Angiotensin-converting Enzyme Inhibitor Lisinopril Research Articles

Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.

Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions. Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1atm, 2weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests. Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P<0.001; Soleus: 11.5% reduction in weight, P<0.001) and weakness (10.0% reduction in peak-isometric torque, P<0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P<0.001), and incomplete strength recovery (92.3% of pre-injury levels, P<0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P<0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P<0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P<0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P<0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy. Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.

Efficacy of the use of angiotensin converting enzyme inhibitors in the complex therapy of gastroduodenal erosions and ulcers in patients with unstable angina

Purpose of the study. To find out the effectiveness of the use of angiotensin-converting enzyme (ACE) inhibitors in the complex therapy of erosive and ulcer lesions of the stomach and duodenum in unstable angina pectoris (UA). Materials and methods. A survey of 109 patients with UA with gastroduodenal erosions and ulcers was carried out, taking into account their clinical signs, endoscopic features and the parameters of gastric secretion. The patients were divided into two groups depending on the nature of the treatment of erosions and ulcers. The first group included 40 patients treated with standard therapy, and the second one included 69 patients who additionally received ACE inhibitor lisinopril at an average dose of 7.27±0.16 mg a day. Results. The therapy by lisinopril resulted in decreasing of pain and dyspeptic syndrome, especially in patients with acute erosions, compared with conventional treatment group. According to endoscopic examination, in patients treated with lisinopril, an acceleration of repair processes in the tissues of the gastroduodenal zone was observed. The depth and size of damages, a reduction in the period of persistence of microbleeding signs and inflammatory changes in the periulcerous zone were also less pronounced in lisinopril patient’s group. In patients with acute erosions a decrease in the number and size of erosive defects of the mucous membrane was observed. The study of the parameters of gastric secretion showed that gastroduodenal erosions and ulcers in UA revealed the activation of the acid-peptic factor and a decreasing in the production of gastromucoproteins. Increased production of pepsinogen and a sharply reduced formation of protective mucus was observed in patients after conventional treatment, despite some positive dynamics. Normalization in pepsinogen secretion with some inhibition of the production of mucopolysaccharides was observed in Lisinopril treated patients at the end of therapy. Acid production in both groups was reduced, which was associated with could be provoked by an uptake of antisecretory agents. Conclusion. The use of ACE inhibitor lisinopril in the complex therapy in patients with UA with gastroduodenal erosions and ulcers is pathogenetically justified and clinically effective. This combination helps to reduce the duration of clinical signs, accelerate the healing of defects and normalize the parameters of gastric secretion.

Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats

This study aimed to investigate the potential protective effects of diminazene, an activator of angiotensin II converting enzyme (ACE2), on kidney function and structure in rats with acute kidney injury (AKI) induced by the anticancer drug doxorubicin (DOX). The impact of diminazene was compared to that of two other drugs: the ACE inhibitor lisinopril and the angiotensin II type 1 (AT1) receptor blocker valsartan. Rats were subjected to a single intraperitoneal injection of DOX (13.5 mg/kg) on the 5th day, either alone or in combination with diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), or valsartan (30 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Additionally, kidney tissues were assessed histopathologically. DOX-induced nephrotoxicity was confirmed by elevated levels of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). DOX also led to increased urinary N-acetyl-β-D-glucosaminidase (NAG) activity and decreased creatinine clearance, albumin levels, and osmolality. Moreover, DOX caused a reduction in renal oxidative stress markers, including superoxide dismutase (SOD), glutathione reductase (GR), and catalase activities, while increasing malondialdehyde (MDA) levels. It also raised plasma inflammatory markers, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). Concurrently administering diminazene significantly mitigated these DOX-induced changes, including histopathological alterations like renal tubule necrosis, tubular casts, shrunken glomeruli, and increased renal fibrosis. Similar protective effects were observed with lisinopril and valsartan. These protective effects, at least in part, appear to result from the anti-inflammatory and antioxidant properties of these drugs. In summary, this study suggests that the administration of diminazene, lisinopril, or valsartan had comparable effects in ameliorating the biochemical and histopathological aspects of DOX-induced acute kidney injury in rats.

Angiotensin-converting enzyme inhibitors and statins therapies-induced changes in omics profiles in humans and transgenic tau mice

BackgroundHypertension and hyperlipidemia are considered risk factors for Alzheimer’s disease (AD) and other related dementias. Clinically approved medications typically prescribed to manage these conditions have shown an association with reduced risk of developing AD and could be explored as potential repurposed therapeutics. ObjectiveWe aimed to explore the effects of the pharmacological treatment with angiotensin-converting enzyme inhibitors (ACEI) and statins (STAT) on AD-related neuropathology and the potential benefits of their concurrent use. MethodsWe investigated the effect of ACEI, STAT or combination of both by exploring the transcriptomic, proteomic and tau pathology profiles after treatment in both human patients and in P301S transgenic mice (PS19) modeling tauopathies and AD. We performed bioinformatic analysis of enriched pathways after treatment. ResultsProteomics and transcriptomics analysis revealed proteins and genes whose expression is significantly changed in subjects receiving treatment with ACEI, STAT or combined drugs. In mice, treatment with the ACEI lisinopril significantly decreased brain levels of total tau (Tau) and phosphorylated tau (pTau)-181, while the STAT atorvastatin significantly reduced the levels of pTau-396. The combined therapy with lisinopril and atorvastatin significantly decreased Tau. Moreover, brain levels of lisinopril were negatively correlated with Tau. Among the others, CD200, ADAM22, BCAN and NCAM1 were significantly affected by treatments in both human subjects and transgenic mice. ConclusionsOur findings provide significant information that may guide future investigation of the potential use of ACEI, STAT, or the combination of the two drug classes as repurposed therapies or preventive strategies for AD and other neurodegenerative diseases.

QSPR Analysis of Some Important Drugs Used in Heart Attack Treatment via Degree-Based Topological Indices and Regression Models

Degree-based topological indices are very useful tools to model and characterize the molecular structure of drugs in order to predict their physicochemical properties without going into laborious and time-consuming laboratory experiments. These indices are numerical descriptors derived for the molecular structures using the principles of graph theory. Degree-based topological indices play a vital role in the QSPR analysis of heart attack drugs by providing molecular descriptors to predict their properties. The main goal of this paper is to compute six degree-based topological indices and a regression model for seven heart attack drugs. These drugs are nitroglycerin, clopidogrel, beta-blockers (metoprolol), ACE inhibitors (lisinopril), statins (atorvastatin), (ARBs) losartan, and beta-adrenergic blockers (propranolol). Regression analysis and degree-based indices correlate with various physicochemical properties related to drug activities, such as molecular weight, complexity, melting point, and boiling point. Correlations provide insights into how the molecular structure influences these properties, helping design and optimize new drugs. In the results, various statistical parameters are used to analyze heart attack drugs.

Effects of combination antihypertensive therapy on intracardiac hemodynamics and blood vessels in patients with coronary heart disease, post-infarction cardiosclerosis and arterial hypertension

The aim of the work is to assess the effectiveness of prescribing a fixed-dose combination of amlodipine with the ACE inhibitor lisinopril or with the angiotensin 2 receptor blocker valsartan in patients with coronary artery disease, acute coronary syndrome with hypertensive disease regarding the impact on the structural and functional parameters of the heart and extracranial branches of the brachiocephalic arteries. Materials and methods. General clinical examination of 108 patients with postinfarction cardiosclerosis and hypertension was done within 12 months. The patients were allocated to two groups. Patients in the first group (n = 50) were assigned a fixed-dose combination of lisinopril and amlodipine (20 mg and 5 mg, respectively), and patients in the second group (n = 58) received a fixed-dose combination of valsartan with amlodipine (160 mg and 5 mg, respectively). The patients were monitored for 12 months, including general clinical examinations, measurements of office blood pressure (BP), 24-hour BP monitoring, echo-dopplerographic examination of the heart and brachiocephalic arteries, determination of the composite endpoint. Statistical analysis of the obtained data was performed using Microsoft Excel, IBM SPSS Statistics v.23. Results. A significant difference in echocardiographic data has been proved (p &lt; 0.05) regarding left ventricle (LV) dimensions in both study groups. A significant decrease in the E/A ratio and an insignificant decrease in E/E’ (p &gt; 0.05) have been found in the first group. When analyzing the indicators of diastolic function in the second group, a highly significant (p &lt; 0.05) decrease in E/A, E/E’, IO of the LA has been revealed; data analysis on the morphofunctional state indicators of the extracranial arteries has shown a CIM reduction and a decrease in PSV and RI. Conclusions. Prescriptions of the fixed-dose combination of amlodipine with the ACE inhibitor lisinopril was more effective in terms of the LV measurements (p &lt; 0.05) and LV diastolic function as evidenced by decreased E/A, E/E’ and IO of the LA (p &lt; 0.05) as compared to the data in the group of amlodipine with the angiotensin 2 receptor blocker valsartan. Both fixed-dose combinations were effective in reducing the CIM thickness, decreasing PSV and RI when analyzing the morphofunctional state findings of the extracranial arteries.

Renal dysfunction in patients with chronic toxic hepatitis and ways of its correction

The aim of the study was to study the effectiveness of the long-acting angiotensin-converting enzyme (ACE) inhibitor Lisinopril in the correction of renal dysfunction in patients with chronic hepatitis (CH).It was found that in patients with СH under conditions of spontaneous diuresis, the glomerular filtration rate (GFR) decreases by 1.33 times against the background of a decrease in water reabsorption (p&lt;0.05) and a tendency to a decrease in sodium excretion. During a 2-hour water load, a 3-fold decrease in GFR (p&lt;0.05) was revealed with a slight decrease in water reabsorption and a decrease in sodium and potassium excretion in the urine (p&lt;0.05). The occurrence of such disturbances in response to exercise indicates functional changes that may be due to intrarenal vasospasm as a result of activation of the interstitial renin-angiotensin system. The іnclusion of Lisinopril at a dose of 2.5 mg in the treatment regimen had a positive effect both on the clinical symptoms of hepatitis - a decrease in the activity of ALT, AST, urea (p&lt;0.05), and on the functional state of the kidneys, mainly due to the effect on filtration processes. This is especially clearly demonstrated by the implementation of the water load: an increase in diuresis by 2 times (p&lt;0.05) against the background of an increase in the glomerular filtration rate by 3 times (p&lt;0.05), excretion of sodium and potassium (p&lt;0.05). This indicates an increase in the adaptive function of the kidneys when included in the treatment ACE inhibitor.

Effective therapy of hypertension from the standpoint of patient-centered medicine

The article presents current data on the choice of antihypertensives from the standpoint of patient-centered medicine. The advantages of combined initial therapy includes high medical adherence, achievement of target blood pressure, and organ protection. Data on the effectiveness of a fixed-dose combination of an angiotensin-converting enzyme inhibitor and a thiazide-like diuretic, in particular, the most commonly used angiotensin-converting enzyme inhibitor lisinopril and long-acting indapamide, are presented. This combination is not only highly effective, but also metabolically neutral, which allows it to be used in patients with obesity, diabetes, and liver diseases. Data are presented on the new favorable effects of lisinopril and indapamide, in particular, on the effect of indapamide on the intestinal microbiota. The potential advantages of this combination as an initial therapy for hypertension in Russian patients are described.

Effect of dual blockade of renin-angiotensin system on renal nephrin and vascular endothelial growth factor – A expression in diabetic-hypertensive rats

Objectives: The effects of early renin-angiotensin system (RAS) blockade using angiotensin-converting enzyme (ACE) inhibitor lisinopril and/or angiotensin receptor blocker valsartan on renal nephrin and vascular endothelial growth factor (VEGF)-A gene expression were investigated in diabetic-hypertensive rats. Materials and Methods: Diabetes and hypertension were induced in adult Wistar rats using streptozotocin (45 mg/kg, i.p.) and Nω-nitro-L-arginine methyl ester (60 mg/kg/12 h) for 4 consecutive days. Experimental animals were allocated into six groups (n = 6): normal control, diabetic control, diabetic-hypertensive control and lisinopril-, valsartan- and combination-treated diabetic-hypertensive groups (5 mg/kg/drug/day, p.o., for 21 days). Blood glucose, blood pressure, body weight, kidney weight to body weight ratio, serum albumin, creatinine, total protein and urea were measured and recorded every week. Nephrin and VEGF-A gene expression were measured using real-time polymerase chain reaction. Renal nephrin protein was measured using ELISA as well as nephrin immunostaining. Results: Blood pressure was significantly decreased by all treatments (P ≤ 0.05). All treatments normalised serum albumin and urea. Serum creatinine significantly decreased, while total protein significantly increased (P ≤ 0.05). Nephrin gene expression had a non-significant decrease in diabetic-hypertensive rats, yet it was statistically increased with individual treatments (P ≤ 0.05) and normalised with combined treatment. Renal nephrin protein significantly decreased in diabetic-hypertensive rats, normalised by lisinopril and significantly increased by valsartan and combined treatments (P ≤ 0.05). VEGF-A expression significantly increased in diabetic-hypertensive rats and significantly decreased with lisinopril and valsartan monotherapy and normalised with combined treatment (P ≤ 0.05). Immunostaining of nephrin also showed an obvious increase in the case of combined treatment. Conclusion: Early dual blockade of RAS in diabetic-hypertensive rats protected against renal damage and improved renal nephrin and VEGF-A gene expression as well as renal nephrin protein expression.

The ACE Inhibitor Lisinopril Stimulates Melanoma Cell Invasiveness by Inducing MMP2 Secretion.

Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study. Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100. Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer. Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2.

Nephroprotective Effects of Semaglutide as Mono- and Combination Treatment with Lisinopril in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease.

Background: Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of the long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor (lisinopril) in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female diabetic db/db mice. Methods: Female db/db mice received a single intravenous injection of ReninAAV 1 week prior to UNx. Six weeks post-nephrectomy, db/db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included blood pressure, plasma/urine biochemistry, kidney histopathology and RNA sequencing. Results: Vehicle-dosed db/db UNx-ReninAAV mice developed hallmarks of DKD characterized by severe albuminuria and advanced glomerulosclerosis. Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, podocyte filtration slit density, urine/renal kidney injury molecule-1 (KIM-1) levels and gene expression markers of inflammation and fibrogenesis in db/db UNx-ReninAAV mice. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis. Conclusions: Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Further benefits on renal outcomes were obtained by adjunctive antihypertensive standard of care. Collectively, our study supports the development of semaglutide for management of DKD.

P182 VALSARTAN LIMITS PULMONARY AND CARDIAC DAMAGE INDUCED BY SARS–COV–2 IN EXPERIMENTAL MODELS BY REDUCING THE EXPRESSION OF ACE2

BackgroundSARS–CoV–2 primarily affects the respiratory system, but cardiac complications also occur very often. The entry of SARS–CoV–2 into host cells is mediated by the interaction between the viral glycoprotein Spike (S) and the host angiotensin–converting enzyme 2 (ACE2) protein. The use of ACE inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) might influence both ACE2 expression and viral infection, but our knowledge about these possible interactions is limited. Aim. To evaluate the effects of ACEIs and ARBs during active viraemia.MethodsWe tested the effects of exposure to the ACEI Lisinopril (100nM and 500nM) and the ARB Valsartan (10µM and 50µM) on three different cell types: green monkey–derived epithelial cells (VERO E6) which are used to replicate SARS–CoV–2, cardiomyocytes derived from hiPSC (iPSC–CMs) as heart model and a lung epithelial cancer cell line (16HBE) as pulmonary model. The SARS–CoV–2 wild strain was inoculated on cell lines for 1 hour. Cell viability was measured 72 hours after infection. The supernatants of the infected cells were collected and titrated by the micro–neutralization assay on VERO E6 cells to verify the presence of the virus. Levels of ACE2 mRNA and protein content on cell lysates were quantified after each treatment by RT–qPCR and western blot, respectively.ResultsACEI and ARB at both concentrations do not affect the viability of the 3 cell lines. Vice versa, viral infection significantly decreases the viability of VERO E6 (–60%, p < 0.0001) and iPSC–CMs (–44%, p < 0.001), while 16HBE cells do not show a cytopathic effect after infection. Viral titration shows that SARS–CoV–2 replicated in cell lines and was actively released into supernatants. Valsartan 50µM decreased virus release in the three cell lines and increased the viability of VERO E6 (+69%, p < 0.01) and iPSC–CMs (+20.5%, p < 0.05) after the infection. Valsartan 50µM also decreases both mRNA (–65% in VERO E6, p < 0.001; –50% in iPSC–CMs, p < 0.05; –60.5% in 16HBE, p < 0.01) and protein levels of ACE2 in all 3 cell lines.ConclusionThe data suggest that ACEIs and ARBs do not worsen the SARS–CoV–2 infection and that Valsartan, by reducing the levels of ACE2 expression, might result protective.

Heart failure correction in patients with chronic renocardiac syndrome

Abstract Funding Acknowledgements Type of funding sources: None. In case of inadequate diagnosis and correction of the basic disease, which triggers the development of chronic heart failure (CHF), left ventricular (LV) remodeling leads to myocardial dysfunction and decompensation. Patients who entered the study EUCLID, demonstrated nephroprotective effect of lisinopril, which reduces the appearance of microalbuminuria. Target Study the effectiveness of lisinopril in the correction of CHF in patients with chronic renocardiac syndrome based on a study of LV diastolic function. Methods 59 patients with chronic renocardiac syndrome were investigated. All patients received lisinopril 10-20 mg per day. LV diastolic function was evaluated for Acuson Sequoia-512 before and after treatment. Results Changes in the kinetics of myocardial contractility were characterized by high amplitude of the interventricular septum, increased by 20%, end-systolic contractility index by 9.1%, the degree of shortening of the left ventricular size by 11.4%. A significant decrease in the rate of diastolic filling by passive relaxation (E) of 23.4% and a filling rate due to atrial contraction (A) at 20%. Violation of intracardiac hemodynamics as manifested by increasing the restrictive properties of the myocardium, as well as reducing the effectiveness of time and deceleration rate of early LV filling flow by 23.2 and 27.4%, increase and decrease of LV filling time active by reducing atrial 49.9% . Decreased as the time of isovolumic LV relaxation of the heart. During treatment with lisinopril was an increase in ejection fraction (EF) of 16.4% (p=0.004) or 53.2% (49.1, 58.9) to 61.9% (53.4, 68.0 ). The rate of mitral filling period of relaxation (Ve) increased from 0.53 m/s (0.43, 0.58) to 0.56 m/s (90.47, 0.63), or 5.7 % (p=0.039), while maintaining the diastolic filling due to atrial contraction. This has led to the restructuring of diastolic filling of the normal type, which was confirmed by the change of the reflectance upwards: Ratio of Ve/Va to treatment was 1.45 units. (1.02, 1.63), vand during treatment - 1.58 units (1.21, 1.90), or a 9.0% increase (p = 0.013). Equally, there was a decrease IVRT: from 61.9 ms (54.6, 78.8) to 56.4 ms (50.3, 72.4) or 8.9% (p=0.044). Conclusions Improvement of LV diastolic function is due to improved myocardial relaxation. ACE inhibitor (lisinopril), as a means of LV remodeling, reduce the degree of diastolic dysfunction by improving myocardial relaxation in patients with chronic renocardiac syndrome.

Effects of ACE Inhibitor (Lisinopril) with Folic Acid Supplementation in the Management of Hypertension Associated with Hyperuricemia

Background: Hypertension is one of the leading cause of morbidity and mortality in all over the world as in developed and under developing countries. Hypertension mostly associated with other clinical chronic disorders like diabetes mellitus, hyperuricemia, dyslipidemia etc. The ACE inhibitors are a kind of antihypertensive drug that is widely using all over the world. ACE inhibitors lowers blood pressure, but also lower uric acid levels as well.&#x0D; Aims &amp; Objectives: To evaluate the efficacy of ACE inhibitors alone and along with the folic acid on systolic &amp; diastolic blood pressure &amp; on serum uric acid level.&#x0D; Methodology: This case-control research was carried out at the Medicine Department with the help of the Department of Biochemistry at LUMHS Jamshoro and the PAQSJ Medical Institute in Gambat. A total of 200 mild to moderate hypertension individuals with hyperuricemia were chosen. They were divided into two groups: the control group was taken 10 mg of lisinopril, while the case study group received 10 mg of lisinopril with 0.8 mg of folic acid for 10 to 12 weeks.&#x0D; Results: The mean value of systolic B.P in control group after treatment was126 ± 4.9 (P&lt;0.05) while in case study group after treatment was 118 ± 6.12 mmHg (P&lt;0.05). Diastolic B.P in control group after treatment was 90 ± 4.76 mmHg while in case study group was 82.3 ± 3.66 mmHg (P&lt;0.05). The serum uric acid level after treatment in control group was 6.7 ± 4.78 mg/dl while in case study group, it was 5.5 ± 5.11 mg/dl (P&lt;0.001). Serum Folic acid levels after the treatment in control group was 12.31 ± 2.89 while in case study group it was 27.09 ± 3.47 nmol/L (P&lt;0.001). &#x0D; Conclusion: Folic acid enhances the effectiveness of an ACE inhibitor (lisinopril) and has a substantial influence in the lowering of serum uric acid as therapeutic agent in the cases of mild to moderate hypertension associated with hyperuricemia.

Lisinopril Mitigates Radiation-Induced Mitochondrial Defects in Rat Heart and Blood Cells.

The genetic bases and disparate responses to radiotherapy are poorly understood, especially for cardiotoxicity resulting from treatment of thoracic tumors. Preclinical animal models such as the Dahl salt-sensitive (SS) rat can serve as a surrogate model for salt-sensitive low renin hypertension, common to African Americans, where aldosterone contributes to hypertension-related alterations of peripheral vascular and renal vascular function. Brown Norway (BN) rats, in comparison, are a normotensive control group, while consomic SSBN6 with substitution of rat chromosome 6 (homologous to human chromosome 14) on an SS background manifests cardioprotection and mitochondrial preservation to SS rats after injury. In this study, 2 groups from each of the 3 rat strains had their hearts irradiated (8 Gy X 5 fractions). One irradiated group was treated with the ACE-inhibitor lisinopril, and a separate group in each strain served as nonirradiated controls. Radiation reduced cardiac end diastolic volume by 9-11% and increased thickness of the interventricular septum (11-16%) and left ventricular posterior wall (14-15%) in all 3 strains (5-10 rats/group) after 120 days. Lisinopril mitigated the increase in posterior wall thickness. Mitochondrial function was measured by the Seahorse Cell Mitochondrial Stress test in peripheral blood mononuclear cells (PBMC) at 90 days. Radiation did not alter mitochondrial respiration in PBMC from BN or SSBN6. However, maximal mitochondrial respiration and spare capacity were reduced by radiation in PBMC from SS rats (p=0.016 and 0.002 respectively, 9-10 rats/group) and this effect was mitigated by lisinopril (p=0.04 and 0.023 respectively, 9-10 rats/group). Taken together, these results indicate injury to the heart by radiation in all 3 strains of rats, although the SS rats had greater susceptibility for mitochondrial dysfunction. Lisinopril mitigated injury independent of genetic background.

Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells

Radiation-induced lung injury is a major dose-limiting toxicity for thoracic radiation therapy patients. In experimental models, treatment with angiotensin converting enzyme (ACE) inhibitors mitigates radiation pneumonitis; however, the mechanism of action is not well understood. Here, we evaluate the direct role of ACE inhibition on lung immune cells. ACE expression and activity were determined in the lung immune cell compartment of irradiated adult rats after either high dose fractionated radiation therapy to the right lung (5 fractions×9 Gy) or a single dose of 13.5 Gy partial body irradiation. Mitigation of radiation-induced pneumonitis with the ACE-inhibitor lisinopril was evaluated in the 13.5 Gy rat partial body irradiation model. During pneumonitis, we characterized inflammation and immune cell content in the lungs and bronchoalveolar lavage fluid. In vitro mechanistic studies were performed using primary human monocytes and the human monocytic THP-1 cell line. In both the partial body irradiation and fractionated radiation therapy models, radiation increased ACE activity in lung immune cells. Treatment with lisinopril improved survival during radiation pneumonitis (P=.0004). Lisinopril abrogated radiation-induced increases in bronchoalveolar lavage fluid monocyte chemoattractant protein 1 (chemokine ligand 2) and MIP-1a cytokine levels (P < .0001). Treatment with lisinopril reduced both ACE expression (P=.006) and frequency of CD45+ CD11b+ lung myeloid cells (P=.004). In vitro, radiation injury acutely increased ACE activity (P=.045) and reactive oxygen species (ROS) generation (P=.004) in human monocytes, whereas treatment with lisinopril blocked radiation-induced increases in both ACE and ROS. Radiation-induced ROS generation was blocked by pharmacologic inhibition of either NADPH oxidase 2 (P=.012) or the type 1 angiotensin receptor (P=.013). These data demonstrate radiation-induced ACE activation within the immune compartment promotes the pathogenesis of radiation pneumonitis, while ACE inhibition suppresses activation of proinflammatory immune cell subsets. Mechanistically, our in vitro data demonstrate radiation directly activates the ACE/type 1 angiotensin receptor pathway in immune cells and promotes generation of ROS via NADPH oxidase 2.

Abstract 12174: Valsartan Protects Both Cardiac and Lung Cells From SARS-CoV-2 Infection

Background: Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) disease (COVID-19) mainly affects the respiratory system, but cardiac complications occur very often. SARS-CoV-2 entry in host cells is mediated by the interaction between the viral Spike (S) glycoprotein and the host angiotensin-converting enzyme 2 (ACE2). The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) might influence the expression of ACE2 and viral infection, but not much is known about these interactions. Aim: To evaluate the effects of ACEIs and ARBs during active viraemia. Methods: We tested the ACEI Lisinopril (at 100nM and 500nM) and the ARB Valsartan (at 10uM and 50uM) for one week on two cell types: cardiomyocytes derived from hiPSC (hiPSC-CMs) as heart model and a lung epithelial cancer cell line (16HBE) as pulmonary model. The SARS-CoV-2 wild strain was inoculated in the two treated cell types for one hour. Cell viability was measured 72 hours after infection. Supernatants were collected and titrated to verify the presence of infectious virus using a micro-neutralization assay on VERO-E6 cells. Levels of ACE2 mRNA and protein content on cell lysates were quantified after each treatment by RT-qPCR and western blot, respectively. Results: ACEI and ARB at both concentrations affected the viability of neither hiPSC-CMs nor 16HBE cells in the absence of virus. Vice versa, viral infection significantly decreased viability of both hiPSC-CMs (-46%; p&lt;0,01) and 16HBE (-19%; p&lt;0,05). Viral titration revealed that SARS-CoV-2 replicated in both cell lines and was actively released in supernatants. Importantly, pre-treatment with Valsartan 50uM increased the viability of both hiPSC-CMs and 16HBE after infection, while Lisinopril and the lower dose of Valsartan had neutral effect. Of note, Valsartan 50uM treatment decrease ACE2 mRNA level in both hiPSC-CMs (-47%, p&lt;0,01) and 16HBE (-37%, p&lt;0,01). Also ACE2 protein levels were reduced in cell lysates of hiPSC-CMs and 16HBE treated with Valsartan 50uM. Conclusion: These data suggest that ACEIs and ARBs do not worsen the SARS-CoV-2 infection. On the contrary, Valsartan seems to be protective against SARS-CoV-2 infection, possibly by reducing ACE2 expression.

Comparative efficacy and predictive value of fixed combination of amlodipine and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in patients with coronary heart disease, post-infarction cardiosclerosis and hypertension

The aim of the work – to analyze the effectiveness of a fixed combination of amlodipine and angiotensin-converting enzyme (ACE) inhibitor (lisinopril) or angiotensin II receptor blocker (valsartan) in patients with coronary heart disease (CHD), post-infarction cardiosclerosis (PIC), arterial hypertension (AH) regarding the blood pressure (BP) control and impact on a composite endpoint. Materials and methods. General clinical examination of 108 patients with PIC and AH was done at the Cardiology Department of Shupyk National Healthcare University of Ukraine within 12 months. Patients were divided into two groups. The first group patients (n = 50) were assigned to receive a fixed combination of valsartan and amlodipine (160 mg and 5 mg, respectively), and the second group patients (n = 58) were treated with a fixed combination of lisinopril and amlodipine (10 mg and 5 mg, respectively). Patients were followed-up for 12 months, including general clinical examination, office BP measurements, 24-hour BP monitoring, echodopplerography, monitoring of the composite endpoint. Exclusion criteria were hemodynamically significant heart valve lesions, permanent or temporary cardiac pacing, acute heart failure and implanted cardioverter-defibrillator, permanent form of atrial fibrillation, acute cerebrovascular disorder, decompensation of severe somatic pathology. Statistical analysis of the data obtained was performed using Microsoft Excel, IBM SPSS Statistics v. 23. Descriptive data were presented as arithmetic mean ± standard deviation (M ± SD) in the case of normal distribution of variables, data with distribution other than normal were presented in Me format (Q25; Q75), where Me was the median, Q25, Q75 – lower and upper quartiles (Q25; Q75), or as a percentage for categorical values with Pearson’s Chi-square (χ2) calculation. Differences in mean values were considered statistically significant at a level of Р &lt; 0.05. Results. According to all statistical criteria, BP indicators did not differ in both patient groups. Systolic office BP in the first group was 133.00 (123.00; 140.25) mm Hg., in the second group – 130.00 (122.00; 140.00) mm Hg. In the first group, diastolic office BP was 81.00 (79.50; 81.00) mm Hg and in the second group – 80.00 (75.00; 86.00) mm Hg. No statistically significant differen­ces were found in the study groups when assessing mean BP levels during the 24-hour monitoring. In the assessment of index values, systolic BP load was higher than normal in 58 % of patients in the first group and in 56.9 % of patients in the second group (χ2 = 0.01; P = 0.53). The assessment of diastolic BP load indices revealed increased diastolic BP index in 72 % of patient in the first group and in 75.9 % – in the second group (χ2 = 0.2; P = 0.4). The number of patients with BP higher or less than 130/80 mm Hg was compared. Systolic BP was above and below 130 mm Hg in 56 % and 44 %, respectively, of the first group patients; the distribution was 37.9 % and 62.1 % in the second group. Therefore, the percentage of patients with target systolic BP was higher in the second group (χ2 = 3.52; P = 0.046). Analyzing the composite endpoint, a statistically significant difference in the Kaplan–Meier curves via the statistical criterion using a log-rank test (P = 0.007) was detected. Conclusions. No statistically significant differences were found in the analysis of office blood pressure and 24-hour blood pressure monitoring between amlodipine with lisinopril and amlodipine with valsartan groups. The detailed analysis revealed a greater percentage of patients with target blood pressure below 130/80 mm Hg among those under 65 years of age receiving amlodipine with lisinopril (χ2 = 3.52; P = 0.046). The better prognostic value of the fixed combination of amlodipine with lisinopril compared to the combination of amlodipine with valsartan (P = 0.007) was demonstrated by the endpoint analysis.

Hemodynamic effects of combined antihypertensive therapy during exercise in men with arterial hypertension and chronic venous diseases

Introduction. Currently, there is insufficient data on the effect of modern antihypertensive therapy (AHT) on venous circulation, especially during physiological stress.Aim of the study – the investigation was to study the hemodynamic effects of a combination of a calcium channel blocker (CCB) and an angiotensin-converting enzyme (ACE) inhibitor during exercise in men with arterial hypertension (AH) and chronic venous diseases (CVD).Material and methods. In 46 men 30–50 years old with AH on the background of AHT, a comparative assessment of the dynamics of SBP, DBP, peripheral venous pressure (PVP), ultrasound parameters of venous blood flow of the left leg in response to physical activity (Ruffier’s test) was performed. The parameters were assessed in 23 patients with hypertension without CVD and 23 patients with hypertension and CVD. We studied the reaction before and after 14 days of combined AHT with the use of CCB (Amlodipine) and an ACE inhibitor (Lisinopril).Results. Before treatment, the response to exercise in patients of both groups was the same and was manifested by a twofold increase in the area of the lumen of the veins and a drop in blood flow velocity. Patients with CVD before treatment with exercise were characterized by an altered systemic hemodynamic response, more frequent cases of venous dilatation and decreased blood flow velocity. After AHT with exercise, both groups showed normalization and identity of SBP. DBP, PVP, a decrease in the severity of venous dilatation and a decrease in blood flow velocity. Patients with CVD after AHT in response to exercise are characterized by more pronounced venous dilatation and higher blood flow velocity.Conclusion. After 14 days of antihypertensive therapy in patients with hypertension without chronic venous disease and in patients with hypertension and chronic venous disease during exercise normalization of systolic blood pressure, diastolic blood pressure, PVP, a decrease in venous dilatation and a decrease in blood flow velocity are noted. Patients with CVD after AHT under load are characterized by varicose veins and accelerated venous blood flow.

Влияние лизиноприла на показатели электрокардиографического и эхокардиографического исследований у пациентов с циррозом печени

Chronic diffuse liver diseases (CDLD) of various etiologies remain a serious socio-economic and clinical-epidemiological health problem. Every year more than 1 million people die from cirrhosis of the liver of various etiology all over the world. According to the results of a study by a group of authors, it was found that in the Siberian Federal District there is an unfavorable situation in terms of gastroenterological mortality, in particular, hepatological mortality. CCM is characterized by lengthening of the QT interval, electromechanical dyssynchronization, and chronotropic insufficiency. The duration of the QTc interval in the subgroup of patients with liver cirrhosis who received basic therapy and the drug lisinopril (Diroton) was (418.21 ± 2.74 ms) and was significantly lower than in the subgroup of patients receiving only basic therapy. Evaluating the parameters of transthoracic echocardiography among patients with liver cirrhosis, it was noted that during treatment with basic drugs in combination with lisinopril (Diroton), the volume of LV EDV significantly decreased (p &lt; 0.05). The appointment of an ACE inhibitor lisinopril to patients with cirrhosis of the liver as part of complex therapy leads to an improvement in general well-being, a decrease in shortness of breath, an increase in exercise tolerance, an improvement in basic laboratory parameters, as well as an improvement in some morphometric parameters (EDV) and cardiac electrical systole.