enalapril and Hypercholesterolemia

We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a subanalysis using data from the CSPPT (China Stroke Primary Prevention Trial), a double-blind, randomized controlled trial.. A total of 20 702 hypertensive adults without a history of major cardiovascular disease were randomly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. The primary outcome was first stroke.. The median treatment duration was 4.5 years. For participants not receiving folic acid treatment (enalapril-only group), high total cholesterol (≥200 mg/dL) was an independent predictor of first stroke when compared with low total cholesterol (<200 mg/dL; 4.0% versus 2.6%; hazard ratio, 1.52; 95% confidence interval, 1.18-1.97; P=0.001). Folic acid supplementation significantly reduced the risk of first stroke among participants with high total cholesterol (4.0% in the enalapril-only group versus 2.7% in the enalapril-folic acid group; hazard ratio, 0.69; 95% confidence interval, 0.56-0.84; P<0.001; number needed to treat, 78; 95% confidence interval, 52-158), independent of baseline folate levels and other important covariates. By contrast, among participants with low total cholesterol, the risk of stroke was 2.6% in the enalapril-only group versus 2.5% in the enalapril-folic acid group (hazard ratio, 1.00; 95% confidence interval, 0.75-1.30; P=0.982). The effect was greater among participants with elevated total cholesterol (P for interaction=0.024).. Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke. Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31% among hypertensive adults without a history of major cardiovascular diseases.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Topics: Aged; Antihypertensive Agents; China; Comorbidity; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Folic Acid; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Outcome Assessment, Health Care; Risk; Stroke; Vitamin B Complex

To compare hypotensive and antiischemic efficacy of enalapril combination with trimetazidine or placebo, effects on plasmic lipid spectrum and membrane-cell parameters of erythrocytes and platelets in hypertensive patients with ischemic heart disease (IHD) in the presence of metabolic disturbances.. A randomized placebo-controlled comparative trial included 64 patients (mean age 55.60 +/- 0.52 years) with hypertension stage I-III, IHD (stable effort angina FC II-III, obesity of the first-third degree, diabetes mellitus type 2. The patients were divided into two groups matched by gender, age, duration of the disease, office blood pressure (OBP), functional class (FC) of effort angina, body mass index, glucose levels in the blood. 43 patients of group 1 received enalapril and trimetazidine. 21 patients of group 2 were treated with enalapril and placebo. The efficacy of the treatment was assessed by changes in the 24-h profile of BP and ECG, blood lipid spectrum and membrane-cell parameters.. A significant fall was seen in systolic blood pressure of both groups patients. In group 1 there was an additional lowering of temporal index of systolic pressure, nocturnal diastolic, mean 24-h diastolic, mean 24-h blood pressure, double product of ischemic episodes, total cholesterol, dienic conjugates in platelets. Catalase activity in erythrocytes rose.. An antiischemic effect of the therapy in stabilization of blood pressure, normalization of plasmic lipids and lipoperoxidase in erythrocytic and platelet membranes under multidirectional correlations between clinical and biochemical parameters point to different mechanisms of ischemic correction in enalapril and trimetazidine.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Catalase; Comorbidity; Drug Therapy, Combination; Enalapril; Female; Humans; Hypercholesterolemia; Hypertension; Lipid Peroxidation; Male; Middle Aged; Myocardial Ischemia; Severity of Illness Index; Trimetazidine; Vasodilator Agents

A protective role against atherosclerosis can be attributed to angiotensin converting enzyme inhibitors (ACE-I), since they have been shown to reduce mortality in patients at cardiovascular risk. Since plasma levels of adhesion molecules are considered surrogate markers of endothelial cell activation and atherogenesis, we compared the levels of adhesion molecules after treatment with the ACE-I enalapril or the direct angiotensin- receptor antagonist losartan or placebo. In a randomized, controlled trial, 21 hypercholesterolemic volunteers received 50 mg/d losartan or 20 mg/d enalapril or placebo for twelve weeks. Plasma levels of circulating intercellular adhesion molecule-1 (cICAM-1), vascular adhesion molecule-1 (cVCAM-1), and E-selectin (cE-SEL) were measured by ELISA. Surface expression of ICAM-1 on circulating leukocytes was determined by flow cytometry. Enalapril and losartan but not placebo induced a small but stable decrease of cICAM-1 and cVCAM-1, while cE-SEL and leukocyte expression of ICAM-1 remained unchanged. The lowering of plasma adhesion molecules may indicate an antiatherogenic effect of angiotensin II blockade in hypercholesterolemia. While such preventive effect will have to be proven in clinical trials, our results do not support a preference for either enalapril or losartan with regard to their possible vasoprotective role.

Topics: Angiotensin Receptor Antagonists; Blood Pressure; Cholesterol; Double-Blind Method; E-Selectin; Enalapril; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Hypercholesterolemia; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes; Losartan; Male; Middle Aged; Pilot Projects; Receptors, Angiotensin; Vascular Cell Adhesion Molecule-1; Vascular Diseases

Endothelial dysfunction is an early event in atherosclerotic disease that precedes clinical manifestations and complications. The noninvasive assessment of endothelial function in patients with risk factors undergoing clinical treatment is an important medical advance. In this setting, altered endothelial function in patients with coronary hypercholesterolemia and its modifications by treatment with enalapril and simvastatin, either separately or in combination, was assessed in the brachial artery in a randomized, double-blind, 2-period crossover study.. Thirty-eight patients were separated in 2 groups. Group 1 (18 patients, 3 female, mean age 63 +/- 6.0 years) received simvastatin 10 mg/d for 8 weeks and simvastatin plus enalapril 5 mg/d for another 8 weeks. Group 2 (20 patients, 3 female, mean age 64 +/- 5.8 years) received enalapril 5 mg/d for 8 weeks and enalapril plus simvastatin 10 mg/d for another 8 weeks. All subjects underwent measurements of brachial artery diameter before and after postischemic hyperemia with high-resolution ultrasound at basal conditions (control) and under the effects of the drugs at the end of 8 and 16 weeks.. Cholesterol and LDL cholesterol levels significantly decreased with simvastatin treatment alone or with enalapril. Mean baseline arterial diameter was 5.24 +/- 1.25 mm in group 1 and 4.83 +/- 0.99 mm in group 2 (not significant). In group 1 after the first 8 weeks, endothelium-dependent vasodilation significantly increased with simvastatin treatment (control, 4.4%; 8 weeks, 7.6%; P <.001). After 16 weeks with the addition of enalapril, a further increase in vasodilation was seen (8.6%, P <.05 vs 8 weeks). In group 2, with enalapril treatment an increase in vasodilation versus control was seen (control, 4.3%; 8 weeks, 5.8%; P <.01). After 16 weeks, with the addition of simvastatin an additional increase in vasodilation was observed (9.1%, P <.001 vs 8 weeks). After nitroglycerin, vasodilation in group 1 at control, 8, and 16 weeks was 17%, 17.5%, and 18%, respectively. In group 2, nitroglycerin vasodilation at control, 8, and 16 weeks was 21%, 21%, and 22%, respectively.. Simvastatin significantly increased the postischemic vasodilator response in patients with coronary hypercholesterolemia, either as single treatment or added to enalapril. Similarly, the response was increased by enalapril, either alone or while simvastatin was being administered. Both drugs improve vasodilation and additive effects appear to be present.

Topics: Angiotensin-Converting Enzyme Inhibitors; Brachial Artery; Cholesterol; Coronary Disease; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Endothelium, Vascular; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Simvastatin; Ultrasonography; Vasodilation

Hypercholesterolemia and hypertension are frequently associated with elevated sympathetic activity. Both are independent cardiovascular risk factors and both affect endothelium-mediated vasodilation. To identify the effects of cholesterol-lowering and antihypertensive treatments on vascular reactivity and vasodilative capacity, we studied 30 hypercholesterolemic hypertensive subjects. They received placebo for 4 weeks, either enalapril or simvastatin for 14 weeks, and, finally, both medications for an additional 14 weeks. Postischemic forearm blood flow (MFBF) and minimal vascular resistance (mFVR) were used as indices of vasodilative capacity and structural vascular damage, respectively. Total (resting-stress-recovery phases) cardiovascular (blood pressure [BP] and heart rate [HR]) and regional hemodynamic (FBF and FVR) reactivity to stressful stimuli were calculated as area-under-the-curve (auc) (valuextime). Compared with baseline levels, simvastatin reduced total (TOT-C) and LDL cholesterol (LDL-C) (1.27 mmol/L, P<0.001 and 1.33 mmol/L, P<0.001, respectively). Enalapril also reduced TOT-C and LDL-C (0.6 mmol/L, P<0.001 and 0.58 mmol/L, P<0.05, respectively). MFBF was increased substantially by both treatments (P<0.001). Enalapril had a greater effect (-1.7 arbitrary units (AU), P<0.001) than simvastatin (-0.6 AU, P<0.05) on mFVR. During stress, FBF increased more with enalapril (4.4 FBFxminutes, P<0.001) than with simvastatin (1.8 FBFxminutes, P<0.01). Conversely, FVR stress response was reduced more with enalapril (9.1 FVRxminutes, P<0.001) than with simvastatin (2.9 FVRxminutes, P<0.01). During combination treatment, a significant (0.001>P<0.05) additive effect on hypercholesterolemia, structural vascular damage, BP, and FVR was shown. The findings suggest that angiotensin-converting enzyme (ACE) inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular System; Drug Interactions; Enalapril; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; Male; Simvastatin

Blood pressure (BP) reduction was compared between patients receiving angiotensin-converting enzyme inhibitors alone and patients receiving these medications plus statins after 3 months of dietary intervention. Although BP was similarly reduced at week 4, the statin-treated group had a greater reduction in BP and total cholesterol levels at week 16, suggesting a synergistic effect between cholesterol lowering with statins and angiotensin-converting enzyme inhibitor treatment for hypertensive patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Blood Pressure; Drug Interactions; Enalapril; Female; Heart Rate; Humans; Hypercholesterolemia; Hypertension; Lisinopril; Lovastatin; Male; Middle Aged; Pravastatin

Circulating soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) concentrations were evaluated in 93 nonobese essential hypertensive patients, of whom 16 had impaired glucose tolerance and hyperlipidemia (group I); 25 had impaired glucose tolerance (group II); 28 had hyperlipidemia (group III); and 24 had no metabolic abnormalities (group IV). A group of 22 healthy volunteers served as a control group. All groups were without clinical or ultrasound evidence of vascular lesion and were matched for age, sex, and BMI. Endothelial soluble adhesion molecules were measured at baseline, during an oral glucose tolerance test, and after 12 weeks of either enalapril or placebo treatments. Plasma soluble E-selectin, ICAM-1, and VCAM-1 were higher (P < 0.05) in group I and II than in the other groups (group I: E-selectin, 96.1+/-27.1; ICAM-1, 304.0+/-102.1; VCAM-1, 626.1+/-156.2 microg/l. Group II: E-selectin, 88.0+/-18.0; ICAM-1, 268.0+/-84.1; VCAM-1, 594.1+/-140.9 microg/I. Group III: E-selectin, 70.1+/-18.1; ICAM-1, 195.1+/-68.0; VCAM-1, 495.9+/-110.1 microg/l. Group IV: E-selectin, 65.1+/-16.1; ICAM-1, 168.1+/-64.0; VCAM-1, 472.1+/-108.2 microg/l). Soluble adhesins levels were not higher than normal in groups III and IV. Plasma soluble ICAM-1 concentrations increased in group I after glucose administration and were directly correlated with 2-h insulin levels (r=0.648, P=0.007). Compared with placebo, 12 weeks of enalapril treatment significantly (P < 0.0001) reduced soluble E-selectin, ICAM-1, and VCAM-1. Decrements of soluble adhesins were not dependent on enalapril-related blood pressure changes. Therefore, an early endothelial activation was present in essential hypertensive patients with impaired glucose tolerance, regardless of the presence of hyperlipidemia. ACE inhibition counteracted such endothelial activation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; E-Selectin; Enalapril; Endothelium, Vascular; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Intercellular Adhesion Molecule-1; Male; Solubility; Vascular Cell Adhesion Molecule-1; von Willebrand Factor

Normal blood pressure is a good marker of graft survival after renal transplantation, and effective antihypertensive treatment reduces the progression of graft damage. We conducted a long-term follow-up study of 88 hypertensive renal transplant recipients, all of whom were taking sustained cyclosporine A (CsA) immunosuppression. The patients were treated for at least three years, and initially received 240 mg/day of verapamil (N = 24, group I), 5 mg/day of enalapril (N = 24, group II) or 1 mg/day of doxazosin (N = 40, group III). Baseline creatinine did not differ in the three groups, but proteinuria was higher in the enalapril group (7 patients had proteinuria > 1.5 g/day). Treatment was withdrawn in 5 patients in the verapamil group, 5 in the enalapril group and 2 in the doxazosin group due to drug-related side effects. Blood pressure (BP) control at three years was equivalent in the three groups (systolic BP, group I 157 +/- 12; group II 149 +/- 19; group III 154 +/- 21; diastolic BP, group I 90 +/- 8.7, group II 84 +/- 9.8, group III 90.5 +/- 16; mean BP, group I 113 +/- 7, group II 106 +/- 10, group III 106 +/- 29). Two patients in group I, 3 in group II and 15 in group III required additional antihypertensive drugs. CsA levels increased in the verapamil-treated patients, allowing for an early decrease in CsA doses (1 year doses, 3.3 +/- 1 mg/kg body wt/day in group I, 4.3 +/- 1.6 in group II, 3.7 +/- 1.6 in group III). Six cardiovascular events occurred, 3 in group I, 1 in group II, and 2 in group III patients. One patient died in the enalapril group and another in the doxazosin group. Eight verapamil-treated patients, 8 enalapril-treated patients and 4 doxazosin-treated patients lost their grafts due to biopsy-proven chronic transplant nephropathy. In conclusion, the three antihypertensive agents are effective in reducing blood pressure, with no clear advantage of one above any other. Verapamil allows the CsA dose to be reduced, thus decreasing the cost of immunosupression. Enalapril can be a more effective antiproteinuric agent, but hyperkalemia or impaired allograft function may occur in patients with non-optimal allograft function. Doxazosin offers an excellent safety and efficacy profile, and when not efficient by itself in controlling blood pressure, is an ideal concomitant agent in hypertensive renal transplant patients.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Doxazosin; Enalapril; Female; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Hypertension, Renal; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Postoperative Complications; Verapamil

Doxazosin, a once daily alpha-blocking drug has been demonstrated to reduce both BP and hyperlipidaemia, related risk factors for premature vascular disease. This study was designed to see if a low fat diet altered the favourable effect of doxazosin on blood lipids in adults with mild to moderate hypertension and mild to moderate hypercholesterolaemia (5.6-8.0 mmol/l). Following a six week period on a low fat diet, patients were randomly allocated to additional doxazosin (2-8 mg/day) or enalapril (5-20 mg/day) treatment for a further 10 weeks. Forty-four of 55 subjects completed the study. A low fat diet reduced mean body weight by 2 kg without significantly altering blood lipids (total and HDL cholesterol, triglycerides). Doxazosin (4.5 +/- 2.9 mg/day) and enalapril (12.5 +/- 6.5 mg/day) produced a comparable lowering of sitting and standing BP at all visits and also produced similar 24h BP control. The expected increase in HDL cholesterol concentration previously noted in this patient population in association with doxazosin treatment was not detected suggesting that the low cholesterol-high carbohydrate diet, at least acutely, attenuates this potentially beneficial effect on plasma lipids. In summary, doxazosin has a comparable tolerability and BP lowering ability to enalapril. However, its ability to increase HDL cholesterol may be reduced in patients on low fat diets.

Topics: Adult; Aged; Blood Glucose; Blood Pressure Monitoring, Ambulatory; Diet, Fat-Restricted; Doxazosin; Enalapril; Female; Humans; Hypercholesterolemia; Hypertension; Insulin; Lipids; Male; Middle Aged

Hypertension and hypercholesterolemia are frequently associated with this leading to considerable cardiovascular risk.. An open parallel randomized study was performed in which the effects of doxazosin, an alpha-adrenergic blocker and enalapril, an inhibitor of the angiotensin converting enzyme were compared in 70 patients with essential high blood pressure and plasma cholesterol levels greater than 240 mg/dl. Following 2-4 weeks of placebo administration the patients were randomly treated with one of the two drugs. When required doses were increased and hydrochlorothiazide added until blood pressure lower than 160/95 mmHg was achieved. After this period the patients were observed for a minimum of 8 weeks. The mean length of the study was of 22 weeks.. Both drugs significantly reduced blood pressure without modifying cardiac frequency. Doxazosin tended to favorably modify the lipid profile of the plasma while enalapril significantly reduced the levels of cholesterol, lipids and high density lipoproteins (HDL). Upon termination of the study the total HDL/cholesterol index increased 8.6% in those treated with doxazosin and decreased 5.5% in those receiving enalapril (p < 0.05).. Although doxazosin and enalapril are potent antihypertensive drugs, the effects on plasma lipid obtained with doxazosin indicate that a reduction in cardiovascular risk was achieved with this drug in the patients included in this study.

Topics: Adult; Aged; Doxazosin; Enalapril; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged

Endothelial dysfunction is now widely recognized as an early marker of cardiovascular disease, making its treatment, or complete avoidance, an emerging, interesting therapeutic target. This study investigated the ability of the highly intriguing amino acid L-arginine to influence endothelial function. Its therapeutic potential is also compared to that of known cardiovascular medications, namely nitroglycerin [a nitric oxide (NO) donor] and enalapril [an angiotensin-converting enzyme (ACE) inhibitor]. Fifty male New Zealand rabbits were included in the study, divided into 5 equal groups: control, hypercholesterolemia (untreated), hypercholesterolemia (+L-arginine), hypercholesterolemia (+enalapril), and hypercholesterolemia (+nitroglycerin). Biochemical investigations included measurement of circulating NOx, malondialdehyde (MDA), and lipid profile markers, as well as dimethylarginine dimethylaminohydrolase (DDAH) and ACE activities. Furthermore, aortic ACE activity and blood platelet aggregation were estimated. A histopathological examination and intimal thickness measurement were also conducted. Compared to the untreated hypercholesterolemic group, all agents were capable of positively influencing MDA levels, platelet aggregation and intimal thickness; however, only the L-arginine group was capable of beneficially and significantly altering both NOx levels and serum and aortic ACE activities. No agents were capable of modulating serum DDAH activity inhibited by hypercholesterolemia. Based on the results of this study, L-arginine appears to be a novel cardio-protective agent, illustrated by its ability to ameliorate the deleterious effects of hypercholesterolemia on endothelial function, in a manner comparable to, and sometimes more potent than, commonly used cardiovascular medications.

Topics: Amidohydrolases; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Cardiotonic Agents; Cardiovascular Diseases; Dietary Supplements; Disease Models, Animal; Enalapril; Endothelium, Vascular; Heart; Hypercholesterolemia; Male; Malondialdehyde; Nitric Oxide; Nitroglycerin; Oxidative Stress; Rabbits

This study determined the role of angiotensin-converting enzyme (ACE) on the development of angiotensin I-induced atherosclerosis and the contribution of leukocyte-specific expression of this enzyme.. To define the contribution of ACE-dependent activity to angiotensin II synthesis in atherosclerotic development, male low-density lipoprotein receptor(-/-) mice were fed a fat-enriched diet and infused with either angiotensin I or angiotensin II. The same infusion rate of these peptides had equivalent effects on atherosclerotic development. Coinfusion of an ACE inhibitor, enalapril, ablated angiotensin I-augmented atherosclerosis but had no effect on angiotensin II-induced lesion development. ACE protein was detected in several cell types in atherosclerotic lesions, with a predominance in macrophages. This cell type secreted angiotensin II, which was ablated by ACE inhibition. To study whether leukocyte ACE contributed to atherosclerosis, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with bone marrow-derived cells from either ACE(+/+) or ACE(-/-) mice and fed the fat-enriched diet for 12 weeks. Chimeric mice with ACE deficiency in bone marrow-derived cells had modestly reduced atherosclerotic lesions in aortic arches but had no effects in aortic roots.. ACE mediates angiotensin I-induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atherosclerosis; Bone Marrow Transplantation; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Enalapril; Hypercholesterolemia; Leukocytes; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptidyl-Dipeptidase A; Receptors, LDL; Transplantation Chimera

Inhibition of the renin angiotensin system (RAS) has been consistently demonstrated to reduce atherosclerosis. However, there has been no direct comparison among the three available pharmacological modes of inhibiting the RAS, which are inhibitors of renin, ACE and angiotensin II type 1 receptor. The purpose of this study was to determine the relative effects of these three modes of pharmacological RAS inhibition in reducing atherosclerosis by determining the dose-response relationships.. Male LDL receptor -/- mice were administered either vehicle or any of three doses of aliskiren, enalapril or losartan through s.c. infusion for 12 weeks. All mice were fed a saturated fat-enriched diet during drug infusions. Systolic and diastolic BPs were measured during the study using a non-invasive tail-cuff system. Plasma cholesterol and renin concentrations, atherosclerotic lesions, and renal angiotensin II concentrations were determined at the termination of the study.. Plasma renin concentrations were increased by all three drugs. None of the drugs changed plasma cholesterol concentrations. All drugs produced a dose-related decrease in BP. All three drugs also profoundly reduced atherosclerosis in a dose-dependent manner. The highest dose of each drug markedly attenuated lesion size, with no significant differences between the different drugs. The highest dose of each drug also similarly reduced renal angiotensin II concentrations.. Drugs that inhibit the RAS, irrespective of their mode of inhibition, profoundly affect atherosclerotic lesion development in a dose-dependent manner.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Atherosclerosis; Blood Pressure; Cholesterol; Diet, High-Fat; Enalapril; Fumarates; Hypercholesterolemia; Kidney; Losartan; Male; Mice; Mice, Knockout; Receptor, Angiotensin, Type 1; Receptors, LDL; Renin; 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

Spontaneously hypercholesterolemic (SHC) rats exhibit hypercholesterolemia, proteinuria and focal glomerulosclerosis with age, and they finally die as a result of renal failure. In this study, the renoprotective effects of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, and enalapril, an angiotensin I converting enzyme inhibitor, were examined in SHC rats. Candesartan cilexetil (0.1 and 1 mg /kg) and enalapril (10 mg/kg) were administered orally to 10-week-old SHC rats for a 6-week period. Candesartan cilexetil (1 mg/kg) and enalapril (10 mg/kg) significantly inhibited proteinuria and hypercholesterolemia to a similar extent. In untreated 16-week-old SHC rats, glomerulosclerosis, basophilic change, cast formation and interstitial mononuclear cell infiltration were observed. Candesartan cilexetil (1 mg/kg) inhibited all of these histological changes. Enalapril inhibited glomerulosclerosis and cast formation. These results show that candesartan cilexetil and enalapril have renal protective effects in SHC rats. Thus, angiotensin II might play an important role in renal pathogenesis in a model of focal glomerulosclerosis with hypercholesterolemia.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Body Weight; Cholesterol; Enalapril; Glomerulosclerosis, Focal Segmental; Hypercholesterolemia; Indicators and Reagents; Kidney Diseases; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles

Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensin-converting enzyme inhibitors (ACE-I) prevent the aortic elastin loss in experimental hypercholesterolaemia. Two doses of ACE-I (captopril, enalapril and quinapril) were used: a dose equivalent to that applied to human subjects and a dose 10 times higher. We found that the increase in serum and aortic elastolytic activity in cholesterol-fed rabbits was prevented by high-dose captopril. The elastin content in aorta homogenates from cholesterol-fed rabbits was significantly decreased. The higher dose of captopril, but no other ACE-I, prevented this decrease in aortic elastin content. In cholesterol-fed rabbits the elastin-bound calcium content was significantly elevated. The higher doses of captopril and enalapril lowered the elastin-bound calcium content. In serum and aortic homogenates of cholesterol-fed rabbits, ACE activity was elevated by 15% and 77%, respectively. Both doses of captopril, enalapril and quinapril prevented this cholesterol-induced increase in serum and aortic ACE activity. We conclude that: 1) administration of captopril at doses 10 times higher than those used in humans prevents hypercholesterolaemia increased aortic elastin loss. 2) higher doses of captopril and enalapril prevent the hypercholesterolaemia-induced increase in aortic elastin-bound calcium.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Calcium; Captopril; Cholesterol, Dietary; Dose-Response Relationship, Drug; Elastin; Enalapril; Hypercholesterolemia; Isoquinolines; Male; Quinapril; Rabbits; Tetrahydroisoquinolines

In hypercholesterolemia increased lipid and lipoprotein peroxidation occurs. The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II induces smooth muscle cells proliferation and stimulates oxidation of LDL particles and foam cell accumulation. Inhibition of ang II production leads to decrease in lipid peroxide production. The aim of this study was to assess the lipid peroxidation expressed as concentration of thiobarbituric acid reactive species (TBARS) in sera and aorta homogenates after administration of two doses of angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril and quinapril) in diet-induced hypercholesterolemia in rabbits. Sixty-four New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: i), equivalent to applied to humans, ii), dose 10 times higher. The animals were divided into 8 groups: control, standard fodder; B, special diet; C1, C2, special diet + captopril in doses 2.5 and 25 mg/kg/24 h, respectively; E1, E2, special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 h, respectively; Q1 and Q2, special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. In cholesterol-fed rabbits and in groups receiving lower doses of tested ACE inhibitors, the serum TBARS concentration at 6 months was significantly higher in comparison to the control. The higher doses of enalapril, quinapril and captopril, prevented the cholesterol-induced rise in TBARS concentration. Lower dose of captopril attenuated the rise in TBARS concentration, it was significantly lower in comparison to group B, but higher than in the control group. In animals from groups B, E1, C1, Q1 TBARS concentration in aortae was significantly higher as compared to control group. Both doses of captopril and higher doses of enalapril and quinapril inhibited the rise of lipid peroxides concentration induced by cholesterol-rich diet.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Cholesterol; Diet, Atherogenic; Enalapril; Hypercholesterolemia; Isoquinolines; Lipid Peroxidation; Male; Quinapril; Rabbits; Tetrahydroisoquinolines; Thiobarbituric Acid Reactive Substances

In atherosclerosis numerous qualitative and quantitative changes in connective tissue metabolism parameters in serum and aorta occur. In atherosclerosis there is an enhanced activity of local renin-angiotensin systems. It leads to overexpression of ANG II, both in serum and arterial wall. ANG II stimulates SMC to over-synthesize the collagens type I and III. Hyper-cholesterolemia is a form of metabolic injury which can both induce phenotypic change of SMC and activate RA system in arterial wall. ACEI lower the accumulation of collagens type I and III, and enhance elastin content in arterial wall in experimental hypertension. The aim of this study was to assess the influence of captopril, enalapril and quinapril on connective tissue metabolism of the aorta in experimental hyper-cholesterolemia. 64 male New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: 1st--equivalent to doses applied to human subjects (in mg/kg of body weight), 2nd--dose 10 times higher. The animals were divided into 8 equal groups: K--standard fodder, B--special diet, C1, C2--special diet + captopril in doses 2.5 and 25 mg/kg/24 hours, respectively, E1, E2--special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 hours, respectively, Q1 i Q2--special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. The experiment lasted for 6 months. After 24 weeks the animals were sacrificed and aortae were excised for collagens assay. The statistical analysis was performed using ANOVA, followed by LSD test; p < 0.05 was considered statistically significant. The aorta collagens content of cholesterol-fed rabbits significantly increased. The tested ACEI (captopril, enalapril in both doses and quinapril in lower dose) had a preventive effect against the increase of aorta collagen content.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Collagen; Connective Tissue; Enalapril; Hypercholesterolemia; Isoquinolines; Male; Quinapril; Rabbits; Tetrahydroisoquinolines

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalapril; Humans; Hypercholesterolemia; Hypertension; Losartan; Male; Middle Aged

TCV-116 and enalapril were given in two stages: (early phase) for 6 to 10 weeks to 5/6 nephrectomized (NX) rats two weeks after nephrectomy, 12-week-old Wistar fatty (WF) rats and 7-week-old spontaneously hypercholesterolemic (SHC) rats; and (late phase) for 6 to 16 weeks to 5/6 NX rats 11 weeks after nephrectomy, 27-week-old WF rats and 10-week-old SHC rats. Urinary albumin, blood pressure (BP), glomerular filtration rate (GFR) and renal histology were examined. In the early phase, both agents inhibited proteinuria and tended to inhibit glomerulosclerosis. TCV-116 also inhibited interstitial inflammation. The antiproteinuric effects did not necessarily correlate with the BP-lowering effects. In the late phase, both agents showed equal antiproteinuric and antihypertensive effects. In 5/6NX and WF rats, TCV-116 inhibited tubulointerstitial inflammation/fibrosis, glomerulosclerosis and renal dysfunction, but enalapril had little effect on these parameters. In the SHC rats, TCV-116 inhibited renal tubulointerstitial inflammation and glomerulosclerosis, but enalapril inhibited only glomerulosclerosis. After drug administration, there was a positive correlation between proteinuria and BP, and a negative correlation between the severity of tissue damage and GFR, but not BP. These findings suggest that initial BP-independent tubulointerstitial inflammation may enhance glomerulosclerosis in the late phase, and TCV-116 might prevent the development of glomerulosclerosis through inhibition of angiotensin II-mediated tubulointerstitial damage in these models.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Glomerular Filtration Rate; Glomerulonephritis; Hypercholesterolemia; Kidney Glomerulus; Nephritis, Interstitial; Prodrugs; Proteinuria; Rats; Rats, Wistar; Tetrazoles

The effect of enalapril and terazosin on serum lipid profile was investigated in 36 patients with primary hypertension and hypercholesterolemia (total cholesterol 5.2 mmol l). 6- and 12-week monotherapy with these drugs did not produce any unfavourable changes in: total cholesterol, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B as well as in serum lipids. Enalapril and terazosin seem to be very useful as a first step monotherapy especially in patients with hypertension and lipid disturbances.

Topics: Adrenergic alpha-Antagonists; Adult; Enalapril; Female; Humans; Hypercholesterolemia; Hypertension; Lipids; Male; Middle Aged; Prazosin

Topics: Adsorption; Anaphylaxis; Blood Component Removal; Blood Pressure; Contraindications; Dextran Sulfate; Enalapril; Heart Rate; Humans; Hypercholesterolemia; Lipoproteins, LDL