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Objective: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats. Methods: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin–eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-β (TGF-β) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR. Key finding: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-β and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril. Conclusions: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-β/Smad 2/3. [ABSTRACT FROM AUTHOR]

Background Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder resulting from a mutation of alpha-galactosidase A gene (GLA), causing deficiency in alpha-galactosidase activity. The enzyme deficit can lead to storage of globotriaosylceramide in various organs including heart. Studies suggest that vasospastic angina (VSA) is associated with AFD. Case summary This clinical case series aimed to present two female patients with AFD, including progressive cardiac involvement: a 50-year-old woman (patient number 1) and a 39-year-old woman (patient number 2) who are siblings with a male AFD patient harbouring p. Arg342Glu missense variant in alpha-galactosidase A gene (GLA), who suffered VSA and subsequent ventricular fibrillation. Enzymatic tests and genetic analysis confirmed AFD in both female patients and histological tests revealed globotriaosylceramide deposits in their hearts. In patient number 1, a 12-lead electrocardiography and transthoracic echocardiography revealed cardiac hypertrophy. Coronary angiography revealed no organic coronary artery stenosis and vasospasms was induced by spasm provocation test. In patient number 2, no signs of cardiac hypertrophy were found, and coronary arteries had no organic stenosis with negative spasm provocation test. Both patients received enalapril therapy and enzyme replacement therapy (ERT). Discussion Different phenotype of AFD was occurred even with the same genetic variant in female heterozygote patients. The duration of exposing accumulation of Gb3 might affect cardiac hypertrophy and vasospasms. Coronary angiography with acetylcholine provocation test should be considered in female AFD patient, especially in case with cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Studies on interventions that can delay or treat frailty in humans are limited. There is evidence of beneficial effects of angiotensin converting enzyme (ACE) inhibitors on aspects related to frailty, such as physical function, even in those without cardiovascular disease. This study aimed to longitudinally investigate the effect of an ACE inhibitor on frailty in aging male and female mice. Frailty was assessed with a clinical frailty index (FI) which quantifies health-related deficits in middle-aged (9-13 months) and older (16-25 months) mice. Chronic treatment with enalapril (30 mg/kg/day in feed) attenuated frailty in middle-aged and older female mice, and older male mice, without a long-term effect on blood pressure. Enalapril treatment resulted in a reduction in the proinflammatory cytokines interleukin (IL)-1α, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1a in older female mice, and an increase in the anti-inflammatory cytokine IL-10 in older male mice compared with control animals. These sex-specific effects on inflammation may contribute to the protective effects of enalapril against frailty. This is the first study to examine the longitudinal effect of an intervention on the FI in mice, and provides preclinical evidence that enalapril may delay the onset of frailty, even when started later in life. [ABSTRACT FROM AUTHOR]

We report the case of a 7-year-old unimmunized boy who presented with generalized anasarca for the first time, along with nephrotic-range proteinuria, hypoalbuminemia, microscopic hematuria and hypertension. Special investigations revealed ELISA test to be positive for hepatitis B surface antigen (HBsAg) and hepatitis B envelope antigen (HBeAg); hepatitis B viral DNA load (HBV DNA) level (real-time polymerase chain reaction) was 54 360 903 IU/ml. For hepatitis B virus (HBV)-related glomerulopathy, he was started on enalapril and lasilactone, and percutaneous renal biopsy was performed, which revealed membranous nephropathy (MN). A diagnosis of MN secondary to HBV infection contracted via horizontal transmission was made. The patient was started on peginterferon alfa-2b (50 μg/week) for 24 weeks. He failed to attain remission and seroconversion after interferon (IFN) therapy. Then, oral therapy with entecavir was started, and he attained remission as well as seroconversion after 3 months of therapy. He maintained his seroconversion status at his 6-month and the recent 12-month (quantitative HBV DNA level was 373 IU/ml) follow-up visit. Entecavir seems a promising drug for HBV-related glomerulopathy, especially in IFN-resistant cases. [ABSTRACT FROM AUTHOR]

A new chromatographic-densitometric method has been developed for the qualitative and quantitative determination of the active ingredients in a simulated mixture corresponding to the PolyIran polypill, composed of acetylsalicylic acid, hydrochlorothiazide (HCT), enalapril (ENA), and atorvastatin (ATR), whose efficacy in the treatment and prevention of cardiovascular disease has been documented in clinical trials. Chromatographic separation was performed using TLC silica gel 60 plates with fluorescent indicator F254 as the stationary phase and a mixture of n-hexane-ethyl acetate-methanol-water-acetic acid (8.4 + 8 + 3 + 0.4 + 0.2, v/v/v/v/v) as the mobile phase. Densitometric measurements were carried out at λ = 210 nm when determining ENA and at λ = 265 nm in the case of the other drugs. Peaks of examined substances were well separated in the recorded chromatograms, enabling the evaluation of the results in terms of both qualitative and quantitative analysis. The method was specific for the analyzed components and was characterized by high sensitivity. The LOD was between 0.043 and 0.331 µg/spot, and LOQ was between 0.100 and 0.942 µg/spot. Recovery was in the range of 97.02-101.34%. The linearity range was broad and ranged from 0.600 to 6.000 µg/spot for acetylsalicylic acid, from 0.058 to 1.102 µg/spot for HCT, from 0.505 to 6.560 µg/spot for ENA, and from 0.100 to 1.000 µg/spot for ATR. The method was characterized by good precision, with RSD values that ranged from 0.10 to 2.26%. [ABSTRACT FROM AUTHOR]

Aims Clinical studies suggest beneficial effects of renin–angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicininduced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity Methods and results Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/ AKT/mTOR pathway along with normal levels of CTGF Conclusion Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications. [ABSTRACT FROM AUTHOR]

The official method for the determination of Enalapril Maleate and its related substances in European Pharmacopoeia (EP) is a gradient liquid chromatographic method. The method used styrene-divinylbenzene copolymer column, mobile phase buffer pH 6.8 and column oven temperature 70°C. In this method, the separation between main component Enalapril and Ph. Eur. Imp-A was not completed hence the achieving system suitability requirement is a tough task and it requires quite often adjustment in chromatographic parameters. Moreover, column oven temperature 70°C is not user friendly to HPLC instruments and users. In this study, several changes were introduced to the method in order to improve the separation, peak shapes and to overcome the column oven temperature. A new user-friendly stability-indicating RP-HPLCmethod was developed for Enalapril related substances analysis. The developed method uses a ZORBAX Eclipse XDB-C18 column with column oven temperature at 55°C and mobile phase containing acetonitrile and a phosphate buffer at pH 3.0. The method is capable of separating all the known impurities with resolution more than 3.5, which is much better than that obtained with the existing monograph methods. The optimized method was validated and demonstrated to have acceptable specificity, sensitivity, linearity, accuracy, precision, robustness, solution stability and equivalency to the EP method. The developed method proved to be applicable to a wide number of C18 reversed-phase columns. In addition, the Enalapril assay method also presented with 20 min run time. [ABSTRACT FROM AUTHOR]

The article presents the discussion on angiotensin receptor-neprilysin inhibition in acute myocardial infarction. Topics include comparison with a standard dose of enalapril in patients with chronic HF with reduced ejection fraction (HFrEF); and use of valsartan showing to be safe but not superior to captopril in reducing all causing mortality.

Objectives To extrapolate enalapril efficacy to children 0-6 years old, a pharmacokinetic/pharmacodynamic ( PKPD) model was built using literature data, with blood pressure as the PD endpoint. Methods A PK model of enalapril was developed from literature paediatric data up to 16 years old. A PD model of enalapril was fitted to adult literature response vs time data with various doses. The final PKPD model was validated with literature paediatric efficacy observations (diastolic blood pressure ( DBP) drop after 2 weeks of treatment) in children of age 6 years and higher. The model was used to predict enalapril efficacy for ages 0-6 years. Key findings A two-compartment PK model was chosen with weight, reflecting indirectly age as a covariate on clearance and central volume. An indirect link PD model was chosen to describe drug effect. External validation of the model's capability to predict efficacy in children was successful. Enalapril efficacy was extrapolated to ages 1-11 months and 1-6 years finding the mean DBP drop 11.2 and 11.79 mmHg, respectively. Conclusions Mathematical modelling was used to extrapolate enalapril efficacy to young children to support a paediatric investigation plan targeting a paediatric-use marketing authorization application. [ABSTRACT FROM AUTHOR]

Introduction Erectile dysfunction ( ED) is frequently associated to hypertension and antihypertensive drugs; however, the penile morphological aspects on these situations are poorly known. Aim Evaluate the penile morphology of untreated hypertensive rats and rats treated with enalapril or sildenafil alone or in combination to verify the hypothesis that morphological alterations promoted by hypertension on corpus cavernosum could be ameliorated by the use of angiotensin-converting enzyme inhibitors and/or phosphodiesterase type 5 inhibitors. Methods Fifty male rats were assigned into five groups: normotensive rats, untreated spontaneously hypertensive rats ( SHRs), and SHR treated with enalapril or sildenafil alone or in combination. Blood pressure was measured weekly. At the conclusion of the study, the rats were euthanized, and their penises were collected for histomorphometrical analysis. Main Outcome Measures The cross-sectional areas of the penis, tunica albuginea, and corpus cavernosum were measured. The density of the corpus cavernosum structures was quantified. Results Both groups of SHR rats treated with enalapril became normotensive. Untreated SHR showed no difference in penile and cavernosal cross-sectional area compared with normotensive rats; however, those rats treated with enalapril or sildenafil alone demonstrated an increase in these parameters. Rats receiving combination therapy showed no cross-sectional area differences compared with normotensive rats. Cavernosal connective tissue density was increased, while the sinusoidal spaces were diminished in untreated SHR. All treatments were effective in maintaining connective tissue density in comparison with normotensive animals. Cavernosal smooth muscle density was similar in all groups, with the exception of the combination therapy group, which demonstrated a reduction in smooth muscle. Conclusions Hypertension promoted structural alterations in the corpus cavernosum that may be related to ED. Enalapril- and sildenafil-treated animals had preservation of normal corpus cavernosum structure and an increase in penile and cavernosal cross-sectional area. The combination of these drugs showed less benefit than individual use. Felix-Patrício B, Medeiros JL, Jr, De Souza DB, Costa WS, and Sampaio FJB. Penile histomorphometrical evaluation in hypertensive rats treated with sildenafil or enalapril alone or in combination: A comparison with normotensive and untreated hypertensive rats. J Sex Med 2015;12:39-47. [ABSTRACT FROM AUTHOR]

Multiple sclerosis ( MS) is a chronic inflammatory disease of the central nervous system ( CNS). Bradykinin is the end-product of the kallikrein/kinin system, which has been recognized as an endogenous target for combating CNS inflammation. Angiotensin-converting enzyme ( ACE) inhibitors influence the kallikrein/kinin system and reportedly have immunomodulatory characteristics. The objectives of this study were to determine whether bradykinin is involved in the pathogenesis of experimental autoimmune encephalomyelitis ( EAE), an animal model of MS, and whether bradykinin control by the ACE inhibitor could be a therapeutic target in MS. The ACE inhibitor enalapril (1·0 or 0·2 mg/kg/day) was administered orally to EAE mice and the serum levels of bradykinin and cytokines in EAE mice were analysed. As a result, the administration of enalapril increased serum bradykinin levels, decreased the clinical and pathological severity of EAE and attenuated interleukin-17-positive cell invasion into the CNS. Additionally, bradykinin receptor antagonist administration reduced the favourable effects of enalapril. Our results suggest that bradykinin is involved in the pathomechanism underlying CNS inflammation in EAE, possibly through inhibiting cell migration into CNS. Control of the kallikrein/kinin system using ACE inhibitors could be a potential therapeutic strategy in MS. [ABSTRACT FROM AUTHOR]

Aims: This study investigated the effects of irbesartan vs. enalapril, with early vs. late treatment, on markers of inflammation and ischaemic heart disease in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). [ABSTRACT FROM PUBLISHER]

Purpose. A case of apparent seizure and atrial fibrillation associated with paliperidone is reported. Summary. A 46-year-old man arrived at the emergency room (ER) via ambulance. Earlier that morning, his wife observed him awakening in a panic, drifting back to sleep, and then subsequently awakening in a panic with an apparent seizure lasting one to two minutes. The episode included tongue biting and urinary incontinence. His medical history included bipolar disorder, diabetes mellitus, hyperlipidemia, and hypertension. The patient's medications included metformin, insulin glargine, insulin lispro, simvastatin, enalapril, escitalopram, lamotrigine, and clonazepam and had not changed for many months except for the recent addition of paliperidone four days before his arrival at the ER. Electrocardiography revealed atrial fibrillation, a ventricular rate of 151 beats/min, a Q-Tc interval of 461 msec, and no significant changes in the ST segment or T wave. He had no chest pain, and all other laboratory test results and vital signs were normal. The patient was admitted for evaluation and given a single oral dose of potassium chloride. Diltiazem i.v. was administered with resultant conversion to normal sinus rhythm, after which the patient's heart rate and Q-Tc interval normalized. The patient was discharged after one day. Conclusion. A man taking paliperidone and multiple other drugs experienced atrial fibrillation and a possible seizure. Although these are known adverse effects of atypical antipsychotics, it is unusual to have both events occur concurrently and with lowto- average dosages, and these events have not been associated with paliperidone in published case reports. [ABSTRACT FROM AUTHOR]

Background: Blood pressure control is the main influential variable in reducing microalbuminuria in patients with type 2 diabetes. In this subanalysis of the Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetics with micrOalbuminuRia (NESTOR) study, we have compared the effectiveness of indapamide sustained release (SR) and enalapril in reducing blood pressure and microalbuminuria in patients ≥65 years of age. Methods: Of the 570 hypertensive patients with type 2 diabetes and persistent microalbuminuria in the NESTOR study, 187 (33%) individuals ≥65 years of age were included in this analysis. Of these, 95 patients received indapamide SR 1.5 mg and 92 patients received enalapril 10 mg, taken once daily in both cases. Adjunctive amlodipine and/or atenolol was added if required. Results: The urinary albumin-to-creatinine ratio decreased by 46% in the indapamide SR group and 47% in the enalapril group. Noninferiority of indapamide SR over enalapril was demonstrated (P = .0236; 35% limit of noninferiority) with a ratio of 0.95 (95% CI: 0.68, 1.34). Mean arterial pressure decreased by 18 mm Hg and 15 mm Hg in the indapamide SR and the enalapril groups, respectively (P = .1136). The effects of both treatments seen in these elderly patients were similar to those observed in the main population, although the extent of the reduction in microalbuminuria was slightly higher. Both treatments were well tolerated, and no difference between groups was observed regarding glucose or lipid profiles. Conclusion: Indapamide SR is not less effective than enalapril in reducing microalbuminuria and blood pressure in patients aged >65 years of age with type 2 diabetes and hypertension. [Copyright &y& Elsevier]

Background: It is suggested that appropriate chronic exercise (EX) may produce improvements of the physical strength in patients with chronic renal failure (CRF). Because acute exercise causes proteinuria and decreases the renal blood flow and glomerular filtration rate, it is necessary to consider the influence of EX on renal function. Therefore, we assessed the renal and peripheral effects of moderate to intense EX as well as the effects of the combination of EX and enalapril (ENA) in a rat model of CRF. Methods: Male 5/6-nephrectomized Wistar-Kyoto rats were divided into six groups according to the following treatment: 1) no exercise (C); 2) ENA (2 mg/kg/day, subcutaneously); 3) moderate exercise with treadmill running (20 m/min for 60 min/day, 5 days/week) (EXm); 4) intense exercise with treadmill running (28 m/min for 60 min/day, 5 days/week) (EXi); 5) EXm+ENA; and 6) sham operation (S). The rats were then treated for 12 weeks. Results: Both EX and ENA blocked the development of hypertension, blunted increases in proteinuria, reduced serum creatinine and blood urea nitrogen, and improved the index of glomerular sclerosis (IGS) and the relative interstitial volume of the renal cortex (RIV). Moreover, IGS and RIV in the EXm+ENA group were the lowest among all other nephrectomized groups. Furthermore, EXm+ENA enhanced capillarization as well as the proportion of type-I fiber in the soleus muscle. Conclusions: These results suggest that EX and ENA have renoprotective effects. The findings also suggest that EXm+ENA provided greater renoprotective effects than those of ENA alone, and that EXm+ENA had some additional peripheral effects without any complications in this rat model. [Copyright &y& Elsevier]

Background: Most treated hypertensive patients do not achieve adequate blood pressure (BP) control. Initiating therapy with two drugs has been suggested when BP is >20/10 mm Hg above goal. To ensure patients’ compliance, such treatment needs to be well tolerated and must not compromise health-related quality of life (HRQL). The primary objective of this study was to compare the effects on HRQL of initiating treatment with felodipine + metoprolol (F+M) fixed combination tablets, or enalapril (E), or placebo (P). Methods: A total of 947 patients of both sexes with primary hypertension (diastolic BP 95 to 110 mm Hg), aged 20 to 70 years, participated in this randomized, double-blind, parallel group, 12-week, multicenter trial. Treatment was initiated with F+M 5 + 50 mg, or E 10 mg, or P. Doses were doubled after 4 or 8 weeks if diastolic BP was >90 mm Hg. The HRQL was measured at baseline and at the last visit using two validated questionnaires: the Psychological General Well-being Index (PGWB) and the Subjective Symptom Assessment Profile (SSA-P). Office BP was measured at trough, that is, 24 h after the previous dose. Results: The HRQL was high at baseline and generally well maintained during the study. For example, the mean (SD) PGWB total score was 104 (16) at baseline and 105 (16) at 12 weeks in all three treatment groups. The BP reductions after F+M (18/14 mm Hg) and E (12/9 mm Hg) were significantly greater than after P (7/7 mm Hg), and the reduction after F+M was significantly greater than after E. Conclusions: The HRQL is maintained in the presence of substantial BP reduction during antihypertensive treatment with F+M fixed combination tablets. [Copyright &y& Elsevier]

Background: Tissue factor (TF), the main trigger of coagulation is important in the propagation of cardiovascular diseases. Based on an in vitro study, we hypothesised that enalapril may blunt the endotoxin-induced, TF-triggered coagulation in humans. Methods: In a randomised, controlled trial, 30 healthy male volunteers received 2 ng/kg of lipopolysaccharide (LPS) after pre-treatment with placebo or enalapril for 5 days or with enalapril 2 h before LPS infusion. Results: Infusion of LPS increased interleukin-6 levels 400 fold, and induced a 10-fold increase in prothrombin fragment, a fourfold increase in d-dimer, and a fivefold increase in plasmin–antiplasmin complexes. However, pre-treatment with enalapril did not blunt LPS-induced coagulation. Conclusions: Our trial provides evidence against a modulatory role of angiotensin converting enzyme in LPS-induced, TF-triggered coagulation. [Copyright &y& Elsevier]

: BackgroundRecent studies indicate that the coexistence of hypertension and glucose intolerance leads to impairment in saline volume-induced diuresis and natriuresis. Furthermore, taurine and enalapril affect renal function and blood pressure (BP). Therefore, we tested the hypothesis that therapy combining taurine and enalapril would confer greater antihypertensive activity and responsiveness to saline volume loading in the hypertensive glucose-intolerant (HGI) rat than either agent alone.: MethodsHypertensive (H) and HGI rats were treated from 6 weeks to 6 months with tap water containing no addition, taurine (0.25%), enalapril (15 mg/kg/day), or the taurine–enalapril combination. Hemodynamic and renal responses to an intravenous isotonic saline volume load were then determined in the conscious animal.: ResultsThe vehicle-treated HGI rats displayed reduced saline volume-induced diuresis and natriuresis relative to their H counterparts. Although none of the three drug regimens affected BP, they were similarly effective in increasing the renal excretory responses to saline volume loading and in eliminating differences that existed between the untreated H and HGI groups. Although reduced tubular reabsorption activity contributed to the taurine- and enalapril-mediated augmentation in renal excretory function, enalapril also enhanced glomerular function. The augmentation in the glomerular filtration rate was greatest in the HGI rat treated with the combination of taurine and enalapril. Furthermore, all three drug regimens significantly reduced protein excretion in both H and HGI rats.: ConclusionsDespite exerting no influence on BP, all three drug regimens were renoprotective, as indicated by the drug-mediated improvement in kidney function of the HGI rat. [Copyright &y& Elsevier]

: BackgroundMany alterations in extracellular metabolism of calcium have been associated to hypertension, but the number of studies relating this disease with osteoporosis is extremely low. This study clarifies the therapeutic effect of three treatments—quinapril, quinapril + hydrochlorothiazide (HCTZ), enalapril—on bone remodeling markers, bone mineral density (BMD) in hypertensive patients, and relationship with angiotensin converting enzyme (ACE) polymorphism.: MethodsThis open, prospective study included 134 patients with low-to-moderate hypertension and stable BMD according to Joint National Committee criteria and 96 patients completed the study. After a washout period, patients were randomized to one of the three treatments, which they received for 1 year. Analyses of blood and urine samples and densitometric studies on lumbar spine were performed.: ResultsCalcium and 25-hydroxyvitamin D levels increased (9.5 ±0.3 and 9.6 ±0.3 mg/dL, P = .01 and 46 ±22 and 58 ±22 nmol/L, P = .026, respectively) in the quinapril-treated group and calcium levels increased (9.4 ±0.6 and 9.8 ±0.4 mg/dL, P = .001) in the quinapril-HCTZ-treated group. The 1, 25-dihydroxyvitamin D levels, calciuria, and calcium/creatinine ratio decreased (64 ±23 and 43 ±16 nmol/L, P = .0001;209 ±93 and 161 ±93 mg/24 h, P = .0022;0.21 ±0.09 and 0.17 ±0.11, P = .04, respectively). In the enalapril-treated group 1, 25-dihydroxyvitamin D levels (61 ±27 and 42 ±19 nmol/L, P = .0022) decreased. Only women presented a statistical significance (1.064 ±0.16 g/cm2, P = .034) between ID+II polymorphism and BMD decrease, and between DD polymorphism with less BMD under baseline conditions and a BMD increase (1.070 ±0.16 g/cm2, P = .017) after ACE inhibitor treatment.: ConclusionsThe ACE inhibitors have a beneficial effect on BMD and calcium metabolism alterations in hypertensive subjects. Concerning BMD response, women presenting with the II+ID polymorphism had a poor response to antihypertensive drug treatment, whereas women with the DD polymorphism responded better. This is the first study demonstrating a relationship between ACE polymorphism and BMD response and antihypertensive ACE inhibitor treatment. [Copyright &y& Elsevier]

Evidence links the insulin resistance syndrome with endothelial dysfunction. Previously, we have described a decreased endothelial nitric oxide synthase (eNOS) activity in both aortic endothelium and cardiac tissue, and an increased proliferation of aortic primary cultured vascular smooth muscle cells (pC-VSMCs), obtained from fructose-fed rats (FFR), an experimental model of syndrome X. Because the participation of the renin-angiotensin system (RAS) in this model is still unclear, the present study examined the effect of chronic administration of an angiotensin converting enzyme (ACE) inhibitor enalapril (E) on pC-VSMCs proliferation and eNOS activity in a conduit artery (aorta) and in resistance vessels (mesenteric vascular bed) from fructose-fed rats. Male Wistar rats were used: Control, FFR, Control + E, and FFR + E (n = 8 in each group). After 8 weeks, tissue samples were obtained and 10% fetal calf serum (FCS) proliferative effect was examined in pC-SMCs of aortic and mesenteric arteries by [3H]thymidine incorporation. The eNOS activity was estimated in endothelial lining from both origins by conversion of [3H]arginine into [3H]citrulline. The FFR aortic and mesenteric pC-VSMCs showed a significantly increased 10% FCS-induced [3H]thymidine incorporation compared to controls. The FFR aortic and mesenteric endothelium eNOS activity was significantly decreased. Chronic treatment with E abolished the increased proliferation and restored eNOS activity. These data confirm that changes in VSMCs proliferation and endothelial dysfunction at different levels of the vascular system are involved in syndrome X, and that the inhibition of angiotensin II production can revert those changes, suggesting an important role for RAS and possibly kinins, in the physiopathologic mechanism of this model of syndrome X. [Copyright &y& Elsevier]

: BackgroundThe excess morning risk of myocardial infarction and stroke may be attributable to the rapid rise in blood pressure (BP) and heart rate in the hours after awakening. The aim of this randomized, double-blinded, placebo-controlled, multicenter study was to compare once-daily, controlled-onset, extended-release (COER-24) verapamil to enalapril and losartan on BP and heart rate during the postawakening morning phase as well as throughout the 24-h period.: MethodsA total of 406 patients were randomized to an 8-week forced-titration period with one of the following: 1) COER-24 verapamil 240 mg/day titrated to 360 mg/day; 2) enalapril 10 mg/day titrated to 20 mg/day, 3) losartan 50 mg/day titrated to 100 mg/day, or 4) placebo. Office BP and heart rate and ambulatory 24-h BP monitoring was performed at baseline, 4 weeks, and 8 weeks.: ResultsEach active treatment, as compared with placebo, lowered BP both during the morning hours as well as the entire 24-h period. COER-24 verapamil was more effective in lowering morning systolic (−16.6 mm Hg) and diastolic (−11.9 mm Hg) BP than either enalapril or losartan (P < .001). For the entire 24-h period, the effects of COER-24 verapamil (−11.6/−8.4 mm Hg) were comparable to enalapril (−13.4/−8.3 mm Hg; P = NS). Losartan achieved a similar 24-h effect on systolic pressure (−9.3 mm Hg) but was less effective on diastolic pressure (−5.4 mm Hg; P = .004 v COER-verapamil). Unlike losartan or enalapril, COER-24 verapamil was the only treatment to lower the heart rate over both the 24-h period (−4.6 beats/min; P < .001) and during waking hours (−4.6 beats/min; P < .001). A blunted rate of rise in BP, heart rate, and rate–pressure product occurred during the postawakening period with COER-verapamil (P = .03) but not with either of the other treatment arms. Lastly, the decline in BP at night was similar for COER-verapamil and losartan and greater with enalapril (P = .014): ConclusionsCOER-24 verapamil produces changes in BP and pulse that more closely match the normal circadian hemodynamic rhythms than either do enalapril or losartan. [Copyright &y& Elsevier]

BackgroundAngiotensin converting-enzyme (ACE) inhibitors used for the treatment of heart failure relieve symptoms, increase exercise performance, reduce hospital admissions and prolong life. The large survival studies have used higher doses of ACE inhibitors than those commonly used in clinical practice. NETWORK was set up to compare the effect of dose on the clinical outcome of ACE inhibition.Methods and patients1532 patients with heart failure drawn from primary care (n=619) and hospital sources (n=913) were randomized to receive enalapril 2·5mg twice daily (n=506), 5mg twice daily (n=510) or 10mg twice daily (n=516). The mean age was 70 years and 65% were male. Coronary heart disease was the cause of heart failure in 71%. Sixty-five percent were in NYHA class II and 35% in class III or IV. The mean left ventricular end-diastolic diameter was 59 (SD11)mm. The incidence of the primary end-point of death, heart failure related hospitalization or worsening heart failure was assessed after follow-up of each patient for 24 weeks.FindingsThe number of patients reaching the primary end-point was 62 (12·3%) in the 2·5mg twice daily group, 66 (12·9%) in the 5mg twice daily group and 76 (14·7%) in the 10mg twice daily group. Deaths in each group were 21 (4·2%), 17 (3·3%) and 15 (2·9%), respectively. There were no significant differences in the results between the three groups. The crude relative risk for the combined end-point in the 10mg twice daily group compared to the 2·5mg twice daily group was 1·20 (95% CI 0·88 to 1·64).InterpretationNETWORK did not demonstrate a relationship between dose of enalapril and clinical outcome in patients with heart failure selected from both primary care and hospital practice. [ABSTRACT FROM PUBLISHER]

Blood pressure should be controlled over 24 h to reduce or prevent cardiac hypertrophy and reduce the prevalence of sudden death, myocardial infarction and myocardial ischaemia at the time of the morning rise in blood pressure. Anti-hypertensive medication is usually given once-daily in the morning and the dose is titrated on the basis of post-dose (peak) blood pressure. This frequently leads to inadequate control prior to the next drug dose unless drugs with appropriate pharmacokinetics or pharmacodynamics are used. ACE inhibitors exhibit an Emax plasma concentration:blood pressure response relationship, and thus short-acting ACE inhibitors can exert an effect over 24 h if titrated based on pre-dose (trough) blood pressure. However, when titrated in clinical practice on post-dose (peak) blood pressure response, doses are used that are inadequate to control blood pressure for 24 h. ACE inhibitors with appropriate pharmacokinetics such as perindopril can control blood pressure when titrated at peak provided a dose is used (4 or 8 mg) that is known to have a T:P close to 1·0. Shorter-acting ACE inhibitors frequently give inadequate control when titrated at peak.An understanding of the pharmacokinetics and pharmacodynamics of a drug, coupled with knowledge of the time the drug was taken, together with the time of blood pressure measurements, enables control to be achieved with once-daily therapy even if the drug is titrated at peak response. [ABSTRACT FROM PUBLISHER]

Objective The present study was designed to evaluate the effects of early angiotensin converting enzyme (ACE) inhibition on left ventricular enlargement in patients with anterior wall infarction following reperfusion therapy. Methods Seventy-one consecutive patients with an anterior wall myocardial infarction were randomly allocated to enalapril (n=36) or placebo (n=35). All patients received either thrombolytic therapy (n=46) or underwent primary coronary angioplasty (n=25). Medication was started within 48 h admission to hospital and continued for 48 weeks. The process of left ventricular remodelling was assessed with two-dimensional echocardiography at 3 weeks and 1 year after the acute onset, and was related to the severity of the residual stenosis of the infarct-related artery. Results Baseline left ventricular ejection fraction was 39·2±8·7%. During the study period, left ventricular end-diastolic volume index increased from 48·2±9·9 ml. m−2 to 54·6±12·2 ml. m−2 at 3 weeks, and to 59·4±170 ml. m−2 after 1 year in control patients (P<0·001). In the enalapril-treated patients, left ventricular end-diastolic volume index increased from 50·0±16·1 to 57·7±19·3 ml. m−2 at 3 weeks, and to 61·9±22·7 ml. m−2 after 1 year (P<0·001). Both at 3 weeks and after 1 year, no overall differences in left ventricular volumes were observed between the enalapril and the placebo group (both ns). However, patients with a residual stenosis severity of ≥70% in the infarct-related artery (n=43) showed significant attenuation of remodelling by enalapril (n=22) when compared to placebo (n=21). In patients on enalapril, left ventricular end-diastolic volume index increased from 470±130 to 53·7±17·7 ml. m−2 compared to 48·0±9·6 to 60·3±16·3 ml . m−2 in control patients (P<0·03). Also diastolic filling parameters were significantly improved in patients with ≥70% residual stenosis. Conclusion In patients with an anterior wall infarction and a severe residual infarct-related coronary artery stenosis following reperfusion, treatment with enalapril prevents the process of left ventricular remodelling. As left ventricular dilatation is an early process we suggest that treatment with ACE inhibition should be started as soon as possible in this group of patients. [ABSTRACT FROM PUBLISHER]

Angiotensin converting enzyme inhibitors improve symptoms and prolong life in congestive heart failure, but the dose in the individual patient is uncertain. A randomized, 48-week, double-blind study was performed to investigate the safety and efficacy of 0‘high’ in comparison to continued ‘low’ angiotensin converting enzyme inhibitor therapy in severe heart failure. Eighty-three patients (56 ±11 years; 69 men, 14 women) in New York Heart Association functional class III/TV on digoxin, furosemide and ‘low’ angiotensin converting enzyme inhibitors (captopril ≤50mg.day−1 or enalapril ≤10 mg. day−1) were included. After a ≤14 day run-in on lOmg.day−1 enalapril, digitalis and furosemide, right heart catheteriz-ation at rest and exercise was performed. All patients presented with atrial pressure >10mmHg and/or pulmonary artery pressure >35mmHg, and/or cardiac index <2·51. min−1. m−2 at rest. Patients then received enalapril 5 mg twice daily (n=42), or 20 mg twice daily (n=41) in random order. Thus, patients randomized to low doses of enalapril actually had no change in therapy from baseline to 48 weeks. Forty-three patients (52%) completed the study, 19 patients on the low dose and 24 patients on the high dose. Both dosages equally influenced survival with 15 (18%) deaths, eight on low dose and seven on high dose. After 48 weeks, functional capacity by New York Heart Association class improved more on the high dose than on the low dose (P=004). In contrast, alterations in invasive haemodynamic variables at rest and exercise as well as maximal exercise capacity were comparable in both groups. Diastolic blood pressure decreased and the change between both groups was statistically significant (P=0·01). Changes in plasma creatinine levels did not differ between high and low dose treatment and no patients had to be withdrawn because of deterioration in kidney function. With regard to neurohumoral activity, a tendency to a discrepant response to both treatments was observed with a blunted increase in noradrenaline on high versus low enalapril dose. Thus, high-dose enalapril treatment proved superior to low dose as regards symptomatology in severe heart failure after long-term treatment, despite similar effects on haemodynamics and on maximal exercise capacity. [ABSTRACT FROM PUBLISHER]

In this double-blind placebo-controlled study with enalapril, 74 patients with acute myocardial infarction were followed at 0, 7, 30, 60 and 180 days after the event. Platelets and leukocytes were activated during the first 7 days. During the 6-month period fibrinogen, leukocytes, elastase, and Bβ 30–43 remained elevated in 50, 15, 30 and 80% of the patients, respectively, but there was no detectable angiotensin converting enzyme activity in platelets. Enalapril did not modulate fibrinogen, leukocyte count or elastase, while Bβ 30–43 peptide showed decreased levels, although the proportion of patients with values above the reference limit did not differ from placebo. In conclusion, in the 6-month post acute myocardial infarction period, while platelet function is activated only during the first week after acute myocardial infarction, fibrinogen and leukocyte function continue to be activated throughout the 6 months in a considerable proportion of patients. These signs may indicate an ongoing atherosclerotic process. Enalapril has no major influence on these reactivities. [ABSTRACT FROM PUBLISHER]

Large-scale drug trials have focused primarily on mortality and morbidity and less on the functional state of the myocardium. A model was developed to assess myocardial contractile state in patients with left ventricular (LV) dysfunction and to address the questions of differences in function between patients with and without overt heart failure, effects of enalapril, and best predictors of functional outcome. Pressure-angiographic data were obtained from 16 patients with overt heart failure and 47 without heart failure. Repeat studies were conducted in 41 patients following 1 year's treatment with enalapril or placebo. Left ventricular silhouettes were divided into 18 segments to estimate regional ejection fraction, wall stress and myocardial damage (% myocardial damage). Contractile state was assessed and ranked by ejection rate-preload-afterload relationships and by a score method based on 10 myocardial and ventricular function parameters. End-diastolic and end-systolic volumes (EDV, ESV) were significantly greater (P<0·001), ejection fraction (EF) lower (P<0·009), % myocardial damage greater (P<0·008) and contractile state more depressed in patients with overt heart failure. Changes in EDV and ESV (Δplacebo vs Δenalapril) were significant (ΔEDV, P<0·003; ΔESV, P<0·014). Directional shifts in the diastolic pressure-volume relationships with enalapril or placebo depended primarily on the basal contractile state and diastolic volume range. The best single predictors of post-treatment EF were the score index (a surrogate parameter for the contractile state) and ESV. Added benefits of enalapril include the prevention of further dilatation in patients with less depressed contractile state and delay in the onset of heart failure. Asymptomatic patients with LV dysfunction should also be considered for angiotensin converting enzyme (ACE) inhibitor therapy. [ABSTRACT FROM PUBLISHER]

In view of growing scepticism as to the efficacy and safety of agents with predominant phosphodiesterase inhibiting properties in heart failure, the clinical efficacy and safety of pimobendan, a calcium-sensitizing and partially phosphodiesterase-inhibiting compound, was compared with enalapril in 242 patients with mild to moderate heart failure (NYHA classification II-III) despite diuretics and digitalis, and abnormal haemodynamics at baseline. Patients were randomly assigned to either pimobendan (average 10.3 mg. day, 1, n=119), or enalapril (average 10.7 mg. day, n=123) in a double-blind fashion for 6 months. Forty-two pimobendan and 37 enalapril patients stopped the treatment, five pimobendan and six enalapril due to worsening of failure without death, whereas 13 and eight patients, respectively, died from cardiac disorders (ns). Other reasons for discontinuation and adverse events not leading to discontinuation were also comparable. Although Holier analysis at 14 days, but not at 6 months, indicated increased ventricular extrasystoles in pimobendan patients, these did not lead to serious clinical events. NYHA classification improved similarly in both groups, from 2.51 to 2.16 (pimobendan) and from 2.40 to 2.06 (enalapril). The number of patients needing a change in background therapy or hospitatization did not differ between the two groups. Haemodynamic variables at rest were improved by both compounds after 6 months. In contrast, only enalapril improved haemodynamics during exercise, and reduced the cardiothoracic ratio. The primary endpoint, exercise capacity, increased significantly during the first 3 months by 45 and 53 s, under pimobendan and enalapril, respectively, but, although unchanged thereafter, the improvement was no longer statistically significant at 6 months in either group. These data indicate that the calcium sensitizer and partial phosphodiesterase inhibitor pimobendan improves clinical status and exercise tolerance during long-term treatment in mild to moderate heart failure. With the doses used in this study, there was no significant difference between pimobendan and enalapril in therapeutic efficacy and, within the limitations of the study, in safety. This suggests that the usefulness of pimobendan as adjunct ive therapy to diuretics and, possibly, to converting enzyme inhibitors in heart failure patients, should be further evaluated. [ABSTRACT FROM PUBLISHER]

The effects of angiotensin converting enzyme (ACE) inhibitors on mortality following acute myocardial infarction (MI) has recently been studied in several clinical trials. The rationale for the use of these drugs following an injury to the myocardium is largely based on their ability to attenuate left ventricular volume expansion and modulate neurohormonal activation. Left ventricular dilatation following MI is due to complex structural changes in the infarcted myocardium as well as alterations in the non-infarcted contractile myocardium. The magnitude of this remodelling is associated with adverse prognosis. Neurohormonal systems are activated in the early phase of acute Ml. Prolonged neurohormonal activation mainly occurs among patients with marked left ventricular dysfunction. The CONSENSUS II trial examined the effects on mortality of the ACE inhibitor enalapril, when initiated within 24 h from the onset of the infarct and continued for 6 months. There were 6090 patients randomly assigned to placebo (n = 3046) or enalapril (n= 3044). At the end of the trial, 598 patients had died: 286 (9.4%) in the placebo group and 312 (10.2%) in the enalapril group (P = 0.26). These results are in contrast to some other studies in which mortality was reduced by ACE inhibitor therapy post-MI. It is considered likely that the positive effects of ACE inhibitors following MI are confined mainly to patients with marked left ventricular dysfunction and prolonged neurohormonal activation. [ABSTRACT FROM PUBLISHER]

Plasma neurohormones were sequentially analysed in 98 patients with acute myocardial infarction randomized to treatment with enalapril or placebo for 4–6 months. Plasma angiotensin converting enzyme activity was rapidly suppressed by enalapril, but unaffected by placebo ( = 0.0001). No significant differences were found in the plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide, noradrenaline, adrenaline or dopamine between the two treatment groups. Among patients with infarct size above median, plasma angiotensin II increased during head-up tilt at one month in the placebo group, but not in the enalapril group. Left ventricular end-diastolic volume (LVEDV) and left ventricular endsystolic volume (LVESV) were evaluated by echocardiography in 28 patients (placebo 15, enalapril 13) and changes in left ventricular volumes between baseline and 4–6 months were calculated. Only in the placebo group was a positive correlation found between plasma levels of noradrenaline at day 5–7 and the subsequent increase in LVEDV (r = 0.78, = 0.005) and LVESV (r = 0.75, = 0.008). The same trend was found for angiotensin II, adrenaline and dopamine levels at days 5–7 and the subsequent increase in left ventricular volumes. In the placebo group a negative correlation was found between plasma aldosterone at days 5–7 and the subsequent increase in left ventricular ejection fraction (r = −0.77, = 0.006) during the study period. Although circulating neurohormones were not significantly influenced by enalapril treatment, it is concluded that enalapril may influence the relationship found between sustained neurohormonal activation and left ventricular remodelling after acute myocardial infarction. [ABSTRACT FROM PUBLISHER]

Ten patients with severe (NYHA III) heart failure were compared with 10 age-matched healthy subjects in terms of oxygen uptake and minute ventilation at rest and during exercise and calf and forearm blood flow measured by venous occlusion plethysmography at rest and after a standardized exercise test. Patients performed a symptom-limited treadmill exercise test and were then treated with enalaprilfor 5 weeks; the various measurements were repeated at weekly intervals. Oxygen consumption (VO) at rest was similar in the patients and controls. During exercise, patients VO, tended to be lower at each workload, but this was not affected by enalapril treatment. Minute ventilation was higher at rest and at each exercise stage in the patients than in the control subjects, and this was significantly reduced by enalapril treatment. Compared with the controls (2.94±0.10 and 2.93±0.20 ml, 100 mlmin) forearm and calf blood flow measured by venous occlusion plethysmography was reduced at rest in the patients (1.34±0.18 and 1.24±0.11 ml. 100 ml . minmin), but was significantly increased by enalapril treatment (1.73±0.15 and 1.60±0.16 ml. 100 ml . min). Submaximal leg exercise to a fixed VO, showed attenuation of the normal vasoconstriction in the forearm and vasodilatation of the calf; enalapril treatment changed these responses significantly towards normal but a marked abnormality of flow pattern persisted. [ABSTRACT FROM PUBLISHER]

Bv using biopsies, skeletal muscle metabolism was investigated in 22 patients with severe chronic heart failure. All the patients were in New York Heart Association functional class IV and constituted a subgroup of the previously published CONSENSUS trial. After this initial investigation of muscle metabolism in patients with chronic heart failure, the influence of the angiotensin converting enzyme inhibitor, enalapril, on skeletal muscle metabolism was studied by randomizing the patients in a double-blind manner to receive either placebo (n = 11) or enalapril (n =11) in addition to conventional treatment. At the time of inclusion, the muscle content of energy-rich compounds, i.e. glycogen and the high energy phosphates, adenosine triphosphate (A TP) and phosphocreatine, was reduced as compared with healthy subjects and muscle lactate content tended to be higher than normal. Following study treatment, no significant changes occurred, neither within nor between the two subgroups. Thus, patients with severe chronic congestive heart failure display metabolic derangement in muscle, which, in this study, was not corrected by treatment with enalapril. [ABSTRACT FROM PUBLISHER]

The effects of flosequinan and enalapril on exercise capacity (bicycle exercise duration), quality-of-life symptomatology (visual analogue scales) and New York Heart Association (NYHA) grading, were compared in 61 patients with chronic heart failure (N YHA, grade III). Bicycle exercise duration improved similarly with flosequinan ( + 27%) and enalapril ( +18%); in patients completing the study, flosequinan produced a significantly greater increase in exercise time at week 12, compared with enalapril (P = 0.02). Improvements in visual analogue scores relating to general health, energy and vitality, ability to perform physical activities and breathing performance, were equivalent for both drugs. Changes in N YHA classification showed that 27 (55% ) of 49 patients completing the study had improved by at least one N YHA grade (15 (68%) patients on flosequinan; 12 (44%) on enalapril). The overall safety and tolerability of the two treatments was similar; 18 patients reported adverse effects while on flosequinan, compared with 19 patients on enalapril. Neither treatment was associated with any clinically important changes in haematological or biochemical variables, although some treatment-related effects were observed. This study confirms that flosequinan achieved similar efficacy to enalapril in the symptomatic relief of chronic heart failure. The effect of flosequinan on survival in chronic heart failure has not been tested; pending such studies, our data suggest that it may prove a useful alternative therapy in patients where ACE inhibitors are contraindicated or poorly tolerated. [ABSTRACT FROM PUBLISHER]

To investigate the electrolyte and water content in peripheral skeletal muscle in patients suffering from severe chronic congestive heart failure, New York Heart Association functional class IV, and to study the influence of the angiotensincon verting enzyme inhibitor, enalapril, 22 patients were randomized in a double-blind study to receive either placebo (n= 11) or enalapril (n= 11) in addition to their conventional treatment. The patients included a subgroup in the previously published CONSENSUS study. At the beginning of the study, the content of potassium and magnesium was signficantly reduced in muscle as compared with healthy subjects while sodium and water were increased. The muscle content was not predictable from the serum concentrations of the electrolytes. Following study treatment no significant changes occurred, neither within nor between the two subgroups. Thus, patients with severe chronic congestive heart failure, New York Heart Association functional class IV, displayed disturbed electrolyte and water content in muscle, which, in this study, was not corrected by treatment with enalapril. [ABSTRACT FROM PUBLISHER]

We evaluated the cardiopulmonary exercise lest results before and after long-term (16 weeks) treatment with the dihydropyridine calcium antagonist, felodipine (10 mg b.i.d., n = 9), and the ACE inhibitor, enalapril (10 mg b.i.d., n = 11), in 20 patients with New York Heart Association class 111 congestive heart failure. There were no significant differences at baseline. After 16 weeks patients in the enalapril group showed a significant increase in exercise duration and VO, without changes in arterial pressures and heart rate. In the felodipine group, exercise duration and VO did not change significantly, but arterial pressures and heart rate were significantly reduced at all exercise levels. Between group analysis showed a significant reduction in arterial pressures and heart rate'in the felodipine group compared with enalapril, but no differences in aerobic capacity and exercise duration. These results demonstrate that felodipine and enalapril have essentially different effects on cardiopulmonary exercise results in patients with congestive heart failure. [ABSTRACT FROM PUBLISHER]

An earlier controlled trial showed that over an average of 26 months, enalapril slowed the progression of chronic renal failure. Following completion of the trial, the patients continued to receive antihypertensive treatment according to ordinary clinical criteria. All but four patients in the enalapril group remained on that drug, and two patients in the control group were switched to an angiotensin-converting enzyme (ACE) inhibitor. In the present study the fate of the 70 patients 44 months after termination of the trial was investigated, with a total follow-up of around 7 years. In the original enalapril group, 12 of the 35 patients (34%) were alive without renal replacement therapy versus five of the 35 patients (14%) in the control group. This difference of 20% in favour of having been in the enalapril group in the original trial was significant (=0.05; 95% confidence limits 0.5–39.5%). The influence of baseline proteinuria on clinical outcome was analysed. In the original control group, baseline renal clearances of albumin (C) and immunoglobulin G (C) were significantly lower in patients surviving without renal replacement therapy at follow-up than in patients who ultimately developed end-stage renal failure (ESRF) (<0.05). In the original enalapril group, these baseline clearances were equal in the two renal outcome groups. In all patients, baseline C and C were negatively correlated with the rate of change in GFR during the controlled trial (=−0.37, <0.01 and =−0.28, P<0.05). In all patients alive without renal replacement therapy at follow-up, independent of their original treatment, the initial (1–8 weeks) fractional Caib was 79% of baseline, significantly less than 100% in patients who ultimately developed ESRF (<0.05). Baseline total plasma cho lesterol was lower in patients alive without replacement therapy, 5.8 (range, 4.5–8.8) as compared with 6.9 (4.4–12.7) mmol/l in patients with ultimate ESRF (<0.05) and 7.2 (5.3–9.2)mmol/l in patients with non-renal death (<0.05). The clinical outcome was not associated with differences in baseline high-density lipoprotein or plasma triglyceride. These observations suggest that enalapril treatment improves long-term dialysis-free survival in patients with progressive chronic renal failure. Renal function outcome appears to be influenced by the magnitude and type of proteinuria, the initial antiproteinuric response to treatment, and the plasma cholesterol level. [ABSTRACT FROM PUBLISHER]

To evaluate the effect of delayed treatment with enalapril or lovastatin on the progression of glomerulosclerosis and to examine if the combined treatment with enalapril and lovastatin show synergistic effect, a total of 31 Sprague-Dawley rats were studied for 16 weeks following 5/6 nephrectomy (NPX). Treatment was delayed until 8 weeks after NPX. In untreated control rats (=8), sustained systemic hypertension with increasing proteinuria, serum cholesterol, triglyceride, BUN and widespread glomerulosclerosis and mesangial expansion were observed. Treatment with enalapril alone (R, =8) reversed systemic hypertension, prevented a further increase in proteinuria, and significantly reduced glomerulosclerosis relative to the control group. Treatment with lovastatin alone (L, =7) also reduced glomerulosclerosis and serum cholesterol compared to the controls. The drug also prevented a further increase in proteinuria and systemic blood pressure although the difference from the control rats did not reach statistical significance. Treatment with both enalapril and lovastatin (RL, =8) almost completely prevented glomerulosclerosis and significantly reduced mesangial expansion, systemic blood pressure, serum cholesterol, and proteinuria compared to controls. Only the combined treatment stabilized BUN and reduced mesangial expansion compared to control R, or L groups. Conclusion. Delayed treatment with enalapril or lovastatin is effective in preventing the progression of glomerulosclerosis, and combined treatment appears to show synergistic effect in 5/6 nephrectomized rat model. [ABSTRACT FROM PUBLISHER]

Renal growth often precedes scarring in experimental models of chronic renal failure in rats. Its control may therefore influence the subsequent development of renal scarring and failure in these animals. In this study we have attempted to manipulate, by pharmacological interventions, compensatory renal growth in rats who have undergone uninephrectomy. The effects of three drugs—enalapril, verapamil and indomethacin—were investigated. Compensatory renal growth was found to be 15.33 ± 13.76% (mean±SD)1 week after uninephrectomy in control adult male Wistar rats. Compensatory renal growth was significantly inhibited by pretreatment with enalapril 7.38 ± 8.88% (P<0.05) but was unaffected by indomethacin; the effect of verapamil was inconclusive. In controls, both the protein and DNA content of the remaining kidney increased, indicating a mixed hypertrophic and hyperplastic response. Enalapril inhibited the hyperplastic component of compensatory renal growth. We conclude that following uninephrectomy in rats, compensatory hypertrophy can be manipulated by pharmacological interventions, in particular angiotensin-convertingenzyme inhibition by enalapril. [ABSTRACT FROM PUBLISHER]

Heart failure is associated with poor prognosis, but recent large-scale investigations have generated valuable and practical information to help improve clinical management and patient survival. This review presents an overview of the findings of recent heart failure survival studies and how these may affect therapeutic strategy for patients with this condition. [ABSTRACT FROM PUBLISHER]

The effects of a short-term oral treatment with captopril or enalapril, two converting enzyme inhibitors (CEIs) administered in equipotent antihypertensive doses, on the systemic vasopressor and on the renal, mesenteric and hind-limb vascular responses to cirazoline and UK 14304, respectively alpha1- and alpha2- adrenoceptor specific agonists, were investigated in the adult pithed SHR. Cirazoline and UK 14304 induced vasoconstrictor responses in the three investigated territories, demonstrating the location and a functional role at these levels of the two sub-types of alpha-adrenoceptors. Both captopril and enalapril reduced, to the same extent, the systemic pressor and the regional vasoconstrictor responses, especially in the renal and mesenteric territories, elicited by cirazoline and UK 14304, demonstrating that both subtypes of alpha-adrenoceptors are involved in the CEIs-induced attentuation of sympathetic responses. [ABSTRACT FROM PUBLISHER]

The purpose of this experiment was to determine whether use of the angiotensin-converting enzyme (ACE) inhibitor, enalapril, would prevent the occurrence of ovarian hyperstimulation syndrome (OHSS) in the rabbit model. A total of 20 adult female New Zealand white rabbits were studied. All rabbits received 75 IU of human menopausal gonadotrophin s.c. each day for 7 days. On day 8, all rabbits received 2500 IU of human chorionic gonadotrophin (HCG). Ten rabbits were randomly chosen to receive enalapril orally. Five received 1 mg/kg of enalapril and five received 2 mg/kg of enalapril twice daily. The remainder received placebo orally twice daily. On day 10, all rabbits underwent surgical exploration. Total body weight was found to increase significantly in the placebo group (by 293 g, P < 0.001) but not in either group receiving enalapril. Haematocrit also increased significantly in the placebo group (by 3%, P < 0.013) but not in the enalapril groups. Ovarian weights were highest for the 2 mg/kg enalapril group (5.80 +/- 0.52 g), followed by the 1 mg/kg enalapril group (3.64 +/- 0.45), and least for the placebo group (2.69 +/- 0.17). All 10 placebo rabbits met criteria for severe OHSS whereas only six in the enalapril groups did. We concluded that angiotensin II may play a significant role in the development of weight gain, third space fluid accumulation and intravascular fluid depletion in OHSS. ACE inhibition resulted in a 40% decrease in the incidence of OHSS in the rabbit model. [ABSTRACT FROM AUTHOR]

The purpose of this experiment was to determine whether use of the angiotensin-converting enzyme (ACE) inhibitor, enalapril, would prevent the occurrence of ovarian hyperstimulation syndrome (OHSS) in the rabbit model. A total of 20 adult female New Zealand white rabbits were studied. All rabbits received 75 IU of human menopausal gonadotrophin s.c. each day for 7 days. On day 8, all rabbits received 2500 IU of human chorionic gonadotrophin (HCG). Ten rabbits were randomly chosen to receive enalapril orally. Five received 1 mg/kg of enalapril and five received 2 mg/kg of enalapril twice daily. The remainder received placebo orally twice daily. On day 10, all rabbits underwent surgical exploration. Total body weight was found to increase significantly in the placebo group (by 293 g, < 0.001) but not in either group receiving enalapril. Haematocrit also increased significantly in the placebo group (by 3%, < 0.013) but not in the enalapril groups. Ovarian weights were highest for the 2 mg/kg enalapril group (5.80 ± 0.52 g), followed by the 1 mg/kg enalapril group (3.64 ± 0.45), and least for the placebo group (2.69 ± 0.17). All 10 placebo rabbits met criteria for severe OHSS whereas only six in the enalapril groups did. We concluded that angiotensin II may play a significant role in the development of weight gain, third space fluid accumulation and intravascular fluid depletion in OHSS. ACE inhibition resulted in a 40% decrease in the incidence of OHSS in the rabbit model. [ABSTRACT FROM PUBLISHER]

A correction to the article "How to Slice the Pie: Heart Failure Subgroups and Their Clinical Meaning" what was published in the 2020 issue is presented.

Purpose. A case of presumed lisinopril-induced hepatotoxicity is reported. Summary. A 30-year-old woman had complained of fatigue and yellow eyes for two days. Her medical history included hypertension and nephrotic syndrome. Her medications included furosemide 20 mg daily (for almost 6.5 years) and lisinopril 10 mg daily (for eight months). She had been treated with quinapril, enalapril, and lisinopril in the past by different primary care physicians without any adverse effects. She did not abuse alcohol and denied any liver-related problems in the past. Her physical examination revealed icterus and right-upper-quadrant abdominal tenderness. Initial laboratory tests revealed elevated liver enzyme values. Ultrasonography and computed tomography (CT) scans of the patient's abdomen suggested hepatocellular disease with mild hepatomegaly and a normal biliary tract. Due to worsening bilirubin and liver enzyme values, lisinopril was stopped. In the absence of a probable cause of the patient's hepatotoxicity, a CT-guided liver biopsy was performed. Histological examination of the liver tissue showed moderate chronic inflammatory cell infiltrates in the portal area, predominantly composed of lymphocytes with mild-to-moderate interface hepatitis. No centrolobular necrosis or steatosis was seen. After lisinopril was discontinued, there was a rapid improvement in the patient's clinical and biochemical pictures. On her follow-up clinic visit approximately two months later, all of her liver enzyme values had normalized. Conclusion. A woman who had received quinapril, enalapril, and lisinopril in the past without apparent adverse effects developed hepatocellular disease that became evident eight months after lisinopril therapy was reinstituted. The presumed hepatotoxicity resolved after discontinuation of lisinopril. [ABSTRACT FROM AUTHOR]

Five patients (median age 63 years) with severe crescentic glomerulonephritis had acute renal failure (median plasma creatinine 930, range 690–1390). Following induction of immunosuppressive treatment all patients achieved recovery of adequate renal function (median creatinine 440, range 290–570 μmol/1). After 3–6 months of continuous remission, all patients, despite stable renal function developed increasing proteinuria (median 4.4 g/24 h, range 3.2–6.1), and enalapril (5–20 mg per day) was substituted or introduced as antihypertensive therapy. Immunosuppression was not altered.After 1 year, renal funtion remained stable in four patients and plasma creatinine increased initially in one patient before becoming stable: proteinuria was reduced substantially in all patients to a median of 0.8 g/24 h, range 0.2–1.3). Patients with severe crescentic glomerulonephritis may develop persistent or increasing proteinuria despite successful treatment of acute disease. We have used enalapril to reduce proteinuria and maintain function in such patients. [ABSTRACT FROM PUBLISHER]

Renal effects of enalapril maleate in ten hypertensive patients with glomerulonephritis were evaluated after 1 and 16 weeks of therapy. Systemic blood pressure decreased, glomerular filtration rate was not significantly changed, and sodium fractional excretion and renal plasma flow increased, whereas renal vascular resistances and filtration fraction decreased acutely at the end of the study. Proteinuria diminished, but no variations in qualitative pattern were observed. ACE inhibitors, promoting efferent rather than afferent arteriolar vasodilatation and reduction of glomerular permeability coefficient, may reduce glomerular capillary hypertension and the development of proteinuria. [ABSTRACT FROM PUBLISHER]