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Query: UMLS:C0011849 (diabetes)
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Effect of two angiotensin convertase inhibitors, enalapril and captopril, on blood plasma and erythrocyte lipid peroxidation and plasma peroxyl radical-trapping capacity was studied in rats with streptozotocin-induced diabetes. A progressive increase in blood erythrocyte malondialdehyde (MDA) level was observed in diabetic rats after 6 and 12 weeks. Blood plasma MDA level increased while plasma peroxyl radical-trapping capacity was decreased after 12 weeks. Captopril (2 mg/kg body weight) augmented the diabetes-induced changes in MDA content after 6 weeks and prevented them after 12 weeks increasing also the peroxyl radical-trapping capacity. Enalapril (1 mg/kg body weight) counteracted the diabetes-induced changes in MDA content after both 6 and 12 weeks but did not affect the plasma peroxyl radical-trapping capacity. These results suggest a possibility of a therapeutic use of angiotensin convertase inhibitors to attenuate the effects of oxidative stress in diabetes.
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PMID:Effect of angiotensin convertase inhibitors on lipid peroxidation and peroxyl radical-trapping capacity in rats with experimental diabetes. 973 55

Both hypertension and diabetes mellitus are multifaceted dynamic expressions of pathophysiological disequilibrium that are closely related with and even intermingled by a number of common factors. Hyperinsulinaemia and insulin resistance may be possible links between hypertension and diabetes mellitus. While working on the effect of different antihypertensive agents in several animal models of simultaneously occurring diabetes-mellitus and hypertension it was found that most antihypertensives prevented streptozotocin (STZ)-induced hypertension in rats. Hydralazine, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers (CCB) and clonidine prevented STZ-induced cardiomyopathy, hyperlipidaemia and glucose tolerance. It was further demonstrated that atenolol produced many unfavourable effects like hyperlipidaemia and decreased cardiac functions. We also used other animal models of simultaneously occurring diabetes-mellitus and hypertension such as genetically hypertensive or spontaneously hypertensive (SH), Deoxycorticosterone acetate (DOCA)-hypertensive and neonatal streptozotocin-induced NIDDM rats. Results of our studies suggest that SH, neonatal STZ-induced NIDDM, and fructose hypertensive rat models may be considered as models for insulin resistance - the concept that has come into limelight in recent years. DOCA may have some influence on glucose homeostasis and insulin sensitivity and some sort of counteraction to STZ-induced cardiovascular and metabolic changes occur with DOCA. Hence, it may not be considered as an ideal model to study the metabolic and cardiovascular complications of hypertension associated with diabetes-mellitus. Among ACE inhibitors, perindopril, spirapril, and among calcium channel blockers (CCB) used in our study amlodipine and nifedipine were found to produce an increase in insulin sensitivity. Enalapril, ramipril, lisinopril and nitrendipine failed to alter insulin sensitivity as far as the glycaemic control is concerned. Extension of the results of these experiments to the clinical practice substantiated many of the findings and a good correlation between results obtained from experimental studies and clinical data was found.
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PMID:Hyperinsulinemia and insulin resistance in hypertension: differential effects of antihypertensive agents. 1005 52

1. The influence of angiotensin-converting enzyme (ACE) inhibitor is investigated in enalapril on renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneously non-insulin-dependent diabetes (NIDDM). 2. Enalapril (5 mg/kg) or vehicle was administered once daily by gastric gavage to 22-week-old male OLETF rats for 32 weeks. Blood pressure, albuminuria, creatinine clearance, plasma glucose, serum insulin and lipids were determined before and during the treatment. Renal haemodynamics was examined at the end of the treatment. 3. Enalapril lowered blood pressure mildly but significantly. In the vehicle-treated rats, urinary albumin excretion increased from 0.75 +/- 0.16 mg/mg creatinine (Cr) to 8.65 +/- 0.78 mg/mg Cr. Enalapril significantly blunted the development of albuminuria from 0.66 +/- 0.12 mg/mg Cr to 5.19 +/- 0.67 mg/mg Cr (P < 0.008) without significant influence on creatinine clearances. Enalapril also significantly blunted the rise in serum cholesterol and triglyceride prior to the development of massive albuminuria. Enalapril did not affect bodyweight, plasma glucose or insulin levels. Renal haemodynamics assessed by inulin and p-aminohippuric acid clearances were similar in both groups at the end of the treatment. 4. These results reconfirmed that the ACE inhibitor has protective effects on nephropathy in NIDDM. Massive albuminuria was preceded by increase in serum lipids in OLETF rats, which supports the view that hyperlipidaemia exacerbates glomerular injury in chronic renal disease. Enalapril attenuated the rise in serum lipids, suggesting that the beneficial effects of the compound on renal injury in OLETF rats might also be mediated through the action of affecting serum lipids.
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PMID:Hyperlipidaemia and the progression of nephropathy in OLETF rats: effect of angiotensin-converting enzyme inhibitor, enalapril. 1047 73

In the treatment of diabetic nephropathy, ACE inhibitor therapy reduces albumin excretion and slows the rate of decline in glomerular filtration rate (GFR). Our study was designed to investigate whether these effects lay in amelioration of the underlying glomerular structural abnormalities. A total of 54 type 1 diabetic patients with albuminuria and blood pressure (BP) <150/90 mmHg were randomized to receive 10 mg enalapril once daily, 10 mg nifedipine retard twice daily, or placebo in a multicenter double-blind study of 3 years' duration. Renal biopsy was performed at baseline and follow-up, and tissue was analyzed by standard morphometric methods. BP, GFR, albumin excretion rate (AER), and HbA1c were measured every 6 months. Enalapril lowered AER after 6 months by 26% (P < 0.05); however, this reduction was not sustained at 3 years. There was no significant effect of nifedipine or placebo on AER. GFR decreased by a similar average rate of 4.1 ml x min(-1) x year(-1) (95% CI 2.6-5.6) in all three groups. BP and HbA1c were unchanged throughout the study in all groups. At baseline, nearly all biopsies showed classic appearances of diabetic glomerulopathy. There was no detectable effect of enalapril compared with either nifedipine or placebo on renal structure over 3 years. However, we found that patients with increased AER have established glomerulopathy and a progressive average decline in GFR of 4.1 ml x min(-1) x year(-1) in the absence of overt hypertension, and baseline AER appeared predictive of subsequent mesangial volume fraction (r = 0.20, P = 0.0018). In this small cohort of nonhypertensive patients studied for 3 years, disease evolution appears unaffected by treatment with either enalapril or nifedipine.
Diabetes 2001 Apr
PMID:Effect of 3 years of antihypertensive therapy on renal structure in type 1 diabetic patients with albuminuria: the European Study for the Prevention of Renal Disease in Type 1 Diabetes (ESPRIT). 1128 51

Oxidative stress is involved in both the pathogenesis and complications of diabetes. ACE inhibitors can slow the progression of cardiac and renal impairments related to diabetes. The effect of enalapril treatment on oxidative stress and tissue injury was studied in hearts, kidneys, and livers from streptozotocin-induced diabetic rats. Twenty-four rats were divided into the following groups: streptozotocin (65 mg/kg, single intraperitoneal dose), streptozotocin+enalapril (20 mg enalapril/L drinking water), and control (intraperitoneal saline). Seven months after streptozotocin injection, organs were studied by light microscopy and collagen III immunolabeling. Tissue lesions and collagen labeling were graded by a semiquantitative score (0 to 4). Total glutathione content, glutathione redox status (reduced/oxidized glutathione), antioxidant enzyme activities, protein-associated sulfhydryls, thiobarbituric acid-reactive substances, and fluorescent chromolipids were determined in tissue homogenates. Glycemia was higher in both the streptozotocin and streptozotocin+enalapril groups relative to the control group. In the streptozotocin group, creatinine clearance and body weight were lower, and systolic blood pressure and urinary albumin excretion were higher than in the streptozotocin+enalapril and control groups. Heart, kidney, and liver lesion/labeling scores were significantly higher in the streptozotocin group compared with the streptozotocin+enalapril and control groups. Kidney and liver total glutathione was lower in the streptozotocin group relative to the control group (P<0.05). Enalapril treatment significantly attenuated the reduction of total glutathione. In the heart, kidney, and liver, both glutathione and proteins were relatively more oxidized in the streptozotocin group relative to the control group (P<0.05). Protein and glutathione oxidation were attenuated in the streptozotocin+enalapril group in the 3 tissues studied (P<0.05). Enalapril treatment attenuated the oxidation of lipids in the heart and kidney (P<0.05). Tissue fibrosis scores were inversely correlated with (1) both total glutathione and reduced/oxidized glutathione in heart, kidney, and liver and (2) glutathione reductase activity in the kidney. These results suggest that in streptozotocin-induced diabetic rats, the protective action of enalapril might be mediated, at least in part, by its effect on tissue oxidant/antioxidant status.
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PMID:Enalapril attenuates oxidative stress in diabetic rats. 1171 10

We have studied the effects exerted by the angiotensin converting enzyme inhibitor (ACEI) Enalapril upon the glycemic profile in diabetic rats. With respect to the subacute character of our experiment (15 days), the following parameters have been recorded: diuresis, glycosuria, ketonuria and glycemia. In the diabetic rats treated with ACEI we haven noted slight, statistically insignificant improvements in glycosuria and glycemia, compared to the untreated diabetic subjects. Conversely, a statistically significant improvement of ketonuria has been noted in the diabetic rats receiving ACEI compared to the untreated ones. The short-term administration of ACEI in experimental diabetes mellitus acutely improves the glycemic profile, probably by the amelioration of the tissular sensitivity to insulin.
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PMID:[The metabolic effects of the angiotensin converting enzyme inhibitors in experimental diabetes mellitus]. 1208 27

We have investigated the effect of potassium (E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]-2-phenylenthenesulfonamidate (YM598), a selective endothelin ET(A) receptor antagonist, on renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598 (0.1 or 1 mg kg(-1)), enalapril (5 mg kg(-1)), an angiotensin-converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male Otsuka Long-Evans Tokushima Fatty rats for 32 weeks. Enalapril but not YM598 mildly lowered blood pressure in the diabetic rats. YM598 blunted the development of albuminuria in a dose-dependent manner. High dose of YM598 reduced albuminuria comparable to enalapril. Urinary endothelin-1 excretion was greater in the diabetic than in the control rats, and was not substantially influenced by the agents. These data suggest that endothelin is involved in the progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats, and an endothelin ET(A) receptor antagonist may be useful for the treatment of diabetic nephropathy.
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PMID:Renal protective effect of YM598, a selective endothelin ET(A) receptor antagonist, against diabetic nephropathy in OLETF rats. 1220 57

Little is known about baroreflex control of renal nerve sympathetic activity (RSNA) or the effect of angiotensin II (ANG II) on the baroreflex in diabetes. We examined baroreflex control of RSNA and heart rate (HR) in conscious, chronically instrumented rats 2 wk after citrate vehicle (normal) or 55 mg/kg iv streptozotocin (diabetic) before and after losartan (5 mg/kg iv) or enalapril (2.5 mg/kg iv). Resting HR and RSNA were lower in diabetic versus normal rats. The range of baroreflex control of HR and the gain of baroreflex-mediated bradycardia were impaired in diabetic rats. Maximum gain was unchanged. The baroreflex control of RSNA was reset to lower pressures in the diabetic rats but remained otherwise unchanged. Losartan decreased mean arterial pressure (MAP) and increased HR and RSNA in both groups but had no influence on the baroreflex. Enalapril decreased MAP only in normal rats, yet the increase in HR and RSNA was similar in both groups. Thus in diabetic rats enalapril produced a pressure-independent increase in HR and RSNA. Enalapril exerted no effect on the baroreflex control of HR or RSNA in either group. These data indicate that in conscious rats resting RSNA is lower but baroreflex control of RSNA is preserved after 2 wk of diabetes. At this time, the baroreflex control of HR is already impaired and blockade of endogenous ANG II does not improve this dysfunction.
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PMID:Effect of blockade of endogenous angiotensin II on baroreflex function in conscious diabetic rats. 1252 45

Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24 mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were tested in a spatial version of the Morris water maze. After 16 weeks of diabetes, in the same groups, blood flow in the hippocampus and thalamus was measured by hydrogen clearance microelectrode polarography. In a separate study, hippocampal long-term potentiation was measured after 26 weeks of diabetes. Water maze performance and hippocampal long-term potentiation were impaired in diabetic rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic controls. Enalapril treatment significantly improved water maze performance (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats.
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PMID:Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats. 1261 50

Although recent trials have shown that antihypertensive treatment can bring about a reduction in stroke, coronary heart disease, heart failure and renal disease, the situation is no longer improving. This is due to the fact that the percentage of hypertensive patients with satisfactory blood pressure is still very poor. International guidelines on hypertension indicate the importance of assessing the absolute risk of patients and the use of a lower dose of drugs to improve the efficacy-tolerability profile. Diuretics used at lower dosage than in the past are effective in reducing morbidity and mortality and continue to be drugs of first choice in the treatment of hypertension. Indapamide sustained release (Natrilix SR) 1.5 mg has an antihypertensive effect equivalent to indapamide immediate release 2.5 mg with a 50% reduction in incidence of serum potassium levels <3.4 mmol/l. Natrilix SR has proved to have a neutral effect both on lipid and glucose profiles and to reduce microalbuminuria in diabetic hypertensive patients. Recent multicentre European clinical trials have shown that Natrilix SR decreases diastolic blood pressure to <90 mmHg in about 75% of patients treated for 1 year. In elderly patients with isolated systolic hypertension, Natrilix SR has been proven to be as effective as amlodipine 5 mg and significantly more effective than hydrochlorothiazide 25 mg. Natrilix SR produces regression of left ventricular hypertrophy which, in the Left ventricular hypertrophy: Indapamide Versus Enalapril study was greater than that induced by enalapril. Natrilix SR represents an appropriate choice not only as a first-line drug in many hypertensive patients but also in at-risk patients like the elderly, subjects with other cardiovascular risk factors, target organ damage, diabetes, or impaired renal function.
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PMID:Clinical role of Natrilix SR in the treatment of at-risk hypertensive patients. 1276 62


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