enalapril 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

Blood pressure and proteinuria are important determinants of progressive renal failure in patients with renal diseases. In a 53-year-old man with hypertension and nephrotic-range proteinuria, lowering the blood pressure to a value of 125/75 mmHg resulted in a disappearance of the proteinuria. Recent literature data indicate that the treatment of blood pressure in patients with proteinuria, with emphasis on the benefits of reaching a blood pressure target of 125/75 mmHg and the use of angiotensin-converting enzyme inhibitors, may lead to a serious improvement in their prognosis.

Topics: Antihypertensive Agents; Atenolol; Chlorthalidone; Dose-Response Relationship, Drug; Enalapril; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Male; Middle Aged; Obesity; Proteinuria; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Heart rate variability has attracted attention as an index of the effects of the autonomic nerve system on the heart rhythm. Heart rate variability (HRV) is low in patients at risk for sudden death. We evaluated the effects of caffeine, whole-day work without sleep and drugs on HRV. Caffeine had no effects on HRV or ventricular extrasystoles in young adults but aggravated those in obese middle-aged subjects. Whole-day work without sleep increased blood catecholamines and decreased HRV. These findings also suggest the usefulness of HRV as an index in health management. Tofisopam, enalapril and aprindine significantly improved HRV. These drug may be useful for maintaining normal autonomic nerve activity and preventing autonomic nerve diseases or sudden cardiac death in this stressful society.

Topics: Adult; Anti-Anxiety Agents; Aprindine; Autonomic Nervous System; Benzodiazepines; Caffeine; Electrocardiography, Ambulatory; Enalapril; Female; Heart Rate; Humans; Male; Middle Aged; Obesity

Angioedema of the face and neck is a rare but potentially fatal complication of angiotensin-converting enzyme inhibitor (ACEI) use. We retrospectively reviewed five cases of ACEI angioedema seen at our institution over the past 2 1/2 years. Four of the cases occurred with enalapril and one with lisinopril. Onset of symptoms varied from two days to ten months. Importantly, three of the five patients had been receiving medication three months or longer, suggesting clinicians must consider this complication during long-term administration of these agents. Three of the five patients were markedly obese, had a history of previous face and neck surgery, or had been intubated in the past. Thus, we propose that previous manipulation or trauma of the upper airway, perhaps resulting in airway narrowing, may represent a risk factor for upper airway obstruction secondary to ACEI-induced angioedema.

Topics: Adult; Aged; Aged, 80 and over; Airway Obstruction; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Causality; Dipeptides; Enalapril; Female; Humans; Lisinopril; Male; Middle Aged; Obesity; Retrospective Studies; Time Factors

Arterial hypertension is by definition a haemodynamic disorder. At least 3 different subsets of cardiovascular pathophysiological features can be identified in so-called essential hypertension: The young lean patient characterised by an elevated cardiac output and renal blood flow, elevated plasma renin activity and circulating catecholamine levels, as well as symptoms and signs of hyperadrenergic hypertension. The elderly patient characterised by a low cardiac output often with left ventricular hypertrophy, elevated total peripheral resistance, nephrosclerosis, and symptoms and signs of target organ disease. The obese patient (and to a lesser degree the black patient) characterised by expanded fluid volume state, elevated cardiac output, a normal to low total peripheral resistance, and symptoms and signs of volume overload. To initiate antihypertensive therapy, the drug of choice in the young patient is a beta-adrenergic receptor blocker; in the elderly it is a haemodynamic vasodilator (anti-adrenergic drug, slow channel calcium blocker, or converting enzyme (ACE) inhibitor), and in black or obese patients it remains a thiazide diuretic. Enalapril, a new ACE inhibitor is indicated as a first-step agent in the great majority of hypertensive patients in whom the elevated arterial pressure should be reduced by a decrease in total peripheral resistance, without compromising systemic or regional blood flow. In contrast to other antihypertensive agents, enalapril will lower preload and afterload to the left ventricle while improving systemic and regional flow in elderly patients with latent or manifest congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arrhythmias, Cardiac; Cardiomegaly; Coronary Disease; Enalapril; Heart; Hemodynamics; Humans; Hypertension; Obesity; Racial Groups

Leptin, an adipocyte-derived hormone, is involved in the regulation of body weight and is associated with obesity-related complications, notably cardiovascular disease (CVD). A putative link between obesity and CVD could be induction of plasminogen activator inhibitor-1 (PAI-1) synthesis by leptin. In this study, we hypothesized that the beneficial effect of the angiotensin-converting enzyme inhibitor (ACE

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Double-Blind Method; Enalapril; Female; Fibrinolysis; Gene Expression Regulation; Humans; Leptin; Male; Middle Aged; Myocardial Infarction; Obesity; Plasminogen Activator Inhibitor 1; Protein Binding; Sex Factors; Signal Transduction; Tissue Plasminogen Activator

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Felodipine; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Male; Metabolome; Middle Aged; Norepinephrine; Obesity; Random Allocation; Sympathetic Nervous System

Obesity exacerbates hypertension and stimulates the renin-angiotensin-aldosterone system (RAAS). Full-dose RAAS inhibition could be a therapeutic option in overweight or obese patients with hypertension. This study compared four RAAS inhibitors at full therapeutic doses to determine their effect on blood pressure (BP) and cardiovascular risk factors in these patients.. We conducted a 24-week, single-blind, randomized, parallel-group study in 120 overweight or obese patients (body mass index ≥27 kg/m(2)) with hypertension, aged 18-60 years. The primary endpoint was the change in mean 24-h systolic BP and diastolic BP from baseline to study end. Central BP, arterial stiffness, and metabolic and cardiac indices were also investigated. Patients were randomly allocated to perindopril 10 mg/day, enalapril 20 mg/day, losartan 100 mg/day or telmisartan 80 mg/day. Nonpharmacological interventions were also recommended.. Reductions in mean 24-h systolic BP (and diastolic BP) were all significant (p < 0.05 versus baseline) for perindopril, enalapril, losartan and telmisartan: systolic BP -22, -11, -12 and -15 mmHg, respectively; (and diastolic BP -13, -6, -13 and -12 mmHg, respectively). Aortic elasticity improved with perindopril and telmisartan. Perindopril was associated with the greatest reductions in central aortic BP and leptin levels [30 % versus 2 %, 7 % and 14 % with enalapril, losartan and telmisartan, respectively (all p < 0.05 versus perindopril)]. Reductions in other BP, echocardiographic, metabolic and anthropometric parameters occurred with all treatments.. Full-dose RAAS inhibition, particularly with perindopril, effectively reduces BP, improves arterial structure and regulates cardiovascular risk factors in overweight or obese patients with hypertension.

Topics: Adult; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Enalapril; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Obesity; Overweight; Perindopril; Single-Blind Method; Telmisartan

The prognostic impact of body mass index (BMI) in patients following acute myocardial infarction (AMI) may be altered by neurohormonal blockade.. The impact of neurohormonal blockade on the association between BMI and mortality was examined in 5548 patients following AMI (CONSENSUS II), 50% receiving enalapril and 7% beta-blockade, and in 4367 patients with coronary artery disease (CAD) (4S), 79% with prior AMI, 12% receiving ACEi and 67% beta-blockade. Median follow-up was 0.4 and 5.2 years, respectively. Patients were categorized into 4 BMI groups: Underweight, < 22.00; normal-weight, 22.00-24.99; overweight, 25.00-29.99; obese, > or = 30.00 kg/m2. Multivariable analysis adjusted for demographics, patient history, physical examination, biochemistry and medication.. CONSENSUS II: Overall, adjusted mortality (n=301) risk was similar across BMI groups. Comparing overweight with normal-weight patients, the hazard ratios (HRs) for mortality differed significantly (P=0.028) between patients randomized to placebo (HR 1.41) and enalapril (HR 0.75). 4S: Overall, adjusted mortality (n=421) risk was similar for normal-weight, overweight and obese patients. In a time-dependent analysis for drug use, comparing obese with normal-weight patients, the HRs for mortality differed significantly (P=0.047) between patients without (HR 1.86) and those with (HR 0.97) neurohormonal blockade.. In patients after AMI or with CAD, high BMI was associated with increased mortality risk among patients not receiving neurohormonal blockade, but with decreased or neutral mortality risk among those receiving neurohormonal blockade. Tests for interaction indicate that neurohormonal blockade may attenuate the relationship between high BMI and increased mortality risk. Neurohormonal blockade may thus partly explain the so-called obesity paradox.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Body Mass Index; Coronary Artery Disease; Enalapril; Female; Humans; Male; Middle Aged; Myocardial Infarction; Obesity; Prognosis; Proportional Hazards Models; Risk Factors

To define efficacy and safety of enarenal in patients with arterial hypertension (AH).. A total of 235 physicians from 13 towns of Russia and 4291 patients aged 30-70 years with AH of the first-second degree (60% women) participated in the trial. Patients with AH of the second degree were older, more frequently had obesity, diabetes mellitus, hyperlipidemia.. Target blood pressure (TBP) was achieved in 69.5% patients. The target was more frequently achieved in AH of the first degree (87.6%) than of the second (51.4%), in the first degree AH it was achieved with the same frequency in men and women. In AH of the second degree the success with TBP achievement was more frequent in men. Obesity decreased treatment efficacy only in women (TBP was achieved in 88.3% and 79.6% normal and obese women, respectively. Smoking had no effect on the treatment efficacy. In diabetes mellitus systolic blood pressure target (< 140 mm Hg) was seen in 54.2%, < 130 mm Hz--in 28.6%, by diastolic pressure (< 90 mm Hz)--in 88% patients, < 80 mm Hg--in 57%. The response was evaluated according to 5-score scale (from bad to good). The treatment improved the condition of the patients from 2.83 to 3.59 scores after 4 weeks of therapy and to 4.04 after 8 weeks of therapy. Side effects were not registered in 77.6% patients, only 1.9% patients discontinued the drug because of toxicity.. Enarenal, generic of enalapril, demonstrated efficacy comparable to that of the other ACE inhibitors, good tolerance and is recommended for treatment of hypertension.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus; Enalapril; Female; Follow-Up Studies; Humans; Hyperlipidemias; Hypertension; Incidence; Male; Middle Aged; Obesity; Russia; Treatment Outcome

In rats leptin increases sympathetic activity, and an inhibitory effect on leptin synthesis and release has been demonstrated for the catecholamines, both in adipocyte cell cultures and in healthy experimental animals. The aim of this study was to evaluate the relationship between leptin and heart sympathetic activity as well as changes in leptin levels after the administration of drugs that modify sympathetic activity.. We performed a randomized, blinded, before-after trial in 81 normotensive obese and non-obese subjects. They were studied before and after treatment with enalapril (5 mg every 12 hours) or clonidine (0.1 mg every 12 hours) for 7 days.. Obese subjects had higher values for percent body fat (p < 0.0005), triglycerides (p < 0.05), leptin (p < 0.0005), and low frequency/high frequency ratio at night (LF/HFn, p = 0.05). After enalapril or clonidine treatment, leptin levels were not modified. Both drugs significantly diminished the systolic and diastolic blood pressures. In the obese group, clonidine and enalapril diminished the LF/HFn ratio (p < 0.05). The LF/HF index showed a univariate correlation with body mass index, leptin, systolic blood pressure, insulin, age and triglyceride levels. In the multiple regression analysis for factors associated with the LF/HF ratio, only leptin, age and insulin were included in the model. The r2 of the model was 0.3 (p = 0.0003).. A higher level of heart sympathetic activity is found in normotensive obese as compared with non-obese subjects. Both clonidine and enalapril reduced heart sympathetic activity in obese subjects without a change in fasting leptin levels.

Topics: Adipose Tissue; Adrenergic alpha-Agonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Body Mass Index; Clonidine; Diastole; Enalapril; Female; Heart Rate; Humans; Hypertension; Leptin; Male; Middle Aged; Obesity; Statistics as Topic; Systole; Treatment Outcome

Obesity is a significant risk factor for hypertension and the cardiovascular sequelae of hypertension. Weight loss has been shown to be effective in lowering blood pressure in overweight individuals. The purpose of this study was to show the impact of a weight loss intervention on overall medication requirements for obese, hypertensive patients. This was a substudy of the Hypertension Optimal Treatment (HOT) study. HOT study patients who had a body mass index > or =27 kg/m2 were randomized to receive either the weight loss intervention, which included dietary counseling and group support, or to serve as the control group. Patients' weights and number of medication steps (per HOT protocol) required to achieve target diastolic blood pressure were measured at 3, 6, 12, 18, 24, and 30 months. Patients in the weight loss group lost significantly more weight than the control group only at 6 months (-3.2+/-4.3 v. -1.8+/-2.7 kg [mean +/- SD] for weight loss group versus control, respectively, P = .05). The weight loss group tended to regain weight after the first 6 months of the study. However, patients in the weight loss group used a significantly fewer number of medication steps than the control group at all time intervals except 3 months. Weight loss appears to be a useful tool in blood pressure management in patients who require medication to control their blood pressure.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Body Mass Index; Calcium Channel Blockers; Diet; Disease Progression; Drug Therapy, Combination; Enalapril; Felodipine; Female; Humans; Hypertension; Male; Metoprolol; Middle Aged; Obesity; Risk Factors; Treatment Outcome; Weight Loss

Resistance to the capacity of insulin to suppress lipolysis may be an important link in the association between abdominal obesity and hypertension. Furthermore, a more active renin-angiotensin system in adipose tissue may contribute to insulin-resistant lipolysis in abdominally obese hypertensive subjects. We determined nonesterified fatty acid concentrations and turnover as well as lipid oxidation under basal conditions and during steady-state euglycemia with two levels of insulinemia (72 and 287 pmol/L) in lean normotensive, abdominally obese normotensive, and abdominally obese hypertensive subjects. To assess the role of the renin-angiotensin system in determining non-esterified fatty acid turnover, we repeated studies in the abdominally obese hypertensive subjects after double-blind random assignment to placebo or enalapril for 1 month each. The main findings were the following: (1) Nonesterified fatty acid flux was significantly higher in abdominally obese hypertensive subjects at both levels of insulinemia than in either abdominally obese normotensive or lean normotensive subjects and correlated significantly with both mean blood pressure and total systemic resistance during the higher level of insulinemia. (2) Enalapril significantly improved insulin-resistant lipolysis in the abdominally obese hypertensive subjects. The improvement in insulin suppressibility of nonesterified fatty acid flux at the high hormonal concentrations correlated positively with the magnitude of reduction in blood pressure. (3) Basal lipid oxidation and suppression in response to insulin were similarly impaired in both obese groups. Resistance to the antilipolytic actions of insulin is thus a characteristic feature in abdominally obese hypertensive subjects and may be linked to the elevated blood pressure in these individuals. A more active renin-angiotensin system may partly explain the insulin-resistant lipolysis in this form of hypertension.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Body Constitution; Body Mass Index; Calorimetry, Indirect; Data Interpretation, Statistical; Enalapril; Fatty Acids, Nonesterified; Female; Hemodynamics; Humans; Hypertension; Insulin; Insulin Resistance; Lipolysis; Male; Obesity; Placebos; Renin-Angiotensin System

We evaluated the effects of enalapril [angiotensin converting enzyme (ACE) inhibitor] in comparison with atenolol (beta-blocker) on insulin sensitivity and serum lipoprotein concentration in obese hypertensive dyslipidemic patients. Twenty-eight hypertensive [mean blood pressure (MAP) 152 +/- 3/103 +/- 1 mm Hgl], obese [mean body mass index (BMI) 30 + 1 kg/m2A], dyslipidemic [total triglycerides 2.0 +/- 0.2 mM and/or high density lipoprotein (HDL) cholesterol 1.1 +/- 0.1 mM and low density lipoprotein (LDL) cholesterol 4.5 +/- 0.2 mM] outpatients were randomized in two groups receiving enalapril or atenolol for 12 weeks, in an investigator-blinded, parallel, comparative two-center trial. Insulin sensitivity was assessed by a modified insulin suppression test. Blood pressure (BP), insulin sensitivity, and serum lipoprotein concentrations were compared before and after each treatment and between the two treated groups. BP decreased significantly and comparably during enalapril and atenolol treatment (p < or = 0.01). The sensitivity to insulin improved by 15% (p = 0.03) in the enalapril group and worsened by 17% (p < or = 0.01) in the atenolol group. Serum lipoprotein concentrations were not modified by any treatment. The improvement in insulin sensitivity caused by enalapril treatment appears to be an advantage as compared with atenolol treatment in hypertensive obese and dyslipidemic patients, whereas the BP-lowering efficacy of the two drugs is similar. Because this effect has been reported with other ACE inhibitors, it appears to be characteristic of the entire class of ACE inhibitors.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Blood Glucose; Enalapril; Female; Humans; Hyperlipidemias; Hypertension; Insulin; Lipoproteins; Male; Obesity

To compare the metabolic effects of nifedipine and enalapril, we studied 21 obese patients (BMI of 31.6 +/- 1.1) with mild-to-moderate hypertension and glucose intolerance. None of the patients were receiving insulin or hypoglycemic agents. After a washout period of 15 days, blood pressure was recorded and fasting blood glucose, insulin, and lipid concentrations were determined. At random, 11 patients were started on nifedipine and 10 patients on enalapril. At the 90th day of treatment, clinical and laboratory tests were again performed. Both of the drugs reduced blood pressure values comparably. No significant variation of metabolic parameters was found after 90 days of treatment in the enalapril group. In the nifedipine group, the fasting insulin level was decreased and the glucose/insulin ratio was significantly increased, suggesting an improvement in insulin sensitivity; moreover, total plasma cholesterol was significantly reduced. Enalapril and nifedipine seem to be effective and safe drugs in the treatment of hypertensive subjects with obesity and glucose intolerance. Nifedipine can ameliorate insulin resistance and the lipid state.

Topics: Blood Glucose; Cholesterol; Enalapril; Glucose; Humans; Hypertension; Insulin; Middle Aged; Nifedipine; Obesity

Obesity-related metabolic diseases occur as a result of disruptions in white adipose tissue (WAT) plasticity, especially through visceral fat accumulation and adipocyte hypertrophy. This study aimed to evaluate the impact of renin-angiotensin system (RAS) and bradykinin receptors modulation by enalapril treatment and/or exercise training on WAT morphology and related deleterious outcomes.. Male C57BL/6 mice were fed either a standard chow or a high-fat (HF) diet for 16 weeks. At the 8th week, HF-fed animals were divided into sedentary (HF), enalapril treatment (HF-E), exercise training (HF-T), and enalapril treatment plus exercise training (HF-ET) groups. Following the experimental protocol, body mass gain, adiposity index, insulin resistance, visceral WAT morphometry, renin-angiotensin system, and bradykinin receptors were evaluated.. The HF group displayed increased adiposity, larger visceral fat mass, and adipocyte hypertrophy, which was accompanied by insulin resistance, overactivation of Ang II/AT1R arm, and favoring of B1R in bradykinin receptors profile. All interventions ameliorated visceral adiposity and related outcomes by favoring the Ang 1-7/MasR arm and the B2R expression in B1R/B2R ratio. However, combined therapy additively reduced Ang II/Ang 1-7 ratio.. Our results suggest that Ang 1-7/MasR arm and B2R activation might be relevant targets in the treatment of visceral obesity.

Topics: Adipose Tissue, White; Adiposity; Animals; Diet, High-Fat; Enalapril; Insulin; Insulin Resistance; Intra-Abdominal Fat; Male; Mice; Mice, Inbred C57BL; Obesity; Obesity, Abdominal; Physical Conditioning, Animal; Receptors, Bradykinin; Renin-Angiotensin System

This study investigated whether regulation of the renin-angiotensin system (RAS) by enalapril and/or aerobic exercise training (AET) causes browning of the subcutaneous white adipose tissue (sWAT). C57BL/6 mice were fed either a standard chow or a high-fat (HF) diet for 16 weeks. At Week 8, HF-fed animals were divided into sedentary (HF), enalapril (HF-E), AET (HF-T), and enalapril plus AET (HF-ET) groups. Subsequently, sWAT was extracted for morphometry, determination of RAS expression, and biomarkers of WAT browning. The HF group displayed adipocyte hypertrophy and induction of the classical RAS axis. Conversely, all interventions reduced adiposity and induced the counterregulatory RAS axis. However, only AET raised plasma irisin, increased peroxisome proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 levels, and the expression of PR-domain containing 16 in sWAT. Therefore, we concluded that AET-induced sWAT browning was independent of the counterregulatory axis shifting of RAS in HF diet-induced obesity.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Biomarkers; Diet, High-Fat; Enalapril; Male; Mice; Mice, Inbred C57BL; Obesity; Physical Conditioning, Animal; Renin-Angiotensin System; Running; Subcutaneous Fat

The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.. We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome-the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.. RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA. These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fatty Liver; Glucose Tolerance Test; Hypertension; Insulin Resistance; Kidney Glomerulus; Liver Cirrhosis; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Rats; Rats, Zucker

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

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

We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Obesity Agents; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Enalapril; Fish Oils; Hypoglycemic Agents; Male; Neuralgia; Non-alcoholic Fatty Liver Disease; Obesity; Rats, Sprague-Dawley; Streptozocin; Weight Loss

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

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

We gave perindopril (10 mg/day) for 24 weeks to 30 patients with arterial hypertension and obesity and proved its ability to effectively lower arterial pressure, exert cardio-, angio-, and nephro-protection, improve parameters of lipid, carbohydrate and purine metabolisms in these patients. Moreover perindopril in these patients diminished manifestations of insulin resistance, hyperleptinemia, and inflammation; it also exerted pronounced positive effect on anthropometric parameters and percent of fat deposits. Basing on the aggregate of clinical and pharmacodynamics effects perindopril can be considered the drug of choice for treatment of arterial hypertension at the background of obesity.

Topics: Adipose Tissue; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Body Mass Index; Drug Monitoring; Enalapril; Female; Heart Function Tests; Humans; Hypertension; Insulin Resistance; Kidney Function Tests; Male; Metabolism; Middle Aged; Obesity; Perindopril; Protective Agents; Therapeutic Equivalency; Treatment Outcome

Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Leptin; Male; Mice; Mice, Obese; Mice, Transgenic; Obesity; Peptidyl-Dipeptidase A; Renin-Angiotensin System; RNA, Messenger

Obese Zucker rats, animal model for the metabolic syndrome, develop a diabetes-like neuropathy that is independent of hyperglycemia. The purpose of this study was to determine whether drugs used to treat cardiovascular dysfunction in metabolic syndrome also protect nerve function.. Obese Zucker rats at 20 weeks of age were treated for 12 weeks with enalapril or rosuvastatin. Lean rats were used as controls. Vasodilation in epineurial arterioles was measured by videomicroscopy. Endoneurial blood flow (EBF) was measured by hydrogen clearance and nerve conduction velocity was measured following electrical stimulation of motor or sensory nerves.. Enalapril treatment decreased serum angiotensin-converting enzyme (ACE) activity and both drugs reduced serum cholesterol levels. In obese Zucker rats at 32 weeks of age superoxide levels were elevated in the aortas and epineurial arterioles, which were reduced by treatment with either drug. Nitrotyrosine levels were increased in epineurial arterioles and reduced with enalapril treatment. EBF was decreased and corrected by treatment with either drug. Motor nerve conduction velocity was decreased and significantly improved with enalapril treatment. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and this was significantly improved with either treatment. Treatment with either enalapril or rosuvastatin significantly reversed the decrease in acetylcholine-mediated vascular relaxation of epineurial arterioles in obese Zucker rats.. Even though obese Zucker rats have normal glycemia vascular and neural dysfunctions develop with age and can be improved by treatment with either enalapril or rosuvastatin.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Cardiovascular System; Disease Models, Animal; Enalapril; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Metabolic Syndrome; Motor Neurons; Neural Conduction; Neurons, Afferent; Nociceptors; Obesity; Peripheral Nerves; Pyrimidines; Rats; Rats, Zucker; Rosuvastatin Calcium; Sciatic Nerve; Sulfonamides; Superoxides; Tyrosine; Vasodilator Agents

Epidemiological studies have proven that obesity is a significant risk factor for type 2 diabetes. Long-term progression of diabetes leads to various microvascular complications, of which diabetic nephropathy has become of increasing importance, and is the main cause of end-stage renal failure in occidental countries. Microalbuminuria is the first marker of incipient diabetic nephropathy, an early stage glomerulopathy which can progress to renal failure and which historically has been treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists. We report a severely obese diabetic patient on treatment for diabetic nephropathy with ACE-inhibitors and poor results, which resolved after Roux-en-Y gastric bypass.

Topics: Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Comorbidity; Diabetic Nephropathies; Enalapril; Female; Gastric Bypass; Humans; Middle Aged; Obesity; Postoperative Period; Treatment Failure

This study was conducted to evaluate the mechanisms of weight loss-induced blood pressure (BP) reduction focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels, and to delineate the additional influence of antihypertensive drug therapy. Each of five groups of obese hypertensives were treated with the long-acting calcium channel blocker (CCB) amlodipine, the angiotensin converting enzyme (ACE) inhibitor enalapril with or without a weight reduction program, or a weight reduction program alone. The goal BP was less than 140/90 mm Hg for the pharmacologic treatment groups. The weight reduction program groups with or without pharmacologic treatment were divided into two groups; weight loss groups who succeeded in weight reduction (> or = 10%) and nonweight loss groups who failed in weight reduction (<10%) in the first 6 months. The final dose of CCB and ACE inhibitor were less in the combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups or in the pharmacologic and nonweight loss groups. In the weight reduction groups regardless of pharmacologic treatment, the percent reductions from baseline in plasma insulin, leptin, and norepinephrine (NE) were greater in the weight loss groups (> or = 10%) than in the nonweight loss groups (<10%). The reductions in plasma NE, insulin, and leptin were significantly greater and earlier in combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups. In ACE inhibitor groups, the reductions in plasma NE, in insulin, and especially in leptin were greater than the other groups. In the CCB alone group, reductions in insulin and leptin occurred, but there was no change in plasma NE. Reductions in insulin and leptin in CCB groups were less and occurred later than in the ACE inhibitor groups or the weight reduction alone group. These results show that weight loss associated with favorable metabolic improvements and these improvements are amplified when combined with pharmacologic treatment. Therefore, weight loss should be regarded as an essential component of any treatment program for obesity-related hypertension. A novel finding from this study is that ACE inhibition had a striking effect to lower plasma leptin. Suppression of sympathetic activity, insulinemia, and leptinemia appeared to play a role in the BP reduction accompanying weight loss.

Topics: Adult; Amlodipine; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Combined Modality Therapy; Enalapril; Humans; Hypertension; Male; Middle Aged; Obesity; Sympathetic Nervous System; Weight Loss

A 50-year-old very obese man had suffered from hypertension for more than 20 years and had undergone various treatment regimens, the last being with an ACE inhibitor. Since his hypertension had nevertheless increased, and he developed dizziness and headaches, a combination of ACE-inhibitor and calcium antagonist was now tried, followed--when this treatment proved unsuccessful--by the fixed-combination preparation containing enalapril plus hydrochlorothiazide. This at last led to a reduction in his blood pressure to approaching normal values, and his subjective symptoms cleared up.

Topics: Drug Combinations; Enalapril; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Obesity

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

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

Hypertension in obese patients is associated with hyperinsulinemia and salt sensitivity. Very low salt diets may exacerbate hyperinsulinemia, perhaps by activating the renin-angiotensin system. Therefore, the effects of a low salt diet alone and with enalapril on blood pressure and the insulin response to an oral glucose tolerance test were studied in 9 obese (body mass index 35 +/- 2 kg/m2) men with mild hypertension. Measurements were first obtained after a 2-week high-salt (20 mEq/day sodium diet+eleven 1 g salt tablets per day) baseline period. The same measurements were repeated after 2 weeks on a low salt diet (20 mEq/day) and after 2 weeks on low salt diet with enalapril in random sequence. The insulin area under the curve increased from 12.8 +/- 3.0 mU-min/dl during high salt to 16.6 +/- 3.2 mU-min/dl (p < 0.001). Plasma renin activity also increased with salt restriction from 1.4 +/- 0.2 to 3.0 +/- 0.5 ng/ml/hour, p = 0.01. With addition of enalapril to the low sodium chloride diet, the insulin area under the curve (14.5 +/- 2.6 mU-min/dl) was not significantly different from that during the high sodium chloride phase. Mean blood pressure in the laboratory was 105 +/- 1 mm Hg with high salt versus 99 +/- 1 mm Hg with low salt, p < 0.05. Addition of enalapril to the low-salt diet reduced mean blood pressure to 87 +/- 1 mm Hg (p < 0.01 vs low salt), largely by reducing total systemic resistance (p < 0.05). Salt restriction decreases laboratory BP while raising insulin levels in obese men with mild hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Diet, Sodium-Restricted; Enalapril; Humans; Hyperinsulinism; Hypertension; Insulin; Male; Obesity; Renin; Sodium, Dietary

Angiotensin-converting enzyme inhibitors may ameliorate experimental glomerular injury by either hemodynamic or nonhemodynamic mechanisms. In a long-term study, we examined the effects of 30 wk of enalapril treatment on the development of glomerular disease in obese Zucker rats (OZR). Enalapril significantly (P less than 0.05) lowered blood pressure, fasting serum cholesterol, and urine albumin excretion in OZR throughout the experimental period. At 38 wk of age, enalapril-treated OZR had a sixfold reduction in the percent glomeruli exhibiting focal glomerulosclerosis and a 20-30% reduction in kidney weight and glomerular area. A separate micropuncture study in 22- to 26-wk-old rats revealed that untreated OZR with albuminuria and increased blood pressure had elevated glomerular capillary pressure (Pgc). Enalapril-treated OZR had less albuminuria and lower blood pressure, but Pgc was not reduced. The value of the transcapillary hydraulic pressure difference (delta P) in enalapril-treated OZR was intermediate between values in untreated OZR and lean Zucker rats. Thus enalapril markedly attenuated the development of glomerular injury in OZR. The salutary effects of enalapril may have involved a reduction in delta P coupled to a nonhemodynamic action, possibly restriction of glomerular growth or lowering of serum cholesterol.

Topics: Albuminuria; Animals; Enalapril; Glomerulosclerosis, Focal Segmental; Hemodynamics; Kidney; Kidney Glomerulus; Longitudinal Studies; Obesity; Punctures; Rats; Rats, Zucker

The treatment of arterial hypertension in diabetic patients still raises numerous problems. In this type of patients, the most commonly prescribed drugs (beta-blockers, diuretics, antihypertensive agents acting on the central nervous system) have troublesome and potentially detrimental effects (e.g. effects on lipids). The new categories of antihypertensive drugs recently introduced (angiotensin-converting enzyme inhibitors, calcium antagonists) are likely to be most useful in these patients. In an open trial in non-insulin-dependent diabetics with arterial hypertension followed-up for 1 year, enalapril administered alone has proved effective and devoid of clinical and biochemical side-effects. If these results are confirmed, angiotensin-converting enzyme inhibitors will rank high as first-choice treatment of arterial hypertension in diabetics.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Captopril; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Enalapril; Humans; Hypertension; Obesity; Vasodilator Agents