Effect Of Ramipril Research Articles

Effects of Ramipril on Biomarkers of Endothelial Dysfunction and Inflammation in Hypertensive Children on Maintenance Hemodialysis: the SEARCH Randomized Placebo-Controlled Trial.

Hypertension, endothelial dysfunction, and inflammation are associated with increased cardiovascular mortality in end-stage kidney disease. We evaluated the effects of ACE (angiotensin-converting enzyme) inhibition on biomarkers of endothelial dysfunction and inflammation in hypertensive children with end-stage kidney disease on maintenance hemodialysis. In a randomized, double-blind, placebo-controlled trial, 135 (72 males/63 females) children and adolescents (age 7-15 years) were randomly assigned to treatment with either 2.5 mg once daily ramipril (n=68) or placebo (n=67) for 16 weeks. Primary outcome were the serum concentrations of asymmetrical dimethylarginine, a marker of endothelial dysfunction and hs-CRP (high-sensitivity C-reactive protein), a marker of inflammation. Changes in IL-6 (interleukin-6), TNF-α (tumor necrosis factor-alpha), systolic (S), and diastolic (D) blood pressure were secondary outcomes. Change in potassium levels and incidence of hyperkalemia were among the safety parameters. Ramipril, but not placebo, significantly reduced serum levels of asymmetrical dimethylarginine (-79.6%; P<0.001), hs-CRP (-46.5%; P<0.001), IL-6 (-27.1%; P<0.001), and TNF-α (-51.7%; P<0.001). Systolic blood pressure and diastolic blood pressure were significantly lowered in both groups with a greater reduction in children receiving ramipril (median between-group differences -12.0 [95% CI -18.0 to -9.5] and -9.0 [95% CI -12.0 to -4.5]; P<0.001, respectively). Changes in asymmetrical dimethylarginine, hs-CRP, IL-6, or TNF-α in the ramipril group did not significantly correlate with blood pressure reductions. No severe cases of hyperkalemia or other serious treatment-associated adverse events were observed. Ramipril improves biomarkers of endothelial dysfunction and inflammation in hypertensive children on maintenance hemodialysis in addition to its efficacious and safe potential to lower blood pressure. URL: https://www. gov; Unique identifier: NCT04582097.

FC 121: The Combination of Empagliflozin and Atrasentan on Top of RAS Blockade Ameliorates Cardiorenal Injury in a Type 2 Diabetic Mouse Model

Abstract BACKGROUND AND AIMS sodium-glucose 2 cotransporter inhibitors (SGLT2i) prevent cardiovascular events in diabetic patients. Moreover, their diuretic effect could attenuate the adverse events of endothelin receptor antagonists (ERA), which have also shown kidney protective effects in diabetes. The present study aimed to evaluate the beneficial cardiorenal impact of the combination of SGLT2i, ERA and ramipril versus treatment with ramipril alone in experimental diabetes. METHOD Twelve-week-old db/db mice were treated for 8 weeks with different combinations of an SGLT2i (empagliflozin, 10 mg/Kg/day), an ERA (atrasentan, 7 mg/Kg/day) and an RAS blocker (ramipril, 8 mg/Kg/day). Vehicle-treated diabetic and nondiabetic mice were included as controls. During the experiment, blood pressure (BP), glomerular filtration rate (GFR) and echocardiographic parameters were measured. Kidney and heart were collected at the end for histological studies. RESULTS The triple therapy with empagliflozin, atrasentan and ramipril was superior to ramipril alone in reducing BP (mean BP 61.0 mmHg versus 67.10 mmHg in the ramipril group), preventing diabetic hyperfiltration (214.3 μL/100 g/min GFR decrease versus 34.7 μL/100 g/min decrease in the ramipril group) (Figure 1), and improving echocardiographic parameters of diastolic dysfunction, including left atrium diameter and isovolumetric relaxation time. Moreover, the combined therapy offered protection against diabetic injury in kidney and heart by a reduction of mesangial matrix expansion (46.0% of glomerular mesangial matrix versus 46.9% in the ramipril group), as well as left ventricle cardiomyocyte hypertrophy (mean cardiomyocyte area 125 μm2 versus 131 μm2 in the ramipril group) and heart collagen deposition (Figure 1). CONCLUSION In experimental diabetes, combined therapy of ramipril, empagliflozin and atrasentan promotes both heart and kidney protective effects that outweigh the beneficial effects of ramipril alone.

Metabolic effects of ramipril and indapamide in hypertensive patients with non-alcoholic fatty liver disease

Objective. To assess the effects of combined antihypertensive therapy with ramipril and indapamide on insulin resistance, carbohydrate, lipid and purine metabolism, as well as the structure and function of the liver in hypertensive patients with non-alcoholic fatty liver disease (NAFLD).Design and methods. In a pre-post study, we included 30 patients with hypertension (HTN) 1–2 degrees in combination with NAFLD (Fatty Liver Index (FLI) &gt; 60) aged 45 to 65 years. Patients discontinued antihypertensive therapy 5–7 days before the initial examination. After that one of the fixed combinations of ramipril (2,5/5 mg/day) and indapamide (0,625/1,25 mg) were prescribed along with the lifestyle and weight reduction recommendations (the Mediterranean type of diet, a decrease in calorie intake by 500–1000 kcal from baseline, and physical aerobic exercise at least 150 minutes per week). All patients underwent clinical examination, measurement of office blood pressure (BP), ambulatory BP monitoring (ABPM), anthropometric parameters, assessment of the visceral obesity index (VAI), anthropometric parameters, VAI, the degree of adipose tissue dysfunction (ATD), the percentage of visceral and subcutaneous fat by the bioelectrical impedance method. We also assessed lipid, carbohydrate, purine metabolism and the structural and functional state of the liver before and after the treatment.Results. After 24-week therapy with a fixed combination of ramipril and indapamide (average dosage of 4,04 ± 1,24 and 1,01 ± 0,31 mg, respectively) HTN patients with NAFLD achieved target BP. There was a decrease in both office systolic BP (SBP) (p &lt; 0,001) and office diastolic BP (DBP) (p = 0,007) in 100 % of patients, as well as in ABPM indices. We observed a decrease in waist and hip circumferences (p ≤ 0,001 and p ≤ 0,001, respectively), the proportion of subcutaneous (p = 0,0134) and visceral (p = 0,002) fat. The number of patients with normal ATD increased (p = 0,030), while the proportion of patients with dysfunction decreased (p = 0,039). There was also a significant increase in high-density lipoprotein cholesterol (p = 0,027) and a decrease in insulin resistance (p = 0,002) and metabolic index (p = 0,030). We also found an improvement in carbohydrate metabolism with no change in purine metabolism. There was a favorable effect on the liver structure and function, and the number of patients with high alaninaminotransferase &gt; 40 U/L decreased (5 (16,7 %) vs 0, p = 0,026).Conclusions. Twenty-fourweek treatment with a fixed combination of ramipril and indapamide, together with recommendations for lifestyle changes and weight loss, led to a significant decrease in BP levels, the severity of insulin resistance, and visceral obesity. In addition, the treatment had a beneficial effect on the parameters of carbohydrate and lipid metabolism, as well as liver structure and function (decreased severity of steatosis and fibrosis).

Effect of ramipril on kidney, lung and heart ACE2 in a diabetic mice model

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19). The main organ affected in this infection is the lung and the virus uses the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the target cells. In this context, a controversy raised regarding the use of renin-angiotensin system (RAAS) blockers, as these drugs might increase ACE2 expression in some tissues and potentially increase the risk for SARS-CoV-2 infection. This is specially concerning in diabetic patients as diabetes is a risk factor for COVID-19. Methods12-week old diabetic mice (db/db) were treated with ramipril, or vehicle control for 8 weeks. Non-diabetic db/m mice were included as controls. ACE2 expression and activity were studied in lung, kidney and heart of these animals. ResultsKidney ACE2 activity was increased in the db/db mice as compared to the db/m (143.2% ± 23% vs 100% ± 22.3%, p = 0.004), whereas ramipril had no significant effect. In the lung, no differences were found in ACE2 when comparing db/db mice to db/m and ramipril also had no significant effect. In the heart, diabetes decreased ACE2 activity (83% ± 16.8%, vs 100% ± 23.1% p = 0.02), and ramipril increased ACE2 significantly (83% ± 16.8% vs 98.2% ± 15%, p = 0.04). ConclusionsIn a mouse model of type 2 diabetes, ramipril had no significant effect on ACE2 activity in either kidneys or in the lungs. Therefore, it is unlikely that RAAS blockers or at least angiotensin-converting enzyme inhibitors increase the risk of SARS-CoV-2 infection through increasing ACE2.

COMPARATIVE STUDY ON RAMIPRIL AND TELMISARTAN-ASSOCIATED HYPONATREMIA

Objectives: This study was planned to study the association of ramipril and telmisartan with hyponatremia and to compare the hyponatremia effect of ramipril and telmisartan.&#x0D; Methods: The study was conducted in a tertiary care hospital. Serum sodium levels were assayed in patients taking ramipril and telmisartan. Fifty-one patients were recruited. The patient’s age, gender, drug dosage, and frequency of drug administration were collected using a pro forma. Statistical analysis of data was performed using SPSS version 23.0.&#x0D; Results: About 35.3% (28 out of 51) of the study population administered with ramipril and telmisartan developed hyponatremia. Predisposition to develop hyponatremia was high in males compared to females. Incidence of hyponatremia was 43.8% (7 out of 16) in the age group of 50–60 years. Although, incidence of hyponatremia was 56.5% (13 out of 23) in ramipril group compared to 17.9% (5 out of 28) in telmisartan group, it was not statistically significant.&#x0D; Conclusion: The current study laid emphasis on the requisite for monitoring of serum sodium level in patients on ramipril and telmisartan administration to avoid morbidity and mortality due to unexpected adverse reactions.

Ramipril reduces incidence and prolongates latency time of radiation-induced rat myelopathy after photon and carbon ion irradiation.

To test the hypothesis that the use of an angiotensin-converting enzyme inhibitor (ACEi) during radiotherapy may be ameliorative for treatment-related normal tissue damage, a pilot study was conducted with the clinically approved (ACE) inhibitor ramipril on the outcome of radiation-induced myelopathy in the rat cervical spinal cord model. Female Sprague Dawley rats were irradiated with single doses of either carbon ions (LET 45 keV/μm) at the center of a 6 cm spread-out Bragg peak (SOBP) or 6 MeV photons. The rats were randomly distributed into 4 experimental arms: (i) photons; (ii) photons + ramipril; (iii) carbon ions and (iv) carbon ions + ramipril. Ramipril administration (2 mg/kg/day) started directly after irradiation and was maintained during the entire follow-up. Complete dose-response curves were generated for the biological endpoint radiation-induced myelopathy (paresis grade II) within an observation time of 300 days. Administration of ramipril reduced the rate of paralysis at high dose levels for photons and for the first time a similar finding for high-LET particles was demonstrated, which indicates that the effect of ramipril is independent from radiation quality. The reduced rate of myelopathy is accompanied by a general prolongation of latency time for photons and for carbon ions. Although the already clinical approved drug ramipril can be considered as a mitigator of radiation-induced normal tissue toxicity in the central nervous system, further examinations of the underlying pathological mechanisms leading to radiation-induced myelopathy are necessary to increase and sustain its mitigative effectiveness.

The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients

The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients

Angiotensin converting enzyme and neprilysin inhibition alter pain response in dexhamethasone-induced hypertensive rats.

We hypothesized that renin-angiotensin system and neprilysin (NEP) inhibition can modulate the nociceptive parameters on hypertensive rats. The aim of this study is to assess the preventive and therapeutic effects of ramipril and sacubitril on the pain hypersensitivities, and their interaction mechanisms with high blood pressure. Antinociceptive effects of ramipril and sacubitril were compared with those of diclofenac. Threshold of pain assesments were recorded before drugs administration. After a 18 days treatment, normotensive and dexamethasone-induced hypertensive rats were evaluated on thermal hyperalgesia and mechanical allodynia tests. Blood pressure of rats were verified by mean arterial pressure measurement. Hypertensive rats showed significantly high pain threshold on thermal plantar test compared to that of normotensives. Among hypertensive rats, pain hypersensitivity was lowest in diclofenac group, followed by sacubitril group, while ramipril caused increased thermal and mechanical hypersensitivities. We found that NEP inhibition may play a role in nociception in hypertensive rats. NEP inhibitors may be suitable choice for the management of hypertension and pain because of their therapeutic and preventive effects on nociception and arterial blood pressure.

Effects of Ramipril and Telmisartan on Plasma Concentrations of Low Molecular Weight and Protein Thiols and Carotid Intima Media Thickness in Patients with Chronic Kidney Disease.

Hypertension, a common feature in chronic kidney disease (CKD), is an independent risk factor for CKD progression and cardiovascular disease. Although inhibitors of the renin-angiotensin system (RAS) exert salutary effects on blood pressure control and proteinuria in CKD patients, their activity towards traditional and novel oxidative markers is largely unknown. We studied the effects of 6-month treatment with telmisartan versus a combination of telmisartan and ramipril on plasma concentrations of low molecular mass (LMW, including homocysteine and cysteine) and protein thiols (PSH) plasma concentration and their relationships with carotid intima media thickness (IMT), in 24 hypertensive CKD patients (age 60 ± 12 years, 8 females and 16 males). Pretreatment PSH concentrations were independently associated with IMT (r = −0.42, p = 0.039). Neither treatment affected plasma LMW thiols, in both reduced and total form. By contrast, both treatments increased PSH plasma concentrations and reduced IMT, although significant differences were only observed in the combined treatment group. Our results suggest that the beneficial effects of combined RAS inhibitor treatment on IMT in hypertensive CKD patients may be mediated by a reduction of oxidative stress markers, particularly PSH.

Ramipril and Losartan Exert a Similar Long-Term Effect upon Markers of Heart Failure, Endogenous Fibrinolysis, and Platelet Aggregation in Survivors of ST-Elevation Myocardial Infarction: A Single Centre Randomized Trial.

Introduction. Blocking the renin-angiotensin-aldosterone system in ST-elevation myocardial infarction (STEMI) patients prevents heart failure and recurrent thrombosis. Our aim was to compare the effects of ramipril and losartan upon the markers of heart failure, endogenous fibrinolysis, and platelet aggregation in STEMI patients over the long term. Methods. After primary percutaneous coronary intervention (PPCI), 28 STEMI patients were randomly assigned ramipril and 27 losartan, receiving therapy for six months with dual antiplatelet therapy (DAPT). We measured N-terminal proBNP (NT-proBNP), ejection fraction (EF), plasminogen-activator-inhibitor type 1 (PAI-1), and platelet aggregation by closure times (CT) at the baseline and after six months. Results. Baseline NT-proBNP ≥ 200 pmol/mL was observed in 48.1% of the patients, EF < 55% in 49.1%, and PAI-1 ≥ 3.5 U/mL in 32.7%. Six-month treatment with ramipril or losartan resulted in a similar effect upon PAI-1, NT-proBNP, EF, and CT levels in survivors of STEMI, but in comparison to control group, receiving DAPT alone, ramipril or losartan treatment with DAPT significantly increased mean CT (226.7 ± 80.3 sec versus 158.1 ± 80.3 sec, p < 0.05). Conclusions. Ramipril and losartan exert a similar effect upon markers of heart failure and endogenous fibrinolysis, and, with DAPT, a more efficient antiplatelet effect in long term than DAPT alone.

Roles and Clinical Applications of Biomarkers in Cardiovascular Disease

Due to the high rates of mortality and morbidity caused by Cardiovascular and Peripheral Vascular Disease (CPVD), great efforts have been made in order to improve diagnosis and primary and secondary prevention and treatment, even by discovering and using related biomarkers. As such, the articles contained in the present issue include both reviews and research articles focused on characterizing several biomarkers in order to evaluate their role in the field of CPVD. The review by S. de Franciscis et al. considers the current evidences of novel biomarkers with clear implications in the risk assessment, prevention strategies, and medical decision making in the main fields of CPVD, such as Hypertension, Coronary Heart Disease, Arterial Aneurysms, Carotid Artery Disease, Peripheral Artery Disease, Chronic Venous Disease, and Venous Thromboembolism. The study by Y. Hao et al. shows multiple metabolites that associated with risk of developing Hypertension (HYT). Specifically, low amino acid levels and gut microbiome seem to play an important role in the pathogenesis of this disease. J. Xu et al. confirm the already known association of genetic polymorphisms of ATP2B1 with the susceptibility to HYT in the Han Chinese population, particularly in the females, and found that the interaction of high BMI and ATP2B1 variants increased even more the susceptibility to Hypertension. Acute heart failure (AHF) is the most common reason of hospitalization in patients aged 65 and older, with mortality rate up to 30–40% within one year, and, in this context, Y. Wang et al. show that sequential monitoring of changes of N-terminal probrain natriuretic peptide (NT-proBNP) within the first days after acute heart failure (AHF) may be helpful for guiding clinical management of AHF patients. In ST-elevation myocardial infarction (STEMI) patients, it is pivotal to prevent AHF and recurrent thrombosis, and, in this context, M. Marinsek and A. Sinkovic show the beneficial effects of Ramipril and Losartan associated with dual antiplatelet therapy (DAPT) in respect to DAPT alone, by means of measuring the level of several biomarkers such as NT-proBNP, ejection fraction (EF), plasminogen-activator-inhibitor type 1 (PAI-1), and platelet aggregation by closure times (CT). As atherosclerosis and vascular calcification are dynamic processes, T.-L. Chuang et al. studied the association between the bony microarchitecture score (trabecular bone score, TBS) and coronary artery calcification (CAC) in adult subjects undergoing health exams and they found that advanced age was significantly associated with high CAC, while increased TBS was associated with moderate CAC, independent of age and other risk factors, and they concluded that further evidences were needed to confirm their data. Osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), are known players in osteoblastogenesis and osteoclastogenesis. In fact, they now represent also new biomarkers in the atherosclerosis and vascular calcification fields, as described by S. Bernardi et al. with evidences pointing towards a proatherogenic role for OPG and an antiatherogenic role for TRAIL. Misdiagnosis in Pulmonary Embolism (PE) may increase the related high mortality, and E. Gul et al. investigated the role of serum adiponectin levels and they found that adiponectin levels were significantly low in the patient group with PE compared to patients without PE, and they concluded that these findings may have important implications in the diagnosis of PE. The current literature abundantly describes that microRNAs (miRNAs) and long noncoding RNAs are potential new biomarkers for most pathophysiological processes, including cardiovascular diseases and metabolic disorders. In this special issue, L. Louvet et al. show, using a human in vitro model of vascular smooth muscle cells, that several miRNAs are implicated in the preventive role of magnesium towards vascular calcifications. A. Carino et al. show that the levels of several circulating miRNAs are altered during the switch from clopidogrel to ticagrelor. Their results hint at the possibility of using miRNAs as noninvading biomarkers to determine primary end points in the CPVD field, although further work will be necessary to clearly establish that. Finally, the very recent discovery of long noncoding RNAs, defined as non-protein coding transcripts longer than 200 nucleotides, opens new horizons in the CPVD field, as evidenced by the paper of Y. Yan et al., that shows that the circulating level of the long noncoding RNA UCA1 is altered during AHF. We hope that this special issue would throw light on the major issues in the area of biomarkers in CPVD and would attract the interest of scientific community in order to pursue further investigations leading to the discovery of novel biomarkers and to their rapid implementation into clinical practice. Stefano de Franciscis Laurent Metzinger Raffaele Serra

Notice of Retraction: Ahimastos AA, et al. Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent Claudication: A Randomized Controlled Trial. JAMA. 2013;309(5):453-460.

Notice of Retraction: Ahimastos AA, et al. Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent Claudication: A Randomized Controlled Trial. JAMA. 2013;309(5):453-460.

The Effect of Ramipril When Administered Early After Coronary Artery Bypass Grafting Surgery

The Effect of Ramipril When Administered Early After Coronary Artery Bypass Grafting Surgery

Новые перспективы в достижении контроля артериального давления: в фокусе новый сартан — азилсартана медоксомил

Азилсартана медоксомил является новым представителем класса блокаторов ангиотензиновых рецепторов (сартанов). Он обладает уникальной способностью прочно связываться с АТ1-рецепторами и медленно от них диссоциировать, что ведет к мощному угнетению ренин-ангиотензин-альдостероновой системы и развитию выраженного гипотензивного эффекта. Стартовая доза азилсартана медоксомила у большинства пациентов составляет 40 мг 1 раз в день, максимальная — 80 мг 1 раз в день. Эффективность азилсартана медоксомила в обычной дозе превышает эффективность рамиприла и ряда других сартанов (кандесартан, валсартан). Активность максимальной дозы препарата превышает таковую олмесартана. Азилсартана медоксомил хорошо переносится, побочные эффекты возникают редко и носят легкий/умеренный характер. В настоящее время препарат рекомендован в качестве монотерапии или в сочетании с другими лекарственными средствами для лечения эссенциальной артериальной гипертензии у взрослых.

Ramipril protects the endothelium from high glucose-induced dysfunction through CaMKKβ/AMPK and heme oxygenase-1 activation.

This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKβ (Ca(2+)/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKβ/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKβ or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-β, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.

Secretion of adiponectin from human subcutaneous and omental adipose tissue: effects of ramipril and TNFα

Adiponectin secreted by adipose tissue, an insulin sensitizer, has beneficial effect in type 2 diabetes mellitus (T2DM). The study was designed to test the effect of anti-diabetic agent pioglitazone, antihypertensive agent ramipril and Tumor necrosis Factor α (TNF α) on adiponectin secretion from human adipose tissue in depot dependent manner. Subcutaneous adipose tissue (SAT) and omental adipose tissues (OAT) were obtained from 19 subjects (six non-obese controls, seven obese and six diabetic patients). Adipose tissue was treated with pioglitazone, ramipril and TNF α. Adiponectin secreted into the culture medium after treatment at different time interval (0, 24, 48, 96 h) was determined by ELISA and normalized for cellular DNA content. Pioglitazone and ramipril stimulated while TNFα inhibited (~10–40 %) adiponectin secretion. Responsiveness to ramipril and pioglitazone treatment was more in SAT. Interestingly diabetic patients show 40 % higher stimulation of adiponectin secretion in response to ramipril treatment than pioglitazone. These data suggest that, SAT, appears to be a major contributor to regulation of adiponectin in circulation. The effects of pioglitazone and ramipril, in improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of T2DM.

Ramipril protects the endothelium from hyperglycaemia‐induced dysfunction through AMPK and HO‐1 activation (851.10)

Aims: To investigate the effects of ramipril (RPL), an angiotensin‐converting enzyme (ACE) inhibitor, on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model.Methods and results: The effect of RPL on vasodilatory function in fat‐fed, streptozotocin‐treated rats was assessed. RPL treatment for 16 weeks starting at 8 weeks attenuated the decrease in endothelium‐dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGEs) concentration. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis and accumulation of AGEs in HAEC. These effects were abolished by RPL incubation. In addition, RPL increased nuclear factor erythroid 2‐related factor‐2 (Nrf‐2) activation in a CaMKKβ/AMPK pathway dependent manner. RPL treatment increased the expression of the Nrf‐2‐regulated antioxidant enzyme, heme oxygenase‐1 (HO‐1).Conclusion: Ramipril ameliorates endothelial dysfunction in diabetes by enhancing vasodilation in addition to reducing oxidative stress. These effects are mediated by ramipril activation of CaMKK‐β, which in turn activates the AMPK‐Nrf‐2‐HO‐1 pathway for enhanced endothelial function.Grant Funding Source: Supported by Shanghai Key Laboratory of Human Performance(SUS) 11DZ2261100

The effect of ramipril and telmisartan on serum potassium and its association with cardiovascular and renal events: Results from the ONTARGET trial

In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes. A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis. Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs. 264 (1.6%) patients on monotherapy (p < 0.001 vs. dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs. 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use. With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.

Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: A randomized controlled trial. Journal of the American Medical Association 2013; 309: 453–460

The objective of the trial was to examine whether ramipril, an angiotensin-converting enzyme (ACE), improves walking distance and health-related quality of life in patients with peripheral artery disease (PAD) associated with claudication. The study enrolled 212 patients with risk factors and symptoms of PAD treated by conventional therapies at three centers in Australia. All patients had an ankle-brachial index (ABI) of less than 0.90 at rest and intermittent claudication in at least one leg, which were stable for at least 6 preceding months along with the medication regimen. The patients were excluded if blood pressure was not controlled (brachial blood pressure of 160/100 mmHg or greater); if there was current or recent use of either ACE inhibitors or angiotensin II receptor blockers, potassium-sparing diuretics, or potassium supplements; renal failure (serum creatinine level 2.3 mg/dL or greater [200 µmol/L]); renal artery stenosis; previous coronary or peripheral artery revascularizations, recent myocardial infarction and other health conditions other than PAD that could adversely influence walking ability at the time of screening and for 1 year thereafter. This was a randomized, placebo-controlled, triple blinded study of ramipril at the high daily dose (10 mg) for 6 months. Primary outcomes were pain-free and maximum walking times assessed by a standard treadmill exercise test. Secondary outcomes were ABI changes; symptoms and functional status assessed by the Walking Impairment Questionnaire (WIQ)(1); health-related quality of life assessed by the Short-Form 36 Health Survey (SF-36)(2); and stenosis severity assessed by duplex ultrasound of the lower limb arteries. At baseline and at follow-up, pain-free and maximum walking distances were assessed by the standard constant load treadmill exercise test performed at a speed of 3.2 km/h and a grade of 12%.(3) ABI was calculated in both legs. Duplex ultrasonography was used to determine stenosis in lower-limb vessel segments. Functional changes per WIQ, and perceived disability assessed on the Physical Component Summary and the Mental Component Summary of the SF-36 were self-reported. Sample size was calculated as 100 patients per each group needed to provide a power of 80% at an α of 0.05 to detect a 120-second change in walking time and a 65-second change in pain-free walking time. A two-sided p-value of less than 0.05 was considered significant. Baseline variables were compared using the χ(2) test and one-way analysis of variance. The analysis of covariance model with baseline and post-treatment values after 6 months used Kruskal-Wallis analysis of variance. Imputations for missing 6-month data were performed. Data were analyzed on the intention-to-treat basis. Of 921 potential participants screened, 212 eligible participants were randomized into equal-sized ramipril and placebo groups where baseline parameters were not different. Compliance was monitored by pill count and adverse effects were monitored through interval clinical assessments, laboratory tests, and telephone calls. There was a 100% adherence rate to the study medications among 200 patients who completed the study. Ramipril was associated with a 75-second increase in mean pain-free and a 255-second increase in maximum walking time. There was a modest (less than 5 mmHg) blood pressure reduction and a small (0.1) ABI increase at rest and after exercise compared to placebo. The maximum walking time increase after ramipril therapy compared to placebo was greater in the subgroup of patients with femoropopliteal disease (286 seconds) than in those with aortoiliac disease (127 seconds). Patients treated with ramipril showed improvement of the median distance, speed and stair climbing scores on the WIQ, as well as of the Physical, but not the Mental, Component Summary score on the SF-36. The most frequent side effect was dizziness, more common in the ramipril (8.5%) than in the placebo (2.8%) group. Persistent cough occurred in 6.6% of patients on ramipril, causing their withdrawal from the study.

Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent Claudication. A Randomized Controlled Trial

In patients with intermittent claudication, 24 weeks of treatment with ramipril improves pain-free and maximum treadmill walking times compared with placebo and is associated with a significant increase in the physical functioning component of the Short-Form 36 Health Survey (SF-36; Quality Metrics, Lincoln, RI).