

The relative contributions of the hemodynamic and morphological (vascular and cardiac) modifications induced by long-term administration of an angiotensin I-converting enzyme inhibitor, quinapril, to the drug's long-lasting preventive effects vis-à-vis genetic hypertension development (GHD) have been investigated in young spontaneously hypertensive rats (SHRs). Two groups of SHRs were given quinapril (10 mg/kg/day) or distilled water from 5 to 20 weeks of age. The drug was then stopped, but observations continued for another 7 weeks. At selected times systemic and regional hemodynamic parameters as well as cardiac and vascular morphological effects were investigated. During the treatment period, quinapril partially opposed GHD and limited the early rise in total peripheral and regional vascular resistances observed in control animals. Quinapril's partial preventive effect vis-à-vis GHD persisted, but faded after treatment withdrawal. From a morphological point of view, quinapril strongly opposed aortic wall hypertrophy as evidenced by significant reductions in media thickness and wall to lumen ratio and by a significant increase in aortic nuclear density. Quinapril also limited vascular fibrosis development. At the cardiac level, quinapril reduced heart weight to body weight ratio and opposed myocardial hypertrophy and cardiac collagen synthesis. All these vascular and cardiac morphological changes were delayed (starting after 9-15 weeks of treatment) as compared to quinapril's hemodynamic effects. Finally, the drug's vascular and cardiac antihypertrophic properties persisted after treatment withdrawal. In conclusion, our data indicate that the early systemic and regional hemodynamic effects of quinapril initiate its antihypertensive action, but the drug-induced delayed and prolonged vascular morphological changes later take over and may be partly responsible for quinapril's residual blood pressure lowering effects after treatment withdrawal.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiac Output; Collagen; Coronary Circulation; Elastin; Enalapril; Heart; Heart Rate; Hemodynamics; Hypertension; Isoquinolines; Male; Organ Size; Quinapril; Rats; Rats, Inbred SHR; Tetrahydroisoquinolines; Ventricular Function, Left

The hypotensive effects of three different angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril, and lisinopril) and two angiotensin II (AII) analogues ([Sar1Ile5Ala8]AII and [Sar1Ile5Thr8]AII) were compared in conscious, freely-moving Brattleboro rats after 14 h of water deprivation. There was no difference between the hypotensive effects of the three ACE inhibitors. Neither was there any difference between the hypotensive effects of the two AII antagonists, although when administered following ACE inhibition, [Sar1Ile5Thr8]AII caused a transient pressor effect that was significantly less than that caused by [Sar1Ile5Ala8]AII. ACE inhibition caused a greater fall in blood pressure (BP) than AII antagonism and caused an additional fall in BP during AII antagonism. These results indicate an additional hypotensive effect of ACE inhibitors, over that of AII antagonists, that is not readily accounted for in terms of nonspecific effects of the former or agonistic properties of the latter.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Captopril; Enalapril; Heart Rate; Lisinopril; Male; Rats; Rats, Brattleboro; Saralasin; Water Deprivation

Renal growth often precedes scarring in experimental models of chronic renal failure in rats. Its control may therefore influence the subsequent development of renal scarring and failure in these animals. In this study we have attempted to manipulate, by pharmacological interventions, compensatory renal growth in rats who have undergone uninephrectomy. The effects of three drugs--enalapril, verapamil and indomethacin--were investigated. Compensatory renal growth was found to be 15.33 +/- 13.76% (mean +/- SD) 1 week after uninephrectomy in control adult male Wistar rats. Compensatory renal growth was significantly inhibited by pretreatment with enalapril 7.38 +/- 8.88% (P less than 0.05) but was unaffected by indomethacin; the effect of verapamil was inconclusive. In controls, both the protein and DNA content of the remaining kidney increased, indicating a mixed hypertrophic and hyperplastic response. Enalapril inhibited the hyperplastic component of compensatory renal growth. We conclude that following uninephrectomy in rats, compensatory hypertrophy can be manipulated by pharmacological interventions, in particular angiotensin-converting-enzyme inhibition by enalapril.

Topics: Animals; Body Weight; Enalapril; Hypertrophy; Indomethacin; Kidney; Male; Nephrectomy; Organ Size; Rats; Rats, Inbred Strains; Verapamil

Topics: Body Weight; Captopril; Enalapril; Humans; Schizophrenia; Schizophrenic Psychology; Water Intoxication

When enalapril, an angiotensin-converting enzyme (ACE) inhibitor, was orally administered to inseminated rabbits at dosages of 0.1 to 30 mg/kg/day for 13 days in a range-finding study, nephrotoxicity, as measured by elevated serum urea nitrogen concentrations, occurred at 1 mg/kg/day and higher dosages and significant (p less than or equal to 0.05) increases in fetal wastage were observed at dosages as low as 3 mg/kg/day. Saline supplementation during treatment prevented this rise in urea nitrogen. Fetal wastage was significantly (p less than or equal to 0.05) increased in the absence of maternotoxicity when saline-supplemented females were treated with enalapril at 30 mg/kg/day. A developmental toxicity study of enalapril in saline-supplemented rabbits produced no evidence of teratogenicity at 3, 10, and 30 mg/kg/day. The period of sensitivity of fetuses to the toxic effects of enalapril was found to be limited to middle-to-late gestation (Gestational Days 14-27). A single oral dose of enalapril (30 mg/kg) on Day 26 of gestation resulted in 100% fetal deaths. On the basis of the work done by Broughton Pipkin et al. [1982, J. Physiol. (London) 323, 415-422] and Broughton Pipkin and Wallace (1986, Brit. J. Pharmacol. 87, 533-542), which demonstrated that the sheep fetus becomes markedly hypotensive when the dam is treated with captopril or enalapril during late pregnancy, we believe that the observed fetotoxicity of enalapril in rabbits is also due to fetal hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Urea Nitrogen; Body Weight; Enalapril; Female; Fetus; Gestational Age; Pregnancy; Pregnancy, Animal; Rabbits; Teratogens

Three groups of spontaneously hypertensive rats (SHR) were given enalapril (25 mg/kg/day) from 4 to 9 weeks, 4 to 14 weeks, and 14 to 20 weeks of age. The drug was stopped and observations continued for another 16-21 weeks. At selected times, we measured blood pressure, in vitro hindquarter vascular resistance properties, left ventricular weight/body weight ratio, and skeletal muscle vessel norepinephrine kinetics in treated and untreated SHR and in Wistar-Kyoto (WKY) rats. At the end of each treatment period, all cardiovascular variables were close to values of WKY rats and well below those of untreated SHR, and the norepinephrine or fractional rate constant was about 25% below those levels. After enalapril was stopped, blood pressure and left ventricular weight/body weight ratio increased in parallel to levels ranging from 30% to 50% of the normal difference between untreated SHR and WKY rats. However, in SHR treated from 4 to 9 weeks and from 4 to 14 weeks of age, hindquarter resistance properties remained close to WKY rat levels for the entire observation period of 16-21 weeks after treatment, suggesting suppression of the enhanced resistance responses of SHR (amplifier properties). In SHR treated from 14 to 20 weeks of age, suppression of amplifier properties was more transient, and they redeveloped partially 5-6 weeks after cessation of therapy. When enalapril was given up to 14 weeks of age, the long-term suppression of amplifier properties was probably mainly through prevention of smooth muscle hypertrophy in resistance vessels and possibly through other mechanisms (e.g., "rarefaction").(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Enalapril; Hypertension; Male; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; Vascular Resistance

To assess angiotensin (ANG II) dependence of evolving neonatally induced coarctation hypertension (NICH) in inbred pups, we randomized sex-matched littermates to high-dose converting enzyme inhibitor (CEI: MK-421, 3 mg/kg) or placebo from the time of neonatal aortic banding (coarcted) vs. no banding (control). During phase 1 studies over 4 mo postbanding during ad libitum Na+ intake (Bagby and Fuchs, Hypertension Dallas in press). CEI failed to prevent evolution of proximal blood pressure (BP) excess or to impair renal function. Phase 2 studies examine, in the same pups, responses to low Na+ (LS) diet superimposed on chronic CEI at 4 mo, timed to allow development of BP increase in untreated NICH. The present report details metabolic handling and balances of Na+, K+, and fluid for 3 days before (normal Na+ intake) and daily for 11 days after initiation of LS diet, a companion paper describes BP, renin-angiotensin (RA), and renal functional responses. In no case did metabolic responses of coarcted pups to LS diet differ from those of controls, whether on CEI or placebo, whereas responses to LS diet and to CEI reveal positive findings of independent interest. LS diet induced expected renal and fecal Na+ conservation, no net effect on K+ balance, and, despite unexpected free-water diuresis, mild hyponatremia. Chronic CEI impaired maximal renal (but not fecal) Na+ conservation during LS diet, caused exaggerated free-water diuresis but no change in fluid balance, and thus, with the larger Na+ deficit, accounted for greater hyponatremia. CEI caused no net effect on K+ balance. Results indicate normal renal handling of fluid, Na+, and K+ in evolving NICH and provide no evidence for selective intrarenal RA activation or exaggerated ANG II dependence. Findings also suggest that, during LS diet, ANG II is 1) essential for maximum renal Na+ conservation and normal free-water handling, and 2) not essential for fecal Na+ and water conservation or for maintenance of normal water and K+ balances. Results are also compatible with a CEI-induced thirst stimulation and/or osmotic insensitivity and with functional vasopressin deficiency during LS diet.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Diet, Sodium-Restricted; Dogs; Enalapril; Female; Hypertension; Male; Potassium; Reference Values; Sodium; Water-Electrolyte Balance

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

The effect of zinc depletion and of additional angiotensin I-converting enzyme (ACE) inhibitor treatment was studied on ACE in aortic and other tissues, in plasma and on systolic blood pressure of the rat. Zinc deprivation significantly reduced plasma zinc concentration, plasma and testicular ACE activities and blood pressure, but stimulated aortic ACE while lung values remained constant. Zinc deficiency combined with ACE inhibition further suppressed plasma ACE and stimulated the aortic enzyme earlier. Zinc repletion experiments (in vitro) suggest the existence of a feedback mechanism controlling ACE synthesis depending on plasma ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Enalapril; Enalaprilat; Feedback; Lung; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; Renin; Testis; Zinc

We studied the effects of mid-term enalapril administration on protein-load-induced renal responses in 10 patients with early chronic renal failure (serum creatinine 2.70 +/- 1.0 mg/dl). The oral protein load was performed twice, before and after a 10-day therapy with enalapril. Glomerular filtration rate (125I-iothalamate clearance) rose from 22.5 +/- 10.6 to 60.1 +/- 32.8 ml/min after the protein load before enalapril; it did not change after the protein load during enalapril therapy. Percent fractional excretion of sodium, urinary osmolality and free water clearance were significantly affected only by the protein load before enalapril. Enalapril blunts the protein-load-induced changes in glomerular filtration rate and in tubular function; these effects might be mediated by angiotensin II blockade.

Topics: Adult; Angiotensin II; Blood Pressure; Body Weight; Creatinine; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Urea

The potential pathogenic role of angiotensin-II (AII) in early progressive diabetic and renal ablation-induced glomerulosclerosis was explored and compared in the Sprague-Dawley (SD) rat and the mongrel dog. Male SD rats were divided into control and streptozotocin-treated (65 mg/kg, iv) groups. Unilateral surgical nephrectomy (Nx) was performed in half of each group. Enalapril (E; 50 mg/liter in the drinking water) was administered to half of each subgroup. Enalapril (high E; 250 mg/liter) was given to another 13 streptozotocin rats. All diabetic rats were treated with sc NPH insulin (4 U/day), and blood glucose was 520 +/- 124 mg/dl (mean +/- SD). Microalbuminuria was measured by RIA in 24-h urine collections; wet kidney weights were compared. [125I]AII binding assays were performed on isolated glomeruli. In control rats the high affinity binding dissociation constant (Kd) was 0.59 +/- 0.15 nM (n = 26; mean +/- SD) and receptor number (Ro) was 732 +/- 195 fmol/mg glomerular protein. At 3 weeks, the diabetic glomerular AII receptor Kd was 0.38 +/- 0.07 nM (n = 6; P less than 0.02 vs. control) and Ro was 784 +/- 97 fmol/mg protein (P = NS vs. control); diabetic high E Kd was 0.39 +/- 0.06 nM (n = 6; P less than 0.02 vs. control), and Ro was 873 +/- 105 fmol/mg protein (P = NS vs. diabetes without E). By 10 weeks, a Kd of 0.49 +/- 0.12 nM (n = 32; P less than 0.01 vs. control) and a Ro of 780 +/- 174 fmol/mg protein (P = NS vs. control) were observed when all of the diabetic group data were pooled. Neither Nx nor low or high dose E altered Ro. This is evidence that intraglomerular AII levels are normal or reduced after diabetes, Nx, or both. In the diabetic group, low dose E partially prevented, and high E abolished, Nx-enhanced microalbuminuria and renal hypertrophy. In nine pancreatectomized insulin-treated mongrel dogs over a 12- to 24-month period, despite moderately poor glucose control (300 +/- 75 mg/dl) and combined unilateral Nx in five dogs (12 months), elevated microalbuminuria was not observed. [125I]AII binding to isolated normal and diabetic dog glomeruli revealed the Kd to be of low affinity (1.86 +/- 0.28 to 13.80 +/- 1.88 nM), identifying the presence of type B receptors. Hence, the SD rat and mongrel dog differ in susceptibility to glomerular AII receptor type and progressive diabetic glomerulopathy.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Albuminuria; Angiotensin II; Animals; Body Weight; Diabetic Nephropathies; DNA; Dogs; Enalapril; In Vitro Techniques; Kidney; Kidney Glomerulus; Male; Nephrectomy; Organ Size; Proteins; Rats; Rats, Inbred Strains; Reference Values

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

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

The long-term survival of rats with healed myocardial infarction and congestive heart failure treated with milrinone, enalapril and the combination of milrinone plus enalapril, was documented. Seven days after sham or coronary ligation, 200 rats (99 sham and 101 myocardial infarcted) were randomized based on electrocardiographic criteria to receive tap water, milrinone (20-40 mg/l drinking water), enalapril (17-25 mg/l) or the combination of milrinone plus enalapril (20-40 mg/17-25 mg per l). The date of spontaneous death was recorded and heart weights and myocardial infarct size (by planimetry) were determined. Long-term enalapril therapy prolonged survival with a median 50% survival (MS50) of 233 days compared to 203 days in the tap water group. Milrinone therapy also prolonged survival with a MS50 of 297 days. The combination therapy prolonged survival with a MS50 of 277 days. In general, there were three times as many rats alive in the treatment groups at the end of one year compared to untreated control groups. Cardiac hypertrophy was evident in all myocardial infarcted groups and heart weights were significantly reduced by all treatments. The average myocardial infarct sizes and the distribution of infarct sizes were not different between groups (36.8-43% of left ventricle). This study demonstrates that long-term therapy with enalapril and milrinone prolongs survival in rats with healed myocardial infarctions. The prolongation of survival was comparable in the milrinone plus enalapril groups, indicating that there was no synergy with these two agents with survival as the end point.

Topics: Animals; Body Weight; Cardiomegaly; Cardiotonic Agents; Electrocardiography; Enalapril; Heart Failure; Male; Milrinone; Myocardial Infarction; Organ Size; Pyridones; Rats; Rats, Inbred Strains

Although the serotonin uptake inhibitors have been shown to reduce alcohol intake in both animals and man, the mechanism of this effect is unclear. It is known that enhanced serotonergic activity can stimulate activity in the renin-angiotensin system and that elevated activity in the renin-angiotensin system can reduce voluntary alcohol intake. Therefore, serotonin uptake inhibitors such as fluoxetine might exert their effect on alcohol intake, in part, through the renin-angiotensin system. The present experiment assesses this possibility by examining the effect of the angiotensin converting enzyme inhibitor, enalapril, on the fluoxetine-induced decrease in alcohol intake. Four groups of rats were offered limited access to alcohol for 1 hr each day. When intake stabilized each group was injected with 2.5, 5.0 or 10.0 mg/kg of fluoxetine or the saline vehicle 1 hr prior to the access to alcohol. Fluoxetine produced a dose-dependent decrease in alcohol intake. Following this, all groups received injections of 1 mg/kg of the angiotensin converting enzyme inhibitor, enalapril, 40 min prior to the fluoxetine. Enalapril had no effect on alcohol intake in the saline group, but reversed the suppression in alcohol intake produced by the 2.5 mg/kg and 5.0 mg/kg doses of fluoxetine and partially reversed the effect of the 10.0 mg/kg dose. These findings indicate that the fluoxetine-induced reduction in alcohol intake may, in part, be mediated through the renin-angiotensin system.

Topics: Alcohol Drinking; Animals; Body Weight; Enalapril; Fluoxetine; Male; Rats; Rats, Inbred Strains; Reference Values; Renin-Angiotensin System

The interactions of blood pressure, salt intake and angiotensin converting enzyme (ACE) inhibition were investigated in the Dahl salt-sensitive (DS) and salt-resistant (DR) strains of rats. Eight-week-old DS and DR (40 of each) were separately randomized to receive a low- (0.4% NaCl) or a high- (8% NaCl) salt diet for 3 weeks. Thereafter the rats were further separated randomly to receive the ACE inhibitor lisinopril (3-8 mg/kg per day) or no drug treatment for 11 weeks. In untreated DS rats blood pressure rose, paralleled by a higher left ventricular mass (ratio left ventricular weight/body weight) irrespective of salt intake. Lisinopril lowered blood pressure to normotensive levels in all groups except DS rats on a high-salt diet, despite doses of up to 100 mg/kg per day, although there was a significant fall in blood pressure. Lisinopril reduced left ventricular mass significantly on the low- but not on the high-salt diet. Plasma renin activity increased on lisinopril treatment in all groups except DS rats on the high-salt diet. Regression of an increased left ventricular mass by ACE inhibition seemed to be impaired by a high salt intake, even when blood pressure was lowered. Therefore, although for regression of left ventricular hypertrophy, reduction of afterload was the leading factor, this might be adversely affected by a high salt intake.

Topics: Aldosterone; Animals; Body Weight; Cardiomegaly; Enalapril; Hypertension; Lisinopril; Peptidyl-Dipeptidase A; Rats; Rats, Mutant Strains; Renin; Sodium, Dietary

We tested the hypothesis that a metabolic error may be the triggering mechanism which leads to blood-vessel hypertrophy and hypertension. Young spontaneously hypertensive rats (SHR) were fed a moderately high salt diet to exacerbate the purported metabolic error. Haematocrit values and rubidium transport were measured as evidence of renal ATP deficiency and blood-vessel adaptation. The renin system was inhibited in two groups of SHR by giving them enalapril to determine whether angiotensin II was involved in blood-vessel adaptation. Spontaneously hypertensive rats fed the moderately high salt diet had higher haematocrit values than normotensive rats fed the same diet or SHR fed Purina rat food, suggesting a renal ATP deficiency. Spontaneously hypertensive rats had higher Na+,K+-ATPase activity in thoracic aorta after 60 min incubation than a similar group given enalapril (P less than 0.001), suggesting blood-vessel adaptation. Possibly, angiotensin II within the vasa vasorum stimulates hypertrophy which, according to the Folkow hypothesis, leads to higher blood pressure, but may concomitantly increase the respiratory chain units which provide ATP for renal function and ion transport.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Body Weight; Enalapril; Hematocrit; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Rubidium

We have recently shown that circulating atrial natriuretic polypeptide (ANP) in adult spontaneously hypertensive rats (SHR) is higher than that in age-matched Wistar-Kyoto rats (WKY). The present experiment was designed to examine the possible effects of chronic treatment with angiotensin I converting enzyme inhibitors (ACEI) on plasma ANP levels in SHR. Captopril and enalapril lowered blood pressure and reduced relative ventricular weight in SHR but not to the level of WKY. Plasma ANP levels were decreased by captopril and enalapril compared with untreated SHR. These results suggest that the ANP release may be suppressed in ACEI-treated SHR compared with untreated SHR. We speculate that a reduction of cardiac overload by ACEI may in part explain the decline of circulating ANP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Captopril; Enalapril; Heart Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Essential hypertension is characterized by increased renal vascular resistance, which also has definite implications for renal sodium handling. We studied the possibility of correcting these abnormalities by inhibiting angiotensin-converting enzyme with enalapril. Enalaprilic acid produced renal vasodilation. This, particularly postglomerular, vasodilation was accompanied with an increase in sodium excretion. The natriuresis was positively correlated to initial plasma renin activity. During continuous treatment with enalapril up to 12 weeks, this vasodilation persisted in 22 patients with essential hypertension. We also showed that orally administered enalapril induces natriuresis, both during a 50-mmol and during a 200-mmol sodium intake a day. This natriuresis caused a net negative sodium balance of approximately 120-140 mmol Na after 1 week of enalapril therapy. This was accompanied with a fall in body weight. We conclude that enalapril in essential hypertension alleviates the angiotensin-II-mediated abnormalities in renal hemodynamics and sodium excretion.

Topics: Administration, Oral; Adult; Angiotensin II; Body Weight; Enalapril; Enalaprilat; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Middle Aged; Natriuresis; Potassium; Renal Circulation; Renin; Sodium; Vasodilation

We evaluated the effect of additional chlorthalidone therapy on blood pressure and body fluid volumes in 10 patients with essential hypertension who did not respond to chronic converting enzyme inhibition with enalapril. Values assessed after 3 days and 6 weeks of combined enalapril and chlorthalidone therapy were compared with initial values during enalapril monotherapy. After 3 days the mean arterial pressure (MAP), plasma volume (PV), blood volume (BV), and extracellular fluid volume (ECFV) decreased. There was a positive correlation between the percentage decreases in MAP and BV. After 6 weeks the MAP decreased further, but the decreases in PV, BV, and ECFV were less pronounced. At this time there was a positive correlation between the percentage decreases in MAP and ECFV. Our results support the hypothesis that contraction of the ECFV is an antihypertensive mechanism of diuretics. The antihypertensive effect of diuretics is enhanced during converting enzyme inhibition, while the body remains protected against volume deficits, possibly by the lower blood pressure itself.

Topics: Aged; Aldosterone; Blood Pressure; Body Fluids; Body Weight; Chlorthalidone; Creatinine; Drug Evaluation; Drug Therapy, Combination; Enalapril; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renin

Antihypertensive effect of enalapril (MK-421), an orally active non-sulfhydryl-containing converting enzyme inhibitor, was examined in stroke-prone spontaneously hypertensive (SHRSP) rats. The treatment was started at 14-15 weeks of age with tail blood pressure over 240 mmHg and was continued for 11 weeks. We used captopril as the reference drug. The dose of enalapril and captopril was 10 and 30 mg/kg per day, p.o., respectively. Enalapril showed a sustained antihypertensive effect from the 1st to the 11th week of the treatment. This antihypertensive effect was substantiated by the good increase in body weight; decrease in heart weight; decrease in incidences of vascular disease, nephrosclerosis, stroke and death. Enalapril treatment also prevented the increases in urine volume, and excretion of osmotically active solutes, Na, Cl and K with age. Captopril treatment showed about the same antihypertensive effect. No side effects were seen in the enalapril or captopril treated group. The antihypertensive potency of enalapril was about 3 times more than that of captopril. Enalapril and captopril slightly increased plasma renin concentration. Urinary excretion of PGE2 was not changed by enalapril or captopril treatment. These results clearly demonstrate the efficacy of long-term treatment with enalapril to prevent development of malignant hypertensive cardiovascular disease in SHRSP rats.

Topics: Animals; Blood Pressure; Body Weight; Cerebrovascular Disorders; Dinoprostone; Electrolytes; Enalapril; Heart Rate; Male; Prostaglandins E; Rats; Rats, Inbred SHR; Renin; Time Factors

Nineteen patients (12 male and seven female) with essential hypertension (mean arterial pressure ranging from 113-162 mmHg) were studied at rest, supine and sitting, and during bicycle exercise (50, 100 and 150 W). Intra-arterial blood pressure and heart rate were recorded continuously. Cardiac output was measured by dye dilution (Cardiogreen). The patients were treated with enalapril 10-40 mg (mean 33 mg) once-daily; seven patients received in addition 25-50 mg hydrochlorothiazide daily. After 5-13 months (mean 10 months) patients were restudied. Blood pressure fell (P less than 0.001) in all - at rest sitting from 184/108 to 150/89 mmHg (-19%) and during 100 W bicycle exercise from 225/118 to 197/101 mmHg (-13%). Pretreatment total peripheral resistance index (TPRI) was markedly increased and fell at rest sitting from 4087 to 3514 dyn s/cm-5 m2 (-14%) (P less than 0.05). No significant change was seen in cardiac output, heart rate or stroke volume. Overall body weight and body fluid volume (isotope dilution technique) remained unchanged, but in the subgroup receiving enalapril + hydrochlorothiazide, blood volume fell by 12% (P less than 0.01). No side-effects were seen. In conclusion, enalapril monotherapy reduces blood pressure in two-thirds of patients with moderately severe essential hypertension at rest and during exercise, associated with a significant reduction in TPRI. One-third of patients require a diuretic in addition to enalapril. In this subgroup the reduction in TPRI was about twice the reduction seen during enalapril treatment alone, and there was a fall in blood volume.

Topics: Adult; Aged; Blood Pressure; Body Fluids; Body Weight; Cardiac Output; Drug Therapy, Combination; Enalapril; Female; Heart Rate; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Stroke Volume; Vascular Resistance

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

MK 421, at the dose of 25 mg/kg, administered daily by gavage to spontaneously hypertensive rats (SHRs) from their 4th to 15th weeks of age almost completely inhibited development of genetic hypertension. Since heart rate and cardiac and systolic indexes were not affected by the drug, prevention of genetic hypertension development was solely related to an early, potent and long-lasting reduction of the progressive increase of the peripheral resistance which generally develops in SHRs during ageing. MK 421 reduced body growth but did not modify fluid intake, plasma NA+ and urine volume, thus water and salt retention did not develop. MK 421 enhanced vascular responsiveness to norepinephrine and angiotension II and reduced myocardial hypertrophy. Plasma renin concentration was increased and urinary antidiuretic hormone did not change. Finally, MK 421's preventive effects against genetic hypertension development persisted up to 10 weeks after discontinuation of treatment.

Topics: Aging; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Captopril; Dipeptides; Enalapril; Hemodynamics; Hypertension; Male; Norepinephrine; Rats