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1.  Inhibition of NF-κB-induced inflammatory responses by angiotensin II antagonists in aged rat kidney 
Experimental gerontology  2011;46(7):542-548.
In this study, we explored the mechanisms by which the angiotensin converting enzyme inhibitor (ACEI), enalapril, and the Ang II receptor blocker (ARB), losartan suppress oxidative stress and NF-κB activation-induced inflammatory responses in aged rat kidney. The experimentations were carried out utilizing aged (24-month-old) Brown Norway x Fischer 344 (F1) male rats which were randomized into 3 groups and administered enalapril (40 mg/kg), losartan (30 mg/kg) or placebo for 6 months (daily p.o.). The level of reactive species (RS), peroxynitrite (ONOO−), GSH/GSSG and lipid peroxidation were measured. The activity of the pro-inflammatory transcription factor NF-κB, and gene expression of proteins in upstream signaling cascades were measured by electro-mobility shift assay (EMSA) and Western blotting. Enalapril and losartan differentially attenuated redox imbalance and the redox-sensitive transcription factor, NF-κB pathway. Furthermore, stimulation of the NF-κB activation pathway by phosphorylation of p65 was attenuated by both compounds. Moreover, mediation of phosphorylation of p65 by phosphorylation of IκB kinase αβ (IKKαβ) and mitogen- and stress-activated protein kinase-1 (MSK1), were also inhibited by enalapril and losartan. Finally, both compounds also lowered expression of NF-κB-dependent inflammatory genes, such as cyclooxygenase-2 (COX-2),) and inducible NO synthase (iNOS). Only losartan lowered levels of 5-lipoxygenase (5-LOX). These findings indicate that enalapril and losartan differentially suppress inflammatory responses via inhibition of oxidative stress-induced NF-κB activation in aged rat kidney.
doi:10.1016/j.exger.2011.02.011
PMCID: PMC3104080  PMID: 21377515
2.  Differential effects of late-life initiation of low-dose enalapril and losartan on diastolic function in senescent Fischer 344 × Brown Norway male rats 
Age  2011;34(4):831-843.
No proven pharmacological therapies to delay or reverse age-related diastolic dysfunction exist. We hypothesized that late-life low-dose (non-blood-pressure-lowering) angiotensin-converting enzyme inhibition vs. angiotensin II receptor blockade would be equally efficacious at mitigating diastolic dysfunction in the senescent Fischer 344 × Brown Norway rat. Enalapril (10 mg/kg/day; n = 9) initiated at 24 months of age and continued for 6 months, increased myocardial relaxation (e'), reduced Doppler-derived indices of filling pressure (E/e'), favorably lowered the ratio of phospholamban–SERCA2 and reduced oxidative stress markers, Rac1 and nitrotyrosine, in aged hearts. Treatment with losartan (15 mg/kg/day; n = 9) similarly mitigated signs of cardiac oxidative stress, but impairments in diastolic function persisted when compared with untreated rats (n = 7). Our findings favor the idea that the lusitropic benefit of low-dose angiotensin-converting enzyme inhibitor initiated late in life may be related to an antioxidant-mediated modulation of SERCA2, resulting in improved relaxation rather than via overt effects on cardiac structure or blood pressure.
doi:10.1007/s11357-011-9283-8
PMCID: PMC3682061  PMID: 21720770
Angiotensin-converting enzyme inhibitor; Angiotensin II receptor blocker; Diastolic dysfunction; Oxidative stress; SERCA2; Tissue Doppler
3.  Unilateral ureteric obstruction: Role of renin angiotensin system blockade on renal recovery: An experimental study 
Aims:
To study and compare the effects of angiotensin II antagonist (Losartan) and angiotensin converting enzyme (ACE) inhibitor (Enalapril) on renal recovery following reversal of iatrogenic unilateral upper ureteric obstruction.
Materials and Methods:
Unilateral upper ureteric obstruction was created in 96 adult Wistar rats that were reversed after predetermined intervals. Losartan and Enalapril were given to different subgroups of rats following relief of obstruction. Rats were sacrificed and kidneys were subjected to planimetric and histopathological analysis.
Results:
Dorsal lumbotomy approach provided a rapid and safe approach to kidneys in rats. The planimetric and histopathological changes were most severe in the group of rats in whom obstruction was not relieved before sacrifice. Addition of Enalapril and Losartan significantly hastened the reversal of renal changes following relief of obstruction as compared with the group in which no treatment was given following reversal of blockade.
Conclusions:
Renin angiotensin system (RAS) is the major pathway responsible for renal damage following outflow obstruction. However, this damage can be reversed with the use of drugs acting on the RAS.
doi:10.4103/0971-9261.93960
PMCID: PMC3326821  PMID: 22529547
Hydronephrosis; renin angiotensin system; ureteric obstruction
4.  Comparison of the effect of enalapril and losartan in conjunction with surgical coronary revascularisation versus revascularisation alone on systemic endothelial function 
Heart  2005;91(8):1053-1057.
Objectives: To investigate the effect of enalapril, losartan, and surgical coronary revascularisation on endothelial function, and the role of the angiotensin converting enzyme (ACE) insertion (I)/deletion (D) polymorphism.
Design: Randomised, controlled, blinded end point study.
Setting: University tertiary referral cardiac centre.
Patients and interventions: 49 men awaiting coronary artery bypass grafting (CABG) were randomly assigned to treatment with losartan, enalapril, or control for two months before and three months after surgery.
Main outcome measures: Endothelial function was blindly analysed by brachial artery flow mediated dilatation (FMD) and ACE I/D genotype was determined.
Results: FMD was impaired at baseline (1.0–1.7%) and after five months had improved to 5.2% with enalapril (p  =  0.015), 5.0% with losartan (p  =  0.0004), and 3.0% with CABG alone (p  =  0.05). Patients with the II genotype had lower baseline FMD than those with DI or DD (0.1% v 1.7%, p  =  0.038) and after enalapril or losartan treatment had greater improvement in FMD (mean (SEM) 7.1 (1.1)%) than patients with DI (3.1 (1.3)%, p  =  0.024) or DD genotype (3.1 (1.1)%, p  =  0.02).
Conclusions: Enalapril and losartan, with surgical coronary revascularisation, significantly improve systemic endothelial function. Revascularisation alone produces a quantitatively smaller, but still significant, improvement. The ACE genotype significantly modulates this response. Patients with the II genotype have a more pronounced impairment in endothelial function at baseline and a greater improvement in response to treatment with these agents.
doi:10.1136/hrt.2004.036897
PMCID: PMC1769026  PMID: 16020596
ACE genotype; ACE inhibitors; coronary bypass surgery; endothelial function
5.  Angiotensin II Type 2 Receptor Signaling Attenuates Aortic Aneurysm in Mice Through ERK Antagonism 
Science (New York, N.Y.)  2011;332(6027):361-365.
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor–β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal–regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.
doi:10.1126/science.1192152
PMCID: PMC3097422  PMID: 21493863
6.  Anti-Hypertensive Drugs Have Different Effects on Ventricular Hypertrophy Regression 
Clinics  2010;65(7):723-728.
OBJECTIVES:
There is a direct relationship between the regression of left ventricular hypertrophy (LVH) and a decreased risk of mortality. This investigation aimed to describe the effects of anti-hypertensive drugs on cardiac hypertrophy through a meta-analysis of the literature.
METHODS:
The Medline (via PubMed), Lilacs and Scielo databases were searched using the subject keywords cardiac hypertrophy, antihypertensive and mortality. We aimed to analyze the effect of anti-hypertensive drugs on ventricle hypertrophy.
RESULTS:
The main drugs we described were enalapril, verapamil, nifedipine, indapamina, losartan, angiotensin-converting enzyme inhibitors and atenolol. These drugs are usually used in follow up programs, however, the studies we investigated used different protocols. Enalapril (angiotensin-converting enzyme inhibitor) and verapamil (Ca++ channel blocker) caused hypertrophy to regress in LVH rats. The effects of enalapril and nifedipine (Ca++ channel blocker) were similar. Indapamina (diuretic) had a stronger effect than enalapril, and losartan (angiotensin II receptor type 1 (AT1) receptor antagonist) produced better results than atenolol (selective β1 receptor antagonist) with respect to LVH regression.
CONCLUSION:
The anti-hypertensive drugs induced various degrees of hypertrophic regression.
doi:10.1590/S1807-59322010000700012
PMCID: PMC2910862  PMID: 20668631
Hypertrophy; Cardiomyopathy; Hypertrophic; Left ventricle hypertension; Cardiology
7.  Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state. 
British Heart Journal  1985;54(3):305-312.
Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.
PMCID: PMC481900  PMID: 2994698
8.  Effects of enalapril on myocardial noradrenaline overflow during exercise in patients with chronic heart failure. 
British Heart Journal  1989;61(1):23-28.
The effects of the angiotensin converting enzyme inhibitor enalapril on myocardial sympathetic tone, as represented by noradrenaline overflow, were studied in 14 men with congestive heart failure (mean ejection fraction 20%) in a double blind crossover comparison with placebo. Arterial and coronary sinus catecholamine concentrations and oxygen content, and coronary sinus blood flow, were measured at rest and during peak symptom limited upright exercise on a bicycle ergometer. There were no significant changes four hours after the first dose of enalapril, but after six weeks of treatment (10-20 mg/day) enalapril reduced myocardial overflow of noradrenaline at peak exercise. The external workload (exercise duration) increased from baseline values after both placebo and enalapril, and there was no difference between placebo and enalapril at six weeks. Heart work, however, was lower after enalapril: stroke work index was reduced at rest and the double product was lower at peak exercise. The reduction in maximal myocardial oxygen consumption after enalapril did not reach statistical significance. Coronary sinus adrenaline concentrations after enalapril and after placebo were not significantly different. The long term reduction of myocardial sympathetic activity on exercise may represent a significant benefit from angiotensin converting enzyme inhibition in heart failure and may reflect a reduced cardiac workload.
PMCID: PMC1216616  PMID: 2537095
9.  Effect of Combination Therapy with a Calcium Channel Blocker and an Angiotensin-Converting Enzyme Inhibitor on Renal Hypertrophy and Urinary Albumin Excretion in Diabetic Rats 
Experimental Diabesity Research  2003;4(3):191-199.
The objective of this study was to compare the effect of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker on the development of renal changes in diabetic rats. Diabetes was induced by an intravenous injection of streptozotocin in normotensive Wistar rats. Treatment was commenced immediately in 1 set of rats with 4 treatment arms: nitrendipine (250 mg/kg fodder), enalapril (35 mg/L drinking water), both treatments in combination, or placebo. Treatment was continued for 9 weeks. Another set of rats was left with untreated diabetes for 3 months followed by 7 weeks treatment as above. When starting treatment right after induction of diabetes, nitrendipine significantly reduced urinary albumin excretion (UAE) to the nondiabetic level (P < .05) without reducing blood pressure (BP), whereas enalapril failed to significantly reduce UAE despite a reduction in BP. Combining the two treatments showed no further reduction in UAE compared to monotherapy with nitrendipine, despite a lower BP. When leaving diabetic rats untreated for 3 months, only the coadministration of nitrendipine and enalapril showed a significant reduction in UAE compared to monotherapy and placebo treatment, but showed no significant effect on BP.
doi:10.1155/EDR.2003.191
PMCID: PMC2478604  PMID: 15061647
10.  Efficacy of Enalapril in Migraine Prophylaxis: A Randomized, Double-blind, Placebo-controlled Trial 
Background:
Some angiotensin converting enzyme (ACE) inhibitors have previously been shown to be effective in migraine prophylaxis. The aim of this study was to evaluate whether Enalapril is effective in migraine prophylaxis.
Methods:
In this randomized, double-blind, placebo-controlled clinical trial, the effects of 10 mg Enalapril given daily were compared with those of matched placebo in 40 migraineurs for 2 months. Response to treatment was assessed at 0, 1, and 2 months after the start of intervention according to headache parameters like frequency, severity, and duration. This trial is registered with Iranian Registry of Clinical Trials (IRCT), number IRCT138711011570N1.
Results:
A significant effect on reducing migraine attack more than 50% at first and second months (P=0.016) occurred in Enalapril group. Indeed, at the first and second months of treatment, the severities (P=0.000 and P=0.000) and duration (P=0.037 and 0.003) in the Enalapril treated group were significantly lower than in the placebo group.
Conclusion:
Enalapril may be effective in migraine prophylaxis according to its effect in decreasing the frequency, severity, and duration of headaches. The results support the previous suggestions on usage of ACE inhibitors in migraine prophylaxis.
PMCID: PMC3570915  PMID: 23413003
Angiotensin converting enzyme inhibitors; Enalapril; migraine disorders
11.  Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial 
Diabetologia  2010;54(1):44-50.
Aims/hypothesis
To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy.
Methods
We performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease.
Results
At month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium ≥5.0 mmol/l and ≥5.5 mmol/l, (p < 0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0–3.9). Serum potassium at month 6 ≥ 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00–1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan’s renoprotective effect from 21% (6–34%) to 35% (20–48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium.
Conclusions/interpretation
In this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question.
doi:10.1007/s00125-010-1922-6
PMCID: PMC2995871  PMID: 20882268
Angiotensin receptor blocker; Losartan; Nephropathy; Potassium; Type 2 diabetes
12.  Puerarin Attenuated Early Diabetic Kidney Injury through Down-Regulation of Matrix Metalloproteinase 9 in Streptozotocin-Induced Diabetic Rats 
PLoS ONE  2014;9(1):e85690.
Radix puerariae, a traditional Chinese herbal medication, has been used successfully to treat patients with early stage of diabetic nephropathy. However, the underlined mechanism of this renal protective effect has not been determined. In the current study, we investigated the effects and the mechanism of puerarin in Streptozotocin (STZ)-induced diabetic rats. We treated STZ-rats with either puerarin or losartan, an angiotensin II receptor blocker, as compared to those treated with vehicle. We found that both puerarin and losartan attenuated kidney hypertrophy, mesangial expansion, proteinuria, and podocyte foot process effacement in STZ rats. In addition, both puerarin and losartan increased expression of podocyte slit diaphragm proteins such as nephrin and podocin. Interestingly, we found that puerarin treatment induced a more pronounced suppression of oxidative stress production and S-nitrosylation of proteins in the diabetic kidneys as compared to losartan treatment. Furthermore, we found that matrix metalloproteinase-9 (MMP-9), which is known to be activated by oxidative stress and S-nitrosylation of proteins, was also suppressed more extensively by puerarin than losartan. In conclusion, these data provide for the first time the potential mechanism to support the use of puerarin in the treatment of early diabetic nephropathy.
doi:10.1371/journal.pone.0085690
PMCID: PMC3893265  PMID: 24454919
13.  Effects of intradermal bradykinin after inhibition of angiotensin converting enzyme. 
Inhibitors of angiotensin converting enzyme may cause angio-oedema. To see if this might be due to potentiation of the tissue effects of bradykinin the thickness of weals raised by intradermal injection of saline or 1, 3, or 10 micrograms bradykinin was measured before and three times after single doses of captopril, enalapril, or placebo. The mean thickness increased with increasing doses of bradykinin. It did not change with time after the administration of placebo or captopril but increased from 0.61 mm before enalapril to 1.12 mm two and a half hours and 1.06 mm five hours after enalapril was given. Five subjects flushed when given bradykinin after captopril and four after enalapril, but none flushed when given bradykinin after placebo. It is concluded that angiotensin converting enzyme inhibitors potentiate the effects of intradermal bradykinin in vivo and that this may partially explain why they cause angio-oedema in susceptible patients.
PMCID: PMC1246284  PMID: 3034372
14.  Synergistic actions of enalapril and tempol during chronic angiotensin II induced hypertension 
Vascular pharmacology  2006;46(2):144-151.
Experiments were designed to test the hypothesis that antioxidant treatment would increase the antihypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170± 8 vs. 128± 4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165± 7 and 164± 6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137± 5 mmHg). Plasma 8-isoprostane increased in Ang II infused rats when compared with control untreated rats (69± 14 vs. 23± 0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29± 6 and 34± 7 pg/ml, respectively). In additional experiments, we used the bradykinin B2 antagonist, icatibant to determine if increased B2 receptor contributes to the antihypertensive effect of combined tempol and enalapril in Ang II infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B1 receptor protein expression in renal cortex of Ang II infused rats was observed compared to control suggesting that the bradykinin receptors activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.
doi:10.1016/j.vph.2006.09.004
PMCID: PMC2746434  PMID: 17112788
superoxide; oxidative stress; angiotensin converting enzyme inhibitors; 8-isoprostane; arterial pressure; rats
15.  Lessons Learned from a Pediatric Clinical Trial: The Pediatric Heart Network Angiotensin Converting Enzyme Inhibition in Mitral Regurgitation Study 
American heart journal  2011;161(2):233-240.
Background
Mitral regurgitation is the most common indication for re-operation in children following repair of atrioventricular septal defect (AVSD). We hypothesized that angiotensin converting enzyme (ACE) inhibitor therapy would decrease the severity of mitral regurgitation and limit left ventricular volume overload in children following AVSD repair.
Methods
The Pediatric Heart Network designed a placebo-controlled randomized trial of enalapril in this population. The primary aim was to test the effect of enalapril on the change in left ventricular end-diastolic dimension body surface area-adjusted Z-score. Prior to the launch of the trial, a feasibility study was performed to estimate the number of patients with at least moderate mitral regurgitation following AVSD repair.
Trial Experience
Seventeen months after the start of the study, 349 patients were screened, 8 were trial eligible and only 5 were enrolled. The study was subsequently terminated due to low patient accrual. Several factors led to the problems with patient accrual including: 1) the use of criteria to assess disease severity in the feasibility study that were not identical to those used in the trial; 2) failure to achieve equipoise for the study among clinicians and referring physicians; 3) reliance on methodology developed in adult populations with different disease mechanisms; 4) absence of adequate data to define the natural history of the disease process under study. Progress in the treatment of children with cardiovascular disease will depend on the future of multi-center collaborative clinical trials. The lessons learned from this study may contribute to improvements in this research.
doi:10.1016/j.ahj.2010.10.030
PMCID: PMC3053082  PMID: 21315203
16.  Combining salicylate and enalapril in patients with coronary artery disease and heart failure. 
British Heart Journal  1995;73(3):227-236.
OBJECTIVE--To study the effects of adding a salicylate to the angiotensin converting enzyme inhibitor enalapril in patients with heart failure due to coronary artery disease. DESIGN--Double blind, crossover study for three days in hospital followed by an extended similar study outside hospital over two months of once daily enalapril plus salicylate and enalapril plus placebo. SETTING--Tertiary referral centre. PATIENTS--20 patients with heart failure due to myocardial infarction (New York Heart Association class II or III) and an ejection fraction less than 0.40. Twelve patients completed the two parts of the study. MAIN OUTCOME MEASURES--Blood pressure, plasma converting enzyme activity; plasma angiotensin II and noradrenaline concentrations; excretion of metabolites of renal and systemic prostanoids. RESULTS--The unloading effect of first and second dose of enalapril in the morning lasted only during the day; in the extended study it lasted 24 hours because of the drug's accumulation. Converting enzyme inhibitors attenuate the breakdown of bradykinin and therefore enhance prostaglandin E2 synthesis mediated by bradykinin. Evidence was found of such a prostaglandin E2 mediated contribution to ventricular unloading by enalapril, which was blocked by salicylate. The contribution, however, was small and variable, and salicylate addition had on average no significant de-unloading effect during the day. Unloading was abolished in only three of the 20 patients in the short term study and in one of the 12 in the extended study. At night, when other effects of enalapril on blood pressure had waned and the bradykinin induced effect persisted, salicylate significantly reduced the remaining small unloading effect. No effect was seen of salicylate addition on reversal of remodelling. Enalapril reduced angiotensin II induced synthesis of systemic and renal prostaglandin I2 and thromboxane A2, initially only during the day, but later also at night. It thereby masked suppression of thromboxane A2 synthesis by salicylate, which is the effect to which reinfarct prevention by salicylate is attributed. CONCLUSION--The risk is low that salicylate will substantially reduce the benefit of enalapril in patients with heart failure by de-unloading the ventricle. Like other effects induced by bradykinin significant de-unloading occurs in only a minority of the patients. In the presence of enalapril, however, salicylate will probably not be as effective as expected in reducing reinfarction risk, because enalapril already reduces thromboxane A2 synthesis effectively in patients with heart failure and no further reduction by salicylate was found.
Images
PMCID: PMC483803  PMID: 7727181
17.  Haemodynamic, hormonal, and electrolyte effects of enalapril in heart failure. 
British Heart Journal  1983;50(2):163-169.
Enalapril, the new converting enzyme inhibitor, was administered to eight patients with heart failure (NYHA Functional Class II to IV) during standardised and intensive haemodynamic, hormone, and electrolyte monitoring. The first dose (5 mg) of enalapril induced a fall in plasma angiotensin II and noradrenaline levels, and prolonged decrements in systemic vascular resistance, arterial pressure, heart rate, and right heart pressures. Maximum haemodynamic effects were evident four to eight hours after the first dose, with return to baseline by 24 hours. Plasma angiotensin II levels, however, were still suppressed at 24 hours. The magnitude of haemodynamic response was related closely to baseline (pre-enalapril) activity of the renin-angiotensin system and the sympathetic system. Enalapril treatment over three days induced a positive cumulative balance of sodium and potassium, and a small increase in plasma potassium. Urine aldosterone excretion decreased in a stepwise fashion. Continued enalapril administration for four to eight weeks resulted in improved clinical status (NYHA Functional Class) and exercise tolerance in patients who initially were most severely incapacitated, but little change was observed in healthier subjects. We conclude that in heart failure, enalapril is a long acting converting enzyme inhibitor with clear cut beneficial haemodynamic effects in the short term. Long term controlled studies of enalapril in heart failure are warranted.
PMCID: PMC481390  PMID: 6309203
18.  Comparative Evaluation of Enalapril and Losartan in Pharmacological Correction of Experimental Osteoporosis and Fractures of Its Background 
Journal of Osteoporosis  2013;2013:325693.
In the experiment on the white Wistar female rats (222 animals), the osteoprotective effect of enalapril and losartan was studied on experimental models of osteoporosis and osteoporotic fractures. It was revealed that in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of osteal tissue develops, resulting in occurrence of osteoporosis and delay of consolidation of experimental fractures. Enalapril and losartan prevented the reduction of microcirculation in bone, which was reflected in slowing the thinning of bone trabeculae and in preventing the occurrence of these microfractures, as well as increasing quality of experimental fractures healing.
doi:10.1155/2013/325693
PMCID: PMC3562670  PMID: 23401845
19.  Enalapril in the treatment of hypertension with renal artery stenosis. 
The converting enzyme inhibitor enalapril, in single daily doses of 10-40 mg, was given to 20 hypertensive patients with renal artery stenosis. The blood pressure fall six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II and to the concurrent fall in angiotensin II. Blood pressure fell further with continued treatment; the long term fall was not significantly related to pretreatment plasma renin or angiotensin II concentrations. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, fallen further. The rise in active renin during long term treatment was proportionally greater than the rise in angiotensin I; this probably reflects the fall in renin substrate that occurs with converting enzyme inhibition. Enalapril alone caused reduction in exchangeable sodium, with distinct increases in serum potassium, creatinine, and urea. Enalapril was well tolerated and controlled hypertension effectively long term; only two of the 20 patients required concomitant diuretic treatment.
PMCID: PMC1549614  PMID: 6315126
20.  Antiarrhythmic Effects of Losartan and Enalapril in Canine Pulmonary Vein Sleeve Preparations 
Introduction
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II-receptor blockers (ARBs) are prototypes of “upstream” therapy for the management of atrial fibrillation (AF). Ectopic activity arising from the PV sleeves plays a prominent role in the development of AF.
Methods
Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (ACh, 1 µM), isoproterenol (1 µM), high calcium ([Ca2+]o=5.4mM) or a combination was used to induce early or delayed afterdepolarizations (EADs or DADs) and triggered activity.
Results
The ARB losartan (1 µM, n=5) and the ACE inhibitor enalapril (10 µM, n=5) produced no significant change in action potential duration, maximum rate of rise of action potential upstroke (Vmax), action potential amplitude or take-off potential at basic cycle lengths of 200 to 2000 ms. Losartan (1 µM) and enalapril (10–20 µM) markedly attenuated or suppressed EADs and DAD–induced triggered activity elicited by exposure of the PV sleeves to ACh, isoproterenol or high calcium following rapid pacing in 6 of 6 (losartan) and 4 of 5 (enalapril) PV sleeve preparations. Neither losartan or enalapril altered Ca2+ or K+ channel currents in enzymatically-dissociated atrial myocytes at these concentrations.
Conclusions
Our data suggest that in addition to their “upstream” effects to reduce atrial structural remodeling, ACE inhibitors and ARBs exert a “direct” antiarrhythmic effect by suppressing triggers responsible for the genesis of AF and other atrial arrhythmias.
doi:10.1111/j.1540-8167.2010.01972.x
PMCID: PMC3061245  PMID: 21159010
atrial fibrillation; antiarrhythmic drugs; sodium channel blocker; angiotensin-converting enzyme inhibitor; angiotensin receptor blocker
21.  Controlled trial of enalapril in congestive cardiac failure. 
British Heart Journal  1985;54(4):405-414.
Twenty five patients with chronic congestive cardiac failure had enalapril (n = 13) or placebo (n = 12) added to their existing regimen of digoxin and frusemide in a randomised double blind trial. Four hours after the first 5 mg dose, the enalapril group showed significant falls in blood pressure, heart rate, and concentrations of plasma angiotensin II, angiotensin converting enzyme, and noradrenaline. During the 12 week trial heart failure became worse in one enalapril treated patient (8%) and in seven placebo treated patients (58%). There were no significant changes in cardiac ejection fraction or exercise duration in either group. Plasma noradrenaline response to graded exercise and maximum exercise rate-pressure product were significantly reduced after four and 12 weeks of active treatment but unchanged with placebo treatment. There was a sustained increase in plasma potassium and a slight rise in plasma creatinine in the enalapril group. Plasma concentrations of the active drug, enalaprilate, were dose related and log enalaprilate correlated significantly with percentage of plasma angiotensin converting enzyme activity (r = -0.66). Enalapril was well tolerated and produced no adverse effects. The drug appears to be superior to placebo and offers considerable promise for the treatment of this condition.
PMCID: PMC481919  PMID: 2996575
22.  Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. 
BMJ : British Medical Journal  1988;297(6656):1092-1095.
STUDY OBJECTIVE--To assess the effectiveness of inhibition of angiotensin converting enzyme in preventing diabetic nephropathy. DESIGN--Randomised follow up study of normotensive diabetics with persistent microalbuminuria (30-300 mg/24 hours) treated with enalapril or its matched placebo for one year. Double blind for first six months, single blind for last six months. SETTING--Diabetic clinic in tertiary referral centre. PATIENTS--Treatment group and placebo group each comprised 10 normotensive diabetics with persistent microalbuminuria. INTERVENTIONS--Treatment group was given enalapril 20 mg daily and controls matched placebo. Patients were given antihypertensive treatment after one year. END POINT--Albumin excretion, arterial pressure, and renal function. MAIN RESULTS--In last three months of trial three of 10 patients taking placebo had diabetic nephropathy (albumin excretion greater than 300 mg/24 hours). No patients taking enalapril developed nephropathy and five showed normal albumin excretion (less than 30 mg/24 hours) (p = 0.005, Mann-Whitney test). Mean arterial pressure was reduced by enalapril throughout study (p less than 0.005) but increased linearly with placebo (p less than 0.05). Albumin excretion decreased linearly with enalapril but not placebo. An increase in albumin excretion with placebo was positively related to the increase in mean arterial pressure (r = 0.709, p less than 0.05, Spearman's rank test). With enalapril total renal resistances and fractional albumin clearances improved progressively (time effect, p = 0.0001). CONCLUSION--Inhibition of angiotensin converting enzyme prevents development of nephropathy in normotensive diabetics with persistent microalbuminuria. This may be due to reduction in intraglomerular pressure and to prevention of increased systemic blood pressure. Future studies should compare long term effects of inhibitors of converting enzyme with other antihypertensive drugs.
PMCID: PMC1834866  PMID: 2848604
23.  Losartan and diabetic nephropathy: commentaries on the RENAAL study 
The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study is a multinational, double-blind, randomized, placebo controlled trial which was recently published. It was aimed to evaluate the effect of the angiotensin receptor blocker losartan in patients with diabetic nephropathy. The primary efficacy measure was the time to the first event of the composite end point of a doubling of serum creatinine, end-stage renal disease, or death. The conclusion was that losartan led to significant improvement in renal outcomes, that was beyond that attributable to blood pressure control in patients with type 2 diabetes and nephropathy.
The perusal of the report raises concern, regarding to both the patient population as well as the outcome measures. At randomization, the placebo group included more patients with angina, myocardial infarction and lipid disorders than the losartan group. Information on glucose metabolism was disregarded, and data on antihyperglycemic therapy – which may have undesirable influences on cardiac performance – were not included in a multivariate analysis. In addition, only data on first hospitalization were reported, whilst information on total specific-cause hospitalizations was disregarded, thus potentially masking further unfavorable events. Furthermore, creatinine seems not to be a reliable surrogate end point. Based on its mechanism of action, losartan may possess favorable renoprotective properties. However, due to the methodological flaws and the incomplete data in the RENAAL study, the question of the effectiveness and safety of this drug in diabetic nephropathy remains yet unanswered.
doi:10.1186/1475-2840-1-2
PMCID: PMC116616  PMID: 12119058
Angiotensin receptor blockers; Clinical trials; Diabetes mellitus; Losartan; Nephropathy; RENAAL study
24.  Renin-Angiotensin System Blockers Protect Pancreatic Islets against Diet-Induced Obesity and Insulin Resistance in Mice 
PLoS ONE  2013;8(7):e67192.
Background
The 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.
Methods
C57BL/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.
Results
All 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.
Conclusion
Our 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.
doi:10.1371/journal.pone.0067192
PMCID: PMC3718820  PMID: 23894285
25.  Three-Year Safety and Effectiveness of Fixed-Dose Losartan/Hydrochlorothiazide Combination Therapy in Japanese Patients with Hypertension Under Clinical Setting (PALM-1 Extension Study) 
Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension.
doi:10.3109/10641963.2012.666606
PMCID: PMC3507276  PMID: 22533546
losartan; hydrochlorothiazide; Japanese; uric acid; hypertension

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