ramipril and Arteriosclerosis

Results from experimental and epidemiologic studies suggest an influence of oxidative stress on development and progression of atherosclerosis in man. Prospective endpoint studies failed to support this hypothesis. The current literature is summarized in this review.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; Aspirin; beta Carotene; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Free Radicals; Humans; Male; Nutritional Physiological Phenomena; Oxidative Stress; Placebos; Platelet Aggregation Inhibitors; Primary Prevention; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Tocopherols; Vitamins

Topics: Angioplasty, Balloon, Coronary; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Cardiomegaly; Clinical Trials as Topic; Coronary Restenosis; Humans; Hypertension; Hypertension, Renal; Insulin Resistance; Losartan; Ramipril; Receptor, Angiotensin, Type 1

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; C-Reactive Protein; Cardiovascular Diseases; Humans; Inflammation; Myocardial Infarction; Prognosis; Ramipril; Risk Factors; Stroke

Reduced activity of the endogenous fibrinolytic system contributes to intramural deposition of microthrombi in atherogenesis and to intraluminal deposition of thrombi leading to acute complications of atherosclerosis such as acute coronary syndromes. Endogenous fibrinolytic activity is predominantly regulated by the plasminogen activator inhibitor type 1 (PAI-1). Increased activity of PAI-1 leading to reduced endogenous fibrinolytic activity has been identified as an important independent risk factor for cardiovascular disease. Vascular endothelial cells form a barrier between the circulating blood with its dynamic balance between ongoing thrombosis and fibrinolysis and the subendothelial layers of the vascular wall with their prothrombotic activity. In addition, endothelial cells synthesize and secrete substantial amounts of plasminogen activators and their inhibitor PAI-1. Thus, endothelium plays an important role in the regulation of endogenous fibrinolysis. After describing the components of the endogenous fibrinolytic system and its interactions, this review focuses on the impact on endogenous fibrinolysis by the renin angiotensin system, the kallikrein kinin system, and type 2 diabetes mellitus. Investigations using transgenic and knock-out animal models--the results of which are also summarized--have improved our understanding of the interaction between endogenous fibrinolysis and endothelium. In each section of the review therapeutic implications and potentials are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arteriosclerosis; Atherectomy; Cells, Cultured; Clinical Trials as Topic; Coronary Disease; Diabetes Mellitus, Type 2; Endothelium, Vascular; Fibrinolysis; Gene Expression; Humans; Kallikrein-Kinin System; Mice; Mice, Knockout; Mice, Transgenic; Placebos; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Activators; Rabbits; Ramipril; Rats; Renin-Angiotensin System; Risk Factors; RNA, Messenger

From pharmacologic investigations and clinical studies it is known that angiotensin-converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained simply by interference with the renin-angiotensin system with subsequent inhibition of angiotensin II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK), potentiation of BK might be responsible for these additional effects of ACE inhibitors. To prove the specificity of BK-mediated effects by ACE inhibition, we used the specific B2 kinin receptor antagonist HOE 140 in different models: endothelial cell cultures; atherosclerosis in high-cholesterol-fed rabbits; neointima formation with smooth cell proliferation and migration after endothelial denudation in rats; myocardial ischemia in rats, rabbits, and dogs; and left ventricular hypertrophy in rats. The beneficial effects of ramipril or BK given in non-blood pressure-lowering doses in these models were abolished by HOE 140 (icatibant). Ramipril exerts cardioprotective effects in different experimental models. The formation of the endothelial autacoids nitric oxide and prostacyclin, enhanced when BK degradation is inhibited by ACE inhibition, may contribute to the observed beneficial effects.

Topics: Amino Acid Sequence; Animals; Arteriosclerosis; Bradykinin; Cattle; Cholesterol; Diet, Atherogenic; Dogs; Drug Interactions; Endothelium, Vascular; Heart; Humans; Hypertrophy, Left Ventricular; Molecular Sequence Data; Muscle, Smooth, Vascular; Myocardial Ischemia; Rabbits; Ramipril; Rats; Rats, Inbred SHR

Endothelin-1 (ET-1) and angiotensin II may contribute to endothelial dysfunction, which is associated with increased risk of events in patients with coronary artery disease. The objective was to test whether dual ETA/ETB receptor antagonism improves endothelium-dependent vasodilatation (EDV) in atherosclerotic patients, also on treatment with angiotensin converting enzyme (ACE) inhibitor.. EDV and endothelium-independent vasodilatation were determined in 37 patients with atherosclerosis during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. The patients were then randomized to treatment with ramipril 10 mg o.d. (n=21) or placebo (n=16) for 3 months in a double-blind fashion.. Intra-arterial infusion of the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788 (both 10 nmol min(-1)) increased basal FBF by 42 +/- 4% (P <0.001) and enhanced EDV (P <0.001). Following 3 months ramipril treatment, ET receptor blockade still enhanced EDV. Acetylcholine 10 and 30 mg min(-1) increased FBF by 68 +/- 12 and 64 +/- 12 mL min(-1)/1000 mL before vs. 101 +/- 17 and 101 +/- 16 mL min(-1)/1000 mL following ET receptor blockade in the ramipril group (P <0.001).. Dual ETA/ETB receptor blockade improves endothelial function and exerts direct vasodilator effects in patients with atherosclerosis, also on treatment with ramipril suggesting that ET receptor blockade may have important therapeutic effects when added to ACE inhibition in these patients.

Topics: Acetylcholine; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Biomarkers; Double-Blind Method; Endothelin Receptor Antagonists; Endothelins; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intra-Arterial; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Ramipril; Vasodilation; Vasodilator Agents

Some medications have been shown to produce reductions in hs-CRP levels after initiating therapy. Whereas the role of the renin-angiotensin system in the inflammatory process has been documented in more detail during the last few years, the impact of an ACE-inhibitor therapy on this process has not been fully understood so far. The aim of this study was to investigate the effect of a therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on hs-CRP plasma concentrations in patients with atherosclerosis.. A total of 24 patients were enrolled in this prospective, uncontrolled, open-label multicenter study. Inclusion criteria were documented atherosclerosis, baseline high-sensitivity C-reactive protein between 3 and 12 mg/l, LDL-Cholesterol < or =150 mg/dl and no previous treatment with ACE inhibitors or angiotensin receptor blockers. Ten patients, pretreated with statins, and 10 patients not previously treated with statins were eligible for statistical analysis. Baseline high-sensitivity C-reactive protein was significantly decreased from 3.99+/-1.61 mg/l (mean+/-SD) to 2.72+/-1.19 mg/l (-32%) after 3 months treatment with 10 mg ramipril daily (p=0.0002). The decrease was more pronounced in patients who had not been treated with statins previously (-1.50 mg/l+/-1.44 mg/l) compared to those who were pretreated (-0.90 mg/l+/-0.93 mg/l).. The ACE inhibitor ramipril administered in a daily dose of 10 mg to patients with atherosclerosis reduces the high-sensitivity C-reactive protein concentration. This effect may contribute to cardiovascular risk reduction mediated by ramipril aside from the blood pressure lowering effect.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Blood Pressure; Cholesterol, LDL; Coronary Artery Disease; Coronary Disease; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Middle Aged; Premedication; Prospective Studies; Ramipril; Treatment Outcome

The effectiveness of aggressive management of traditional risk factors for accelerated atherosclerosis in systemic lupus erythematosus (SLE) has been advocated but not proven. We conducted a pilot, randomized, controlled trial of known prevention medications (pravastatin, ramipril, aspirin, and a combination B vitamin) plus individualized cardiovascular prevention education. We describe our experience in recruiting and retaining patients with SLE in this trial.. Patients with SLE by American College of Rheumatology criteria who lived within 1 hour of the hospital and had visits within the past 3 years were screened. All eligible patients were contacted by the principal investigator who was not their physician. The reasons for nonparticipation were elicited in a nonjudgmental manner.. A total of 662 patients met the selection criteria for the study. Of these, 295 patients (45%) with contraindications to study medications were excluded. Ninety-seven (40%) of 244 eligible patients refused to participate. More than 40% of those phoned were unwilling to participate and, among those, 19% felt they were too sick, too well, or taking too many medications already. A total of 41 patients were enrolled in the trial, and 22 dropped out within 4 months.. SLE is a chronic disease, and the development and testing of interventions aimed at the prevention of long-term sequelae are of paramount importance. Prevention trials in SLE face serious challenges, including the recruitment and retention of participants. Our experience provides insights into the barriers to participation in randomized prevention trials in SLE.

Topics: Anticholesteremic Agents; Antihypertensive Agents; Arteriosclerosis; Aspirin; Drug Therapy, Combination; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Patient Dropouts; Patient Selection; Pilot Projects; Pravastatin; Ramipril; Treatment Refusal; Vitamin B Complex

Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3x2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients.. A total of 732 patients >/=55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-alpha-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (P=0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo.. Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Blood Pressure; Carotid Artery Diseases; Creatinine; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Compliance; Potassium; Prospective Studies; Ramipril; Risk Factors; Treatment Outcome; Ultrasonography; Vitamin E

Experimental and epidemiological evidence suggests that activation of the reninangiotensin-aldosterone system and oxidative modification of low density lipoprotein cholesterol both play important roles in atherosclerosis. A substudy of the HOPE (Heart Outcomes Prevention Evaluation) trial, the SECURE trial (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E), evaluated the effects of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor, ramipril, and with vitamin E on atherosclerosis progression in high risk patients. A total of 732 patients were enrolled into the study. These patients were 55 years or older, had vascular disease or diabetes with at least one other cardiovascular risk factor, but did not have heart failure or low ejection fraction. Patients were randomly assigned according to a three-by-two factorial design to receive placebo, ramipril 2.5 mg/day or ramipril 10 mg/day and placebo or vitamin E 400 IU/day. Progression of atherosclerosis was evaluated by B-mode carotid ultrasonography. The primary outcome evaluated was the annualised progression slope of the mean maximum carotid intimal-medial thickness (IMT) across 12 pre-selected carotid arterial segments. The average follow-up was 4.5 years. The progression slope of the mean maximum IMT was 0.0217 +/- 0.04 mm/year in the placebo group, 0.018 +/- 0.44 mm/year in the ramipril 2.5 mg/day group and 0.0137 +/- 0.04 in the ramipril 10 mg/day group (P = 0.33 for the overall effect of ramipril and P = 0.028 for the comparison between patients receiving ramipril placebo and ramipril 10 mg/day). The reduction in atherosclerotic progression observed with ramipril remained significant after adjusting for systolic and diastolic blood pressure changes (P = 0.043) and after multivariate adjustment (P = 0.046). Administration of vitamin E 400 IU/day had no impact on atherosclerosis progression. The SECURE study is the first demonstration, in human subjects, of an effect of ACE inhibition on atherosclerotic progression. This benefit cannot be explained by the lowering of blood pressure alone. Vitamin E 400 IU/day had a neutral effect on the ultrasound measurements of atherosclerosis progression in the SECURE trial.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Carotid Arteries; Drug Therapy, Combination; Humans; Middle Aged; Ramipril; Treatment Outcome; Ultrasonography; Vitamin E

Atherosclerotic cardiovascular disease remains a major cause of mortality and morbidity in most developed countries. Experimental and clinical evidence suggests that angiotensin-converting enzyme inhibitors and vitamin E therapy may retard the atherosclerotic process; however, definitive proof in humans is lacking. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) is designed to assess the effects of ramipril--an angiotensin-converting enzyme inhibitor, at 2 doses: 2.5 mg daily (which has little effect on lowering blood pressure) and 10 mg daily--and the antioxidant vitamin E, 400 IU daily, on atherosclerosis progression in 732 patients using a factorial 3 x 2 study design. High-risk patients with a documented history of significant cardiovascular disease or with diabetes and additional risk factors were enrolled and will be followed for 4 years. The extent and progression of atherosclerosis are assessed noninvasively by B-mode carotid ultrasonography. The SECURE trial is a substudy of the larger Heart Outcomes Prevention Evaluation (HOPE) study of 9,541 high-risk patients evaluating the effects of ramipril and vitamin E on major cardiovascular events (cardiovascular death, myocardial infarction, and stroke). The 2 studies are complementary. Whereas HOPE is expected to provide information on major clinical outcomes, SECURE will shed light on the mechanisms by which these effects may be mediated.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Carotid Artery Diseases; Coronary Artery Disease; Disease Progression; Double-Blind Method; Female; Humans; Intracranial Arteriosclerosis; Male; Ramipril; Research Design; Risk Factors; Ultrasonography; Vitamin E

Clinical Pharmacology is commonly accepted to be a bridging discipline between basic science observations and clinical practice. Today, it should be a major task of the clinical pharmacologist in academia to provide support in the interpretation of preclinical and clinical study data, to develop evidence-based treatment guidelines and to serve as drug expert supporting all disciplines of clinical medicine with specific pharmacological and therapeutic knowledge. The results of the ONTARGET-trial confront both researchers and clinicians with the unexpected truth that AT(1)-receptor-blockade with an angiotensin-receptor-blocker (ARB) does not seem to have superior therapeutic benefit compared with an ACE-inhibitor (ACE-I) at reducing fatal and nonfatal cardiovascular events. The combination of the two drugs was associated with more adverse events without an increase in benefit. Therefore, the crucial question 'ACE-I, ARB, or both?' requires a new and critical appraisal depending on the medical indication for which these renin-angiotensin-system (RAS)-inhibitors are used: In a population of high-risk patients suffering from cardiovascular disease or diabetes mellitus, the evidence to favor an ARB over an ACE-I is still limited after ONTARGET and because of the higher costs for ARBs one can rather support the old therapeutic advice that ARBs are equally effective as ACE-Is and therefore therapeutic alternatives for patients with ACE-I intolerance. With respect to a very moderate additive BP-lowering effect of dual therapy with an ACE-I and an ARB seen in metaanalysis which was not even clearly attributable to dual RAS-inhibition and the increased adverse event rate in the combination treatment group of ONTARGET, this regimen seems not to be recommendable for the treatment of hypertension. Dual-RAS-blockade using an ACE-I-ARB-combination is an effective therapy to treat proteinuria and might be of therapeutic benefit especially in diabetic patients without concomitant diseases. There may be a therapeutic rationale to prefer ARBs over ACE-Is in well-selected patients with congestive heart failure (CHF) because a considerable amount of angiotensin II (Ang II) is produced independent of angiotensin-conversion-enzyme (ACE) in the failing heart and is therapeutically unaffected by ACE-I treatment. The results of the Val-HeFt and the CHARM-added-study revealed additive effects of an ARB on heart failure related morbidity and mortality when added to existing therapy w

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Kidney Diseases; Ramipril; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan

To observe the effect of angiotensin II (Ang II) on expression of gap junction channel protein connexin 43 (Cx43) in the proliferation process of vascular smooth muscle cells (VSMCs) during the early stage of arteriosclerosis.. Thirty-two adult male rabbits were randomly divided into 4 groups. Rabbits in Group A were fed common diet while others in Groups B, C, and D were fed high-cholesterol diet. Losartan (10 mg/(kg.d)) and ramipril (0.5 mg/(kg.d)) were added in the diet of Groups C and D, respectively. The animals were sacrificed after 8 weeks and abdominal aortas were removed and dissected. The expression of Cx43 was assayed using RT-PCR and Western Blotting analysis.. Cx43 was increased markedly in both protein and mRNA level in Groups B, C, and D fed high-cholesterol diet compared with that in control group (P<0.01). Cx43 level in losartan or ramipril treated groups was higher than that in control group (P<0.01, P<0.05), but lower than that in high-cholesterol diet groups (P<0.05, P<0.01).. Cx43 level was upregulated in VSMCs during early atherosclerosis. Losartan and ramipril can inhibit the expression of Cx43.

Topics: Angiotensin II; Animals; Arteriosclerosis; Body Weight; Cholesterol; Connexin 43; Losartan; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rabbits; Ramipril; RNA, Messenger

To explore the relationship between angiotensin converting enzyme (ACE) (I/D) gene polymorphism and the level of high-sensitivity C-reactive protein (hsCRP) in type 2 diabetic patients with atherosclerosis treated with ramipril.. A total of 118 in type 2 diabetic patients with atherosclerosis aged 35 years or older without clinical proteinuria, heart failure, or low ejection fraction (<40%), who were not taking ACE inhibitors or (ARB), were randomized into two groups to receive treatment with ramipril (ACEI group, beginning with 2.5 mg/d till reaching 5 mg/d) or placebo for 3 months. The 99 patients in ACEI group were further divided into 3 subgroups according to ACE (I/D) genotypes DD, ID and II, each group consisting of at least 20 patients. The level of hsCRP was detected by enzyme-linked immunosorbent assay before and after the therapy.. After therapy, hsCRP level significantly decreased, but hsCRP levels showed no significant differences between the groups of different ACE genotypes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Ramipril

The renin-angiotensin-aldosterone system is involved in the pathogenesis of atherosclerosis, partially because of its pro-oxidative properties. We questioned the effect and mechanisms of action of administration of aldosterone to apolipoprotein E-deficient (E(0)) mice on their macrophages and aorta oxidative status and the ability of pharmacological agents to block this effect.. Aldosterone (0.2 to 6 microg. mouse(-1) x d(-1)) was administered to E(0) mice alone or in combination with eplerenone (200 mg x kg(-1) x d(-1)), ramipril (5 mg x kg(-1) x d(-1)), or losartan (25 mg x kg(-1) x d(-1)). Mouse aortic atherosclerotic lesion area and macrophage and aortic oxidative status were evaluated. Aldosterone administration enhanced the mouse atherosclerotic lesion area by 32%. Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably mediated by NADPH oxidase activation, because increased translocation of its cytosolic component p47phox to the macrophage plasma membrane was observed. THP-1 macrophages incubated in vitro with aldosterone (10 micromol/L) exhibited a higher capacity to release superoxide ions by 110% and increased ability to oxidize LDL by 74% compared with control cells. Aldosterone administration enhanced mouse peritoneal macrophage ACE activity and mRNA expression by 2.3-fold and 2.4-fold, respectively. Only cotreatment of eplerenone with ramipril or losartan completely blocked the oxidative effects of aldosterone.. Aldosterone administration to E(0) mice increased macrophage oxidative stress and atherosclerotic lesion development. Blocking of the mineralocorticoid receptor and inhibition of tissue ACE and/or the angiotensin receptor-1 reduced aldosterone deleterious pro-oxidative and proatherogenic effects.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Cell Line; Enzyme Induction; Eplerenone; Hormone Antagonists; Humans; Lipid Peroxidation; Lipoproteins, LDL; Losartan; Macrophages, Peritoneal; Membrane Proteins; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Peptidyl-Dipeptidase A; Phosphoproteins; Protein Transport; Ramipril; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone; Superoxides

Although atherosclerosis is today seen as presenting a distinct clinical picture, there are almost no data available about the impact this has on medical practice and about the point at which a patient is considered high-risk. As part of a larger project on the prevention of heart disease and atherosclerosis, "Aktion plus leben", 1,117 physicians were polled in a scientific survey. The study was carried out in some 100 hospitals throughout Austria, above all in departments of internal medicine, but also in neurological departments, and in a number of other units. The results showed that in fact over 90% of those questioned see atherosclerosis as a separate, treatable illness in the context of risk prevention. The most frequent methods of diagnosis were specified as ultrasound and the clarification of symptoms of coronary heart disease. Atherosclerosis prevention is initiated above all in patients with coronary heart disease, myocardial infarction and stroke, but also very frequently in those with diabetes, peripheral vascular occlusive disease, hyperlipidemia and hypertension. Of particular interest to us was the respondents' evaluation of the effect of ramipril, the angiotensin-converting enzyme (ACE) inhibitor used in the HOPE study. The majority of those questioned see a broad range of indications for this ACE inhibitor and ascribe to it a profibrinolytic, antiinflammatory and plaque-stabilising action. Although the survey sought assessment of just one particular medication as a possible treatment option, the study documents the importance of a more inclusive concept of atherosclerosis prevention.

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Attitude of Health Personnel; Austria; Clinical Trials as Topic; Coronary Artery Disease; Health Promotion; Humans; Ramipril; Risk Factors; Treatment Outcome

Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis. This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O2-) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet. At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73 2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%. Six weeks feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food subsequently being changed to a normal chow. All measured parameters indicated a significant favourable effect on endothelial dysfunction as a result of the two treatment regimens. Endothelial function measured in the organ chamber showed somewhat greater improvement in the ACE-NEP treated group than in the ACE-I treated group. The treatment with ramipril, as well as with AVE 7688, restored endothelial function by increasing the ratio of NO to O2- concentration and bioavailability of NO. In this study, a

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Diet, Atherogenic; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Heterocyclic Compounds, 3-Ring; Hypercholesterolemia; Male; Neprilysin; Prodrugs; Rabbits; Ramipril

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arteriosclerosis; Diabetes Mellitus; Disease Models, Animal; Humans; Hypertension; Imidazoles; Myocardial Infarction; Olmesartan Medoxomil; Rabbits; Ramipril; Rats; Tetrazoles; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Cerebral Infarction; Clinical Trials as Topic; Humans; Myocardial Infarction; Ramipril; Risk Factors; Simvastatin

Foam cell formation, the hallmark of early atherosclerosis, results from cholesterol accumulation in arterial macrophages. Angiotensin-II stimulates foam cell formation and angiotensin converting enzyme (ACE) inhibitors reduce atherosclerosis in animal models. The goal of the present study was to determine the effect of the ACE inhibitor Ramipril on the progression of atherosclerosis in apolipoprotein-E-deficient (E0) mice with already advanced atherosclerosis. Therefore, 4-month-old atherosclerotic E0 mice were treated with Ramipril for 2 and 4 months and compared to age-matched placebo-treated mice, as well as to control young (4-month-old) non-treated E0 mice, for their atherosclerosis. Histomorphometry showed that Ramipril treatment substantially inhibited atherogenesis as shown by 48 and 72% reduction in lesion size at 6 and 8 months of age, respectively, compared to the lesion size in age-matched placebo-treated mice. Moreover, the size of the atherosclerotic lesions in 6- and 8-month-old Ramipril-treated mice was almost identical to the size of atherosclerosis of the 4-month-old control mice. Moreover, Ramipril treatment of E0 mice, significantly reduced oxidized low-density lipoprotein (Ox-LDL) uptake by their peritoneal macrophages (MPM) by 32%, compared to Ox-LDL uptake by MPM from 6-month-old placebo mice, and even reduced it by 12% in comparison to Ox-LDL uptake by MPM from 4-month-old control mice. A significant decrease in the mRNA levels of the Ox-LDL receptor CD36 by 58% was observed in macrophages from 6-month-old Ramipril-treated mice compared to macrophages from the 6-month-old placebo-treated mice. There was even a significant reduction (by 32%) in CD36 mRNA levels in macrophages from the 6-month-old Ramipril-treated mice, compared to the CD36 mRNA levels in macrophages from the 4-month-old control mice. We thus conclude that administration of the ACE inhibitor Ramipril to E0 mice, which already exhibit significant atherosclerosis, blocked the progression of the atherosclerotic lesion build-up, a phenomenon that could be related to Ramipril-induced inhibition of Ox-LDL uptake by macrophages.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Arteriosclerosis; CD36 Antigens; Cholesterol; Disease Models, Animal; Foam Cells; Lipoproteins, LDL; Macrophages, Peritoneal; Mice; Ramipril; RNA, Messenger

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Clinical Trials as Topic; Diabetic Angiopathies; Humans; Myocardial Infarction; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Carotid Arteries; Carotid Artery Diseases; Humans; Ramipril; Ultrasonography; Vitamin E

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Carotid Stenosis; Disease Progression; Humans; Ramipril; Randomized Controlled Trials as Topic; Vitamin E

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Humans; Peptidyl-Dipeptidase A; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Rupture, Spontaneous

We investigated the mechanism of the antiatherosclerotic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, in the apolipoprotein (apo) E-deficient mice. Mice that received a high dose (5 mg/kg/day) of ramipril supplemented in their drinking water for 10 weeks showed reduced aortic lesion size by 75% compared with placebo-treated mice. At this dosage, ramipril significantly reduced blood pressure from 95+/-5 mm Hg before treatment to 68+/-4 mm Hg at the end of the treatment period. Ramipril also increased the resistance of the mouse low-density lipoprotein (LDL) to CuSO4-induced oxidation, as shown by a prolongation of the lag time required for the initiation of LDL oxidation from 90 min in the placebo-treated mice to >180 min in the ramipril-treated mice. Similarly, a reduction in the maximal LDL-associated conjugated dienes after 180 min of oxidation by 250% in comparison with placebo-treated mice was noted. Ramipril (1 mg/kg/day) that was still adequate to reduce their plasma ACE activity and LDL propensity to lipid peroxidation was insufficient to reduce their blood pressure. This dosage also inhibited the progression of atherosclerosis in the apo E-deficient mice by 74%. The contribution of bradykinin potentiation to the ACE-inhibitor action was assessed by cotreatment of ramipril with the bradykinin B2-receptor antagonist, icatibant (HOE-140, 0.5 mg/kg given subcutaneously twice a day) for a period of 10 weeks. HOE-140 had no effects on ACE activity, LDL lipid peroxidation, blood pressure, or atherosclerosis. In combination with ramipril, no additional effect of HOE-140 on LDL oxidation or on atherosclerosis was noted in comparison with ramipril treatment alone. We thus conclude that the antiatherogenic effect of ramipril in E(0) mice is independent of blood pressure reduction and is not mediated by bradykinin. It seems, therefore, that most of its antiatherosclerotic and antioxidative effects are mediated through the inhibition of angiotensin II production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Apolipoproteins E; Arteriosclerosis; Blood Pressure; Bradykinin; Cholesterol; Disease Progression; Dose-Response Relationship, Drug; Drug Synergism; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Myocardium; Oxidation-Reduction; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Cardiovascular Diseases; Humans; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Clinical Trials as Topic; Humans; Prognosis; Ramipril

Associations between coronary events and plasma renin activity, and between coronary risk reduction and angiotensin-converting enzyme (ACE) inhibitors, are now well recognized. Improvement in endothelial function may explain, in part, some of the effects of ACE inhibitors in reducing the rates of adverse cardiovascular outcomes observed in clinical trials. ACE inhibitors have been shown to restore the endothelium-mediated vascular relaxation response in animal models of severe atherosclerosis. Clinical trials are now under way to examine the effect of ACE inhibitors on surrogate outcomes that allow assessment of endothelial function in the progression of carotid and coronary atherosclerosis. The recently completed Trial on Reversing ENdothelial Dysfunction (TREND) demonstrated improved coronary endothelium-dependent vasomotor function after 6 months of treatment with quinapril. In addition, quinapril treatment was associated with a trend toward an increase in microvascular blood flow response. Other studies in progress will assess the effect of ACE inhibitors on clinical coronary risk and plaque progression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Endothelium, Vascular; Humans; Ramipril; Randomized Controlled Trials as Topic

Application of periarterial collars induced atheroma-like lesions in the carotid arteries of normocholesterolemic rabbits. Vessel segments taken from the mid-region of the collar (cuffed region) and control regions of the same artery were studied at 7 days after surgery. A group of placebo rabbits was provided ad libitum with regular tap water, and treated animals were supplied for 14 days (beginning 7 days before collar application) with water containing perindopril (daily intake of approximately 0.3 mg/kg). Perindopril treatment reduced plasma angiotensin-converting enzyme (ACE) activity by 88% but did not significantly alter arterial blood pressure or heart rate. The sensitivity of arterial rings to angiotensins I and II did not differ between control and cuffed arteries in either placebo or perindopril-treated rabbits, but in rings from both groups of rabbits the sensitivity to the vasoconstrictor action of serotonin was higher in the cuffed segments, as in previous studies. In addition, in placebo rabbits the endothelium-dependent vasorelaxant response to acetylcholine (which results from the release of nitric oxide) was weaker in cuffed arteries than in controls, whereas in the perindopril-treated animals, this impairment of relaxation was restored to the extent that, in cuffed vessels, it was no longer significantly different from the controls. Similar results were obtained in rabbits treated with another ACE inhibitor (ramipril). In contrast, acute treatment with the metabolite, perindoprilat, in vitro (1.0 microM) did not alter the response to acetylcholine in control or cuffed rings from placebo rabbits. Morphologically, vessel segments taken from the center of the cuffed artery of placebo rabbits showed a thickened intima with marked smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Carotid Arteries; Endothelium, Vascular; Indoles; Nitric Oxide; Perindopril; Rabbits; Ramipril; Tunica Intima; Vasoconstriction; Vasodilation

This study was designed to compare the effects of a calcium antagonist (isradipine) and a converting enzyme inhibitor (ramipril) on progression and regression of atherosclerosis in hypercholesterolemic rabbits. Sixty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group II received the 0.3% cholesterol diet, group III received cholesterol diet with isradipine (0.33 mg/kg/day), and group IV received cholesterol with ramipril (0.33 mg/kg/day) for 12 more weeks. A group of 20 rabbits received a standard diet throughout the study (group I). After 16 weeks, 10 rabbits were randomly chosen from each group and used in the progression study. The other rabbits were placed on a standard diet and remained on their respective drug regimen for 12 more weeks. In the progression phase of the study, ramipril significantly attenuated the percentage of aortic lesions in group IV (35 +/- 6%) as compared with group II (56 +/- 6%, p < 0.05), whereas isradipine had no effect. Acetylcholine (ACh)-induced maximum endothelium-dependent relaxations (EDR) of aortic rings were significantly reduced by the atherogenic diet to 37 +/- 4 versus 77 +/- 2% in group I (p < 0.05). Treatment with ramipril significantly improved maximum EDR to 53 +/- 3% (p < 0.05 vs. group II). Isradipine had no significant effect on impaired EDR. Aortic rings with endothelium from group II developed supersensitivity to sodium nitroprusside (SNP) and had significantly reduced basal cyclic GMP levels as compared with those of group I. Both drugs prevented development of supersensitivity to SNP and blunted the cholesterol-induced reduction in basal cyclic GMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Cyclic AMP; Diet, Atherogenic; Endothelium, Vascular; Isradipine; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Phospholipids; Rabbits; Ramipril; Triglycerides

We report the effects of isradipine and ramipril on regression of diet-induced atherosclerosis in rabbits. Regression of diet-induced atherosclerosis was not significantly affected by ramipril, but isradipine significantly retarded regression. Thirty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group IIr received the 0.3% cholesterol diet, group IIIr received the 0.3% cholesterol diet with isradipine (0.33 mg/kg/day), and group IVr received the 0.3% cholesterol diet with ramipril (0.33 mg/kg/day) for 12 more weeks. The rabbits then received a standard diet and remained on their respective drug regimen for 12 more weeks. Group Ir (10 rabbits) received a standard diet for 28 weeks. Acetylcholine (ACh)-induced maximal endothelium-dependent relaxations (EDR) of aortic rings were significantly less in group IIr (22.8 +/- 3.2%) than in group Ir (66.4 +/- 4.0%; p < 0.05). Ramipril and isradipine did not improve EDR as compared with group IIr. Regression of atherosclerosis was accompanied by an improved endothelium-dependent releasing factor (EDRF) release from the endothelium, but ramipril and isradipine did not promote this process. In addition, regression was associated with increasing sensitivity of vascular smooth muscle to EDRF that was significantly retarded by isradipine but not ramipril. Basal cyclic GMP levels were significantly reduced in aortic rings from group IIr as compared with group Ir. Ramipril, but not isradipine, restored basal cyclic GMP levels to control values. Both isradipine and ramipril protect against endothelial degeneration in hypercholesterolemic rabbits. However, isradipine but not ramipril inhibits regression of diet-induced atherosclerosis in rabbits.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arteriosclerosis; Biomarkers; Cholesterol; Cholesterol, Dietary; Cyclic AMP; Cyclic GMP; Diet, Atherogenic; Endothelium, Vascular; In Vitro Techniques; Isradipine; Male; Muscle Relaxation; Nitric Oxide; Nitroprusside; Phospholipids; Rabbits; Ramipril; Triglycerides

This investigation was performed to assess the effect of treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril, on human tissue renin levels. A total of 41 patients were studied (32 males and 9 females, aged 48-71 years). Twenty-two of these patients received up to 5 days treatment with the ACE inhibitor ramipril (5 mg p.o.) prior to surgery, the remaining 19 patients served as controls (no ramipril treatment). Under surgery vascular tissues were removed and renin-like activities measured in carotid and renal arteries. Plasma renin and ACE activity were determined before and after surgical intervention. Vascular renin values were two- to threefold higher in ACE-treated hypertensive patients compared to normotensive and untreated hypertensive controls (irrespective of concomitant atherosclerotic lesions). There were no differences in vascular renin observed between primary (essential) and secondary hypertension. In the hypertensive patients treated with ramipril, blood pressures were markedly (but not significantly) lowered in 12 patients. A similar pattern was observed for treatment-induced changes in plasma renin (increased) and ACE activity (decreased). The findings of this study demonstrate that treatment with an ACE inhibitor, such as ramipril, evokes changes in extrarenal tissues similar to those demonstrable in plasma. Conceivably, the blood pressure-lowering effect of ACE inhibition on human tissue is partially induced at the vascular level.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Blood Vessels; Bridged Bicyclo Compounds; Female; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Ramipril; Renin