ramipril and Obesity

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.

Topics: Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Clinical Trials as Topic; Diabetes Complications; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Irbesartan; Losartan; Nitrobenzenes; Obesity; Olmesartan Medoxomil; Piperazines; Ramipril; Tetrazoles; Valine; Valsartan

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Exercise; Humans; Hypertension; Lisinopril; Male; Obesity; Ramipril; Risk Factors; Weight Loss

Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Chronic Disease; Comorbidity; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Humans; Incidence; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Obesity; Overweight; Proteinuria; Ramipril; Treatment Outcome

Conjugated linoleic acid (CLA) refers to a group of positional and geometrical conjugated dienoic isomers of linoleic acid. Our aim was to investigate the effect of 8-week dietary CLA supplementation on blood pressure, concentrations of plasma adiponecin, leptin, and as well as angiotensin-converting enzyme (ACE) activity in obese hypertensive subjects.. Eighty obese individuals with stage 1 uncontrolled essential hypertension were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 4.5 g/day CLA (nine 0.5-g capsules; a 50:50 isomer blend of c 9,t 11 and t 10,c 12 CLA) with 37.5 mg/day ramipril (group 1) or placebo with 37.5 mg/day ramipril (group 2) for 8 weeks. Baseline and endpoint systolic BP, diastolic BP, and concentrations of plasma adiponecin, leptin, angiotensinogen, and ACE activity were measured.. Treatment with CLA significantly enhanced the reduction effect of ramipril on systolic BP and diastolic BP (P < 0.05). It also increased plasma adiponectin concentration (P < 0.05) and decreased plasma concentrations of leptin and angiotensinogen (P < 0.05); however, significant change was not observed in ACE activity.. An 8-week long supplementation of CLA enhanced the effect of ramipril on blood pressure reduction in treated obese hypertensive patients. The antihypertensive effect of CLA might be related to the changed secretion of hypertensive adipocytokines in plasma.

Topics: Adiponectin; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Female; Follow-Up Studies; Humans; Hypertension; Leptin; Linoleic Acids, Conjugated; Male; Middle Aged; Obesity; Ramipril; Treatment Outcome

Current guidelines for the treatment of hypertension do not provide specific recommendations for obese hypertensive patients. To identify an optimal treatment regimen for obese hypertensive patients, we studied the interactions between a drug-based weight loss approach by sibutramine and different antihypertensive drug regimens.. This was a prospective, 16-week double-blind placebo-controlled randomized multicenter study in 171 obese hypertensive patients. After a 2-week run-in period, patients receiving 1 of the 3 antihypertensive combination therapies (felodipine 5 mg/ramipril 5 mg [n=57], verapamil 180 mg/trandolapril 2 mg [n=55], or metoprolol succinate 95 mg/hydrochlorothiazide 12.5 mg [metoprolol/hydrochlorothiazide; n=59]) were assigned randomly to sibutramine (15 mg) or placebo. Sibutramine treatment resulted in a significantly greater decrease in body weight, body mass index, and waist circumference and a significant increase in diastolic blood pressure during 24-hour blood pressure monitoring compared with placebo treatment. Sibutramine-induced weight loss and reduction of visceral obesity were markedly attenuated in the metoprolol/hydrochlorothiazide group compared with the other groups. Consistently, improvement in glucose tolerance and hypertriglyceridemia by sibutramine was abrogated in the cohort treated with metoprolol/hydrochlorothiazide compared with the other groups.. The present study demonstrates for the first time that an antihypertensive combination therapy regimen with angiotensin-converting enzyme inhibitors and calcium channel blockers is more advantageous than a beta-blocker/diuretic-based regimen in supporting the weight-reducing actions and concomitant metabolic changes induced by sibutramine in obese hypertensive patients. These data may help to develop future comprehensive treatment strategies and guidelines for this high-risk patient population.

Topics: Adult; Aged; Antihypertensive Agents; Appetite Depressants; Blood Pressure; Body Weight; Cyclobutanes; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Felodipine; Female; Humans; Hydrochlorothiazide; Hypertension; Indoles; Male; Metoprolol; Middle Aged; Obesity; Prospective Studies; Ramipril; Treatment Outcome; Verapamil

Obesity-induced hypertension and essential hypertension in lean patients are two different forms of hypertension. The main goal of this study was to test whether there are differences in biochemical parameters between subjects with obesity-associated hypertension and those with essential hypertension. We examined whether the biochemical responses to angiotensin-converting enzyme inhibitor (ACEI) ramipril therapy reveal properties of these two conditions that might explain the differences in clinical outcome. Before ramipril therapy, the hypertensive group exhibited increases in ACE activity (p<0.05), plasma malondialdehyde (MDA) concentration and the malondialdehyde/nitric oxide end-product ratio (MDA/NO(x)) (p<0.05), and decreases in xanthine oxidase (XO) activity (p<0.05) and plasma nitric oxide end-product (NO(x)) level (p<0.01). Before medication, plasma endothelin-1 (ET-1), plasma leptin, and leptin receptor levels were normal. Following ramipril treatment, ACE activity normalized. Before ACE inhibitor treatment, the obese-hypertensive group exhibited elevated levels of plasma ET-1 (p<0.05), plasma leptin (p<0.01), XO activity (p<0.05), plasma MDA and MDA/NO(x) (p<0.05), and reduced levels of plasma NO(x)(p<0.01) and leptin receptors (p<0.001). Following medication, the plasma NO(x) level, MDA/NO(x), and XO activity returned to normal while ACE activity decreased (p<0.001). In patients with essential hypertension, NO availability and ACE activity, and in those with obesity-associated hypertension, hyperleptinemic effects, NO level, endothelin-1 concentration and XO activity, may be important factors in the pathology.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Endothelin-1; Female; Humans; Hypertension; Leptin; Male; Malondialdehyde; Nitric Oxide; Obesity; Peptidyl-Dipeptidase A; Ramipril; Xanthine Oxidase

Whether ACE inhibition is useful for type 2 diabetic patients with micro- and macroalbuminuria remains unknown. The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril (DIABHYCAR) Study was set up to address this issue through a multicenter double-blind parallel placebo-controlled > or = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients.. The main selection criteria were as follows: men or women aged > or = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level < 150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentration > or = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account.. There were 25,455 patients screened for urinary albumin (20,296 from France, 918 from Germany, 1,019 from Northwest Europe, 969 from Central Europe, 959 from Mediterranean Europe, and 1,294 from North Africa). Of these patients, 4,937 were randomized. Compared with the nonrandomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic blood pressure and plasma glucose, smoked more tobacco, drank more alcohol, and had complications more frequently. Using a logistic regression analysis, all the above-mentioned items appeared as independent determinants for randomization into the study, with the exception of alcohol intake. The contribution of each item varied slightly from one geographical origin to another.. The physical, biological, and behavioral characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the DIABHYCAR Study because of micro- and macroalbuminuria. Testing the usefulness of ACE inhibition for the type 2 diabetic patients with microalbuminuria seems feasible through the DIABHYCAR Study.

Topics: Africa, Northern; Albuminuria; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Europe; Female; Humans; Male; Middle Aged; Obesity; Placebos; Ramipril; Smoking

To assess the effects of angiotensin converting enzyme (ACE) inhibitor on insulin action in obesity, five normotensive non-diabetic obese women were examined on two occasions as part of a double-blind, randomized, cross-over study involving ten days of treatment with either 1.25 mg ramipril or placebo. The study consisted of a euglycaemic hyperinsulinaemic clamp (two periods of insulin infusion at rates of 0.4 and 1 mU/kg/min, 2 h for each step) combined with indirect calorimetry. The most notable results involved a significantly faster time-course of glucose infusion rates during the first 30 min of each insulin infusion period [analysed by calculating slopes (S1 and S2)] after ramipril than placebo administration. The mean glucose infusion rates reached during the last 30 min of each insulin infusion period (G1 and G2), as well as the increases in carbohydrate oxidation rates during the clamp (C1-C0 and C2-C0) and the decreases in plasma nonesterified fatty acids (A0-A1 and A0-A2), were not significantly different after ramipril and placebo. According to robust principal component analysis of S1, S2, G1, G2, C1, C2, A1 and A2 (orthogonally to C0 and A0), insulin sensitivity was improved with ramipril as compared to placebo (p = 0.013). This study strongly suggests that a low dose of an ACE inhibitor increases the activation phase of insulin action in normotensive nondiabetic obese patients and may accelerate insulin action.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin Resistance; Middle Aged; Obesity; Oxidation-Reduction; Pilot Projects; Ramipril; Time Factors

Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Fenofibrate; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Insulin; Liraglutide; Male; Metformin; Obesity; Ramipril; Rats; Rats, Sprague-Dawley; Rats, Zucker; Rosuvastatin Calcium; Somatostatin

Overweight and obesity decrease the effectiveness of antihypertensive therapy despite the more frequent use of polytherapy. One method for improving therapy effectiveness is by decreasing non-compliance with the use of fixed-dose combinations (FDC). The aim of this study was to assess the effectiveness, tolerance, and satisfaction with ramipril/amlodipine FDC antihypertensive therapy in relation to nutritional status.. The survey enrolled 24,240 hypertensive patients recently switched to ramipril/amlodipine FDC (EGIRAMLON) at the same doses as previously prescribed separate pills.. The effectiveness of antihypertensive therapy increased during follow-up from 32.9% to 76.5%. Overweight and obesity were associated with the increased risk of not attaining the recommended BP values [adjusted for age OR=0.74 (95% CI 0.67-0.83) and 0.70 (0.61-0.81) for overweight; 0.54 (0.47-0.60) and 0.49 (0.42-0.57) for obese, at the first and the second examination, respectively]. "Very good" or "good" the FDP tolerance was reported by 98.8%, 97.6% and 96.4%, respectively. Adverse events (AE) were reported in 0.35% of patients regardless of nutritional status. High levels of satisfaction with the FDC were reported by 57.0% of patients with normal weight, 54.5% of overweight, and 50.6% with obesity. Effectiveness and convenience were the most important for patients.. The effectiveness of therapy with ramipril/amlodipine FDC in the study population was high, but slightly lower in overweigh and obese. This FDC was well tolerated and a significant number of patients satisfied with the therapy regardless of nutritional status. Although the perceived tolerance and satisfaction with treatment were lower in obese and overweight than in normal weight patients; the incidence of AE and perceived benefit from the use of a single-pill, compared to multiple tablets, were comparable irrespective of nutritional status.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Combinations; Humans; Hypertension; Medication Adherence; Nutritional Status; Obesity; Overweight; Patient Satisfaction; Ramipril

Combination therapies are becoming increasingly important for the treatment of high blood pressure. Little is known about whether double blockade of angiotensin II (AT(1) ) receptors and angiotensin-converting enzyme (ACE) exert synergistic metabolic effects.. Spontaneously hypertensive rats were allowed to choose between palatable chocolate bars and standard chow and were simultaneously treated with the AT(1) blocker telmisartan (8 mg·kg(bw) (-1) ·day(-1) ), the ACE inhibitor ramipril (4 mg·kg(bw) (-1) ·day(-1) ) or a combination of the two (8 + 4 mg·kg(bw) (-1) ·day(-1) ) for 12 weeks.. Although food-dependent energy intake was increased by telmisartan and telmisartan + ramipril compared with ramipril or controls, body weight gain, abundance of fat and plasma leptin levels were decreased. Increased insulin levels in response to an oral glucose tolerance test were comparably attenuated by telmisartan and telmisartan + ramipril, but not by ramipril. During an insulin tolerance test, glucose utilization was equally as effectively improved by telmisartan and telmisartan + ramipril. In response to a stress test, ACTH, corticosterone and glucose increased in controls. These stress reactions were attenuated by telmisartan and telmisartan + ramipril.. The combination of telmisartan + ramipril was no more efficacious in regulating body weight and glucose homeostasis than telmisartan alone. However, telmisartan was more effective than ramipril in improving metabolic parameters and in reducing body weight. The association between the decrease in stress responses and the diminished glucose levels after stress supports our hypothesis that the ability of telmisartan, as an AT(1) receptor blocker, to alleviate stress reactions may contribute to its hypoglycaemic actions.

Topics: Adipose Tissue; Adrenocorticotropic Hormone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Benzoates; Blood Glucose; Blood Pressure; Corticosterone; Drug Therapy, Combination; Feeding Behavior; Heart Rate; Leptin; Male; Obesity; Ramipril; Rats; Rats, Inbred SHR; Telmisartan; Weight Gain

Obesity increases oxidative stress, endothelial dysfunction, and inflammation, but the effect of obesity on postoperative AKI is not known. We examined the relationship between body mass index (BMI) and AKI in 445 patients undergoing cardiac surgery and whether oxidative stress (F(2)-isoprostanes), inflammation (IL-6), or antifibrinolysis (plasminogen activator inhibitor-1 [PAI-1]) contribute to any identified relationship. Overall, 112 (25%) of the 445 patients developed AKI. Higher BMI was independently associated with increased odds of AKI (26.5% increase per 5 kg/m(2) [95% confidence interval, 4.3%-53.4%]; P=0.02). Baseline F(2)-isoprostane (P=0.04), intraoperative F(2)-isoprostane (P=0.003), and intraoperative PAI-1 (P=0.04) concentrations also independently predicted AKI. BMI no longer predicted AKI after adjustment for the effect of F(2)-isoprostanes, suggesting that obesity may affect AKI via effects on oxidative stress. In contrast, adjustment for IL-6 or PAI-1 did not substantially alter the association between BMI and AKI. Further, deconstruction of the obesity-AKI relationship into direct (i.e., independent of candidate pathways) and indirect (i.e., effect of BMI on AKI via each candidate pathway) effects indicated that F(2)-isoprostanes, but not IL-6 or PAI-1, partially mediate the relationship between obesity and AKI (P=0.001). In conclusion, obesity independently predicts AKI after cardiac surgery, and oxidative stress may partially mediate this association.

Topics: Acute Kidney Injury; Aged; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Body Mass Index; Cardiac Surgical Procedures; Diuretics; F2-Isoprostanes; Female; Humans; Interleukin-6; Male; Middle Aged; Obesity; Oxidative Stress; Plasminogen Activator Inhibitor 1; Postoperative Complications; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Signal Transduction; Spironolactone

Topics: Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Chronic Disease; Comorbidity; Creatinine; Disease Progression; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Obesity; Proteinuria; Ramipril; Treatment Outcome

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Body Size; Cardiovascular Diseases; Humans; Life Style; Metabolic Syndrome; Obesity; Ramipril; Renin-Angiotensin System; Risk Assessment; Risk Factors; Telmisartan

Diabetes mellitus (DM) is a worldwide epidemic. Its prevalence is rapidly increasing in both developing and developed countries. Coronary heart disease (CHD) is highly prevalent and is the major cause of morbidity and mortality in patients with diabetes. Individuals with prediabetes states, with or without known CHD, should undergo lifestyle modifications aimed at preventing DM. In patients with CHD and DM, routine use of aspirin and an angiotensin-converting enzyme inhibitor, along with strict glycemic, blood pressure, and lipid control, is strongly recommended. Intense insulin therapy may be needed for glycemic control, and high-dose statin therapy may be needed for lipid control. For blood pressure control, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are considered first-line therapy. Noncompliance with medications and/or lifestyle measures and underprescription of evidence-based therapies remain important unsolved problems.

Topics: Antihypertensive Agents; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Life Style; Myocardial Infarction; Obesity; Pioglitazone; Piperidines; Platelet Aggregation Inhibitors; Prediabetic State; Pyrazoles; Ramipril; Rimonabant; Risk Assessment; Thiazolidinediones; Triglycerides; Weight Loss

Among neuroeosinophilic syndromes, neuromuscular disorders are considered as a special group, including perimyosistis, polymyositis and fasciitis. These three disorders are considered as a continuum. They usually without a recognized cause, and are considered to be spontaneous or exercise-induced. We report the case of a 43 year-old woman who experienced angioedema followed by an histologically proven-fasciitis with eosinophilia after Ramipril (Triatec) use. Causal attribution to Ramipril was considered "plausible". To our knowledge this side effect has never been reported with this drug.

Topics: Adult; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Drug Eruptions; Eosinophilia; Fasciitis; Female; Humans; Hypertension; Obesity; Ramipril

The effects of the sodium-hydrogen (Na/H) exchange inhibitor cariporide (HOE642), on insulin sensitivity and vascular function were studied in the JCR:LA-cp rat and the db/db mouse. In the insulin-resistant rat, cariporide reduced fasting insulin levels (42%, P < 0.02) and insulin response in a meal tolerance test (50%, P < 0.01), indicating increased insulin sensitivity. The ACE inhibitor, ramipril, used as a reference agent, reduced the insulin response to the meal, but not fasting levels. The EC50 for acetylcholine-mediated relaxation of phenylephrine-precontracted aortic rings was significantly lower in cariporide-treated rats (P < 0.002), but not in ramipril-treated rats. Flow response of the coronary circulation to bradykinin was significantly greater in both cariporide- and ramipril-treated rats, (3-fold decrease in the EC50, P < 0.05). Cariporide-treated hearts were smaller, slower beating, with greater developed LVP. In the obese db/db mouse, chronic treatment with cariporide obviated vascular hypercontractility and improved endothelial function. Thus, cariporide had beneficial effects on the abnormal insulin metabolism and associated vascular dysfunction in the JCR:LA-cp insulin-resistant rat, which develops advanced cardiovascular disease and ischemic myocardial lesions. It also improved vascular function in a similar mouse model of insulin resistance. These effects were markedly greater than those of ramipril.

Topics: Acetylcholine; Animals; Aorta; Body Weight; Coronary Circulation; Eating; Guanidines; Heart; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Nitroprusside; Obesity; Ramipril; Rats; Receptors, Cell Surface; Receptors, Leptin; Sodium-Hydrogen Exchangers; Sulfones; Vasoconstriction

The insulin-resistant, hyperinsulinemic, normoglycemic, and obese JCR:LA-cp rat was used to study the effects of ramipril (an ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidases) on insulin sensitivity and vascular function. Both compounds reduced the surge of plasma insulin in a meal tolerance test by approximately 50%. Ramipril had no effect on acetylcholine-induced relaxation but increased the sensitivity to sodium nitroprus-side at low concentrations. AVE7688 significantly reduced the EC50 for acetylcholine to relax phenylephrine-contracted aortic rings. None of the compounds affected the baseline coronary flow and reactive hyperemia. Coronary flow response to bradykinin in AVE7688- and ramipril-treated rat hearts showed a significantly lower EC50 than in control rats. Maximum flow rate was not different between groups. In summary, both ramipril and AVE7688 had significant hypoinsulinemic and insulin-sensitizing effects. Whereas ramipril had limited vascular effects, AVE7688 had more marked beneficial vascular effects, probably of endothelial origin and possibly related to lowered insulin levels.

Topics: Acetylcholine; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Aorta, Thoracic; Blood Glucose; Body Weight; Bradykinin; Diet; Disease Models, Animal; Eating; Endothelium, Vascular; Fasting; Heart; Heart Rate; Heterocyclic Compounds, 3-Ring; Insulin; Insulin Resistance; Male; Muscle, Smooth, Vascular; Neprilysin; NG-Nitroarginine Methyl Ester; Nitroprusside; Obesity; Organ Size; Phenylephrine; Ramipril; Rats; Vasoconstriction; Vasodilation

Cardiovascular risk reduction in diabetic patients is a multidimensional task. Long-term decrease of glycaemia by the use of insulin or sulfonylureas had disappointing effects on cardiovascular events, whereas metformin effects are ambiguous. On the contrary, controlling risk factors like hypertension or hypercholesterolaemia decrease the incidence of cardiovascular events in diabetic as in non-diabetic patients. Similarly, clinical trials have shown the efficacy of treatments that decrease cardiovascular risk whatever the cause, such as antiplatelet drugs in secondary prevention and high-dose ramipril in secondary prevention or in hypertensive patients. The absolute benefit conferred by efficient therapies is higher in diabetic patients because they are at an increased risk of events compared with their non-diabetic counterparts.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Cholesterol; Confidence Intervals; Diabetes Mellitus, Type 2; Humans; Hypercholesterolemia; Hypertension; Meta-Analysis as Topic; Obesity; Platelet Aggregation Inhibitors; Primary Prevention; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Humans; Obesity; Ramipril