enalapril and Insulin-Resistance

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

Favorable effects of angiotensin-converting enzyme (ACE) inhibitor treatment on the incidence of cardiovascular and cerebrovascular mortality and morbidity are not limited to patients with elevated blood pressure. As suggested by our previous results, the physicochemical and pharmacokinetic differences between drugs may markedly contribute to the strength of pleiotropic effects of ACE inhibitors.. The present study was aimed at comparing the effects of serum- and tissue-type ACE inhibitors on monocyte release of proinflammatory cytokines in normotensive patients with stable coronary artery disease. The participants were randomized to 90-day treatment with enalapril (20 mg daily, n = 29), perindopril (4 mg daily, n = 27) or placebo (n = 28). Plasma levels of lipids, glucose, insulin and high sensitivity C-reactive protein (hsCRP), as well as monocyte release of proinflammatory cytokines were determined before and after 30 days of therapy, and at the end of the treatment.. Lipopolysaccharide-stimulated monocytes from normotensive patients with stable coronary artery disease released significantly more TNF-α, interleukin-1β and monocyte chemoattractant protein-1 in comparison with monocytes from 23 matched control subjects. Their baseline hsCRP levels were also higher. Perindopril reversed the disease-induced changes in cytokine release and reduced plasma hsCRP, while the effect of enalapril was much more limited. The effect on both drugs on cytokine release was stronger in insulin-resistant than insulin-sensitive subjects.. Our results indicate that perindopril is superior to enalapril in producing monocyte-suppressing and systemic anti-inflammatory effects in normotensive patients with coronary artery disease. This action may contribute to the clinical effectiveness of tissue ACE inhibitors in the therapy of atherosclerosis-related disorders, particularly in insulin-resistant subjects.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Blood Pressure; Cells, Cultured; Chi-Square Distribution; Coronary Artery Disease; Cytokines; Enalapril; Female; Humans; Inflammation Mediators; Insulin Resistance; Lipids; Male; Middle Aged; Monocytes; Perindopril; Poland; Time Factors; Treatment Outcome

The clinical effectiveness of angiotensin-converting enzyme (ACE) in the prevention and treatment of cardiovascular disorders partially results from its anti-inflammatory action. No previous study has investigated the effect of any ACE inhibitor on lymphocyte cytokine release. In this study, we compared the effects of serum- and tissue-type angiotensin-converting enzyme inhibitors on systemic inflammation and lymphocyte secretory function in normotensive patients with stable coronary artery disease. The study included 134 patients with coronary artery disease who were randomized into one of three groups and treated with enalapril (20 mg/d, n = 47), perindopril (4 mg/d, n = 45) or placebo (n = 42), respectively. The control group included 40 age-, sex- and weight-matched healthy subjects. The plasma lipid profile, glucose metabolism markers, hsCRP and lymphocyte cytokine release were examined at the beginning of the study and after 30 and 90 days of treatment. Phytohemagglutinin-stimulated T cells released significantly more interleukin-2, interferon-γ and TNFα than the lymphocytes of control subjects. Neither enalapril nor perindopril treatment was associated with any significant changes in blood pressure. Perindopril treatment inhibited lymphocyte cytokine release and systemic inflammation, while the effect of enalapril was insignificant. Perindopril, and, to a lesser extent, enalapril, strongly reduced lymphocyte cytokine release in insulin-resistant but not insulin-sensitive subjects. Our results indicate that perindopril is superior to enalapril in producing lymphocyte-suppressing and systemic anti-inflammatory effects in normotensive coronary artery disease patients. These effects may contribute to a reduction in the vascular risk of this group of patients, particularly in those subjects who are resistant to insulin, when these patients are treated with tissue-type angiotensin-converting enzyme inhibitors.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Case-Control Studies; Coronary Artery Disease; Cytokines; Double-Blind Method; Enalapril; Female; Humans; Insulin Resistance; Lipids; Lymphocytes; Male; Middle Aged; Perindopril; Phytohemagglutinins; Prospective Studies; Time Factors

Angiotensin II and insulin resistance (IR) have clinical implications in the pathophysiology of chronic heart failure (CHF). However, it is still unclear whether the combination of an angiotensin-receptor blocker and angiotensin-converting enzyme inhibitor (ACEI) improves IR in CHF patients who do not receive β-blockers. Thus, the aim of the present study was to evaluate the effects of losartan on glucose metabolism and inflammatory cytokines in CHF patients treated with ACEI but not β-blockers.. The effect of losartan treatment for 16 weeks on IR was analyzed in 16 CHF patients in a randomized crossover trial. Insulin level and homeostasis model IR index (HOMA-IR) decreased significantly (P<0.05), but fasting plasma glucose did not change significantly. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 levels were significantly decreased with losartan (P<0.05). Furthermore, the changes in IL-6 and MCP-1 levels were significantly correlated with the reduction in HOMA-IR (P<0.05), but the change in TNF-α levels was not significantly correlated.. The addition of losartan to ACEI therapy improved IR and decreased inflammatory cytokines in CHF patients who did not receive β-blockers.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Chemokine CCL2; Chronic Disease; Cross-Over Studies; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Humans; Imidazolidines; Inflammation Mediators; Insulin; Insulin Resistance; Interleukin-6; Japan; Lisinopril; Losartan; Male; Middle Aged; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

High-molecular-weight (HMW) adiponectin has important antiatherosclerotic properties.. This study compared circulating HMW adiponectin concentrations and other parameters between patients with coronary artery disease (CAD) and participants without CAD. We investigated whether treatment with statins and either telmisartan or enalapril might affect HMW adiponectin and other parameters in patients with CAD. Finally, adiponectin concentrations were compared after 6 months of treatment between CAD patients with versus without cardiac events.. Consecutive patients with stable CAD admitted to our hospital (Iwate Medical University School of Medicine, Iwate, Japan) for percutaneous coronary intervention (PCI) and stent implantation and with no previous treatment with renin-angiotensin system blockers or statins were recruited. Patients with CAD who met all eligibility criteria were randomly assigned using computer-generated numbers in a 1:1 ratio to receive telmisartan (40 mg/d) or enalapril (5 mg/d) for 6 months. In addition, all patients with CAD were treated with atorvastatin (10 mg/d). The patients without CAD received no treatment with telmisartan, enalapril, or atorvastatin. Plasma concentrations of total and HMW adiponectin were measured using a highly sensitive ELISA system before PCI or drug treatment (ie, baseline) and after 6 months of treatment. In addition, high-sensitivity C-reactive protein (hs-CRP) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. To evaluate cardiac events, follow-up coronary angiography was performed at least 6 months after PCI.. This study included 70 patients with stable CAD (mean [SD] age, 65.8 [10.9] years; male/female ratio, 55/15) and 25 participants with normal results on coronary angiography (non-CAD) (mean age, 63.5 [11.2] years; male/female ratio, 20/5). Baseline concentrations (mean [SD]) of HMW adiponectin were significantly lower in the CAD group than in the non-CAD group (2.0 [0.3] vs 9.2 [0.5] microg/mL; P < 0.01). The ratio of HMW to total adiponectin was also lower in the CAD group than in the non-CAD group (0.37 [0.02] vs 0.53 [0.02]; P < 0.01). Baseline concentrations of HMW adiponectin were negatively correlated with hs-CRP (r = -0.60) and HOMA-IR (r = -0.30) in patients with CAD. After 6 months of treatment, the telmisartan group showed significantly increased HMW adiponectin concentrations and HMW/total adiponectin ratio (HMW, 3.7 [0.7] vs 2.1 [0.5] microg/mL; P < 0.01 vs baseline; HMW/total, 0.44 [0.02] vs 0.39 [0.02]; P < 0.05 vs baseline), whereas HOMA-IR was significantly decreased (2.86 [1.93] vs 3.39 [1.77]; P < 0.05 vs baseline). HOMA-IR at follow-up was significantly lower in the telmisartan group than in the enalapril group (2.86 [1.93] vs 3.64 [1.45]; P < 0.05). In contrast, treatment with enalapril was not associated with any significant changes in total or HMW adiponectin concentrations, HMW/total adiponectin ratio, or HOMA-IR. Both the telmisartan and the enalapril groups showed significant decreases in hs-CRP after 6 months (P < 0.05 vs baseline). After 6 months of treatment with either telmisartan or enalapril, HMW adiponectin concentrations were 0.7 (0.2) microg/mL with cardiac events versus 3.2 (0.4) microg/mL without (P < 0.05); HMW/total concentrations were 0.25 (0.03) with cardiac events versus 0.43 (0.01) without (P < 0.01). In contrast, hs-CRP concentrations were higher in patients with cardiac events than in those without cardiac events (2.42 [0.52] vs 1.86 [0.45] log10 microg/dL; P < 0.01).. This study found that treatment with telmisartan and statins (but not enalapril and statins) was associated with a significant increase in HMW adiponectin concentrations and a decrease in insulin resistance in these patients with CAD.

Topics: Adiponectin; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; C-Reactive Protein; Coronary Angiography; Coronary Artery Disease; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Humans; Insulin Resistance; Male; Molecular Weight; Prospective Studies; Telmisartan

Genetic factors play an important role in linking insulin resistance and hypertension, also influencing insulin sensitivity changes during antihypertensive treatment. This study was aimed to evaluate whether genetic predisposition to hypertension can also influence left ventricular (LV) changes during antihypertensive treatment.. We enrolled 36 never-treated hypertensives: 18 with both parents hypertensive (F+) and 18 with both parents normotensive (F-), matched for age, gender, and body mass index (BMI). The patients were evaluated twice, before and after 2.5 years of treatment with enalapril. At both evaluations the patients underwent: 24-h blood pressure (BP) monitoring, LV echocardiogram, and oral glucose tolerance test, with measurements of glucose and insulin levels.. At basal evaluation the two groups were not different with regard to gender, age, BMI, 24-h BP, and fasting glucose; glucose metabolic clearance rate was significantly lower in F+. The LV mass index was similar between the groups, whereas diastolic parameters were significantly lower in F+. At second evaluation, 24-h BP and LV mass were decreased to the same extent in both groups; glucose metabolic clearance rate significantly increased in F- and remained unchanged in F+. The improvement of LV diastolic function, found in both group, was significantly greater in F-.. Genetic predisposition to hypertension, in addition to affecting insulin sensitivity, influences LV functional changes during antihypertensive treatment. Despite a similar extent of 24-h BP and LV mass decrease, F+ patients showed no changes in insulin sensitivity and a smaller improvement in LV diastolic function than F-.

Topics: Adult; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cardiomegaly; Electrocardiography; Enalapril; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Heart Rate; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Ventricular Dysfunction, Left

Adiponectin is an adipose tissue-specific protein with antiatherogenic and insulin-sensitizing properties. In patients with essential hypertension, plasma adiponectin concentrations are lower than in healthy subjects. Antihypertensive drugs do not uniformly influence components of the metabolic syndrome. Therefore, the aim of this study was to evaluate the influence of 6 months' monotherapy with different antihypertensive drugs on plasma adiponectin concentration in essential hypertension patients.. Forty essential hypertension patients were randomized to receive enalapril, metoprolol, amlodipine or indapamide. Plasma concentrations of adiponectin, insulin, glucose and body fat content were estimated twice: before and after 6 months of antihypertensive monotherapy.. Plasma adiponectin concentration did not change significantly after enalapril (11.5 +/- 4.8 vs. 11.1 +/- 4.1 mg/l), metoprolol (10.2 +/- 4.2 vs. 9.8 +/- 4.5 mg/l), and amlodipine (9.0 +/- 6.0 vs. 8.5 +/- 5.4 mg/l) treatment. However, a significant decrease of plasma adiponectin concentration (from 11.6 +/- 4.6 to 10.2 +/- 4.2 mg/l, p = 0.047) was observed in patients treated with indapamide. Additionally in these patients, a significant increase of the HOMA-IR index was found (p = 0.021).. Treatment with indapamide was followed by a significant decrease of plasma adiponectin concentration. This may participate in the pathogenesis of carbohydrate metabolism disturbances often found in patients treated with thiazide-type diuretics.

Topics: Adiponectin; Adult; Amlodipine; Antihypertensive Agents; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension, Renal; Indapamide; Insulin Resistance; Lipids; Male; Metoprolol; Middle Aged

To compare the effects of a cardioselective beta-blocker (nebivolol) with those of an angiotensin-converting enzyme inhibitor (enalapril) on parameters of insulin sensitivity, peripheral blood flow and arterial stiffness during one extended glucose clamp experiment.. A randomized, double-blind crossover trial, consisting of two 12-week treatment phases separated by a 4-week wash-out phase.. Patients with type 2 diabetes and arterial hypertension were randomly assigned to one of two treatment sequences (nebivolol-enalapril, enalapril-nebivolol). Haemodynamic, metabolic and other laboratory measurements were carried out on the first and last day of each treatment period by means of a glucose clamp experiment that also involved the measurement of blood flow and arterial stiffness.. Twelve patients were included in this study, of which two dropped out early. Efficacy parameters were therefore available for 10 patients. There was no significant difference in any of the primary efficacy parameters. Moreover, the effects on blood pressure did not significantly differ between both treatments. Six adverse events happened during treatment with nebivolol compared with two during treatment with enalapril, but only one was regarded as possibly related to the treatment.. This pilot study shows that the combined measurement of insulin sensitivity, blood flow and arterial stiffness is feasible. Nebivolol and enalapril did not show different effects with regard to these parameters in hypertensive diabetic patients. If these results are confirmed in larger clinical trials, this would argue against the reservations against beta-blockers as drugs of first choice in patients with diabetes because of potential metabolic side-effects.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Arteries; Benzopyrans; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Elasticity; Enalapril; Ethanolamines; Female; Glucose Clamp Technique; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Nebivolol; Pilot Projects; Plethysmography; Pulsatile Flow

Evidence suggests an association between insulin resistance, hypertension and impaired endothelial function. Studies have shown that insulin resistance precedes the development of hypertension. By improving insulin sensitivity, it may be possible to improve hypertension and the subsequent damage to vessel walls. Some data indicates beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on insulin sensitivity and endothelial function. We aimed to investigate these effects of ACE inhibition in the same group of patients with essential hypertension.. Nine non-smoking, untreated hypertensive patients (38.3+9 years, 4/5 male/female) and 12 age-matched healthy subjects (35.2+6.7 years, 5/7 male/female) were included in the study. Hypertensive patients were given enalapril maleate (5 40 mg/day) for six months. The following parameters were studied at baseline and at the end of treatment period. Whole body insulin sensitivity was measured by a formula derived from an oral glucose tolerance test and named as the insulin sensitivity index (ISI). Insulin was measured by chemiluminescence and glucose by a glucose oxidase method. Endothelial function was evaluated as flow-mediated dilatation (FMD) of the brachial artery by ultrasonography and expressed as a percentage change relative to baseline diameter. Endothelial- independent vasodilatation was measured after sublingual nitroglycerine.. FMD was impaired in the hypertensive group compared with healthy subjects (7.3+3.1% vs. 15.3+4.8%, p<0.0005), and ISI values were 1.18+0.6 vs. 4.4+0.9 (p<0.0001) respectively. Both insulin sensitivity and FMD improved after the treatment period compared with baseline values, FMD increased from 7.3+3.1% to 16.0+2.9% (p<0.0005) and ISI from 1.18+0.6 to 4.2+1.0 (p<0.0001). FMD and ISI showed a significant positive correlation (r=0.67, p<0.001) in the hypertensive group.. Patients with essential hypertension have impaired endothelial function and decreased whole body insulin sensitivity compared with healthy subjects. Treatment for six months with enalapril maleate seems to improve both FMD and ISI. This study confirms the beneficial effects of ACE inhibition on both endothelial function and insulin sensitivity tested in the same group of essential hypertensive patients. The mechanism of these favourable effects of ACE inhibition needs to be clarified.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Vasodilation

Disturbed endothelial function is closely associated with hyperinsulinaemia and insulin resistance in essential hypertension. The aims of this study were: 1) to evaluate whether the two alternative drugs, angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II (Ang II) antagonists, had comparable effects on glucose metabolism and endothelial function. 2) to determine whether they improve endothelial dysfunction through modulating insulin resistance and oxidative stress.. Essential hypertensive patients were randomised into two groups: Twelve (nine patients in final analysis) patients were given enalapril (enalapril group), and twelve (nine patients in final analysis) were given losartan (losartan group). Twelve sex- and age-matched normotensive volunteers were included as controls. Before and after six months of treatment, endothelial function, insulin sensitivity and lipid peroxidation (TBARs) and NO metabolites (NOx) were evaluated.. Endothelial function, measured as flow mediated dilatation (FMD), was improved in both of the treatment groups (p=0.0001). Calculated insulin sensitivity index also improved in the enalapril-treated group (p=0.05) but not in the losartan-treated group, compared with baseline levels. TBARS values decreased significantly in the enalapril group compared with baseline levels (p<0.001). FMD was positively correlated with insulin sensitivity index (r=0.32, p<0.05) and NOx levels (r=0.39, p=0.01) and negatively correlated with TBARS levels (r=-0.53, p=0.0002) in hypertensive patients.. Inhibition of the renin-angiotensin system, either with ACE inhibitors or AT(1)-receptor blockers improves endothelial dysfunction. ACE inhibition has prominent effects on improving insulin sensitivity and decreasing oxidative stress in essential hypertensive patients.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Insulin Resistance; Losartan; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Vasodilation

This study compares the effects of a calcium channel blocker (amlodipine) and an angiotensin converting enzyme inhibitor (enalapril) on in vivo insulin sensitivity in patients with essential hypertension. Forty-six patients with mild and moderate hypertension were studied. After a 2-week single-blind placebo phase, they were randomly assigned to double-blind therapy with either amlodipine (2.5 to 10 mg/day) or enalapril (5 to 40 mg/day) for 16 weeks. Both groups were comparable in terms of demographic characteristics, degree of obesity, metabolic parameters, and arterial blood pressure. Insulin sensitivity was measured at baseline and at week 16 during the active phase using euglycemic hyperinsulinemic clamps. Arterial blood pressure decreased similarly in both groups. Whole body glucose uptake (M-value) increased with amlodipine from 3.63 +/- 0.32 (mean +/- SEM) to 3.97 +/- 0.31 mg/kg/min (P = .02). A similar tendency was observed with enalapril: from 3.59 +/- 0.32 to 3.94 +/- 0.30 mg/kg/min (P = .09). A trend to lower steady-state insulin level during the second clamp (compared to baseline) was observed in both groups. The clamp-derived insulin sensitivity index (that corrects for steady-state insulin levels and glucose levels during the clamp) increased similarly in both groups: from 1.15 +/- 0.11 to 1.39 +/- 0.13 with amlodipine (P = .03) and from 1.25 +/- 0.13 to 1.49 +/- 0.16 with enalapril (P = .01). LDL cholesterol decreased with amlodipine (mean change, -11.3 mg/dL, P = .004). Amlodipine and enalapril were associated with increments in insulin sensitivity. Amlodipine provided an additional benefit with decreased low density lipoprotein cholesterol levels.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Calcium Channel Blockers; Cholesterol; Double-Blind Method; Enalapril; Female; Hemodynamics; Humans; Hypertension; Insulin Resistance; Male; Middle Aged

There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial.. To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers.. Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp.. No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study.. Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Captopril; Cross-Over Studies; Diabetes Mellitus, Type 2; Enalapril; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipoproteins; Male; Middle Aged; Single-Blind Method; Time Factors

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

Hypertension is one of the most important accelerating factors for progression of nephropathies. Its prevalence is about 35% in patients with nephropathies, even in minor or medium severe functional impairment. This is evidence that it is essential to select an optimal therapeutic regimen as soon as possible. A group of 38 patients (14 hypertensive patients) with a minor or medium severe functional impairment were included in a controlled trial. The patients were served a low-protein diet--0.6-0.7 g/kg/day and 2-10mg enalapril/day divided into two doses. The amount of enalapril depended on the blood pressure and enalapril was given also to normotensive patients. The investigation lasted 8 months. In the course of 8 months the authors did not reveal progression of the renal disease, as apparent from results of assessment of the creatinine level and clearance, assessment of uric acid and urea. The authors did not find deterioration of metabolic acidosis, nor of nephrogenic anaemia. Hypertensive patients had a tendency to deteriorating of insulin sensitivity while in normotensive patients a decline of triacylglycerols, VLDL and rise of HDL was recorded. The total cholesterol and LDL cholesterol level did not change. The authors conclude that the combination of a low-protein diet with ACEI in hypertensive and normotensive patients with mild to medium severe functional disorders inhibits the progression of nephropathies, but in hypertensive patients it does not prevent deterioration of insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Female; Glucose Tolerance Test; Humans; Hypertension, Renal; Insulin Resistance; Male; Middle Aged

In a previous open study on the metabolic effects of doxazosin in patients with essential hypertension, subgroup analysis indicated that subjects with an accumulation of risk factors for coronary heart disease (high VLDL triglycerides, low HDL cholesterol and high fasting blood glucose) seemed to benefit most from the metabolic actions of doxazosin treatment. Those results formed the basis of this double-blind, parallel-group study undertaken to elucidate the metabolic effects of 6 months of doxazosin and enalapril treatment in patients with both essential hypertension and hypertriglyceridemia. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method. Hemodynamic evaluation included measurements of office and ambulatory blood pressure and ultrasonic measurements of femoral artery blood flow. Both drugs significantly reduced both office BP and 24-h ambulatory BP. Office systolic BP was significantly better reduced by enalapril. Doxazosin, in contrast to enalapril, significantly increased insulin sensitivity (by 21%, P = .02). It also reduced serum-triglycerides (by 23%, P = .01), VLDL triglycerides (by 30%, P = .008) and VLDL cholesterol (by 24%, P = .02). This lipid-lowering effect of doxazosin was accompanied by an increase in both plasma lipoprotein lipase activity and the elimination rate of an intravenous fat emulsion load. Neither treatment significantly increased femoral artery blood flow. It is speculated that without measurably increasing blood flow in conduit vessels such as the femoral artery, doxazosin, by capillary recruitment, may prolong the transit time for the blood over the muscle bed, which could explain the increased glucose disposal and increased lipoprotein lipase activity.

Topics: Adult; Aged; Antihypertensive Agents; Body Mass Index; Double-Blind Method; Doxazosin; Enalapril; Female; Glucose; Hemodynamics; Humans; Hypertension; Hypertriglyceridemia; Insulin Resistance; Leg; Male; Middle Aged

The effect of 20 mg of enalapril with and without 12.5 mg of hydrochlorothiazide on glucose metabolism insulin sensitivity and lipids was evaluated in hypertensive non-insulin-dependent diabetes. Ten mild to moderate hypertensive patients with non-insulin-dependent diabetes mellitus were treated for 8 weeks with 20 mg enalapril once a day, and then divided into two groups of 5 patients each for a second 8 weeks of treatment with enalapril alone or in combination with hydrochlorothiazide, 12.5 mg once a day. Blood pressure, fasting plasma glucose, lipids and insulin, glycosylated hemoglobin, and insulin sensitivity were measured at baseline and after 8 and 16 weeks. Results were analyzed by the ANOVA test for repeated measures and all values are given as mean +/- SD. Diastolic blood pressure decreased significantly after the first and second period of enalapril and after the combination of enalapril and hydrochlorothiazide. Glycosylated hemoglobin dropped significantly after the first and second period of enalapril monotherapy. Plasma triglycerides and fasting plasma insulin decreased significantly after the 16 weeks of enalapril. Insulin-mediated glucose uptake increased significantly after 8 and 16 weeks of monotherapy with enalapril. No significant difference was observed in any of the metabolic characteristics, including insulin sensitivity, between the values after 8 weeks of enalapril alone and the final values of the enalapril-treated and the enalapril/hydrochlorothiazide-treated groups. It is concluded that enalapril improves some of the metabolic parameters, including insulin sensitivity, of hypertensive diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Enalapril; Female; Glycated Hemoglobin; Humans; Hydrochlorothiazide; Hypertension; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Triglycerides

A double-blind, placebo-controlled, 4-week trial was performed to determine the antihypertensive and metabolic effects of enalapril (20 to 40 mg/d) in 16 hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM) aged 55 +/- 2 years and with a body mass index of 29 +/- 1 kg/m2. Glucose utilization was determined after an overnight fast and during insulin stimulation at 0 and 4 weeks (methods: euglycemic clamp, [3-3H]glucose infusion, indirect calorimetry). Enalapril decreased systolic (166 +/- 4 v 152 +/- 5 mm Hg, P < .05) and diastolic (102 +/- 2 v 95 +/- 2 mm Hg, P < .05) blood pressure. Peripheral insulin sensitivity, ie, insulin stimulation of glucose utilization, increased approximately 30%, or by 4.3 +/- 1.7 mumol/kg.min (13.1 +/- 2.0 v 17.4 +/- 3.5 mumol/kg.min, P < .05, 0 v 4 weeks) during enalapril treatment, but remained unchanged during placebo treatment (15.4 +/- 2.8 v 15.3 +/- 2.7 mumol/kg.min, respectively). The increase in glucose utilization during enalapril treatment was fully explained by an increase of 4.1 +/- 1.7 mumol/kg.min in glucose storage (4.1 +/- 1.2 v 8.1 +/- 2.9 mumol/kg.min, P < .05) while glucose oxidation remained unchanged. High-density lipoprotein (HDL) cholesterol increased by 8% (P < .05) and hemoglobin A1c (HbA1c) improved slightly (7.7% +/- 0.7% v 7.3% +/- 0.7%, P < .05) in the enalapril group, but not in the placebo group. We conclude that enalapril improves insulin sensitivity by increasing glucose storage in hypertensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Glucose; Humans; Hypertension; Insulin Resistance; Lipids; Male; Middle Aged; Peptidyl-Dipeptidase A

Captopril has been shown to improve insulin sensitivity in insulin resistant hypertensive individuals and enalapril has been shown to improve insulin sensitivity in a small group of healthy volunteers, but there has been no direct comparison of the effects of the different angiotensin converting enzyme inhibitors (ACEIs) on insulin sensitivity in either insulin sensitive or insulin insensitive populations.. To compare the impact of two different ACEIs (captopril and enalapril) on insulin mediated glucose uptake in normotensive, non-obese, insulin sensitive subjects.. A single blind cross-over study comparing captopril (6.25 mg twice daily) and enalapril (5 mg once daily) for 28 days with a 28 day washout period between drugs. Insulin mediated glucose uptake was measured by means of the euglycaemic hyperinsulinaemic clamp at the start and completion of each period of drug therapy.. Both drugs resulted in elevations of fasting insulin levels (mean difference +/- SEM for combined data, 2.7 +/- 1.8; p < 0.05) and a reduction in insulin mediated glucose uptake (mean difference for combined data, -0.72 +/- 0.37 mg/kg-1 minute-1; p = 0.056). Results were similar for both agents and suggest a class effect.. The increase in fasting insulin levels, and reduction in insulin mediated glucose uptake in this study are in contrast to findings in obese and hypertensive subjects, and indicate that studies of insulin sensitivity of ACEIs in non-obese, normotensive subjects are inappropriate for predicting likely effects in clinical practice.

Topics: Adult; Captopril; Enalapril; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Single-Blind Method

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

Obesity is a chronic disease caused multiple associated factors that results in excessive body fat accumulation. The Renin-Angiotensin System (RAS) unbalance is now recognized as a key factor on regulating body energy and metabolism.. The aim of the present study was to evaluate the Enalapril (ACE inhibitor) effects on the metabolic function and hepatic steatosis of obese mice evaluating Angiotensin Converting Enzymes (ACEs) expression.. The experiment was performed using 32 male Swiss mice (8 weeks old) equally and randomly divided into 4 groups (n = 8): standard diet (ST), standard diet plus Enalapril (ST + ENAL), hyperlipidic diet (HF) and hyperlipidic diet plus Enalapril (HF + ENAL). Weekly measurements of animal weight and feed consumption were performed. At the end of treatment period a glucose tolerance test (GTT) and insulin sensitivity test (IST) were performed. Ultrasonography was used to evaluate hepatic and epididymal fat pad. Liver samples were submitted to HE histology and gene expression analyses were performed using Real-Time PCR.. The main results showed a decrease in body weight after treatment with Enalapril, as well as a reduced size of epididymal fat pad (EFP). Hepatic echogenicity and steatosis measurement were lower in the obese groups treated with Enalapril also modulating ACE2/ACE expressions.. Enalapril use improved metabolism reducing hepatic steatosis, decreasing ACE expression and increasing ACE2 expression.

Topics: Animals; Blood Glucose; Diet, High-Fat; Enalapril; Insulin Resistance; Liver; Male; Mice; Peptidyl-Dipeptidase A; Renin-Angiotensin System

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

Lipogenesis is a process that involves the fatty acids synthesis. Resveratrol and enalapril have been studied for their beneficial physiological properties on the glucose and lipid metabolism.. The aim of the present study was to evaluate the oral administration of resveratrol and enalapril effects on glucose and lipid metabolism, evaluating the white pad lipogenesis genes expression in mice.. Swiss male mice were divided into four groups and treated for eight weeks as follows: Standard diet ad libitum (G1); Standard diet + Resveratrol (G2); Standard diet + Enalapril (G3); Standard diet + Resveratrol + Enalapril (G4), where resveratrol was administered with the food and enalapril with the water. Body weight, lipid profile, adiposity, glycemic parameters and epididymal adipocytes area were assessed. The expression levels of FAS, ACC, PPARγ and SREBP-1c were assessed by RT-PCR.. The main findings showed an improvement in the insulin sensitivity and glucose tolerance in the group G2 as compared to G1. Similar results were found for the fasting glucose levels. Decreased triglycerides were observed in the animals treated with resveratrol and enalapril, along with decreased weight of the epididymal adipose tissue in the animals of the G2 group. A mild reduction in the group G4 as compared to the group G1 was observed. Decreased mRNA expression of FAS, ACC and PPARγ in the G4 group when compared to the G1 group were observed.. In conclusion the resveratrol and enalapril association improved the glucose and lipid profiles by modulating the expression of some lipogenesis genes, which are critical regulators of metabolic homeostasis.

Topics: Adipocytes; Adipogenesis; Adipose Tissue, White; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Enalapril; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; Male; Mice; Resveratrol; Stilbenes

Adverse cardiac remodeling after myocardial infarction (MI) leads to progressive heart failure. Obese-insulin resistance increases risks of MI and heart failure. Although dipeptidyl peptidase-4 (DPP4) inhibitor is known to exert cardioprotection, its effects on adverse remodeling after MI in obese-insulin-resistant rats are unclear. We hypothesized that DPP4 inhibitor reduces adverse left ventricular (LV) remodeling and LV dysfunction in obese-insulin-resistant rats with MI. Rats were fed either normal diet (ND) or high-fat diet (HFD) for 12 weeks to induce obese-insulin resistance, followed by left anterior descending coronary artery ligation to induce MI. Then, rats in each dietary group were divided into five subgroups to receive vehicle, enalapril (10mg/kg/day), metformin (30mg/kg/day), DPP4 inhibitor vildagliptin (3mg/kg/day), or combined metformin and vildagliptin for 8 weeks. Heart rate variability (HRV), LV function, pathological and biochemical studies for LV remodeling, and cardiomyocyte apoptosis were determined. Obese-insulin-resistant rats had severe insulin resistance and LV dysfunction. HFD rats had a higher mortality rate than ND rats, and all treatments reduced the mortality rate in obese-insulin-resistant rats. Although all drugs improved insulin resistance, HRV, LV function as well as reduced cardiac hypertrophy and fibrosis, vildagliptin effectively reduced cardiomyocyte cross-sectional areas more than enalapril and was related to markedly decreased ERK1/2 phosphorylation. In ND rats with MI, metformin neither improved LV ejection fraction nor reduced cardiac fibrosis. The infarct size and transforming growth factor-β expression were not different among groups. In obese-insulin-resistant rats with chronic MI, DPP4 inhibitor vildagliptin exerts better cardioprotection than enalapril in attenuating adverse LV remodeling.

Topics: Adamantane; Animals; Cardiotonic Agents; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enalapril; Heart Rate; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Myocardial Infarction; Nitriles; Oxidative Stress; Pyrrolidines; Rats; Rats, Wistar; Ventricular Remodeling; Vildagliptin

The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD).. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test.. All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS).. Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.

Topics: Adipose Tissue; Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Enalapril; Fumarates; Gene Expression Profiling; Gene Expression Regulation; Gluconeogenesis; Insulin Resistance; Leptin; Lipid Metabolism; Losartan; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Renin-Angiotensin System

Metabolism of arachidonic acid by cytochrome P450 (CYP) to biologically active eicosanoids has been recognized increasingly as an integral mediator in the pathogenesis of cardiovascular and metabolic disease. CYP epoxygenase-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET + DHET) and CYP ω-hydroxylase-derived 20-hydroxyeicosatetraenoic acid (20-HETE) exhibit divergent effects in the regulation of vascular tone and inflammation; thus, alterations in the functional balance between these parallel pathways in liver and kidney may contribute to the pathogenesis and progression of metabolic syndrome. However, the impact of metabolic dysfunction on CYP-mediated formation of endogenous eicosanoids has not been well characterized. Therefore, we evaluated CYP epoxygenase (EET + DHET) and ω-hydroxylase (20-HETE) metabolic activity in liver and kidney in apoE(-/-) and wild-type mice fed a high-fat diet, which promoted weight gain and increased plasma insulin levels significantly. Hepatic CYP epoxygenase metabolic activity was significantly suppressed, whereas renal CYP ω-hydroxylase metabolic activity was induced significantly in high-fat diet-fed mice regardless of genotype, resulting in a significantly higher 20-HETE/EET + DHET formation rate ratio in both tissues. Treatment with enalapril, but not metformin or losartan, reversed the suppression of hepatic CYP epoxygenase metabolic activity and induction of renal CYP ω-hydroxylase metabolic activity, thereby restoring the functional balance between the pathways. Collectively, these findings suggest that the kinin-kallikrein system and angiotensin II type 2 receptor are key regulators of hepatic and renal CYP-mediated eicosanoid metabolism in the presence of metabolic syndrome. Future studies delineating the underlying mechanisms and evaluating the therapeutic potential of modulating CYP-derived EETs and 20-HETE in metabolic diseases are warranted.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Diet, High-Fat; Eicosanoids; Enalapril; Gene Expression Regulation, Enzymologic; Hypercholesterolemia; Insulin Resistance; Kidney; Liver; Male; Metabolic Syndrome; Mice; Mice, Knockout; Random Allocation; Renin-Angiotensin System; RNA, Messenger; Severity of Illness Index

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

Spontaneously hypertensive rats are an example of an animal model of genetic hypertension with insulin resistance. The aim of this study was to investigate insulin signaling in the heart and in the skeletal muscle of spontaneously hypertensive rats, as well as to evaluate the effects of renin-angiotensin system blockade.. We investigated eight untreated spontaneously hypertensive rats of 12 weeks of age and eight age-matched normotensive Wistar-Kyoto controls. In addition, eight spontaneously hypertensive rats were treated for 8 weeks with the angiotensin receptor blocker olmesartan, and eight spontaneously hypertensive rats with the angiotensin-converting enzyme inhibitor enalapril. The heart and a skeletal muscle (quadriceps femoris) were promptly dissected and frozen. Insulin signaling was evaluated by Western blot analysis of involved proteins; in addition, microvessel density was indirectly evaluated by immunohistochemistry.. Blood pressure values were normalized by both olmesartan and enalapril. In the heart, no statistically significant difference in the expression of proteins involved in insulin signaling was observed between untreated spontaneously hypertensive rats and Wistar-Kyoto controls. On the contrary, in the skeletal muscle of untreated spontaneously hypertensive rats, we noted a significant reduction of insulin receptors, of insulin-receptor substrate-1, and of phosphorylated-mammalian target of rapamycin. The treatment with olmesartan normalized insulin signaling, including expression of glucose transporter-4, whereas the treatment with enalapril was ineffective for the insulin receptor and less effective than olmesartan on the insulin-receptor substrate-1, phosphorylated-mammalian target of rapamycin and glucose transporter-4. There was a significant reduction in microvessel density in the skeletal muscle of spontaneously hypertensive rats compared with Wistar-Kyoto controls, and this was completely prevented by both olmesartan and enalapril.. These results suggest that changes in insulin signaling occur in the skeletal muscle but not in the heart of untreated spontaneously hypertensive rats. In the skeletal muscle, insulin signaling was restored by olmesartan, whereas enalapril was less effective. Effective antihypertensive treatment with olmesartan or enalapril was associated with prevention of microvascular rarefaction.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Enalapril; Glucose Transporter Type 4; Hypertension; Imidazoles; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Myocardium; Quadriceps Muscle; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Insulin; Renin-Angiotensin System; Signal Transduction; Tetrazoles; Transcription Factors

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Indapamide; Insulin; Insulin Resistance; Male; Middle Aged; Time Factors; Treatment Outcome

Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, may augment metabolic and vascular actions of insulin. Therefore, we investigated effects of EGCG treatment to simultaneously improve cardiovascular and metabolic function in spontaneously hypertensive rats (SHR; model of metabolic syndrome with hypertension, insulin resistance, and overweight). In acute studies, EGCG (1-100 microM) elicited dose-dependent vasodilation in mesenteric vascular beds (MVB) isolated from SHR ex vivo that was inhibitable by N(omega)-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase antagonist) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. In chronic studies, 9-wk-old SHR were treated by gavage for 3 wk with EGCG (200 mg.kg(-1).day(-1)), enalapril (30 mg.kg(-1).day(-1)), or vehicle. A separate group of SHR receiving L-NAME (80 mg/l in drinking water) was treated for 3 wk with either EGCG or vehicle. Vasodilator actions of insulin were significantly improved in MVB from EGCG- or enalapril-treated SHR (when compared with vehicle-treated SHR). Both EGCG and enalapril therapy significantly lowered systolic blood pressure (SBP) in SHR. EGCG therapy of SHR significantly reduced infarct size and improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. In SHR given L-NAME, beneficial effects of EGCG on SBP and I/R were not observed. Both enalapril and EGCG treatment of SHR improved insulin sensitivity and raised plasma adiponectin levels. We conclude that acute actions of EGCG to stimulate production of nitric oxide from endothelium using PI 3-kinase-dependent pathways may explain, in part, beneficial effects of EGCG therapy to simultaneously improve metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the metabolic syndrome.

Topics: Animals; Blood Pressure; Catechin; Enalapril; Endothelium, Vascular; In Vitro Techniques; Insulin Resistance; Male; Mesenteric Veins; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WF; Tea; Vasodilator Agents

Angiotensin-converting enzyme (ACE) inhibitors have been associated with an increased risk of acute pancreatitis. The pathogenesis of this condition remains unclear, but an activation of the kinin system and a resultant localized angioedema have been implicated in the initial step leading to acute pancreatic damage. The goal of the present study was to explore the impact of ACE inhibition on pancreatic microcirculation and capillary permeability in normal and insulin-resistant rats.. Chow- or fructose-fed Sprague-Dawley rats were treated with enalapril (dosage, 10 mg.kg.d) or vehicle for 4 weeks before measuring in vivo the extravasation of Evans blue (EB) dye in pancreas. Unanesthetized animals (n = 10-17 per group) were injected with EB 20 mg.kg in the caudal vein 10 minutes before killing, and EB dye was extracted from each pancreas by using formamide.. Relative to controls, enalapril-treated animals showed a 5-fold increase in pancreatic extravasation of EB in the fructose-fed rat model (P < 0.001); smaller changes (2-fold) were observed in the chow-fed animals treated with enalapril (P < 0.001). The increase in pancreatic vasopermeability observed with enalapril in the fructose-fed animals was accompanied by a significant increase in total pancreatic nitric oxide synthase (NOS) activity compared to controls (Delta = +128%; P < 0.001). This increase in NOS activity seemed to be solely attributable to an upregulation of the endothelial NOS isoform because only the eNOS immunoreactive mass (as opposed to nNOS) seemed to be increased in the pancreas of these animals. Treatment with enalapril was not associated with any increase in serum amylase concentrations in either animal subgroup.. Enalapril increases capillary permeability (extravasation of macromolecules) in the pancreas of the fructose-fed rat model. This suggests that ACE inhibition upregulates the eNOS isoform locally, increases vasopermeability of the pancreas, and can therefore result in local edema in the fructose-fed insulin-resistant rat model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Capillary Permeability; Dietary Carbohydrates; Disease Models, Animal; Enalapril; Evans Blue; Fructose; Indicators and Reagents; Insulin Resistance; Male; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Pancreas; Rats; Rats, Sprague-Dawley

Spontaneously hypertensive rats (SHRs) exhibit endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance may contribute to hypertension by causing imbalanced regulation of endothelial-derived vasodilators (e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1 [ET-1]). Treatment of SHRs with rosiglitazone (insulin sensitizer) and/or enalapril (ACE inhibitor) may simultaneously improve hypertension, insulin resistance, and endothelial dysfunction by rebalancing insulin-stimulated production of vasoactive mediators. When compared with WKY control rats, 12-week-old vehicle-treated SHRs were hypertensive, overweight, and insulin resistant, with elevated fasting levels of insulin and ET-1 and reduced serum adiponectin levels. In mesenteric vascular beds (MVBs) isolated from vehicle-treated SHRs and preconstricted with norepinephrine (NE) ex vivo, vasodilator responses to insulin were significantly impaired, whereas the ability of insulin to oppose vasoconstrictor actions of NE was absent (versus WKY controls). Three-week treatment of SHRs with rosiglitazone and/or enalapril significantly reduced blood pressure, insulin resistance, fasting insulin, and ET-1 levels and increased adiponectin levels to values comparable with those observed in vehicle-treated WKY controls. By restoring phosphatidylinositol 3-kinase-dependent effects, rosiglitazone and/or enalapril therapy of SHRs also significantly improved vasodilator responses to insulin in MVB preconstricted with NE ex vivo. Taken together, our data provide strong support for the existence of reciprocal relationships between endothelial dysfunction and insulin resistance that may be relevant for developing novel therapeutic strategies for the metabolic syndrome.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Enalapril; Hypertension; Insulin; Insulin Resistance; Rats; Rats, Inbred SHR; Reference Values; Rosiglitazone; Thiazolidinediones; Vasoconstriction; Vasodilation

Insulin responsiveness was studied in isolated adipocytes from the normotensive Wistar Kyoto (WKY) rat and the spontaneously hypertensive rat (SHR). The effect of insulin (0.1 to 5 nmol/L) on glucose uptake (glucose transport and lipogenesis) was measured, and the maximal effect of insulin (Emax) and the dose of insulin required to elicit 50% of the maximal response (EC50) were calculated. A diminished Emax on lipogenesis without changes in the EC50 was detected in SHRs. The Emax was 0.49 +/- 0.09 (SHR) and 1.16 +/- 0.14 (WKY) micromol/10(5) cells (P < .05), and the EC50 was 0.13 +/- 0.03 and 0.11 +/- 0.02 nmol/L for WKY and SHR, respectively. Similar results were obtained when measuring insulin-stimulated glucose transport. A 30-day long-term treatment with enalapril (20 mg/kg/d) normalized insulin responsiveness in adipocytes from SHRs. The effect of enalapril was suppressed when SHRs were pretreated with enalapril and 150 microg/kg/d of the bradykinin (BK) B2-receptor blocker Hoe 140. Pretreatment with losartan (40 mg/kg/d) did not improve insulin action in the SHR. Since these results were obtained with isolated cells in which glucose availability was not a function of blood flow, and the effect of insulin in the SHR was improved by pretreatment with an angiotensin-converting enzyme (ACE) inhibitor but not with the AT1-receptor blocker, it appears that the insulin resistance linked to the hypertension is not related to changes in blood flow.

Topics: Adipocytes; Animals; Antihypertensive Agents; Biological Transport; Enalapril; Glucose; Hypertension; Insulin Resistance; Losartan; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To study metabolic effects of berlipril-5 (enalapril) in patients with non-insulin-dependent diabetes mellitus (NIDDM) and arterial hypertension (AH).. 24 patients with NIDDM and AH were divided into three groups by the level of basal C-peptide: > 2 ng/ml (group 1), 2-4 ng/ml (group 2) and < 4 ng/ml (group 3).. A correlation was found between the level of basal C-peptide and duration of AH (r = 0.7) and NIDDM (r = -0.47), between the level of triglycerides (TG) and glycolized hemoglobin Hb A1c (r = 0.48). Berlipril treatment reduced basal C-peptide level in groups 2 and 3 by 20.65 +/- 1.95% and elevated it in group 1 by 16.4 +/- 1.5%. Fasting glucose levels lowered by 9.2 +/- 1.95% indicating better sensitivity of the liver to insulin. Blood glucose levels 2 hours after meal fell by 8.3 +/- 0.95% (p < 0.05) and Hb A1c by 8.14 +/- 1.25% showing indirectly diminishing insulin-resistance at the level of peripheral tissues. TG and VLDLP significantly declined.. Inhibitors of angiotensin converting enzyme (enalapril, in particular) produce a positive effect on carbohydrate and lipid metabolism in patients with NIDDM and AH.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Insulin Resistance; Lipoproteins, VLDL; Male; Middle Aged; Treatment Outcome; Triglycerides

Insulin resistance (IR) and secondary hyperinsulinaemia are major risk factors of atherosclerosis and probably also of related glomerulosclerosis. Angiotensin converting enzyme inhibitors (ACEI), while improving IR in essential hypertension, do not improve it in patients with chronic renal disease. Thus, the combination of ACEI and low protein diet was evaluated. Thirty-eight patients with various kidney diseases and mild to moderate impairment of kidney function were included in the study. Thirteen of them suffered from IR. Their dietary protein intake was decreased from > or = 1.0 g/kg/d to 0.6-0.7 g/kg/d. Moreover, they were treated by ACEI enalapril at dosages of 2-10 mg/d depending on the absence/presence and severity of hypertension. The patients were followed for 8 months. No clinically relevant kidney disease progression (KDP) was found. IR patients improved remarkably. IR was examined by the oral glucose tolerance test and glucose, insulin and C-peptide determinations. Their increased plasma triglyceride, VLDL concentrations and proteinuria decreased, HDL concentration increased. Acid-base balance and anaemia did not change. It is concluded that protein restriction in combination with ACEI treatment improve IR and the associated dyslipoproteinaemia and proteinuria.

Topics: Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Female; Humans; Insulin Resistance; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged

Present investigation was undertaken to study the effects of 6 week treatment with spirapril (2 mg/kg po) on insulin sensitivity, and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats. Treatment of rats with spirapril in diabetic and diabetic with hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension, and bradycardia. It also partially but significantly prevented STZ-induced hyperglycaemia in both diabetic Wistar and SH animals. Insulin level was not altered by spirapril treatment. There was significant reduction in cholesterol levels in the diabetic rats. In conclusion, the present investigation presents a number of beneficial effects of spirapril treatment in diabetic and/or hypertensive rats. Spirapril may be considered as one of the drugs of choice in treatment of hypertension when associated with diabetes

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Enalapril; Female; Hypertension; Insulin Resistance; Rats; Rats, Inbred SHR; Rats, Wistar

Topics: Animals; Carnitine O-Palmitoyltransferase; Enalapril; Energy Metabolism; Humans; Insulin Resistance; Microvascular Angina; Myocardium

There are conflicting reports about the effects of ACE inhibitors (ACEI) on insulin sensitivity and glycaemic control. Most studies have used a standard high dose of an ACEI but there have been no studies reported to establish whether any changes in glycaemic control or insulin sensitivity associated with ACEI are dose-related.. To examine the effect of increasing doses of enalapril on insulin sensitivity in normotensive non-insulin dependent diabetic subjects.. The effects of increasing doses of enalapril on insulin sensitivity in ten normotensive non-insulin dependent diabetic subjects were measured, using the hyperinsulinaemic isoglycaemic clamp technique. Following a baseline study, enalapril was commenced at 5 mg daily and increased to 10 mg daily then 20 mg daily at 14 day intervals. Repeat studies were undertaken after 14 days at each dosage.. There was a significant dose-related reduction of systolic blood pressure with enalapril. In contrast enalapril at 5-20 mg daily produced no significant changes in insulin mediated glucose uptake (M-value) or insulin sensitivity index (ISI).. These findings indicate that in this insulin resistant population of normotensive non-insulin dependent diabetics, angiotensin converting enzyme inhibition with enalapril has no significant effect on insulin mediated glucose uptake.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enalapril; Female; Glucose Clamp Technique; Humans; Insulin Resistance; Male; Middle Aged

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

The effect of enalapril, an angiotensin converting enzyme inhibitor, on glucose tolerance and serum insulin response to a glucose load has been evaluated in 8 non-obese patients (3 women and 5 men) with untreated essential hypertension (WHO Stage I or II) and without insulin resistance. Following a 2-month run-in control period, each patient received oral enalapril 10 mg once daily for 6 months, and an intravenous glucose tolerance test (IVGTT) was performed at the end of the run-in control and active treatment periods. Treatment with enalapril significantly lowered both the systolic and diastolic blood pressures. The response of plasma glucose to the IVGTT, glucose disappearance rate (k-value) and area under the serum insulin concentration time curve were comparable between the two phases. The results suggest that long-term treatment with enalapril has no effect on glucose tolerance in non-obese, non-insulin-resistant patients with mild-to-moderate essential hypertension.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Enalapril; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Japan; Male; Middle Aged; Time Factors

Topics: Aged; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Hypoglycemia; Insulin Resistance; Male

Acute hyperinsulinaemia, achieving insulin levels within the physiological range, induces sodium retention. At the same time an activation of the renin-angiotensin system occurs, with a rise in plasma renin activity (PRA) and angiotensin-II level but no change in plasma aldosterone. After administration of higher, pharmacological doses of insulin an increase in systolic blood pressure and heart rate can also be observed, while further increases in PRA and angiotensin-II are noted. To determine whether angiotensin-II is involved in observed insulin actions, we studied the renal and cardiovascular effects of three dosages of insulin (50 (Ins I), 300 (Ins II) and 500 (Ins III) mU kg-1 h-1) in healthy subjects after one week of treatment with the angiotensin-I converting enzyme inhibitor enalapril (10 mg twice a day), using the euglycaemic clamp technique. Control data were obtained from two previously conducted experiments in the same subjects, one with infusion of insulin and one with the insulin solvent only. The effect of insulin on fractional sodium excretion, blood pressure and heart rate was unaffected by enalapril, which precludes any involvement of the renin-angiotensin system with regard to these aspects of insulin action. Insulin sensitivity increased significantly during treatment with enalapril (with enalapril: Ins I: 11.3 +/- 3.0, Ins II: 20.0 +/- 3.4 and Ins III: 20.6 +/- 3.9 mg kg-1 min-1 glucose (mean +/- SD); without enalapril: Ins I: 8.7 +/- 2.3, Ins II: 13.7 +/- 3.0 and Ins III: 15.5 +/- 3.1 mg kg-1 min-1 glucose; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Cardiovascular System; Drug Interactions; Enalapril; Heart Rate; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Kidney; Male; Natriuresis; Renin-Angiotensin System

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glomerular Filtration Rate; Humans; Hypoglycemia; Insulin Resistance