Protective Effects Of Enalapril Research Articles

Renin-Angiotensin System Blockers Protect Pancreatic Islets against Diet-Induced Obesity and Insulin Resistance in Mice

BackgroundThe associations between obesity, hypertension and diabetes are well established, and the renin-angiotensin system (RAS) may provide a link among them. The effect of RAS inhibition on type 2 diabetes is still unclear; however, RAS seems to play an important role in the regulation of the pancreas and glucose intolerance of mice fed high-fat (HF) diet.MethodsC57BL/6 mice fed a HF diet (8 weeks) were treated with aliskiren (50 mg/kg/day), enalapril (30 mg/kg/day) or losartan (10 mg/kg/day) for 6 weeks, and the protective effects were extensively compared among groups by morphometry, stereological tools, immunostaining, Western blotting and hormonal analysis.ResultsAll RAS inhibitors significantly attenuated the increased blood pressure in mice fed a HF diet. Treatment with enalapril, but not aliskiren or losartan, significantly attenuated body mass (BM) gain, glucose intolerance and insulin resistance, improved the alpha and beta cell mass and prevented the reduction of plasma adiponectin. Furthermore, enalapril treatment improved the protein expression of the pancreatic islet Pdx1, GLUT2, ACE2 and Mas receptors. Losartan treatment showed the greatest AT2R expression.ConclusionOur findings indicate that ACE inhibition with enalapril attenuated several of the deleterious effects of the HF diet. In summary, enalapril appears to be responsible for the normalization of islet morphology and function, of alpha and beta cell mass and of Pdx1 and GLUT2 expression. These protective effects of enalapril were attributed, primarily, to the reduction in body mass gain and food intake and the enhancement of the ACE2/Ang (1-7) /Mas receptor axis and adiponectin levels.

Protective effects of enalapril, an angiotensin‐converting enzyme inhibitor, on multiple organ damage following scald injury in rats

The aim of this study is to investigate the effects of enalapril, an angiotensin-converting enzyme inhibitor, on multiple organ damage after scald injury. Healthy adult rats (half male and half female; 8-12 weeks old) were randomly assigned to the following treatments: sham operation, scald injury, and intraperitoneal enalapril (1, 2, and 4 mg/kg body weight) treatment after scalding. At 1, 12, and 24 H postscald, left ventricular and aortic hemodynamics were measured using a multichannel physiological recorder. Functional and pathological changes of the heart, liver, and kidney were examined by biochemical and histological methods. Compared with sham controls, untreated scalded animals showed decreased hemodynamic parameters and increased myocardial angiotensin II, serum creatine kinase heart isoenzyme, and serum cardiac troponin I and histopathological inflammation in the myocardium 12 H postscald. These hemodynamic, functional, and pathological changes were attenuated by 1 mg/kg enalapril. Enalapril reversed scald-induced elevations in aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and blood creatinine 12 H postscald, and ameliorated focal necrosis in the liver and erythrocyte cast formation in renal tubules. However, higher doses of enalapril yielded less or no improvement in organ dysfunction. Enalapril at 1 mg/kg attenuates scald-induced multiple organ damage in rats.

Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms

Diabetes mellitus, a state of persistent hyperglycemia, is a major cause of micro- and macrovascular diseases. It affects nearly every system in the body including the reproductive system. Abnormalities in spermatogenesis and sexual function have been documented in animal models for both types of diabetes. The purpose of the present study is to determine the possible protective effects of enalapril against the germ cell toxicity in diabetic rat. Sprague-Dawley rats were divided into four groups: (1) control, (2) control + enalapril, (3) diabetic, and (4) diabetic + enalapril. Enalapril was administered per orally for 4 and 8weeks continuously. After the treatment, animals were sacrificed and blood glucose level, sperm count, sperm DNA damage, apoptotic cell death, immunohistochemistry of 8-oxo- 7,8-dihydro- 2'-deoxyguanosine, and the cellular toxicity were performed. Furthermore, western blotting was performed to evaluate the expression of NFκB and COX-2 in testes. The results of the present study indicate that intervention of enalapril ameliorates the sperm DNA damage, reduces the oxidative stress, and down-regulates the expression of NFκB and COX-2 expression in streptozotocin-induced diabetic rat.

S-001 ELEVATION OF CARDIAC ACE2 EXPRESSION IN HYPERTENSIVE RATS TREATED WITH ACE INHIBITOR AND AT1 BLOCKADE

Background Angiotensin-converting enzyme 2 (ACE2) is a recently identified homologue of ACE. However, the expression of ACE2 in the heart and maintenance of blood pressure remain poorly understood. In the present study, we investigated whether the cardiac ACE2 expression changes in hypertensive rats treated with ACE inhibitor, enalapril or AT1 blockade, losartan. Methods Suprarenal abdominal aortic coarctation (AAC) was performed as describedpreviously with some modification in SD rats. Rats were randomly divided into 4groups (n = 10 each group): (1) sham operated rats without the aortic coarctation; (2) AAC rats with the aortic coarctation; (3) AAC rats were fed enalapril (20 mg/kg/d) intheir drinking water; (4) AAC animals were fed losartan (30 mg/kg/d) in their drinkingwater. BP was recorded using a tail-cuff method. After 4 weeks of treatment, plasmarenin activity (PRA) and renal tissue renin activity (TRA) were measured by aradioimmunoassay. ACE2 mRNA and its protein levels in the heart were detected byRT-PCR and immunohistochemistry. Results BP increased in AAC rats compared to the control (P < 0.01). Equivalent decrease in BP was obtained in rats given enalapril or losartan. In AAC rats, ACE2 mRNA levelwas decreased in the heart (P < 0.01). After the treatment of enalapril, both of the PRAand TRA levels in the kidney in AAC rats were greater than those in the control rats. The level of ACE2 expression rose in the heart (P < 0.01). In rats with Losartantreatment, there was an increase in cardiac ACE2 mRNA level and PRA in thecirculation (P < 0.05). Conclusion The expression of ACE2 mRNA decreased in the heart in AAC hypertensive rats. Administration of enalapril or losartan increased the expression of cardiac ACE2. Thus, the protective effect of enalapril or losartan is probably related to the reductionof Ang II formation and elevation of ACE2 expression in the heart.

Beneficial Effects of Enalapril on Chlorhexidine Digluconate-Induced Liver Peritoneal Fibrosis in Rats

Peritoneal fibrosis (PF) is a recognized complication of long-term peritoneal dialysis (PD) and can lead to ultrafiltration failure. The present study was designed to investigate the protective effects of enalapril on chlorhexidine digluconate-induced liver PF by decreasing transforming growth factor-β1 (TGF-β1) production in rats. PF was induced in Sprague-Dawley rats by daily administration of 0.5 ml 0.1% chlorhexidine digluconate in normal saline via PD tube for one week. Rats received daily intravenous injections of low dose enalapril (1 mg/kg), or high dose enalapril (2.5 mg/kg), for one week. After 7 days, conventional 4.25% Dianeal (30 ml) was administered via a PD catheter with a dwell time of 4 h and assessment of peritoneal function. At the end of dialysis, the rats were sacrificed and liver peritoneum was harvested for microscopic examination and immunohistochemistry. There was no significant difference in mean arterial pressure and heart rate between groups. After 4 h of PD, the D₄/P₄(urea) level was reduced, the D₄/D₀ glucose level, serum and the dialysate TGF-β1 level was increased, the liver peritoneum was markedly thicker, and the expression of TGF-β1, alpha-smooth muscle actin (α-SMA), fibronectin, collagen and vascular endothelial growth factor (VEGF) were elevated in the PF group compared with the vehicle group. High dose of enalapril decreased the serum and dialysate TGF-β1 levels, decreased the thickness of the liver peritoneum, and decreased the expression of TGF-β1, α-SMA, fibronectin, collagen and VEGF-positive cells in the liver peritoneum. Low dose of enalapril did not protect against chlorhexidine digluconate-induced PF in the rat. Enalapril protected against chlorhexidine digluconate-induced PF in rats by decreasing TGF-β1 production.

Protective effects of enalapril in streptozotocin‐induced diabetic rat: studies of DNA damage, apoptosis and expression of CCN2 in the heart, kidney and liver

Diabetes mellitus is characterized by hyperglycemia, which induces oxidative stress and perturbs a number of pathways, leading to tissue injury. One of the pathological responses to tissue injury is the development of fibrosis and cell death. Enalapril is a non-thiol angiotensin-converting enzyme inhibitor that is commonly used in the treatment of diabetes-associated hypertension. The present study examines the possible beneficial effects of enalapril on the development of diabetes associated fibrosis and DNA damage in rats. Sprague-Dawley rats (250 ± 10 g) were used in the study. Enalapril (10 mg kg(-1) per oral) was administered for four consecutive weeks to the streptozotocin (STZ)-induced diabetic rats. After 4 weeks, all the animals were sacrificed and comet assay (normal and modified) was performed to detect the normal as well as oxidative DNA damage. Expression of profibrotic marker CCN2 and fibrosis was examined in the heart, kidney and liver of diabetic rats. Enalapril treatment significantly restored the malondialdehyde and glutathione content as well as the DNA damage in the heart, kidney and liver of diabetic rat. Significant decrease in the expression of CCN2 was observed in the heart, kidney and liver of diabetic rat receiving enalapril treatment as compared with the diabetic group. Further, the enalapril treatment led to significant decrease in the fibrosis and CCN2 expression in the diabetic group as compared with control. The results of the present study clearly demonstrate that enalapril ameliorates the DNA damage, cell death and expression of CCN2 in the heart, kidney and liver of the STZ-induced diabetic rat.

Enalapril Reduces the Expression of Nuclear Factor-κB and c-Jun N-Terminal Kinase in the Renal Cortices of Five-Sixths-Nephrectomized Rats

Background/Aim: Five-sixths-nephrectomized rats present renal functional and histological abnormalities which are attenuated by enalapril treatment. c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase, and nuclear factor-ĸB (NF-ĸB) pathways can be activated by angiotensin II which has been implicated in renal injury. The aim of this study was to investigate the effect of enalapril on the expression of NF-ĸB and JNK in renal cortices of five-sixths-nephrectomized rats. Methods: Of the 65 rats studied, 25 underwent five-sixths nephrectomy and received no treatment, 15 underwent five-sixths nephrectomy and received enalapril, 15 were sham operated and received no treatment, and 10 were sham operated and received enalapril. On postoperative days 15 and 90, systolic blood pressure, glomerular filtration rate, and albumin excretion were determined. The rats were then killed and the kidneys removed for histology and immunohistochemistry. Results: In five-sixths-nephrectomized rats, we observed functional and structural renal alterations, as well as greater NF-ĸB/JNK expression and higher macrophage counts. Enalapril treatment reduced all of these changes. Conclusion: The protective effect of enalapril on the kidney of five-sixths-nephrec tomized rats might be related to the inhibition of NF-ĸB and JNK activation.

Protective effect of enalapril on vascular reactivity of the rat aorta

Cardiovascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus (DM). Strategies that interrupt the renin–angiotensin system have been shown to reduce the ensuing threatening risk factors. The present study was carried out to investigate the effect of subchronic administration of enalapril on the aortic reactivity of streptozotocin (STZ)-diabetic rats. For this purpose, STZ-diabetic rats received enalapril (10 and 20 mg/kg ip) daily for 2 months. Contractile responses to phenylephrine (PE) and relaxation responses to acetylcholine (Ach) and isosorbide dinitrate (ISD) were obtained from aortic rings. Concentration–response curves from enalapril-treated diabetic (ED) rats to PE were attenuated as compared to vehicle-treated diabetics (VD), especially at a dose of 20 mg/kg for enalapril. In addition, endothelium-dependent relaxation responses induced by Ach was significantly higher in ED rats as compared to diabetic ones. The endothelium-independent relaxation responses for ISD were also found not to be significantly different among the groups. Therefore, subchronic treatment of diabetic rats with enalapril in a dose-dependent manner could prevent the functional changes in vascular reactivity in diabetic rats.

Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat.

The effect of enalapril on glomerular hemodynamics and permselectivity and on subsequent sclerosis was studied in male MWF/Ztm rats which spontaneously develop proteinuria and glomerular structural damage. Untreated group 1 and enalapril-treated group 2 (50 mg/liter, in the drinking water) underwent micropuncture studies after 2 mo of observation. After the same period of treatment, group 3 (untreated) and group 4 (enalapril treated) were used for determination of whole-kidney function and neutral dextran clearances. Group 5 (untreated) and group 6 (enalapril treated) were followed for an additional 4 mo and used for kidney function and morphological studies. Enalapril significantly lowered systolic blood pressure, which was elevated in untreated groups, and significantly reduced proteinuria (295 +/- 64 vs. 128 +/- 24 mg/24 h by the end of the study). Despite the reduced renal perfusion pressure, whole-kidney glomerular filtration rate was higher in enalapril-treated than in untreated rats (0.96 +/- 0.14 vs. 0.81 +/- 0.10 ml/min, P less than 0.05) as was the single nephron glomerular filtration rate (54 +/- 7.1 vs. 46 +/- 4.0 nl/min, P less than 0.05). The single glomerular afferent plasma flow was comparable in both groups. Enalapril reduced mean glomerular capillary hydraulic pressure from the normal value of 51 +/- 1 mmHg (untreated rats) to a value lower than normal (44 +/- 1 mmHg, P less than 0.001). These hemodynamic changes were associated with a significant reduction in afferent (approximately 23%) and efferent (approximately 26%) arteriolar resistance. The mean ultrafiltration coefficient was two times higher in the enalapril (0.126 +/- 0.027 nl/s per mmHg) than in the untreated group (0.061 +/- 0.023 nl/s per mmHg). The clearance of dextran macromolecules relative to that of inulin was significantly reduced for all molecular sizes studied (26-64 A) in enalapril-treated vs. untreated rats. Theoretical analysis of dextran fractional clearances using a heteroporous model of neutral solute transport across the glomerular capillary wall indicated that enalapril affected glomerular membrane size selective properties, reducing uniformly the radius of hypothetical membrane pores. Enalapril treatment also significantly limited (P less than 0.01) the development of glomerular structural lesions (mean percentage of sclerotic glomeruli was 4.2 +/- 3.5% [treated] vs. 28 +/- 15% [untreated] rats at the end of the study) as well as tubulo-interstitial damage. These results suggest that the protective effect of enalapril on the development of proteinuria and glomerular sclerosis in this model is due to its property of ameliorating size selectivity and hydraulic permeability of the glomerular capillaries.