enalapril and Arteriosclerosis

Although clinical reports have suggested that antihypertensive therapy can control blood pressure in patients with renovascular hypertension, adequate randomized studies comparing medical versus surgical management are lacking. It is well recognized that progressive deterioration in renal function can occur despite good blood pressure control. Recent experience suggests that higher-risk patients with atherosclerotic renovascular hypertension can benefit from an aggressive surgical approach, whereas newer medical therapies capable of specific inhibition of the renin-angiotensin system suggest greater potential benefits to other patients. Properly performed randomized trials comparing medical versus surgical therapy of renovascular hypertension are needed.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Atenolol; Captopril; Dipeptides; Enalapril; Female; Humans; Hypertension, Renovascular; Male; Metoprolol; Middle Aged; Nadolol; Pindolol; Propanolamines; Propranolol; Renal Artery Obstruction; Renin-Angiotensin System; Saralasin; Timolol

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

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

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

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

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

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

We studied 22 patients undergoing aortic surgery, allocated randomly to receive, before induction of anaesthesia, a single i.v. dose of enalapril 50 micrograms kg-1 or saline. During infrarenal aortic cross-clamping, we observed similar reductions in oxygen uptake in the two groups, despite greater systemic oxygen delivery in enalapril-treated patients; angiotensin-converting enzyme inhibition prevented the reduction in cardiac output and attenuated the decrease in glomerular filtration. Changes in glomerular filtration secondary to aortic clamping were related positively to changes in renal plasma flow (r = 0.83 (saline group) and r = 0.65 (enalapril group)). Creatinine clearance on the first day after operation was significantly higher in the enalapril compared with the saline group. We conclude that enalapril pretreatment is effective in improving systemic oxygen delivery, renal plasma flow and glomerular filtration during aortic abdominal surgery.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Arteriosclerosis; Blood Flow Velocity; Cardiac Output; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Premedication; Vascular Resistance

To compare the rate of progression of mean maximum intimal-medial thickness (IMT) in carotid arteries, using quantitative B-mode ultrasound imaging, during antihypertensive therapy with isradipine vs hydrochlorothiazide.. Randomized, double-blind, positive-controlled trial.. Nine medical center clinics.. A total of 883 patients with baseline mean +/- SD systolic and diastolic blood pressure (SBP and DBP, respectively) of 149.7 +/- 16.6 and 96.5 +/- 5.1 mm Hg, age of 58.5 +/- 8.5 years, and maximum IMT of 1.17 +/- 0.20 mm.. Twice daily doses of isradipine (2.5-5.0 mg) or hydrochlorothiazide (12.5-25 mg). MAIN OUTCOME MEASURE (PRIMARY END POINT): Rate of progression of mean maximum IMT in 12 carotid focal points over 3 years.. There was no difference in the rate of progression of mean maximum IMT between isradipine and hydrochlorothiazide over 3 years (P=.68). There was a higher incidence of major vascular events (eg, myocardial infarction, stroke, congestive heart failure, angina, and sudden death) in isradipine (n=25; 5.65%) vs hydrochlorothiazide (n=14; 3.17%) (P=.07), and a significant increase in nonmajor vascular events and procedures (eg, transient ischemic attack, dysrhythmia, aortic valve replacement, and femoral popliteal bypass graft) in isradipine (n=40; 9.05%) vs hydrochlorothiazide (n=23; 5.22%) (P=.02). At 6 months, mean DBP decreased by 13.0 mm Hg in both groups, and mean SBP decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in isradipine (P=.002); the difference in SBP between the 2 groups persisted throughout the study but did not explain the increased incidence of vascular events in patients treated with isradipine.. The rate of progression of mean maximum IMT in carotid arteries, the surrogate end point in this study, did not differ between the 2 treatment groups. The increased incidence of vascular events in patients receiving isradipine compared with hydrochlorothiazide is of concern and should be studied further.

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Carotid Arteries; Diastole; Disease Progression; Diuretics; Double-Blind Method; Enalapril; Female; Humans; Hydrochlorothiazide; Isradipine; Likelihood Functions; Male; Middle Aged; Regression Analysis; Sodium Chloride Symporter Inhibitors; Systole; Treatment Outcome; Tunica Intima; Ultrasonography; Vasodilator Agents

Topics: Arteriosclerosis; Bone Marrow Transplantation; Child, Preschool; Cognitive Dysfunction; Diagnosis, Differential; DNA Helicases; DNA Mutational Analysis; Enalapril; Female; Granulocyte Colony-Stimulating Factor; Growth Disorders; Human Growth Hormone; Humans; Kidney Transplantation; Mutation; Nephrotic Syndrome; Osteochondrodysplasias; Primary Immunodeficiency Diseases; Pulmonary Embolism

Angiotensin converting enzyme (ACE) inhibitors prevent a wide variety of key events underlying atherogenesis. Whether these actions depend solely on reduction of angiotensin II (Ang II) generation is still to be determined. This study was undertaken to determine whether enalapril, an ACE inhibitor, prevents atherosclerosis and vascular inflammation induced by Ang II in apolipoprotein E-deficient (apoE-KO) mice. Subcutaneous infusion of Ang II (1.44 mg/(kg day)) for 4 weeks increased blood pressure and accelerated atherosclerosis development in the carotid arteries. The expression of the endothelial adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as the chemokines monocyte chemotactic protein-1 (MCP-1) and macrophage-colony stimulating factor (M-CSF) was up-regulated in the aortas of Ang II-treated mice. Enalapril co-treatment (25 mg/(kg day), in drinking water) prevented the development of atherosclerosis without affecting blood pressure or circulating cholesterol. In addition to preventing the Ang II-induced over-expression of adhesion molecules and chemokines in the aorta, enalapril up-regulated the expression of peroxisome proliferator-activated receptors (PPARs)-alpha and -gamma, potential anti-inflammatory transcription factors. In the aortic arch, a lesion-prone site, the co-treatment with enalapril reduced the percentage of arterial wall occupied by macrophages and foam cells, medial sclerosis and elastin reduplication. Together, these data suggest an important role for Ang II-independent mechanisms in the antiatherogenic and anti-inflammatory effects of ACE inhibitors.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Aortic Aneurysm; Apolipoproteins E; Arteriosclerosis; Cell Adhesion Molecules; Chemokines; Enalapril; Endothelium; Gene Expression; Male; Mice; Mice, Knockout; PPAR alpha; PPAR gamma; RNA, Messenger; Up-Regulation; Vasculitis

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Enalapril; Humans; Hypertension

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apolipoproteins E; Arteriosclerosis; Enalapril; Hyperlipidemias; Hypertension; Kidney Diseases; Mice; Mice, Mutant Strains; Nitric Oxide Synthase

The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P<0.0001). Captopril reduced by 52% aortic lesions compared to placebo (P<0.01 vs. placebo; P<0.05 vs. zofenopril at both doses). Enalapril did not reduce aortic lesions. Furthermore, 0.05 mg/kg/day of zofenopril reduced susceptibility of plasma LDL to in vitro oxidation compared to captopril, enalapril or placebo, as shown by significant reduction of malondialdehyde content (P<0.001 vs. placebo or enalapril; P<0.05 vs. captopril), as well as by the prolongation of lag-time (P<0.01 vs. placebo or enalapril P<0.05 vs. captopril). More importantly, mice treated with 1 mg/ml/day of zofenopril had a significant decrease in the intimal immunohistochemical presence of oxidation-specific epitopes on oxLDL (NA59 monoclonal antibody, P<0.01), macrophages derived foam cells (F4/80 monoclonal antibody, P<0.05) and native LDL (NP monoclonal antibody, P<0.01) compared to placebo, captopril or enalapril. Thus, chronic treatment with the new sulfhydryl ACE-inhibitor zofenopril has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic apoE(-/-) mice. This protection was significantly higher than that reached with captopril and at lower doses of the drug. Treatment with 0.5 mg/kg/day of enalapril did not provide any protective effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve Stenosis; Apolipoproteins E; Arteries; Arteriosclerosis; Blood Pressure; Captopril; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Epitopes; Immunohistochemistry; Lipid Peroxidation; Lipoproteins, LDL; Male; Mice; Mice, Knockout; Oxidation-Reduction; Oxidative Stress; Peptidyl-Dipeptidase A; Random Allocation; Sulfhydryl Reagents; Time Factors; Treatment Outcome

Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction between these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of endothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) have higher blood pressure (BP) and increased atherosclerotic lesion size but no change in plasma lipoprotein profiles compared with normotensive but atherosclerotic (NNee) mice. The nnee mice also develop kidney damage, evidenced by increased plasma creatinine, decreased kidney weight/body weight ratio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice. In striking contrast, a genetic lack of inducible NOS, which does not affect BP, has no effect on the development of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positive relationship between BP and size of atherosclerotic lesions These results suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlling hypertension in preventing atherosclerosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apolipoproteins E; Arteriosclerosis; Blood Pressure; Enalapril; Hypertension; Kidney Diseases; Mice; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organ Size

We have experienced a case of anaphylactoid reaction on receiving autologous blood transfusion through a WBC filter for packed red blood cell (PRBC). The patient was a 71-year-old man with a history of hypertension treated with oral antihypertensive drug; enalapril, an angiotensin converting enzyme (ACE) inhibitor, who received anesthesia for Y-graft replacement. Autologous blood was obtained after the induction of general anesthesia in the operating room. Upon starting to return the stored blood with an unintentional use of a WBC filter, arterial blood pressure (ABP) fell within the first minute of the transfusion. We obtained three blood samples; pre-filtered blood (PRE), postfiltered blood (POST) and arterial blood (CIRC) after the event, and analyzed concentrations of bradykinin (BK), high molecular weight kininogen (HMWK) and high molecular weight kininogen-light chain (HMWK-LC). BK was higher in POST than in PRE. HMWK was lower in POST than in PRE, while HMWK-LC was higher in POST than in PRE. HMWK in CIRC was lower than in PRE, and HMWK-LC was higher in CIRC than in PRE. HMWK and HMWK-LC changes after the event suggest that BK formation cascade in the patient was activated on receiving the transfusion. ACE inhibitors were reported to augment such activation. The WBC filter has the negatively charged surface on filteration material and may activate the cascade. While WBC filters can avoid transfusion related reactions, hemodynamic responses should be watched closely in patients treated with ACE inhibitors.

Topics: Aged; Anaphylaxis; Anesthesia, General; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Blood Transfusion, Autologous; Bradykinin; Enalapril; Humans; Kininogens; Leukapheresis; Male

We performed a retrospective study on 26 patients with moderate renal failure (mean GFR = 51 +/- 21 ml min-1 1.73 m-2), hypertension and atherosclerosis. Apart from three patients who had completely normal renal Doppler ultrasonography, all patients underwent renal angiography. Three groups of kidneys with different atherosclerotic renal artery involvement were identified: Group 1, 24 kidneys with no renal artery stenosis (RAS); Group 2, 18 kidneys with mild (> 25% and < 50% diameter) RAS; and Group 3, 10 kidneys with moderate (> 50% diameter) RAS. We used a two-day protocol with frusemide plus enalapril 99Tcm-MAG3 scintigraphy. The mean parenchymal transit time (MPTT), time to the maximum activity (time to peak) of the renal curve (Tmax), residual activity and split renal uptake were evaluated. The measured parameters did not differ before and after enalapril in Group 1 or in Group 2. In Group 3, MPTT and residual activity differed significantly (P < 0.025) before and after enalapril. The Tmax before and after enalapril, MPTT before and after enalapril and residual activity after enalapril differed significantly (P < 0.05) between Groups 1 and 3 and between Groups 2 and 3. Threshold values were obtained to maximize diagnostic accuracy. The Tmax, MPTT and residual activity after enalapril gave satisfactory results, and MPTT performed best with a 75% positive predictive value and a 98% negative predictive value for the diagnosis of renal artery stenosis. We conclude that MPTT, measured after enalapril administration, is a useful parameter to detect renal artery stenosis in patients with hypertension, atherosclerosis and moderate renal insufficiency.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Diuretics; Enalapril; Furosemide; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Renal Artery Obstruction; Retrospective Studies; Technetium Tc 99m Mertiatide

Many reports have shown inhibitory effects of angiotensin-converting enzyme (ACE) inhibitors on the progression of atherosclerotic plaque lesions in vascular tissue of experimental models. However, no report has shown alterations of ACE activity in vascular tissue during the process of atherosclerosis. We measured ACE activity in plasma and aortic tissue in rabbits fed a cholesterol-rich (1%) or normal diet for 10 weeks. We also evaluated the blood pressure response to angiotensin (Ang) I and II. These data were compared in untreated rabbits and in rabbits receiving chronic treatment with an ACE inhibitor, enalapril (3 mg/kg/day for 10 weeks). ACE activity in aortic tissue, but not in plasma, in cholesterol-fed rabbits was gradually but significantly increased compared with that in noncholesterol-fed rabbits even after the 4-week feeding period, when no atherosclerotic lesion was observed in the aortic tissue. Treatment with enalapril for 10 weeks, but not 4 weeks, significantly reduced the ACE activity in aortic tissue in association with the reductions in the elevated Ang II level and the atherosclerotic plaque area of the aortic tissue. These results indicated that ACE activity in aortic tissue was increased during the early phase of atherosclerotic process.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Blood Pressure; Cholesterol, Dietary; Enalapril; Male; Peptidyl-Dipeptidase A; Rabbits

Based on 2 case presentations - acute renal failure (ARF) due to myeloma kidney and due to angiotensin-converting enzyme inhibitor administration in the presence of transplant artery stenosis - new aspects in the pathogenesis of ARF are presented and discussed. The multifactorial pathogenesis of ARF includes (a) a disturbance of glomerular microcirculation (afferent and perhaps mesangial constriction, inadequate efferent dilatation); (b) a disturbance of medullary microcirculation (medullary capillary congestion) attributed to a combination of endothelial damage and tubular dilatation; (c) tubular cell damage which, though rarely in humans justifying the term 'acute tubular necrosis', promotes both backleak of glomerular filtrate and shedding of brush border vesicles; (d) the latter promotes tubular obstruction by casts which consist of Tamm-Horsfall protein and brush border components. Once ARF is established, repair processes set in which appear to depend on growth factors such as epidermal growth factor and insulin-like growth factor 1, of which there is a relative shortage in established ARF. Experimental therapeutic approaches focus on the restitution of microcirculation (endothelin receptor antagonists, atriopeptins), interference with cast formation (integrin receptor blockers), and the promotion of recovery by growth factors.

Topics: Acute Kidney Injury; Aged; Angioplasty, Balloon; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Arteriosclerosis; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Glomerulus; Kidney Neoplasms; Kidney Transplantation; Male; Multiple Myeloma; Postoperative Complications; Renal Circulation

The effect of two angiotensin converting enzyme (ACE) inhibitors, enalapril maleate and captopril, on the progression of atherosclerosis was investigated. Golden Syrian hamsters were divided into five groups: controls (C), fed a standard chow diet; hypercholesterolemic animals (HH) induced by supplementing the diet with 3% cholesterol and 15% butter; HH treated with enalapril (20 mg/kg/day); HH treated with captopril (60 mg/kg/day) and HH treated simultaneously with enalapril and a calcium channel blocker, diltiazem (45 mg/kg/day). The drugs were administered for one month, concomitantly with the atherogenic diet. As compared to controls, in HH group a significant increase in serum cholesterol (approximately 5 fold) and ACE activity (approximately 3 fold) was found. In HH-treated animals, both drugs maintained the serum ACE activity within the normal values. However, the effect upon serum cholesterol was different: enalapril and its combination with diltiazem had a significant hypocholesterolemic effect (128.8 +/- 25 mg/dl), whereas captopril had no effect on the cholesterol values (326.6 +/- 41.48 mg/dl). Electron microscopical examination of the coronary arteries and aortic valve in all experimental groups indicated a good correlation between the high levels of cholesterol, ACE activity and the development of the atherosclerotic lesions. Captopril treatment inhibits the early phases of atherosclerosis at level of the coronary artery but has no influence upon the lesion development in the aortic valve. By comparison, enalapril and enalapril-diltiazem co-administration impede the development of fatty streaks by decreasing the accumulation of lipids and calcium deposits in the lesion-prone areas examined. These data indicate that: 1) captopril does not have a hypocholesterolemic potential and cannot prevent atheroma formation in heart valves; 2) enalapril, especially combined with diltiazem, has a hypocholesterolemic effect and impedes the development of atheromatous plaque; 3) the anti-atherosclerosis therapy may benefit from the co-administration of an ACE-inhibitor with a calcium antagonist.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve; Arteriosclerosis; Calcium Channel Blockers; Captopril; Cholesterol; Coronary Vessels; Cricetinae; Diet, Atherogenic; Diltiazem; Drug Synergism; Enalapril; Male; Maleates; Mesocricetus; Microscopy, Electron

To investigate how the renin-angiotensin system (RAS) might be involved in cholesterol-induced atherosclerosis, we studied the effects of a nonsulhydryl angiotensin converting enzyme (ACE) inhibitor, enalapril, and an angiotensin II receptor antagonist, E-4177, in cholesterol fed rabbits. Japanese white rabbits were randomly divided into four groups with the following dietary regimens: group A (n = 8) received a standard diet; group B (n = 8) had a 0.5% cholesterol diet; group C (n = 8) had a 0.5% cholesterol diet plus enalapril (10 mg/kg/day, p.o.); group D (n = 8) received a 0.5% cholesterol diet plus E-4177 (20 mg/kg/day, p.o.) and were fed these diets for 5 weeks. Enalapril or E-4177 had no significant effect on either the total plasma or the high density lipoprotein (HDL) cholesterol concentrations. However, the aortic cholesterol content in groups C and D was equally significantly less than that in group B. The plasma and aortic ACE activities were significantly reduced only in group C compared with those in the other groups. The aortic ACE mRNA and AT1 mRNA levels were assessed by a reverse transcription polymerase chain reaction (RT-PCR). The aortic ACE mRNA level was only significantly less in group C than in any of the other groups. The aortic AT1 mRNA level increased significantly in group B compared with that in group A and was significantly and equally reduced in both groups C and D compared with that in group B. These data indicate that angiotensin II rather than ACE may therefore be related to aortic cholesterol content. It follows therefore that the inhibition of angiotensin II by either ACE inhibitor or angiotensin II (type 1) receptor antagonist may play a role in prevention of atherosclerosis.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Cell Division; Cholesterol; Cholesterol, Dietary; Chromatography, High Pressure Liquid; Enalapril; Imidazoles; Lipoproteins; Oligonucleotide Probes; Polymerase Chain Reaction; Pyridines; Rabbits; Random Allocation; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Spectrophotometry

In atherosclerotic mini-pigs, we attempted to determine (i) whether high-fat atherogenic diet disturbs the taurocholate transepithelial transport and incorporation in the ileal epithelium mounted in Ussing chambers, and (ii) whether these processes are sensitive to angiotensin converting enzyme (ACE) inhibitors which slow the development of vascular atherosclerosis. In atherosclerotic mini-pigs, the mucosal to serosal transepithelial fluxes were markedly lower (72% inhibition) and free diffusion was more altered than active processes. Taurocholate incorporation into enterocyte (75% inhibition) paralleled the flux reduction. The transport disturbance observed here might be explained by changes in bile salt permeability in relation to alterations of the membrane properties. Taurocholate absorption was lowered by atherogenic diet, whereas bile salts were not trapped in the enterocyte, therefore atherosclerosis-induced alterations preferentially affected the passage through the brush-border. In the ACE inhibitor treated atherosclerotic mini-pigs, perindopril and enalapril similarly inhibited serum ACE activities. Perindopril further corrected taurocholate fluxes by 50% and fully restored taurocholate incorporation. Since enalapril did not restore the atherosclerosis-induced alterations, the involvement of intestinal ACE in bile acid recycling and of an ACE inhibitor class effect on these mechanisms both remain to be ascertained.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Biological Transport; Enalapril; Epithelium; Ileum; In Vitro Techniques; Indoles; Intestinal Mucosa; Lipids; Perindopril; Swine; Swine, Miniature; Taurocholic Acid

To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a non-sulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8 +/- 3.5%; treated: 31.1 +/- 8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4 +/- 3.2 mg/g tissue; treated: 7.4 +/- 1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Feed; Animals; Arteriosclerosis; Cholesterol, Dietary; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Male; Rabbits; Renin-Angiotensin System; Tetrazoles; Time Factors; Triazoles

Topics: Animals; Aorta, Abdominal; Arteriosclerosis; Blood Flow Velocity; Blood Pressure; Cholesterol; Elasticity; Enalapril; Hindlimb; Lipoproteins; Male; Regional Blood Flow; Swine; Swine, Miniature; Vascular Resistance

Topics: Aged; Arteriosclerosis; Enalapril; Female; Humans; Renal Artery Obstruction

Ten groups of New Zealand white rabbits were used to study the effects of mild, chronic two-kidney, one-clip hypertension (HT) and long-term antihypertensive therapy on atherogenesis. Five groups were fed a normal diet (ND) over the 8-month study period; 2 groups, one of which was given enalapril, remained normotensive (NT) throughout the study. Of the 3 HT groups, one was hypertensive for 7 months; the blood pressures of the other groups were normalized after 2 months with enalapril, or by removal of the clipped kidney. The other 5 groups were similar except that they were fed at 0.1% cholesterol diet (CD). The results showed that: neither mild chronic HT nor abrupt, short-term HT exacerbated atherogenesis in the CD-animals; although fibromuscular vascular lesions were present in the aorta of normal-diet, HT animals no atheroma was observed; enalapril therapy had no effect on atherogenesis; enalapril therapy reduced the total weight and the cholesterol and triglyceride content of the aorta of the ND groups regardless of blood pressure history; the aortic triglyceride content, but not the cholesterol content, of the CD group, was reduced by enalapril; and although heart size was unaffected by either diet or blood pressure levels, the mitochondria volume per unit volume of the left ventricle was reduced in both NT-ND and HT-CD groups treated with enalapril.

Topics: Animals; Aorta; Arteriosclerosis; Cholesterol, Dietary; Enalapril; Hypertension, Renovascular; Lipoproteins; Male; Microscopy, Electron; Myocardium; Organ Size; Rabbits; Renin