Oral Losartan Research Articles

Abstract P209: Six Weeks Oral Losartan Treatment Improves Endothelium-dependent Dilation In Normotensive Women With A History Of Preeclampsia

Women with a history of preeclampsia have a 4-fold increased risk of cardiovascular disease compared to women who had a healthy pregnancy. These women demonstrate microvascular endothelial dysfunction, mediated by reduced nitric oxide (NO)-dependent dilation and increased sensitivity to angiotensin II. We hypothesized that systemic angiotensin II type 1 receptor (AT 1 R) inhibition would improve endothelium- and NO-dependent dilation in the microvasculature of women with a history of preeclampsia. Seven normotensive (seated SBP 118±6; DBP 78±6 mmHg) women (33±6 years of age, 11±7 months postpartum) with a history of preeclampsia participated in a double-blind placebo-controlled crossover study. Following 6 weeks of placebo and losartan treatment (50 mg/day), participants wore a 24-hour blood pressure monitor and completed 1 study visit in which 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusions of acetylcholine (ACh, 10 -7 -10 2 mM) or ACh + 15 mM N G nitro L-arginine methyl ester (L-NAME; NO synthase inhibitor) to assess endothelium- and NO-dependent dilation, respectively. Red blood cell flux was measured over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=Doppler flux/mean arterial pressure) and normalized to maximum (%max; 28 mM SNP + 43°C). Systemic losartan treatment augmented endothelium-dependent (losartan: 96±4 vs placebo: 70±14%max; P <0.001) and NO-dependent (losartan: 35±14 vs placebo: 23±8%; P <0.001) dilation. There was no effect of treatment on 24-hour systolic blood pressure (losartan: 117±4 vs placebo: 117±8 mmHg), diastolic blood pressure (losartan: 72±5 vs placebo: 71±5 mmHg) or mean arterial pressure (losartan: 92±4 vs placebo: 92±6 mmHg; all P>0.05 ). Losartan treatment increased endothelium-dependent vasodilation via NO-mediated pathways in the absence of changes in blood pressure in women with a history of preeclampsia. These data suggest that systemic AT 1 R inhibition may be a viable therapeutic approach to treat persistent microvascular dysfunction in otherwise healthy women who have had preeclampsia.

Losartan in Combination With Bone Marrow Stimulation Showed Synergistic Effects on Load to Failure and Tendon Matrix Organization in a Rabbit Model

To investigate the effects of combining bone marrow stimulation (BMS) with oral losartan to block transforming growth factor β1 (TGF-β1) on biomechanical repair strength in a rabbit chronic injury model. Forty rabbits were randomly allocated into 4 groups (10 in each group). The supraspinatus tendon was detached and left alone for 6 weeks to establish a rabbit chronic injury model and was then repaired in a surgical procedure using a transosseous, linked, crossing repair construct. The animals were divided into the following groups: control group (group C), surgical repair only; BMS group (group B), surgical repair with BMS of the tuberosity; losartan group (group L), surgical repair plus oral losartan (TGF-β1 blocker) for 8 weeks; and BMS-plus-losartan group (group BL), surgical repair plus BMS plus oral losartan for 8 weeks. At 8 weeks after repair, biomechanical and histologic evaluations were performed. The biomechanical testing results showed significantly higher ultimate load to failure in group BL than in group B (P= .029) but not compared with group C or group L. A 2× 2 analysis-of-variance model found that the effect of losartan on ultimate load significantly depended on whether BMS was performed (interaction term F1,28= 5.78, P= .018). No difference was found between the other groups. No difference in stiffness was found between any groups. On histologic assessment, groups B, L, and BL showed improved tendon morphology and an organized type I collagen matrix with less type III collagen compared with group C. Group BL showed the most highly organized tendon matrix with more type I collagen and less type III collagen, which indicates less fibrosis. Similar results were found at the bone-tendon interface. Rotator cuff repair combined with oral losartan and BMS of the greater tuberosity showed improved pullout strength and a highly organized tendon matrix in this rabbit chronic injury model. Tendon healing or scarring is accompanied by the formation of fibrosis, which has been shown to result in compromised biomechanical properties, and is therefore a potential limiting factor in healing after rotator cuff repair. TGF-β1 expression has been shown to play an important role in the formation of fibrosis. Recent studies focusing on muscle healing and cartilage repair have found that the downregulation of TGF-β1 by losartan intake can reduce fibrosis and improve tissue regeneration in animal models.

Paper 09: Revision rate following primary hip arthroscopy in patients given prophylactic oral losartan for the prevention of post-surgical fibrosis versus no losartan

Objectives: To evaluate whether postoperative treatment with Losartan decreased the revision rate in patients undergoing primary hip arthroscopy. Methods: Patients underwent primary hip arthroscopy with labral repair and CAM osteoplasty and rim trimming between 2012 and 2017. Patients who underwent microfracture, labral debridement or reconstruction, core decompression, ligamentous teres repair or reconstruction, or capsular reconstruction were excluded. Losartan was added to all patients’ post-operative protocol in December 2015. Patients who underwent hip arthroscopy prior to November 2015 were included in the no-Losartan group (NOLOS) and patients who had arthroscopy between December 2015 and Dec 2017 were included in the losartan group (LOS). Results: Of the 964 cases, follow-up was obtained on 673 patients (70%). There were 405 patients in the NOLOS group and 268 in the LOS group. There was no difference in gender distribution (P=0.128) between groups. The LOS group was significantly older (36.6 ±13 years) compared to the NOLOS group (34.1±11)(p=0.012). Average follow-up in the NOLOS group was 5.8±2 years and was 4.1±1 years in the LOS group. Revision hip arthroscopy was required in 35 (8.6%) patients in the NOLOS group and 6 (2.2%) patients in the LOS group(p=0.001). There was no difference in age between those patients who required revision (32±11 years) and those who did not(35±12 years)(p=0.137). Conclusions: The prevalence of revision hip arthroscopy was significantly lower (2.2%) in patients who took Losartan as part of their post-operative protocol compared to those who did not (8.6%). Reduction in the need for revision hip arthroscopy can improve patient outcomes and reduce healthcare dollars spent.

Is losartan a promising agent for the treatment of type 1 diabetes-induced testicular germ cell apoptosis in rats?

Diabetes mellitus (DM) is common metabolic disease that poses a major risk to public health and fertility. Previous studies indicate that DM may cause male infertility by triggering oxidative stress and germ cell apoptosis in the testis. Due to the undesirable effects of known antidiabetic drugs, scientists have begun to investigate the use of alternative drugs to control infertility complications observed in men. In this context, present study aimed to investigate the possible antiapoptotic effect of losartan against DM-induced testicular germ cell apoptosis. Expreimental DM model was induced by intraperitoneal injection of streptozocin (STZ, 55mg/kg) to 28 rats, which were then randomly assigned to 4 groups; 1 mL saline solution was given to DM + saline group by oral gavage, 5mg/kg/day oral losartan was given to DM + low-dose losartan, 20mg/kg/day oral losartan was given to DM + mid-dose losartan and, 80mg/kg/day oral losartan was given to DM + high-dose losartan group for 4 weeks. Bax, Bcl-2 and cleaved-Caspase 3 immunoexpression, terminal-deoxynucleotidyl transferase dutp nick end labeling (TUNEL), Annexin-V and Real Time PCR analyses performed to evaluate antiapoptotic effects of losartan on diabetic rats' testis. In addition, biochemical analyzes carried out to evaluate change in oxidative stress. The results showed that losartan may have dose-related antiapoptotic effects on rats' testis via decreasing oxidative stress.

Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses.

Malignant gliomas have a highly immune suppressive tumor microenvironment (TME) which renders them largely unresponsive to conventional therapeutics. Therefore, the present study evaluated a therapeutic protocol designed overcome the immune barrier by combining myeloid cell targeted immunotherapy with tumor vaccination. We utilized a spontaneously occurring canine glioma model to investigate an oral TME modifying immunotherapy in conjunction with cancer stem cell (CSC) vaccination. Dogs were treated daily with losartan (monocyte migration inhibitor) and propranolol (myeloid-derived suppressor cell depleting agent) plus anti-CSC vaccination on a bi-weekly then monthly schedule. Tumor volume was monitored by MRI and correlated with patient immune responses. Ten dogs with histologically confirmed gliomas were enrolled into a prospective, open-label clinical trial to evaluate the immunotherapy protocol. Partial tumor regression was observed in 2 dogs, while 6 dogs experienced stable disease, for an overall clinical benefit rate of 80%. Overall survival times (median = 351 days) and progression-free intervals (median = 163 days) were comparable to prior studies evaluating surgical debulking followed by immunotherapy. Dogs with detectable anti-CSC antibody responses had an increased overall survival time relative to dogs that did not generate antibody responses (vaccine responder MST = 500 days; vaccine non-responder MST = 218 days; p = 0.02). These findings suggest that combining myeloid cell targeted oral immunotherapy with tumor vaccination can generate objective tumor responses, even in the absence of conventional therapy. Overall, this approach has promise as a readily implemented therapeutic strategy for use in brain cancer patients.

Effectiveness of losartan on infrapatellar fat pad/synovial fibrosis and pain behavior in the monoiodoacetate-induced rat model of osteoarthritis pain

Infrapatellar fat pad (IFP)/ synovial fibrosis is closely associated with the clinical symptoms of joint pain and stiffness, which contribute to locomotor restriction in osteoarthritis (OA) patients. Hence, this study was designed to gain insight on whether losartan, a selective angiotensin II type 1 receptor (AT1R) antagonist, has therapeutic benefit to reverse IFP/synovial fibrosis and secondarily to attenuate pain behavior. In male Wistar rats with monoiodoacetic acid (MIA)-induced IFP/synovial fibrosis, a possible role for increased AT1R expression in the pathogenesis of IFP/synovial fibrosis was assessed over an 8-week period. Pain behavior comprised static weight bearing and von Frey paw withdrawal thresholds (PWTs), which were assessed once or twice weekly, respectively. Groups of MIA-rats received oral losartan (30-mg/kg; n = 8 or 100-mg/kg; n = 9) or vehicle (n = 9) for 28-days according to a prevention protocol. Animals were euthanized on day 28 and various tissues (IFP/synovium, cartilage and lumbar dorsal root ganglia (DRGs)) were collected for histological, immunohistochemical and western blot analyses. Administration of once-daily losartan for 28-days dose-dependently attenuated the development of static weight bearing. This was accompanied by reduced IFP/synovial fibrosis and suppression of TGF-β1 expression. Chronic treatment of MIA-rats with losartan had an anti-fibrotic effect and it attenuated pain behavior in this animal model.

Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults.

Losartan is an oral antihypertensive agent that is rapidly metabolized to EXP3174 (angiotensin-subtype-1-receptor blocker) and EXP3179 (peroxisome proliferator-activated receptor gamma [PPARγ] agonist), which was shown in animal studies to reduce inflammation, enhance mitochondrial energetics, and improve muscle repair and physical performance. We conducted an exploratory pilot study evaluating losartan treatment in prefrail older adults (age 70-90 years, N = 25). Participants were randomized to control (placebo) or treatment (daily oral losartan beginning at 25 mg per day and increasing every 8 weeks) for a total of 6 months. Fatigue, hyperkalemia, and hypotension were the most observed side effects of losartan treatment. Participants in the losartan group had an estimated 89% lower odds of frailty (95% confidence interval [CI]: 18% to 99% lower odds, p = .03), with a 0.3-point lower frailty score than the placebo group (95% CI: 0.01-0.5 lower odds, p = .04). Frailty score was also negatively associated with serum losartan and EXP3179 concentrations. For every one standard deviation increase in EXP3179 (ie, 0.0011 ng/μL, based on sample values above detection limit) and EXP3174 (ie, 0.27 ng/μL, based on sample values above detection limit), there was a 0.0035 N (95% CI: 0.0019-0.0051, p < .001) and a 0.0027 N (95% CI: 0.00054-0.0043, p = .007) increase in average knee strength, respectively.

Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice.

Chronic inflammation, oxidative stress, and dysregulation of the renin-angiotensin system are closely linked, and their crosstalk commonly contributes to age-related physical and cognitive decline. The primary dementia-protective benefits of Angiotensin II type 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, there is an independently regulated brain-specific renin-angiotensin system. Here, we examined the impact of 4 weeks of oral Losartan treatment on the brains of aged (100 weeks old) IL-10-/- mice, an animal model of chronic inflammation and frailty. Our data show that aged IL-10-/- mice have higher AT1R and Nitrotyrosine (oxidative stress marker) levels in their frontal cortex tissue but not in cerebellar or hippocampal tissue compared to age- and sex-matched wild type mice. Losartan treatment for 4 weeks is associated with lower AT1R protein level, Nitrotyrosine, and Tau protein in the frontal cortex of aged IL-10-/- mice. Our results highlight the impact of Losartan, an AT1R blocker commonly prescribed for treating high blood pressure, on the brain-specific angiotensin system and AT1R-linked downstream effects such as brain oxidative stress damage and Tau burden in a frailty mouse model.

Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model

Background and aimsPrevious work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in the uninjured sides. MethodsNew Zealand rabbits were divided into 4 groups including normal uninjured (Normal), contralateral uninjured side of osteochondral defect (Defect), osteochondral defect plus microfracture (Microfracture) and osteochondral defect plus microfracture and losartan oral administration (10 mg/kg/day) (Losartan). Rabbits underwent different surgeries and treatment and were sacrificed at 12 weeks. Both side of the normal group and uninjured side of treatment groups tibias were harvested for Micro-CT and histological analysis for cartilage and bone including H&E staining, Herovici's staining (bone and cartilage) Alcian blue and Safranin O staining (cartilage) as well as immunohistochemistry of losartan related signaling pathways molecules for both cartilage and bone. ResultsOur results showed losartan oral treatment at 10 mg/kg/day slightly increase Alcian blue positive matrix as well as decrease collagen type 3 in articular cartilage while having no significant effect on articular cartilage structure, cellularity, and other matrix. Losartan treatment also did not affect angiotensin receptor type 1 (AGTR1), angiotensin receptor type 2 (AGTR2) and phosphorylated transforming factor β1 activated kinase 1 (pTAK1) expression level and pattern in the articular cartilage. Furthermore, losartan treatment did not affect microarchitecture of normal cancellous bone and cortical bone of tibias compared to normal and other groups. Losartan treatment slightly increased osteocalcin positive osteoblasts on the surface of cancellous bone and did not affect bone matrix collagen type 1 content and did not change AGTR1, AGTR2 and pTAK1 signal molecule expression. ConclusionOral losartan used as a microfracture augmentation therapeutic does not have significant effect on uninjured articular cartilage and bone based on our preclinical rabbit model. These results provided further evidence that the current regimen of using losartan as a microfracture augmentation therapeutic is safe with respect to bone and cartilage homeostasis and support clinical trials for its application in human cartilage repair.

Topical losartan inhibits corneal scarring fibrosis and collagen type IV deposition after Descemet's membrane-endothelial excision in rabbits

The purpose of this study was to examine the effect of topical and/or oral angiotensin converting enzyme II inhibitor and TGF-beta signaling blocker losartan on corneal stromal fibrosis that developed in rabbit corneas after Descemetorhexis removal of central Descemet's membrane and corneal endothelium. Twenty-eight New Zealand white rabbits were included and either had 8 mm central Descemetorhexis or sham control surgery without Descemetorhexis in one eye. Groups of 4 eyes without Descemetorhexis were treated for one month with no medications, topical losartan or oral losartan. Groups of 4 eyes with Descemetorhexis were treated with topical and oral vehicle, topical losartan, oral losartan, or both topical losartan and oral losartan for one month. Standardized slit lamp photos were obtained with central opacity intensity measured with ImageJ. The posterior fibrotic zone of corneas was measured on immunohistochemistry for alpha-smooth muscle actin (SMA) and keratocan using QuPath analysis. Collagen type IV expression in the posterior cornea was quantitated with ImageJ and duplex immunohistochemistry for collagen type IV and TGF beta-1. After Descemetorhexis, topical, but not oral, losartan decreased the intensity of central stromal opacity, reduced peripheral corneal scarring, and decreased alpha-smooth muscle actin myofibroblast fibrosis area compared to corneas that had Descemetorhexis and treatment with vehicles alone. Topical losartan decreased posterior stromal cellular, non-Descemet's membrane, collagen type IV production, that is likely stimulated by TGF beta as part of a negative regulatory feedback mechanism, compared to vehicle treatment at one month after Descemetorhexis. Topical losartan is likely to be effective in reducing corneal scarring fibrosis produced by traumatic injury, microbial infection, and some corneal diseases and surgeries.

Losartan Mitigates Oxidative Stress in the Brains of Aged IL10-/- Mice

Abstract Chronic inflammation has been linked to frailty and declined cognition in older adults. Activation of the renin-angiotensin system (RAS) through the angiotensin Type1 receptor (AT1R) has been suggested as a contributory factor that links both inflammation and aging. Here we examined the impact of 4 weeks of oral Losartan treatment on IL10-/- mice brains, a mouse model of chronic inflammation and frailty. Frontal cortex, cerebellar, and hippocampal tissue of aged (100 weeks old) male IL10-/- mice were studied. Western blot techniques were employed to quantify changes in brain AT1R, nitrotyrosine (NT) as an oxidative stress marker, and Tau proteins. Our data show that aged IL-10 mice have significantly higher levels of AT1R in the cortex tissue but not in cerebellar or hippocampal tissue compared to age and sex-matched WT mice (0.63 + 0.35 vs 1.5 + 0.54, WT vs IL10, respectively, P&amp;lt;0.004). When treated with LOS, brain cortical tissue of IL10 -/- mice showed significant decreases in levels of AT1R (1.5 + 0.54 vs 0.98 + 0.50, IL10 vs LOS treated IL10, respectively, P&amp;lt;0.04), NT (0.72 + 0.12 vs 0.42 + 0.10, IL10 vs LOS treated IL10, respectively, P&amp;lt;0.009), and Tau protein (1.3 + 0.31 vs 0.15 + 0.08, IL10 vs LOS treated IL10, respectively, P&amp;lt;0.004) as compared to control IL10-/- mice. Losartan treatment had no significant effect on hippocampal AT1R or NT levels. Our results highlight the impact of Losartan, a drug commonly prescribed for the treatment of high blood pressure, on the brain-specific angiotensin system and its downstream effects on brain oxidative stress and Tau pathology.

Angiotensin Receptor Blockers Potentiate the Protective Effect of Branched-Chain Amino Acids on Skeletal Muscle Atrophy in Cirrhotic Rats.

This study investigated the combined effect of the angiotensin II (AT-II) receptor blocker losartan and branched-chain amino acids (BCAAs) on skeletal muscle atrophy in rats with cirrhosis and steatohepatitis. Fischer 344 rats are fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and treated with oral losartan (30mg kg-1 day-1 ) and/or BCAAs (Aminoleban EN, 2500mg kg-1 day-1 ). Treatment with losartan and BCAAs attenuated hepatic inflammation and fibrosis and improved skeletal muscle atrophy and strength in CDAA-fed rats. Both agents reduced intramuscular myostatin and pro-inflammatory cytokine levels, resulting in inhibition of the ubiquitin-proteasome system (UPS) through interference with the SMAD and nuclear factor-kappa B pathways, respectively. Losartan also augmented the BCAA-mediated increase of skeletal muscle mass by promoting insulin growth factor-I production and mitochondrial biogenesis. Moreover, losartan decreased the intramuscular expression of transcription factor EB (TFEB), a transcriptional inducer of E3 ubiquitin ligase regulated by AT-II. In vitro assays illustrated that losartan promoted mitochondrial biogenesis and reduced TFEB expression in AT-II-stimulated rat myocytes, thereby potentiating the inhibitory effects of BCAAs on the UPS and caspase-3 cleavage. These results indicate that this regimen could serve as a novel treatment for patients with sarcopenia and liver cirrhosis.

Immunoglobulin a nephropathy as the first clinical presentation of Wilson disease: a case report and literature review

BackgroundWilson disease (WD) is a rare genetic disorder of copper metabolism. Differences in copper tissue accumulation lead to various clinical manifestations, including some atypical presentations. The complex clinical features of WD make diagnosis challenging, delaying the best chance for treatment.Case presentationWe report a case of a 26-year-old man with nephritis-range proteinuria and elevated serum creatinine. The renal pathology indicated immunoglobulin A (IgA) nephropathy and tubular injury, which was inconsistent with glomerular lesions. Cirrhosis was also detected by imaging examination. Considering both kidney injury and liver damage, WD was suspected. Based on results showing abnormal copper metabolism, corneal Kayser–Fleischer rings, and genetic disorders in the ATP7B gene, the patient was finally diagnosed with WD. After treatment with oral penicillamine, zinc sulfate and losartan, the patient showed alleviation of both WD and nephropathy after 3 years of follow-up. He maintained a good quality of daily life.ConclusionThis case highlights that unexplained neurological and liver symptoms in patients with IgA nephropathy can be clues for WD.

Histological Study on the effect of losartan in healing of an experimentally induced muscle laceration in adult male albino rat

Abstract Background Skeletal muscle injuries are frequently encountered in athletes and military personnel. Incomplete functional recovery of these injuries usually occurs due to fibrosis of the skeletal muscle. Recently, oral administration of losartan antihypertensive drug was claimed to have a role in improving skeletal muscle healing, but still to be furtherly investigated. Aim of the work This work aimed to assess the healing effect of losartan on the histological structure of induced lacerated skeletal muscle fibers of adult male albino rats. Material and Methods Forty male albino rats were used in this study. They were divided into three groups: Group I: served as a control group and included 15 adult rats. Group II (muscle laceration group): consisted of 15 rats that were subjected to muscle laceration injury. They were subdivided into subgroup IIa: consisted of five rats that were sacrificed one day after injury, subgroup IIb: it included 10 rats that were left for spontaneous recovery for two weeks after injury. Group III (losartan-treated group): it consisted of 10 rats that were subjected to muscle laceration injury then they received oral losartan from day three till end of experiment. All rats, except rats of subgroup IIa, were sacrificed two weeks after injury. Right gastrocnemius muscle specimens were taken and processed for light microscopic examination by H &amp; E and Masson's trichome stains as well as morphometric and statistical analysis. Results In group II, there was almost complete affection of myofibers at site of injury after 1 day of induced laceration in the form of myofibers fragmentation, disorganization and distortion with apparent mononuclear cellular infiltration mainly neutrophils and macrophages. After 2 weeks some myofibers were seen distorted and ended abruptly into connective tissue, others were branched with unclear striations. Mononuclear cellular infiltration between myofibers and apparent dilated blood vessels at laceration site were also noticed. A significant increase in collagen fibers deposition between regenerating muscle fibers (p&amp;lt;0.05) was also demonstrated. Treatment of the muscle laceration by losartan in group III showed apparent partial improvement in the form of significant decrease in collagen fibers deposition (p&amp;lt;0.05) and apparent decrease in mononuclear cellular infiltration as compared to that of group II. Also, some of the regenerated myotubes were noticed with chains of central nuclei. Conclusion Excess collagen fibers deposition between myofibers hinders regular arrangement of generating myotubes. Losartan might enhance muscle regeneration through decreasing collagen fibers deposition. However, it needs longer duration to assure complete muscle healing.

Impaired right and left ventricular function and relaxation induced by pulmonary regurgitation are not reversed by tardive antifibrosis treatment.

Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.

Effects of physical exercise combined with captopril or losartan on left ventricular hypertrophy of hypertensive rats

ABSTRACT Background: Left ventricular hypertrophy (LVH) is an endpoint of hypertensive cardiac alterations. Renin-angiotensin-aldosterone system (RAAS) blockers are among the most effective on LVH regression. Physical exercise combined to antihypertensive drug contributes to arterial pressure (AP) control and LVH prevention. We evaluated the effects of physical exercise combined to captopril or losartan during eight weeks for spontaneously hypertensive rats (SHR) on some cardiac parameters. Methods: SHR (n=5-6 per group) were sedentary or trained 5 days a week in treadmill during 8 weeks; and they were treated with daily oral captopril (12.5, 25, or 50mg/kg), losartan (2.5, 5, or 10mg/kg), or vehicle. At the end, it was obtained systolic AP (SAP), electrocardiogram (ECG), and hearts metalloproteinase 2 (MMP-2) activity and histology. Results: Captopril 25 and 50 mg/kg, and losartan 10 mg/kg lowered SAP of sedentary and trained SHR. Losartan 5 mg/kg combined with physical exercise also lowered SAP. Combined with exercise, captopril 50 mg/kg lowered 13.6% of QT interval, 14.2% of QTc interval, and 22.8% of Tpeak-Tend compared to sedentary SHR. Losartan 5 and 10mg/kg lowered QT interval of sedentary and trained SHR. Losartan 2.5, 5 and 10mg/kg combined with physical exercise lowered respectively 25.4%, 24.8%, and 31.8% of MMP-2 activity. Losartan (10mg/kg) combined with exercise reduced cardiomyocyte diameter. Conclusion: These data support the hypothesis of physical exercise combined with RAAS blockers could improve the benefits on hypertensive LVH treatment.

An Open Label Trial to Assess Safety of Losartan for Treating Worsening Respiratory Illness in COVID-19.

Rationale: Coronavirus disease 2019 (COVID-19) can cause disruption of the renin-angiotensin system in the lungs, possibly contributing to pulmonary capillary leakage. Thus, angiotensin receptor blockers (ARBs) may improve respiratory failure.Objective: Assess safety of losartan for use in respiratory failure related to COVID-19 (NCT04335123).Methods: Single arm, open label trial of losartan in those hospitalized with respiratory failure related to COVID-19. Oral losartan (25 mg daily for 3 days, then 50 mg) was administered from enrollment until day 14 or hospital discharge. A post-hoc external control group with patients who met all inclusion criteria was matched 1:1 to the treatment group using propensity scores for comparison.Measures: Primary outcome was cumulative incidence of any adverse events. Secondary, explorative endpoints included measures of respiratory failure, length of stay and vital status.Results: Of the 34 participants enrolled in the trial, 30 completed the study with a mean age SD of 53.8 ± 17.7 years and 17 males (57%). On losartan, 24/30 (80%) experienced an adverse event as opposed to 29/30 (97%) of controls, with a lower average number of adverse events on losartan relative to control (2.2 vs. 3.3). Using Poisson regression and controlling for age, sex, race, date of enrollment, disease severity at enrollment, and history of high-risk comorbidities, the incidence rate ratio of adverse events on losartan relative to control was 0.69 (95% CI: 0.49–0.97)Conclusions: Losartan appeared safe for COVID-19-related acute respiratory compromise. To assess true efficacy, randomized trials are needed.

Oral Losartan After Limited Mandibulectomy for Treatment of Desmoid-Type Fibromatosis.

Desmoid-type fibromatosis (DF) is a rare soft tissue lesion with an annual incidence of 2 to 4 per million population and peak incidence occurring at approximately 4.5 years of age. While benign, the tumor has a locally aggressive infiltrative growth pattern and a high rate of recurrence. Given the functional and aesthetic implications of excision and reconstruction in the facial skeleton, novel medical treatment options are highly desirable. We describe the case of a 3-year-old boy who presented with an enlarging, asymptomatic mass involving the left mandible. Biopsy revealed an immunohistochemical profile consistent with DF. Despite the high likelihood of recurrence, conservative, mandible-sparing en bloc resection and limited mandibulectomy were performed. Pathological and immunohistochemical analysis of the resection specimen revealed DF with grossly positive margins and elevated expression of angiotensin II type 1 receptor. Postoperative medical treatment with the angiotensin receptor blocker losartan was initiated. The patient remains medically stable and disease progression-free on repeat imaging at 20 months post-resection. We describe for the first time the successful use of the angiotensin blocker losartan following conservative surgery for management of DF.

Effect of Oral Losartan on Orthobiologics: Implications for Platelet-Rich Plasma and Bone Marrow Concentrate-A Rabbit Study.

Recent efforts have focused on customizing orthobiologics, such as platelet-rich plasma (PRP) and bone marrow concentrate (BMC), to improve tissue repair. We hypothesized that oral losartan (a TGF-β1 blocker with anti-fibrotic properties) could decrease TGF-β1 levels in leukocyte-poor PRP (LP-PRP) and fibrocytes in BMC. Ten rabbits were randomized into two groups (N = 5/group): osteochondral defect + microfracture (control, group 1) and osteochondral defect + microfracture + losartan (losartan, group 2). For group 2, a dose of 10mg/kg/day of losartan was administrated orally for 12 weeks post-operatively. After 12 weeks, whole blood (WB) and bone marrow aspirate (BMA) samples were collected to process LP-PRP and BMC. TGF-β1 concentrations were measured in WB and LP-PRP with multiplex immunoassay. BMC cell populations were analyzed by flow cytometry with CD31, CD44, CD45, CD34, CD146 and CD90 antibodies. There was no significant difference in TGF-β1 levels between the losartan and control group in WB or LP-PRP. In BMC, the percentage of CD31+ cells (endothelial cells) in the losartan group was significantly higher than the control group (p = 0.008), while the percentage of CD45+ cells (hematopoietic cells-fibrocytes) in the losartan group was significantly lower than the control group (p = 0.03).

Effect of Adding Losartan to Bevacizumab for Treating Diabetic Macular Edema.

Introduction Diabetic retinopathy is the most common cause of visual loss and blindness in the age group of 20 to 64 years. This study aimed to evaluate the efficacy of oral Losartan adjuvant therapy in combination with intravitreal injection of Bevacizumab in the treatment of diabetic macular edema. Methods In this randomized clinical trial, 61 eyes of 47 patients with normal blood pressure and diabetic macular edema and nonproliferative diabetic retinopathy were studied. Patients were randomly divided into Losartan (n = 33) and control (n = 28) groups. All patients received 3–6 intravitreal injections of Bevacizumab over 6 months. General examination including blood pressure and glycosylated hemoglobin measurements were performed in all patients. Complete ophthalmologic examination and macular OCT were performed at the first, third, and sixth months of treatment in all patients. Results The mean age of the patients studied was 57.1 ± 7.4 years and 37.7% of the patients were male. There was no significant difference between the two groups in terms of initial visual acuity, central macular thickness, and frequency of injections. There was no significant difference in visual acuity and central macular thickness between the two groups at the first, third, and sixth months of treatment. Age, frequency of injection, and initial macular thickness less than 450 microns were effective in patients' final visual acuity. Conclusion Short-term adjuvant treatment with Losartan in patients with diabetic macular edema and nonproliferative diabetic retinopathy has no greater effect than the standard treatment.