enalapril and trandolapril

The Angiotensin Converting Enzyme (ACE) inhibitor class of drugs has been in clinical use since the 1970s for the management of all grades of heart failure, hypertension, diabetic nephropathy and prophylaxis of cardiovascular events. Because of the advantages associated with transdermal delivery compared with oral delivery many researchers have investigated the skin as a portal for administration of ACE inhibitors. This review summarises the various studies reported in the literature describing the development and evaluation of transdermal formulations of ACE inhibitors. Captopril, enalapril maleate, lisinopril dihydrate, perindopril erbumine and trandolapril are the most studied in connection with transdermal preparations. The methodologies reported are considered critically and the limitations of the various skin models used are also highlighted. Finally, opportunities for novel transdermal preparations of ACE inhibitor drugs are discussed with an emphasis on rational formulation design.

Topics: Administration, Cutaneous; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiovascular Diseases; Diabetic Nephropathies; Enalapril; Heart Failure; Humans; Hypertension; Indoles; Lisinopril; Perindopril; Skin

Nowadays angiotensin-converting enzyme inhibitors (ACE-Is) are considered to be a cornerstone in the treatment of congestive heart failure (CHF). These agents have been shown to improve survival and functional status of patients with CHF. It is logical to start therapy with ACE-Is in the first hours or days of acute myocardial infarction (MI) to further improve survival and prevent CHF after MI. The several randomized placebo-controlled trials were performed to assess the effects of early therapy with ACE-Is on the outcomes of MI. Mortality after MI was significantly reduced only in these trials in which therapy with ACE-Is was introduced 3-16 days after MI in patients with clinical evidence of CHF or left ventricular systolic dysfunction as well as in patients with noneffective thrombolysis (or without thrombolysis) or diabetes mellitus.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Complications; Enalapril; Heart Failure; Humans; Indoles; Middle Aged; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Ventricular Dysfunction

Atrial fibrillation is very common in the United States. After a search of Medline, EMBASE, and CINAHL, 4 trials evaluating inhibitors of the renin-angiotensin system were identified for prevention of new-onset atrial fibrillation, facilitation of electrical cardioversion of atrial fibrillation, and prevention of atrial fibrillation recurrence after electrical cardioversion. A meta-analysis was performed using a random-effects model. Use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) was associated with a reduction in new-onset atrial fibrillation (OR [95% CI] = 0.51 [0.36-0.72]), a lower failure rate of electrical cardioversion of atrial fibrillation (0.47 [0.24-0.92]), and a lower rate of recurrence of atrial fibrillation after electrical cardioversion (0.39 [0.20-0.75]). With the exception of the new-onset atrial fibrillation analysis, these findings were not associated with statistical heterogeneity. These hypothesis-generating data suggest that inhibitors of the renin-angiotensin system may provide benefit across the spectrum of atrial fibrillation.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Combined Modality Therapy; Electric Countershock; Enalapril; Humans; Indoles; Losartan; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Secondary Prevention; Tetrazoles; Valine; Valsartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Clinical Trials as Topic; Enalapril; Heart Failure; Humans; Indoles; Lisinopril; Losartan; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Controlled Clinical Trials as Topic; Enalapril; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Myocardial Ischemia; Nifedipine; Perindopril; Placebos; Risk Factors; Surveys and Questionnaires; Time Factors; Vasodilator Agents; Verapamil

The results of the major clinical outcome trials related to the potential antiatherosclerotic effects of the angiotensin convertase (ACE) inhibitors are reviewed after the recently published EUROPA trial results. In the postinfarction clinical situation mortality reduction was revealed in the ISIS-4 (captopril), GISSI-3 (lisinopril), AIRE (ramipril), TRACE (trandolapril), CONSENSUS (enalapril), SAVE (captopril) and in the SOLVD (enalapril) trials. In the HOPE trial performed in a high risk population the preventive antiatherosclerotic, endothel-preserving effects of ramipril resulted in a significant mortality and morbidity reduction. In the EUROPA trial a lower risk population--symptomfree coronary patients--were treated by perindopril, and it was proven also in this cohort, that the long term ACE inhibitor treatment decreased the combined endpoint of cardiovascular mortality, myocardial infarction and resuscitated sudden death. Based on the above data it can be advised, that all coronary patients regardless of left ventricular function and symptoms should receive long term ACE inhibitor treatment besides the other established preventive medications (platelet aggregation inhibitors + statins + beta receptor blockers).

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Clinical Trials as Topic; Coronary Disease; Death, Sudden, Cardiac; Enalapril; Humans; Indoles; Lisinopril; Myocardial Infarction; Perindopril; Ramipril; Treatment Outcome

When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.)

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diabetic Nephropathies; Drug Costs; Enalapril; Fosinopril; Heart Failure; Humans; Hypertension; Indoles; Isoquinolines; Lisinopril; Meta-Analysis as Topic; Myocardial Infarction; Perindopril; Quinapril; Ramipril; Renin-Angiotensin System; Risk; Tetrahydroisoquinolines; United States

Asymptomatic left ventricular dysfunction should be treated as an early stage on the continuum that is chronic heart failure. The author presents the clinical trial data on which current management with angiotensin-converting enzyme inhibitors and beta-blockers is based. Issues surrounding screening are also discussed.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Coronary Disease; Drug Therapy, Combination; Echocardiography; Enalapril; Female; Heart Failure; Humans; Hypertension; Indoles; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

This article discusses the pharmacologic basis on which trandolapril exhibits a more potent and longer-lasting antihypertensive effect than its chemical prototype enalapril. Our studies have shown that 1) trandolapril and its active metabolite trandolaprilat are more lipophilic than enalapril and its active diacid enalaprilat; 2) trandolaprilat is three times more potent than enalaprilat in vitro; and 3) trandolapril is 10 times more effective and longer-acting than enalapril in lowering the blood pressure of spontaneously hypertensive rats. The long duration of action of trandolapril can be attributed to its long-lasting inhibition of the vascular tissue angiotensin converting enzyme (ACE). The long action onto the vascular tissue ACE may be due to the high lipophilicity of trandolapril which may increase its tissue penetration and its elimination half-life from the tissue, and the unique nature of the vascular tissue which, unlike the other tissues, does not respond to trandolapril with the induction of de novo ACE that may counteract the ACE inhibition. These data imply that trandolapril is a potent ACE inhibitor with distinctively long action, which might be a result of its vascular tissue affinity and the lack of any ACE inducing ability of the vascular tissue.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Vessels; Enalapril; Humans; Indoles; Lipid Metabolism

Previous animal studies of chronic heart failure (CHF) suggest that angiotensin-converting enzyme (ACE) inhibitors of differing tissue avidity provide varying levels of renin-angiotensin system (RAS) suppression. Human studies have not consistently confirmed these animal findings. We hypothesised that production of circulating aldosterone (ALDO) would be suppressed to a greater extent in subjects treated with an ACE-inhibitor of higher tissue avidity. We randomised subjects with stable CHF to receive the low-tissue affinity ACE-inhibitor enalapril (ENAL) or the high-tissue affinity ACE-inhibitor trandolapril (TRAN), and assessed circulating ALDO levels at baseline and after eight weeks of treatment.. Thirty clinically stable subjects with CHF and left ventricular ejection fraction (LVEF) < 40% who were in a steady-state fluid balance were enrolled into a prospective, randomised double-blind trial. After a one month run-in period for standardisation to initial ACE-inhibition with ENAL, baseline circulating ALDO levels were measured and patients were randomised to receive ENAL 40 mg versus TRAN 4 mg (or the maximally tolerated doses) for eight weeks. Final determination of ALDO levels were made at the end of the 8-week study period.. Baseline clinical characteristics including age, diabetes, LVEF, serum sodium, potassium and creatinine concentrations, and background medications were similar in both groups. We found no statistically significant difference in circulating ALDO levels between the ENAL and TRAN groups at the end of the 8-week study period. [ENAL (12.6 vs. 13.3 ng/dL); TRAN (12.5 vs. 14.5 ng/dL); p=NS].. We found no statistically significant difference in circulating ALDO levels between high- and low-tissue affinity ACE-inhibitor therapy. Further studies assessing ALDO production at the tissue level is warranted.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Heart Failure; Humans; Indoles; Male; Middle Aged

Experimental studies suggest that angiotensin-converting enzyme (ACE) inhibitors with high tissue affinity confer a greater degree of vascular renin-angiotensin system suppression than those with low tissue affinity despite similar suppression of the circulating renin-angiotensin system. To test this hypothesis in a clinical setting, we randomized subjects with chronic heart failure to receive the low tissue affinity ACE inhibitor enalapril or the high tissue affinity ACE inhibitor trandolapril, and assessed the degree of circulating and vascular renin-angiotensin system suppression. Vascular renin-angiotensin system suppression was determined by measuring the pressor response to intravenous injections of angiotensin I. Circulating renin-angiotensin system suppression was determined by measuring plasma angiotensin II. Vascular and circulating renin-angiotensin system suppression, endothelial function (flow-mediated vasodilation), and maximal exercise capacity (peak oxygen uptake) were assessed after a 4-week run-in period on open-label enalapril 40 mg/day and after 8 weeks of randomized double-blind treatment with enalapril 40 mg/day or trandolapril 4 mg/day. Twenty-six men and 4 women (mean age 52 +/- 11 years; mean left ventricular ejection fraction 25 +/- 9%; New York Heart Association class II [n = 16] and III [n = 14]) were studied. After a 2-month randomized treatment period, vascular renin-angiotensin system suppression, circulating renin-angiotensin system suppression, endothelial function, and exercise capacity did not differ between subjects treated with enalapril and those treated with trandolapril. Despite substantial differences in the tissue affinity of enalapril and trandolapril, the degree of vascular renin-angiotensin system suppression achieved with these agents did not differ in subjects with chronic heart failure during long-term therapy.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Double-Blind Method; Enalapril; Endothelium, Vascular; Exercise Tolerance; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Renin-Angiotensin System

It has been reported that treatment with an angiotensin-converting enzyme (ACE) inhibitor is not adequate to suppress aldosterone, and we previously demonstrated that adding spironolactone to an ACE inhibitor may have beneficial effects on left ventricular hypertrophy (LVH) in selected patients with essential hypertension (EH). We have extended our previous short-term study, and addressed the relative long-term clinical effects of spironolactone and an ACE inhibitor in patients with EH who have LVH. Twenty patients with EH and concomitant LVH participated in this study. Subjects were treated with either an ACE inhibitor alone (group 1: 10 patients) or an ACE inhibitor plus spironolactone at the dose of 25 mg (group 2: 10 patients) for 60 weeks. The baseline clinical and echocardiographic characteristics of the two groups were similar. Final values of blood pressure were also similar between the two groups. The LV mass index (LVMI) decreased significantly in both groups, but the extent of reduction was significantly greater in group 2 at 60 weeks. The early peak to atrial peak filling velosities ratio (E/A ratio) was significantly increased to a similar extent in both groups. Serum procollagen type III amino-terminal peptide (PIIINP) was significantly decreased in group 2, but not in group 1. In group 2, there was a statistically significant correlation between the changes in LVMI and PIIINP. In conclusion, adding spironolactone to therapy with an ACE inhibitor for 60 weeks may have beneficial effects in patients with EH and concomitant LVH. Our study strongly suggests the possibility that attenuation of the effects of cardiac aldosterone in patients with EH by treatment with spironolactone and an ACE inhibitor may become a new goal for the prevention and regression of cardiac hypertrophy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Blood Pressure; Coronary Circulation; Diastole; Drug Therapy, Combination; Echocardiography; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Procollagen; Spironolactone

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

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

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

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

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Carotid Arteries; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Indoles; Kidney Transplantation; Lipids; Lipoproteins; Postoperative Complications; Potassium; Tunica Intima; Tunica Media

A double blind randomised comparison of two angiotensin-converting enzyme (ACE) inhibitors was made in a study in which ambulatory blood pressure was monitored over a steady-state dosage interval and the subsequent 24-h period, the latter being designed to mimic a missed dose of drug. The blood pressure responses on active therapy were compared to an identical recording made at the end of a 3-week placebo run in period. Eighty-eight essential hypertensives were treated with a morning dose of either trandolapril 2 mg or enalapril 20 mg. Mean systolic (SBP) and diastolic blood pressure (DBP) were calculated on each of the following periods: daytime (8:31 a.m.-10:30 p.m.), nighttime (10:31 p.m.-6:30 a.m.), and early morning (6:31 a.m.-8:30 a.m.). Trough/peak was calculated for each group both on active treatment and after a missed dose. Twelve patients were excluded from analysis before opening the randomisation code because of inadequate ambulatory blood pressure monitoring (ABPM) recordings. Demographic data, placebo-period office blood pressure, and ABPM recordings were not significantly different between the two groups. Both trandolapril and enalapril effectively reduced blood pressure over the 24-h period. Twenty four-hour ambulatory SBP and DBP decreased from 148 +/- 14/92 +/- 10 mm Hg to 135 +/- 14/83 +/- 10 mm Hg in the trandolapril group (p < 0.001). The same parameters decreased to a quite similar extent after enalapril, from 143 +/- 13/91 +/- 5 mm Hg to 133 +/- 15/83 +/- 8 mm Hg (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Patient Compliance; Single-Blind Method

Noninvasive ambulatory blood pressure monitoring (ABPM) has proved to be an innovative tool for the assessment of the efficacy of antihypertensive drugs. It enables evaluation of the magnitude of the drug-related blood pressure fall and also of the duration of this effect throughout 24 h. Moreover, ambulatory blood pressures have advantages compared to office blood pressure: they are not affected by the white coat effect occurring at the time of the doctor's visit, are devoid of a placebo effect, are more reproducible than occasional clinic measurements, and may yield important information on the prognosis of hypertensive patients. Ambulatory blood pressure recordings were used to test the antihypertensive effect of a novel angiotensin converting enzyme, trandolapril, in 62 mild to moderate essential hypertensive outpatients. After a 4 week wash-out, period, patients were randomized to 2 mg trandolapril or placebo for 6 weeks. A 4-week wash-out period was scheduled at the end of the treatment period. Ambulatory blood pressure recordings were performed at the end of each period, starting in the morning. Trandolapril (n = 31) significantly reduced 24 h systolic and diastolic blood pressure as compared to pre- and posttreatment periods and to placebo (n = 17). The reduction involved both the daytime and nighttime blood pressure values and was evident also in the last hours of the recording, the trough-to-peak ratio being 0.6 for systolic and 0.7 for diastolic blood pressure. Thus, trandolapril at a dose of 2 mg once daily is an effective long-lasting antihypertensive drug.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Enalapril; Fosinopril; Humans; Hypertension; Indoles; Middle Aged

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Exercise; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles; Male

Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.

Topics: Angiotensin-Converting Enzyme Inhibitors; Carboxylesterase; Carboxylic Ester Hydrolases; Diltiazem; Drug Interactions; Enalapril; Esters; Humans; Hydrolysis; Inactivation, Metabolic; Indoles; Kinetics; Liver; Microsomes, Liver; Nitrophenols; Prodrugs; Ramipril; Recombinant Proteins; Verapamil

The properties of the angiotensin-converting enzyme (ACE) inhibitors have largely been attributed to a class effect. However, this opinion is now increasingly challenged in view of the findings from recent clinical trials, which have demonstrated differential effects of ACE inhibitors, in particular with respect to secondary cardiovascular prevention outcomes. In this experimental study, Sprague-Dawley rats were treated with five different ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) at equihypotensive doses. All ACE inhibitors increased endothelial nitric oxide synthase (eNOS) protein expression and activity in the aorta (both P<0.0001 versus vehicle) and in cardiac myocytes (both P<0.05 versus vehicle). A highly significant effect was observed with perindopril when compared with vehicle in the modulation of eNOS protein expression and activity in aorta (22.52+/-1.09 versus 9.12+/-0.57 AU microg(-1) protein and 1.59+/-0.03 versus 0.77+/-0.02 pmol l(-1) citrulline min(-1)mg protein(-1), respectively) and in cardiac myocytes (17.64+/-0.94 versus 11.30+/-0.59 AU microg(-1) protein and 0.93+/-0.02 versus 0.62+/-0.03 pmol l(-1) citrulline min(-1)mg protein(-1), respectively). On the basis of the eNOS protein expression in the rat aorta, the other ACE inhibitors had similar, but lower effects. Indeed, the rank of potency - based both on eNOS protein expression and activity - was perindopril>trandolapril approximately quinapril approximately ramipril approximately enalapril (P<0.05 perindopril versus trandolapril and ramipril and P<0.01 perindopril versus enalapril, respectively). Levels of circulating nitrite/nitrate, the end-metabolites of nitric oxide, were also significantly affected by ACE inhibition, with the same order of potency. Our findings provide further evidence in favor of differential effects associated with ACE inhibitor therapy and suggest that the clinical benefits associated with these drugs may not solely reflect a class effect extending their benefit beyond blood pressure-lowering effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Enalapril; Immunoblotting; Indoles; Male; Myocytes, Cardiac; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Perindopril; Quinapril; Ramipril; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines

Although angiotensin-converting enzyme inhibitors (ACEIs) have been shown to reduce left ventricular remodeling after acute myocardial infarction (AMI), the effects of angiotensin receptor blockers have yet to be established. This study was conducted to examine the effects of candesartan on left ventricular remodeling after AMI. Consecutive AMI patients were assigned to a candesartan group or ACEI group after successful coronary intervention. The patients in the candesartan group (n = 77, mean age, 62.8 +/- 1.3) received candesartan and the patients in the ACEI group (n = 80, mean age, 63.3 +/- 1.2) received lisinopril, enalapril, or trandolapril. Four mg was the most frequent dose in the candesartan group at 6 months. Lisinopril, enalapril, and trandolapril were administered to 52%, 27%, and 21% of the patients in the ACEI group, respectively. No significant differences in the incidences of cardiac death, nonfatal MI, or hospitalization for heart failure (P = NS) were found between the groups. The candesartan group exhibited a somewhat higher percent increase in left ventricular ejection fraction and significantly lower percent increases in left ventricular end-diastolic volume index and left ventricular end-systolic volume index compared to the ACEI group (P < 0.05, P < 0.05, respectively). Candesartan is more effective than ACEI in preventing left ventricular remodeling after AMI.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Enalapril; Female; Humans; Indoles; Lisinopril; Male; Middle Aged; Myocardial Infarction; Tetrazoles; Ventricular Function, Left; Ventricular Remodeling

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzopyrans; Biphenyl Compounds; Bisoprolol; Captopril; Carbazoles; Carvedilol; Drug Therapy, Combination; Enalapril; Ethanolamines; Evidence-Based Medicine; Guideline Adherence; Heart Failure; Humans; Indoles; Lisinopril; Metoprolol; Mineralocorticoid Receptor Antagonists; Nebivolol; Practice Guidelines as Topic; Propanolamines; Ramipril; Spironolactone; Stroke Volume; Tetrazoles; Valine; Valsartan

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Indoles; Myocardial Ischemia; Perindopril; Quinapril; Ramipril; Tetrahydroisoquinolines

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Enalapril; Heart Failure; Humans; Indoles; Isoquinolines; Myocardial Infarction; Perindopril; Prodrugs; Quinapril; Ramipril; Stroke; Stroke Volume; Tetrahydroisoquinolines; Treatment Outcome; Ventricular Dysfunction, Left

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

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

Role of tissue angiotensin-converting enzyme (ACE) in the development of pressure-overload cardiovascular hypertrophy was examined in rats by comparing the inhibitory effect of trandolapril (high efficiency on tissue ACE) with that of enalapril (low efficiency) at equally antihypertensive doses. Rats with abdominal aorta banded or sham-operated were orally treated with trandolapril (0.5 mg/kg per day), enalapril (20 mg/kg per day) or vehicle for 8 weeks after the surgical maneuvers. In vehicle-treated rats, the banding raised the intra-aortic systolic pressure by 58%, diastolic pressure by 31%, maximum velocity of pressure rise by 65%, left ventricular (LV) weight by 41%, LV hydroxyproline concentration by 56%, aortic mass by 46%, LV ACE activity by 45%, and aortic ACE activity by 265%. Although both drugs equally reduced the aortic systolic pressure to approx. 70% and diastolic pressure to approx. 80% that of banded rats receiving vehicle, trandolapril partially prevented the LV hypertrophy, whereas enalapril yielded nonsignificant suppression. Trandolapril completely prevented the LV increments in hydroxyproline and ACE activity, whereas enalapril partially inhibited the LV hydroxyproline increase with little inhibition of LV ACE activity. In contrast, both inhibitors almost completely prevented the aortic hypertrophy, with the ACE activity of the aorta being potently inhibited. These results suggest that tissue ACE is the principal factor for pressure-induced aortic hypertrophy and an important yet non-essential factor for LV hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Aortic Diseases; Blood Pressure; Cardiomegaly; Enalapril; Heart Ventricles; Hydroxyproline; Indoles; Male; Organ Size; Rats; Rats, Wistar; Time Factors

The present study was designed to evaluate trough-to-peak ratio (T/P) of ACE inhibitors in spontaneously hypertensive rats (SHR) by a continuous monitoring of ambulatory blood pressure for 24 hours with a biotelemetric system. Blood pressure was recorded uninterruptedly with a battery-operated transmitter connected to a sensor catheter. Perindopril (3 mg/kg), trandolapril (1 mg/kg), quinapril (10 mg/kg) and enalapril (6 mg/kg) were given once a day for 7 days. On the first day of the treatment these ACE inhibitors equally decreased blood pressure by 20 mmHg at each peak. The peak and trough blood pressure decreased steadily until day 4, and then they were constant until the end of experiment (day 7). T/P for each inhibitor also increased until day 4, and the ratios in systolic blood pressure at the end of experiments (day 7) were as follows, perindopril: 0.63, trandolapril: 0.62, quinapril: 0.41, enalapril: 0.27. The T/P of perindopril was significantly higher than that of enalapril. The results of the present studies testing four ACE inhibitors are well consistent with those in clinical trials. Thus, the measurement of T/P in SHR would provide a meaningful information for the evaluation of antihypertensive agents like ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Enalapril; Heart Rate; Hypertension; Indoles; Isoquinolines; Locomotion; Male; Perindopril; Quinapril; Random Allocation; Rats; Rats, Inbred SHR; Telemetry; Tetrahydroisoquinolines

Potential involvement of brain endogenous angiotensin II in the nociception was investigated in mice by using ACE inhibitors and an angiotensin II antagonist. The mice were allocated to the groups which were orally treated with spirapril (5 mg/kg), trandolapril (5 mg/kg), enalapril (30 mg/kg), losartan (10 mg/kg), or vehicle for 1 day (single dose groups) and 7 days (repeated doses groups). Significantly longer jump latencies were obtained for the groups repeatedly treated with spirapril, trandolapril and losartan, while the group with enalapril gained no effect. In contrast, the single dosing of all agents failed to show antinociceptive effect. The brain ACE activity was determined ex vivo immediately after the hot-plate test, and showed to be suppressed for the groups repeatedly treated with spirapril or trandolapril. In the group repeatedly treated with losartan, ex vivo autoradiography depicted the marked decrease in angiotensin II-binding capacity to the sites containing exclusively AT1 receptors within the blood-brain barrier. The antinociceptive effects of repeated doses of spirapril and losartan were reversed by naloxone. These results suggest that brain endogenous angiotensin II is likely to be involved in central nociceptive mechanisms by its antagonistic interaction with endogenous opioid system.

Topics: Administration, Oral; Analgesics; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Brain; Enalapril; Imidazoles; Indoles; Losartan; Male; Mice; Naloxone; Pain Measurement; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Tetrazoles

Although pharmacological therapy with angiotensin converting enzyme (ACE) inhibitors has proved to be effective in patients with heart failure (HF), the experimental basis of this effect has not yet been addressed. In the present study, animals with HF were treated with an oral administration of 10 mg/kg/day captopril, 10 mg/kg/day enalapril and 3 mg/kg/day trandolapril from the 2nd to 12th week after the operation. HF was induced by permanent occlusion of the left coronary artery of the rat at 2 mm from its origin. Treatment of the HF rats with the ACE inhibitors enhanced the decrease in mean arterial blood pressure, attenuated the rise in left ventricular end-diastolic pressure, an indirect marker of preload, and diminished the reduction in cardiac output and stroke volume indices of the HF animal. Treatment also reversed the reduction in ATP, creatine phosphate, creatine and the mitochondrial oxygen consumption rate of the viable left and right ventricles of the HF animal. The improvement of the cardiac output index and high-energy phosphate levels of the HF rat by the ACE inhibitors was associated with the recovery of the mitochondrial oxygen consumption rate. In sham-operated animals, treatment with the ACE inhibitors reduced mean arterial pressure and left ventricular systolic pressure, but not metabolic variables concerning myocardial energy metabolism. The present results provide evidence that ACE inhibitor therapy improves cardiac function and myocardial energy metabolism of experimental animals with chronic heart failure. The mechanism underlying the benefit of long-term treatment with ACE inhibitors is probably attributable to recovery or preservation of the mitochondrial function and reduction in preload.

Topics: Adenine Nucleotides; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Enalapril; Energy Metabolism; Heart Failure; Hemodynamics; Indoles; Lactates; Male; Mitochondria, Heart; Myocardial Infarction; Myocardium; Organ Size; Oxygen Consumption; Phosphocreatine; Rats; Rats, Wistar

The aim of the present study was to determine whether the new ACE inhibitor trandolapril was able to inhibit brain ACE activity in spontaneously hypertensive rats (SHRs). Therefore, we have measured ex vivo ACE activity in discrete brain areas of SHRs after a 2-week oral treatment with trandolapril (0.001, 0.01, 0.1 and 1 mg/kg/day). The effects of trandolapril were compared to those of enalapril (10 mg/kg/day), used as a reference compound. Enalapril induced a decrease in ACE activity in brain areas not protected by the blood brain barrier (subfornical organ and median eminence) and in cerebral cortex. Conversely, trandolapril at a dose of 0.01 mg/kg/day and above induced a dose-dependent inhibition of ACE activity in all brain areas assayed, including the supraoptic and paraventricular hypothalamic nuclei, septum, amygdala, hippocampus, cerebellar and cerebral cortex, nucleus of the tractus solitary and caudate nucleus. The inhibition was roughly similar in all brain areas studied. These data suggest that after chronic oral administration in SHRs, trandolapril or its metabolite, in contrast to enalapril or enalaprilat, was able to reach all brain areas of SHRs, including those protected by the blood brain barrier.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Brain; Dose-Response Relationship, Drug; Enalapril; Indoles; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR

The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. To understand the reasons for such discrepancies between ex vivo effects of ACE inhibitors and in vitro actions of their diacid metabolites, we measured the lipophilicities of the compounds and investigated the possibility that trandolapril could display an ACE inhibitory effect by itself. Trandolaprilat was found to be far more lipophilic than enalaprilat, as shown by reverse-phase high-performance liquid chromatography studies performed at pH 7.4 (log kw7.4 = 1.487 vs. 0.108). In addition, trandolapril was practically as active in vitro as its diacid metabolite (IC50 = 2.5 vs. 1.35 nM) in inhibiting ACE activity in the aorta, whereas enalapril was practically devoid of any effect (IC50 = 240 nM). Measurements of relative affinities of inhibitors or metabolites for purified human renal ACE showed that trandolapril displayed about 20% of the affinity of its diacid metabolite (IC50 = 15 vs. 3.2 nM); enalaprilat affinity (34 nM) was within the same range as those of trandolapril and trandolaprilat, whereas enalapril displayed a very low affinity for the purified enzyme (IC50 = 50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Enalaprilat; Indoles; Isoquinolines; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Solubility; Tetrahydroisoquinolines

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 examined the effect of trandolapril ((-)-(2S, 3aR, 7aS)-1-[(S)-N-[(S)-1-ethoxycarbonyl-3- phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid), a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in guinea pigs and compared it with that of enalapril. Chronic treatment with enalapril, at a dose of 3 mg/kg, p.o., significantly enhanced the number of capsaicin-induced coughs. Chronic treatment with trandolapril, at doses of 1 and 3 mg/kg, p.o., slightly enhanced the number of capsaicin-induced coughs. However, there were no significant differences in the number of capsaicin-induced coughs between trandolapril-treated and vehicle-treated animals. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of trandolapril is relatively lower than that of enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capsaicin; Cough; Enalapril; Guinea Pigs; Indoles; Male

To examine the role of the tissue renin-angiotensin system in left ventricular hypertrophy, converting enzyme inhibitors were administered orally to 12-week-old male spontaneously hypertensive rats (SHR) for 4 weeks, and cardiac tissue angiotensin II was measured. Treatment with enalapril (10 mg/kg per day) and trandolapril (1 mg/kg per day) lowered systolic blood pressure, left ventricular weight and left ventricular angiotensin II content. Plasma angiotensin II concentration was increased by the treatment with enalapril whereas trandolapril did not cause any change. There was significantly positive correlation between left ventricular weight and angiotensin II content. Because angiotensin II promotes cell proliferation, these results suggest that cardiac tissue angiotensin II, rather than circulating angiotensin II, may account for the pathophysiology of left ventricular hypertrophy in SHR.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Enalapril; Heart Atria; Heart Ventricles; Indoles; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Renin-Angiotensin System

The angiotensin I-converting enzyme (CE) inhibitors, trandolapril (RU 44570) and enalapril were administered for 2 weeks to SHR at doses (3 and 10 mg/kg/day, p.o., respectively) that produced important and comparable inhibitions of plasma (84 and 88%), aorta (97 and 88%), and atrium (89 and 82%) CE activities. At these doses, the inhibitory effects of trandolapril and enalapril were nonetheless different on CE in heart ventricle (58 and 72%) and kidney (45 and 85%). In addition, although both drugs reduced blood pressure (BP) and heart hypertrophy, trandolapril was more potent despite a lower dose-ratio. All these parameters were reexamined 1, 3, and 8 days after drug withdrawal: BP returned to control levels within 3 days in enalapril-treated rats, whereas it remained low for at least 8 days in trandolapril-treated animals. The reduction of heart hypertrophy owing to trandolapril was still present 8 days after drug discontinuation. On cessation of treatment, plasma CE increased above controls, ventricle CE returned to control levels within 3 days, whereas atrial and aortic CE activities remained inhibited for 8 days in the enalapril group. In contrast, in trandolapril-treated rats, CE activities in serum and tissues were still inhibited after 8 days. These results demonstrate that at the doses used trandolapril is more potent and longer acting than enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Heart Rate; Hemodynamics; Indoles; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Time Factors

Two angiotensin converting enzyme (ACE) inhibitors, trandolapril and enalapril, were compared for their effects on rat food-pad oedema induced by carrageenin, bradykinin, dextran and platelet activating factor (PAF). Trandolapril (0.03-30.0 mg/kg, per os) potentiated carrageenin-induced oedemas. Enalapril produced the same effect at 3-10 fold higher doses (0.3-30.0 mg/kg per os). Both ACE inhibitors were equiactive in potentiating bradykinin-induced oedema. Neither compound affected dextran-induced oedema. In marked contrast PAF-induced oedema was reduced by both ACE inhibitors, trandolapril being approximately 10 fold more active than enalapril. The observed differences in potency between the two ACE inhibitors corresponded with their previously described actions on inhibition of plasma and tissue ACE and in inducing hypotension. The results suggest a crucial role of kinins in the oedemagenic response to carrageenin. The reason why the ACE inhibitors reduced PAF-induced oedema is not clear, but could involve peripheral vasodilation.

Topics: Animals; Bradykinin; Carrageenan; Dextrans; Edema; Enalapril; Foot; Indoles; Male; Platelet Activating Factor; Rats; Rats, Inbred Strains

Trandolapril (3-100 micrograms/kg) and enalapril (10-300 micrograms/kg) were administered orally to conscious rats. Angiotensin-converting enzyme (CE) activity was inhibited in serum, heart ventricle, renal inner cortex, lung, aorta, adrenal cortex and adrenal medulla, but not in the striatum. Inhibition was maximal at 2 h and with trandolapril was maintained for 24 h. Blood pressure and heart rate were not affected by either compound. Trandolapril was 6-10-fold more potent than enalapril. Differences between trandolapril and enalapril in CE inhibition observed in heart ventricle, adrenal cortex and medulla could be due to the presence of more than one type of CE or CE-like activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Heart Rate; In Vitro Techniques; Indoles; Male; Peptidyl-Dipeptidase A; Rats

The inhibition of converting enzyme (CE) activity in target tissues other than blood and lung vascular endothelium may be important for the antihypertensive action of CE inhibitors (ICE) (Unger et al 1983). In order to determine if ICE may have an effect on the transmembrane Na movements implicated in the regulation of vascular tone, we have studied the effects of trandolapril and enalapril on 22Na effluxes from the tail artery of 20 weeks old SHR. In vivo, the chronic oral treatment (14 days) with trandolapril (1.3 mg/kg/day) decreased the ouabain-sensitive 22Na efflux (controls: 0.050 +/- 0.004 min-1 (n = 8); trandolapril (1 mg/kg): 0.030 +/- 0.03 min-1 (n = 10) p less than 0.01), and the ouabain-insensitive 22Na efflux (controls: 0.088 +/- 0.0030 min-1; trandolapril (1 mg/kg): 0.080 +/- 0.003 min-1 (n = 10) p less than 0.05). Enalapril had no effect at the dose of 10 mg/kg/day (14 days). In vitro, trandolapril diacid (RU 44403) decreased the ouabain-sensitive 22Na efflux (controls: 0.045 +/- 0.002 min-1 (n = 6); RU 44403 (10(-9) M): 0.031 +/- 0.002 min-1 (n = 6) p less than 0.01), and the ouabain-insensitive efflux (controls: 0.096 +/- 0.004 min-1 (n = 6); RU 44403 (10(-9) M): 0.084 +/- 0.006 min-1 (n = 6) p less than 0.05). The effects were dose-dependent. Enalapril diacid (MK 422) also dose-dependently decreased 22Na effluxes but it was approximately 10 fold less active.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Cell Membrane; Enalapril; Hypertension; Indoles; Male; Ouabain; Rats; Rats, Inbred SHR; Saralasin; Sodium; Sodium Radioisotopes; Tail

The effects of 5 angiotensin I converting enzyme (ACE) inhibitors--captopril, enalapril, perindopril, trandolapril and ramipril--on general and regional hemodynamics were investigated (using radioactive microspheres) and compared in anesthetized adult spontaneously hypertensive rats. The 5 treatments were administered daily by gavage for 8 days in doses inducing identical decreases in arterial blood pressure. This effect was entirely due to a decrease in total peripheral resistance inasmuch as cardiac index was not affected by the 5 ACE inhibitors. In addition, despite their different chemical structures, all exhibited the same regional vasodilator pattern, which thus appears to be related only to ACE inhibition. The vascular beds resistances were decreased in the following order: renal greater than splenic = liver greater than skin greater than total peripheral greater than muscle = brain. Simultaneously, and despite the decrease in perfusion pressure, most regional blood flows and especially renal blood flow were increased. Finally, renal vasodilator effects of ACE inhibitors were observed even after doses that lacked any effect on total peripheral resistance.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bridged Bicyclo Compounds; Captopril; Enalapril; Indoles; Perindopril; Ramipril; Rats; Rats, Inbred SHR; Regional Blood Flow; Vascular Resistance