Angiotensin Receptor Blocker Losartan Research Articles

Sparsentan improves glomerular hemodynamics, cell functions, and tissue repair in a mouse model of FSGS.

Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive, compared with current standard of care using angiotensin receptor blockers (ARBs). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters; increased or preserved blood flow and single-nephron glomerular filtration rate; attenuated acute ET-1 and AngII-induced increases in podocyte calcium; reduced proteinuria; preserved podocyte number; increased both endothelial and renin lineage cells and clones in vasculature, glomeruli, and tubules; restored glomerular endothelial glycocalyx; and attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared with losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.

#282 Correction of portal hypertension and renal dysfunction with losartan in patients with liver cirrhosis

Abstract Background and Aims To increase the effectiveness of drug correction of portal hypertension, taking into account the functional state of patients with liver cirrhosis, using Angiotensin receptor blockers (ARBs) Method The work summarizes the results of an examination of 35 patients with liver cirrhosis (LC) who were treated in the hepatology department. The patients were divided into two subgroups: the first consisted of 21 patients with liver cirrhosis without ascites, Child-Pugh class A, and the second subgroup included 14 patients with liver cirrhosis with ascites, Child-Pugh class B. We evaluated the effect of the orally active angiotensin II receptor antagonist, losartan, on portal pressure in patients with cirrhosis and portal hypertension. Patients with (hepatic venous pressure gradient [HVPG] ≥ 13 mmHg) portal hypertension at baseline measurement were treated with an oral dose of 25 mg losartan once daily for 1 week. Results The examined patients were analyzed for the functional state of the kidneys and its relationships with the main parameters of portal hypertension and hepatic cellular failure. Comparative characteristics of the main indicators of renal function revealed significant differences in functional parameters depending on the degree of hepatic cellular failure. In the group of patients with cirrhosis with ascites, there was a significant decrease in renal GFR to 77.5 ± 1.4 ml/min, in contrast to the unchanged level of GFR in the group of patients with cirrhosis without ascites - 99.3 ml/min. However, no significant changes in serum creatinine levels were detected. Therapy with Losartan in patients with Child-Pugh class A liver cirrhosis at a dose of 25 mg/day reduces PV pressure gradient by 18.1%, at a dose of 12.5 mg/day does not significantly affect the level of portal hypertension, but improves the functional state of the kidneys (increases FPR by 56%, EPP by 17.3%). Conclusion The present study indicates that angiotensin II blockade with orally administered losartan is safe and highly effective in the treatment of portal hypertension. In patients with liver cirrhosis with the development of impaired renal reabsorption function and a decrease in FPR from 10% to 8% in the treatment of portal hypertension, the drug of choice is an ARBs (losartan 25 mg/day) with blood pressure > 115/60 mmHg.

Impact of Renin Angiotensin System Inhibition on Renal Function in Fructose-induced Salt Sensitive Blood Pressure

Combined dietary intake of fructose with high salt at levels comparable to that in the upper quintile of western population increases blood pressure, decreases glomerular filtration rate, and results in albuminuria and insulin resistance. We tested the hypothesis that chronic treatment with either an angiotensin converting enzyme inhibitor (enalapril) or angiotensin receptor blocker (losartan) will preserve glomerular filtration rate (GFR) and reduce albuminuria. Sprague Dawley rats of both sexes were instrumented with telemetry. After a baseline period on glucose+0.4% NaCl, rats were assigned to the following groups: 20% glucose+0.4%NaCl treated with vehicle (GNS+V) or 20% fructose+4% NaCl and treated with either vehicle (FHS+V), losartan 0.42 mg/kg/hr by osmotic minipump (FHS+L) or enalapril 0.21 mg/kg/hr (FHS+E). The doses of losartan and enalapril were chosen to achieve MAP similar to the control GNS+V group. Body weights did not differ among the groups upon entry into the protocol and increased similarly among the groups. Non-fasting blood glucose was elevated in all groups in both male and female rats. Mean arterial pressure (MAP) was 108±2 mmHg in GNS+V but was elevated in the FHS+V male rats, 118±2 mmHg ( P<0.01). FHS+L and FHS+E displayed MAP similar GNS+V rats: 104±2 and 106±2 mmHg, respectively. GFR assessed by transdermal FITC-sinistrin elimination was similar across all groups: 0.85±0.04 (GNS+V), 0.86±0.08 (FHS+V), 0.94±0.10 (FHS+L), 1.13±0.12 ml/min/100 g bw (FHS+E). Female rats did not display elevated MAP: 108±1 mmHg (FHS+V) vs 105±2 mmHg (GNS+V). Losartan and enalapril did not change MAP, but GFR was higher in female FHS+L rats, 1.14± 0.05, vs GNS+V 0.75±0.06 ( P < 0.05). Thus, male but not female fructose-fed rats on high salt diet display significantly higher blood pressure. Short-term fructose high salt feeding did not change GFR in either male or female rats. RAS inhibition did not impact GFR in male rats, but losartan increased GFR in female rats on high fructose plus high salt diet compared with glucose-fed female rats on normal salt diet. R01 HL163844. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The role of angiotensin receptor blocker (losartan) on decreasing fibrotic process of corpora cavernosa in priapism model of wistar rats

Background Priapism induces regulation of Transforming Growth Factor-β1 (TGF-β1) expression and collagen-type-1 deposition. This will replace the normal corpora cavernosa with fibrotic tissue which eventually resulted in erectile dysfunction. It is also known that the fibrosis process of corpora cavernosa is related to Renin-Angiotensin II System (RAS). Angiotensin II receptor blockers (ARB), especially losartan, inhibit the inflammation process and fibrotic tissue formation. This study evaluated the effect of losartan in reducing fibrosis in priapism by evaluating TGF-β1 and collagen-type-1 in cavernous tissue and determined the effect of losartan in preventing fibrosis in priapism model of Wistar rats assessed by the metavir score. Methods A total of eighteen male Wistar rats mean were divided into five groups. For the priapism models, we applied negative pressure on the penis to make an artificial erection to mimic the priapism process. The control groups were observed and the treatment groups were orally given losartan 15 mg/kg/day. Corpora cavernosa was harvested for TGF-β1 and collagen-type-1 measurement using an enzyme-linked immunosorbent assay (ELISA). The fibrotic tissue of each rat was then collected and assessed histopathologically with the metavir scoring system. Results Penile TGF-β1 concentration in the losartan-treated group was not significantly different on day 10 and day 28 of observation (p10=0,30; p28=0,17). Meanwhile, collagen-type-1 concentration was significantly lower compared to control group (p10=0,002; p28=0,01). There was a significant difference in metavir scores in rats that received losartan and those who did not (p<0,05). Conclusion Losartan could suppress the fibrosis process in the priapism model. It could decrease the collagen type 1 deposition during corpora cavernosa tissue regeneration. Based on the metavir score, the group receiving losartan therapy was better than the control group.

Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial

BackgroundAngiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. MethodsWe investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. ResultsAcute administration of losartan significantly reduced participants’ adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. ConclusionsThis study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development.

Combining angiotensin receptor blockade and enzyme replacement therapy for vascular disease in mucopolysaccharidosis type I

Vascular involvement in the genetic disorder mucopolysaccharidosis type I (MPS I) has features of atherosclerotic disease near branch points of arterial vasculature, such as intimal thickening with disruption of the internal elastic lamina, and proliferation of macrophages and myofibroblasts. Inflammatory pathways are implicated in the pathogenesis of vascular disease in MPS I animal models, evidenced by cytokines like CD18 and TGF-β within arterial plaques. The angiotensin II-mediated inflammatory pathway is well studied in human atherosclerotic coronary artery disease. Recent work indicates treatment with the angiotensin receptor blocker losartan may improve vascular MPS I disease in mouse models. Here, we combined losartan with the standard therapy for MPS I, enzyme replacement therapy (ERT), to measure effects on cytokines in serum and aortic vasculature. Each treatment group (losartan, ERT, and their combination) equally normalized levels of cytokines that were largely differential between normal and mutant mice. Some cytokines, notably CD30 ligand, Eotaxin-2, LIX, IL-13, IL-15, GM-CSF, MCP-5, MIG, and CCL3 showed elevations in mice treated with ERT above normal or mutant levels; these elevations were reduced or absent in mice that received losartan or combination therapy. The observations suggest that losartan may impact inflammatory cascades due to MPS I and may also blunt inflammation in combination with ERT.

ACE2/ACE imbalance mediates bisphenol A-induced lung injury in Wistar rats: Results from captopril versus losartan histo-biochemical study

Bisphenol-A (BPA) is a synthetic chemical compound broadly used in the plastic and epoxy resin industries with a considerable potential for food contamination. Literary reports have suggested that the altered renin-angiotensin system (RAS) is a mechanism for lung injury and inflammation caused by variable agents. The current study sought to investigate the contribution of RAS to BPA-induced lung damage. Moreover, the study assessed whether angiotensin II and/or bradykinin pathways were involved. For this aim, the angiotensin-converting enzyme (ACE) inhibitor captopril (Cap), either alone or combined with bradykinin receptor antagonist icatibant (Icat), was attempted versus the angiotensin receptor blocker losartan (Los). An eight-week study was conducted on forty Wistar male albino rats randomly divided into five equal groups: control, BPA, BPA/Cap, BPA/Los, and BPA/Cap/Icat groups. Captopril (100 mg/mL) and losartan (200 mg/mL) were given orally in drinking water, but icatibant (Icat) was injected subcutaneously (250 μg/kg) during the last two weeks of captopril treatment. Biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung tissues, polymerase chain reaction (PCR) assay for ACE, ACE2, and caspase-3 genes expression, and histological and immunohistochemical studies were carried out to evaluate BPA-mediated pulmonary inflammation/apoptosis. BPA impaired the histological structure of the lungs, increased ACE, ACE2, and caspase-3 expressions at both gene/protein levels, and increased BALF inflammatory cytokines and lung oxidative markers. Inhibiting the ACE activity by captopril maintained the histological lung injury score, restored inflammation and the ACE2/ACE balance, and decreased apoptosis. Further improvement was obtained by the angiotensin II receptor (ATR1) blocker losartan. Icatibant (bradykinin B2 receptor blocker) didn't counteract the observed captopril effects. It was strongly suggested that RAS contributed to BPA-induced lung damage via alteration of ACE2 and ACE expression mediating angiotensin II generation rather than bradykinin.

Angiotensin Receptor Blocker-Related Sprue-like Enteropathy: Review of Food and Drug Administration Adverse Event Reporting System.

Sprue-like enteropathy (SE) related to olmesartan use was first reported in 2012. In 2017, the manufacturer of Benicar paid $300 million for 2300 claims for olmesartan-related SE. A study in 2019 suggested that SE was related to olmesartan and with the possibility of angiotensin receptor blocker (ARB) class effect. To further characterize this condition, our group examined reports of ARB-related SE to Food and Drug Administration Adverse Event Reporting System (FAERS). All reports of ARB-related SE from January 2017 to December 2021 were downloaded from the FAERS database. Gastrointestinal adverse events including SE were reviewed. Reporter categories included physicians, pharmacists, other health care professionals, consumers, and attorneys. A total of 106 590 reports of ARB-related adverse effects were analyzed. Sprue-like enteropathy was identified in 4337 cases (4.1% of total reports). Of these, 4240 cases (98.0%) of ARB-related SE were reported in patients using products with olmesartan, and 97 cases of SE were reported for all other ARBs (eprosartan, losartan, telmisartan, irbesartan, valsartan, and candesartan). Reports of olmesartan-related SE increased rapidly in 2017, continued at a high rate in 2018 and 2019, and essentially stopped in 2020 and 2021. Reports to FAERS for ARB-related SE are mostly related to olmesartan. There was a steep decline in reports of olmesartan-related SE following the lawsuit with potential of lawyer interference. There are reports of SE related to ARBs other than olmesartan, with increased physician awareness and the potential to discover a class effect with future studies.

The role of angiotensin receptor blocker (losartan) on decreasing fibrotic process of corpora cavernosa in priapism model of wistar rats.

Priapism induces regulation of Transforming Growth Factor-β1 (TGF-β1) expression and collagen-type-1 deposition. This will replace the normal corpora cavernosa with fibrotic tissue which eventually resulted in erectile dysfunction. It is also known that the fibrosis process of corpora cavernosa is related to Renin-Angiotensin II System (RAS). Angiotensin II receptor blockers (ARB), especially losartan, inhibit the inflammation process and fibrotic tissue formation. This study evaluated the effect of losartan in reducing fibrosis in priapism by evaluating TGF-β1 and collagen-type-1 in cavernous tissue and determined the effect of losartan in preventing fibrosis in priapism model of Wistar rats assessed by the metavir score. A total of eighteen male Wistar rats mean were divided into five groups. For the priapism models, we applied negative pressure on the penis to make an artificial erection to mimic the priapism process. The control groups were observed and the treatment groups were orally given losartan 15 mg/kg/day. Corpora cavernosa was harvested for TGF-β1 and collagen-type-1 measurement using an enzyme-linked immunosorbent assay (ELISA). The fibrotic tissue of each rat was then collected and assessed histopathologically with the metavir scoring system. Penile TGF-β1 concentration in the losartan-treated group was not significantly different on day 10 and day 28 of observation (p10=0,30; p28=0,17). Meanwhile, collagen-type-1 concentration was significantly lower compared to control group (p10=0,002; p28=0,01). There was a significant difference in metavir scores in rats that received losartan and those who did not (p<0,05). Losartan could suppress the fibrosis process in the priapism model. It could decrease the collagen type 1 deposition during corpora cavernosa tissue regeneration. Based on the metavir score, the group receiving losartan therapy was better than the control group.

An Overview on Chemical Features and Metabolism of Synthetic and Natural Product-Based Medicine for Combating COVID-19

This review article covers the proposed synthetic and natural medicines, and their contribution in aspects of chemistry and metabolism for the management of COVID-19, which is still lacking in many published current studies. Most of the current studies were focused on physiology, epidemiology, and management of COVID-19. However, only a few of such studies mainly focussed on the chemistry of medicine in the management of the disease. In this contest, both natural and synthetic medicines, their synthesis and metabolism are highlighted in the current article. Currently, the entire world is struggling with the COVID-19 pandemic that has disturbed every aspect of life, caused by a newly discovered virus strain named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). The outbreak continues to evolve, several research activities have been continuously carried out for understanding the origin, functions, treatments, and preventions of novel coronavirus (nCoV) infections such as SARS-CoV-2, SARS-CoV-1. There a lot of lines of treatment are being used all over the world but still, the perfect line of treatment for COVID-19 is not available. Various kinds of antiviral, anti-malarial, ACE inhibitors, and immunosuppressant drugs are being trialled worldwide for the management of COVID-19. A synthetic drug such as antimalarial drug (Hydroxychloroquine\Chloroquine), antiviral drug (Favipiravir, Remdesivir, Oseltamivir, EIDD-1931, Lopinavir, and Ritonavir), angiotensin-converting enzyme inhibitors/ angiotensin-receptor blockers (Captopril and Losartan), and immunosuppressant/arthritic drugs (Actemra, Baricitinib, Ruxolitinib, and Kevzara) for the management therapy for COVID-19 herewith complied to describe the chemical features and proposed metabolism process. Further, both chemistry and metabolism of proposed natural drug therapy such as quercetin, patchouli alcohol, baicalin, glycyrrhizic acid, and andrographolide for the management of COVID-19 infection are also included.

Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

S-38-2: PREVENTION OF EXPERIMENTAL GENETIC HYPERTENSION - GENOMIC CLUES FROM THE KIDNEY

Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this reprogramming, but relevant molecular genetic changes are unknown. We studied SHR kidney RNA differential expression (controlling for non-specific effects of lower BP) and DNA methylation 6 weeks after treatment with the angiotensin receptor blocker losartan from 10 to 14 weeks of age. RNA sequencing revealed a significant 6-fold (P &lt; 0.0001) increase in renin gene (Ren) expression during treatment. Six weeks later direct mean arterial pressure remained lower than untreated SHR (123 vs 140 mmHg, P = 0.001) and kidney Ren expression was reduced by 23% (P = 0.03) and DNA methylation within the Ren promoter region was significantly increased (P = 0.04). Experiments with the ACE inhibitor perindopril and renin immunohistochemical analyses confirmed significant long-term reduction in kidney Ren expression following RAS inhibition. Genomic RNA sequencing analysis identified 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4) and the miRNA miR-145-3p that were significantly differentially expressed and correlated closely with decreased Ren expression. Ten of the candidates were central to gene networks that exhibited significant enrichment for genes relevant to BP and the RAS. We propose that reduced renin gene expression is a legacy of early RAS inhibition and responsible for the persistent reduction in BP in SHR.

PS-BPB08-4: IMPAIRED TCA CYCLE METABOLISM IN DIABETIC NEPHROPATHY IS LINKED TO ALBUMINURIA AND KIDNEY INJURY

Objective: Recent work has highlighted potential contributions of impaired renal energy metabolism, including mitochondrial dysfunction and altered fatty acid metabolism, in chronic kidney diseases including diabetic nephropathy (DN). However, causal connections between specific metabolic abnormalities and pathophysiology of DN have been difficult to establish. Here, we approach this question using a mouse model recapitulating characteristic features of human DN and a targeted metabolomics platform designed to assess key metabolic pathways involving amino acids, fatty acids, glycolysis and the TCA cycle. Design and method: We generated a mouse model of DN with underlying activation of the renin-angiotensin system (RAS) by a renin transgene (R) driven by the albumin promoter on the Akita background of type I diabetes (A). We have shown that on a susceptible 129/Sv background, Akita-ReninTg (AR) mice exhibit cardinal characteristics of human DN including high-grade albuminuria and glomerulosclerosis, whereas AR mice on a C57BL/6 background do not develop DN. To assess the impact of genetic background on energy metabolism in DN, kidneys from 24-week-old male AR mice on both backgrounds were evaluated by the targeted metabolome analysis. To further distinguish the impact of RAS activation on relevant pathways associated with kidney disease development, 12-week-old male 129/Sv AR mice were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks. 24-hour urine samples were collected in metabolic cages and urine albumin levels were measured by EIA. Kidneys from age-matched parental 129/Sv and C57BL/6 wild-type mice were analyzed as controls. Results: A distinct metabolic profile was observed in kidneys of DN-susceptible 129/Sv AR mice including reduced levels of C2 acetyl-carnitine that reflect a deficiency in acetyl-CoA, perturbations of TCA cycle intermediates and increased lactate levels. In addition, levels of phosphorylated-AMPK were reduced. These metabolic changes were absent in DN-resistant C57BL/6 AR mice. Treatment of 129/Sv AR mice with the ARB dramatically reduced albuminuria (906 ± 169 vs 193 ± 42 μg/day, p &lt; 0.01) and attenuated kidney pathology while restoring levels of C2 acetyl-carnitine, TCA intermediates, lactate and phosphorylated-AMPK toward normal. ARB treatment also increased kidney ATP content. In 129/Sv mice, there were statistically significant correlations between albuminuria and kidney levels of lactate, acetyl-carnitine, citrate and succinate. Conclusions: Thus, there is a distinct profile of impaired energy metabolism associated with DN susceptibility that is attenuated by RAS blockade. Impaired TCA cycle function and coincident increases in lactate are linked to albuminuria in mice with DN, and may contribute to kidney injury.

Comparison of Gambier Extract (Uncaria Gambier Robx) and Angiotensin Receptor Blocker on Proteinuria Reduction and Antioxidants - Enhancement in Nephrotic Rat Models.

Proteinuria is a significant clinical manifestation that causes edema in several diseases, including Nephrotic Syndrome (NS). Untreated proteinuria is strongly linked to the progression of kidney failure. One of the adjuvant therapies could be used to reduce proteinuria such as Angiotensin Receptor Blocker (ARB) including Losartan®. Gambier is a traditional medicinal plant widely known for its antioxidant effects. Catechin, a compound contained in Gambier Extract (GE), has been used to reduce microalbuminuria in diabetics. However, its application in NS has not been widely studied. This study compared the effects of GE and ARB in reducing proteinuria and increasing antioxidant activity levels, as well as reported histopathological findings in the nephrotic Wistar rat model. An experimental design study with a control group and a posttest was conducted. The experimental animals were divided into four groups: the control group (K1), the group with puromycin aminonucleoside (PAN) injection (K2), the group with PAN injection + GE (K3), and the group with PAN injection + Losartan® (K4). The standard GE used was Sarie Uncariae® by Toyo Brothers, PT while the ARB (Losartan®) was obtained from Novell, PT. Protein urine, the activity level of total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were assessed using the colorimetric method. Renal histopathology was assessed based on Rollerman's criteria. Gambier extract significantly reduced proteinuria, as depicted by a decrease in protein/volume urine (p = 0.009), increased antioxidant activity, as illustrated by an elevation in T-SOD activity levels (p = 0.007), and tended to decrease MDA levels compared to Losartan®. Based on histopathological findings, GE tended to reduce the percentage of kidney damage in rats induced by puromycin. Gambier extract has been shown a higher antioxidant effect by increasing T-SOD activity levels, reducing proteinuria and also exhibiting a tendency to diminish kidney damage.

Angiotensin-receptor blocker losartan alleviates atrial fibrillation in rats by downregulating frizzled 8 and inhibiting the activation of WNT-5A pathway.

Atrial fibrillation (AF) is a common arrhythmia. Angiotensin-receptor blocker (ARB) is related to AF treatment. This study explored the mechanism of ARB in AF. AF rat models were established by Ach-CaCl2 mixed solution injection. Rats were treated with ARB by gavage and injected with pcDNA3.1-based frizzled homolog 8(FZD8) overexpression plasmids (oe-FZD8) through the tail vein. The 12-lead electrocardiogram was recorded by biological signal acquisition and processing system and AF duration was recorded, and atrial effective refractory period (AERP) was monitored by electrophysiology. Atrial fibrosis degree, FZD8 messenger RNA and protein levels, collagen I, collagen III, transforming growth factor β1 (TGF-β1), fibronectin, α smooth muscle actin (α-SMA), WBT-5B, and p-JNK1/2 levels, interleukin 1 β (IL-1β) and interleukin 6 (IL-6) levels were detected by Masson staining, reverse transcription quantitative polymerase chain reaction, western blot assay, immunohistochemistry, and enzyme-linked immunosorbent assay. ACh-CaCl2-induced AF rats showed a large area of fused necrosis, abnormal collagen fibre proliferation, high atrial fibrosis degree, and increased atrial fibrosis area in atrial interstitium, elevated collagen I, collagen III, TGF-β1, fibronectin, α-SMA, IL-1β, and IL-6 levels, whereas these trends were averted by ARB treatment. FZD8 was highly expressed in AF rat myocardium. ARB repressed FZD8 expression, prolonged AERP and reduced AF incidence. FZD8 overexpression annulled the effects of ARB on improving AF rat myocardial fibrosis. ARB inactivated the WNT-5A pathway by suppressing FZD8. ARB inactivated the WNT-5A pathway by silencing FZD8, therefore, alleviating AF rat atrial fibrosis.

The role of angiotensin receptor blocker (losartan) on decreasing fibrotic process of corpora cavernosa in priapism model of wistar rats

Background: Priapism induces regulation of Transforming Growth Factor-β1 (TGF-β1) expression and collagen-type-1 deposition. This will replace the normal corpora cavernosa with fibrotic tissue which eventually resulted in erectile dysfunction. It is also known that the fibrosis process of corpora cavernosa is related to Renin-Angiotensin II System (RAS). Angiotensin II receptor blockers (ARB), especially losartan, inhibit the inflammation process and fibrotic tissue formation. This study evaluated the effect of losartan in reducing fibrosis in priapism by evaluating TGF-β1 and collagen-type-1 in cavernous tissue and determined the effect of losartan in preventing fibrosis in priapism model of Wistar rats assessed by the metavir score. Methods: A total of eighteen male Wistar rats mean were divided into five groups. For the priapism models, we applied negative pressure on the penis to make an artificial erection to mimic the priapism process. The control groups were observed and the treatment groups were orally given losartan 15 mg/kg/day. Corpora cavernosa was harvested for TGF-β1 and collagen-type-1 measurement using an enzyme-linked immunosorbent assay (ELISA). The fibrotic tissue of each rat was then collected and assessed histopathologically with the metavir scoring system. Results: Penile TGF-β1 concentration in the losartan-treated group was not significantly different on day 10 and day 28 of observation (p10=0,30; p28=0,17). Meanwhile, collagen-type-1 concentration was significantly lower compared to control group (p10=0,002; p28=0,01). There was a significant difference in metavir scores in rats that received losartan and those who did not (p&lt;0,05). Conclusion: Losartan could suppress the fibrosis process in the priapism model. It could decrease the collagen type 1 deposition during corpora cavernosa tissue regeneration. Based on the metavir score, the group receiving losartan therapy was better than the control group.

Activation of RAAS Signaling Contributes to Hypertension in Aged Hyp Mice.

High circulating levels of fibroblast growth factor-23 (FGF23) are associated with left ventricular hypertrophy as well as increased morbidity and mortality in patients suffering from chronic kidney disease. However, the mechanisms underlying this association are controversial. Here, we aimed to further characterize the cardiovascular sequelae of long term endogenous FGF23 hypersecretion using 14-month-old male Hyp mice as a model of FGF23 excess. Hyp mice were characterized by a ~10-fold increase in circulating intact FGF23, hypophosphatemia, increased serum aldosterone, but normal kidney function, relative to wildtype (WT) controls. Cardiovascular phenotyping did not reveal any evidence of left ventricular hypertrophy or functional impairment in 14-month-old Hyp mice. Fractional shortening, ejection fraction, molecular markers of hypertrophy (Anp, Bnp), and intracardiac markers of contractility and diastolic function were all unchanged in these animals. However, intraarterial catheterization revealed an increase in systolic, diastolic, and mean arterial pressure of ~12 mm Hg in aged Hyp mice relative to WT controls. Hypertension in Hyp mice was associated with increased peripheral vascular resistance. To test the hypothesis that a stimulation of the renin–angiotensin–aldosterone system (RAAS) contributes to hypertension in aged Hyp mice, we administered the angiotensin receptor blocker losartan (30 mg/kg twice daily) or the mineralocorticoid receptor antagonist canrenone (30 mg/kg once daily) to aged Hyp and WT mice over 5 days. Both drugs had minor effects on blood pressure in WT mice, but reduced blood pressure and peripheral vascular resistance in Hyp mice, suggesting that a stimulation of the RAAS contributes to hypertension in aged Hyp mice.

Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition.

The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.

P615. Sex-Dependent Impact of Losartan on Background Anxiety and Hyperreactivity

PTSD is a debilitating psychiatric disorder with symptoms such as hyperreactivity and increased anxiety, and is 2-3x more prevalent in females. Recent studies have linked PTSD with the renin-angiotensin system, and evidence points to the utility of angiotensin receptor blockers (ARBs) in treating PTSD. We have previously shown that treatment with the ARB losartan accelerates fear extinction, making it a promising potential therapeutic for PTSD. We therefore hypothesized that losartan would reduce fear-potentiated startle (FPS) and anxiety.

Drug Utilization Pattern of Antihypertensives in a Private Healthcare Setting in Enugu, Nigeria

Hypertension is a public health challenge worldwide. Drug utilization study is a component of medical audit that monitors and evaluates prescribing practices and recommends necessary modifications. This study focused on the drug utilization pattern of antihypertensive drugs. The study was a retrospective study of facility records on drug use among hypertensive patients. It was conducted in a private health care setting facility in Enugu. A total of 1,005 prescriptions were evaluated for drug prescribing patterns. The blood pressure control was evaluated. A combination of two drugs was frequently prescribed (42.3%). Drug prescribing pattern showed that Angiotensin receptor blocker (Losartan) was mostly frequently prescribed (38.94%). Drug utilization of antihypertensive drugs was in agreement with JNC 7&amp;8 recommendations. In the study combination of two or more anti-hypertensive drugs was frequently prescribed. The blood pressure control among the population was greater than 90%.