Angiotensin-converting enzyme inhibition prevents l-dopa-induced dyskinesia in a 6-ohda-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.

Vanadocene-functionalized mesoporous silica nanoparticles: platforms for the development of theranostic materials against breast cancer.

Nanoscale materials have demonstrated a very high potential in anticancer therapy by properly adjusting their functionalization and physicochemical properties. Herein, we report the synthesis of some novel vanadocene-loaded silica-based nanomaterials incorporating four different S-containing amino acids (penicillamine, methionine, captopril, and cysteine) and different fluorophores (rhodamine B, coumarin 343 or Alexa Fluor™ 647), which have been characterized by diverse solid-state spectroscopic techniques viz; FTIR, diffuse reflectance spectroscopies,13C and51V solid-state NMR spectroscopy, thermogravimetry and TEM. The analysis of the biological activity of the novel vanadocene-based nanostructured silicas showed that the materials containing cysteine and captopril aminoacids demonstrated high cytotoxicity and selectivity against triple negative breast cancer cells, making them very promising antineoplastic drug candidates. According to the biological results it seems that vanadium activity is connected to its incorporation through the amino acid, resulting in synergy that increases the cytotoxic activity against cancer cells of the studied materials presumably by increasing cell internalization. The results presented herein hold significant potential for future developments in mesoporous silica-supported metallodrugs, which exhibit strong cytotoxicity while maintaining low metal loading. They also show potential for theranostic applications highlighted by the analysis of the optical properties of the studied systems after incorporating rhodamine B, coumarin 343 (possible)in vitroanticancer analysis, or Alexa Fluor™ 647 (in vivostudies of cancer models).

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Angiotensin II-mediated hippocampal hypoperfusion and vascular dysfunction contribute to vascular cognitive impairment in aged hypertensive rats.

INTRODUCTION: Chronic hypertension increases the risk of vascular cognitive impairment (VCI) by ∼60%; however, how hypertension affects the vasculature of the hippocampus remains unclear but could contribute to VCI. METHODS: Memory, hippocampal perfusion, and hippocampal arteriole (HA) function were investigated in male Wistar rats or spontaneously hypertensive rats (SHR) in early (4 to 5 months old), mid (8 to 9 months old), or late adulthood (14 to 15 months old). SHR in late adulthood were chronically treated with captopril (angiotensin converting enzyme inhibitor) or apocynin (antioxidant) to investigate the mechanisms by which hypertension contributes to VCI. RESULTS: Impaired memory in SHR in late adulthood was associated with HA endothelial dysfunction, hyperconstriction, and ∼50% reduction in hippocampal blood flow. Captopril, but not apocynin, improved HA function, restored perfusion, and rescued memory function in aged SHR. DISCUSSION: Hippocampal vascular dysfunction contributes to hypertension-induced memory decline through angiotensin II signaling, highlighting the therapeutic potential of HAs in protecting neurocognitive health later in life. HIGHLIGHTS: Vascular dysfunction in the hippocampus contributes to vascular cognitive impairment. Memory declines with age during chronic hypertension. Angiotensin II causes endothelial dysfunction in the hippocampus in hypertension. Angiotensin II-mediated hippocampal arteriole dysfunction reduces blood flow. Vascular dysfunction in the hippocampus impairs perfusion and memory function.

Sustained drug release behavior of captopril-incorporated chitosan/carboxymethyl cellulose biomaterials for antihypertensive therapy.

Captopril (CTP) is an oral drug widely used to treat high blood pressure and congestive heart failure. In this study, CTP-incorporated biomaterials for antihypertensive therapy were synthesized from chitosan, carboxymethyl cellulose, and plasticizers. The physicochemical properties of the prepared biomaterials were characterized using FE-SEM, FT-IR analysis, and physical properties. CTP release experiments were carried out in buffer solutions at various pH values and temperatures. Results indicated that above 99.0 % of CTP was released within 180 min. Optimization of the experimental conditions for CTP release was analyzed by using response surface methodology (RSM). Results of CTP release through artificial skin indicated that CTP was continuously released above 95.0 % from the prepared biomaterials for 36.0 h. The CTP release mechanisms into a buffer and through artificial skin followed pseudo-Fickian diffusion mechanism and non-Fickian diffusion mechanisms, respectively. Moreover, angiotensin-converting enzyme (ACE) inhibition (related to cardiovascular disease) via the released CTP clearly reveals that the prepared biomaterials have a high potential as a transdermal drug delivery agent in antihypertensive therapy.

Captopril to Lisinopril Conversion in Pediatric Cardiothoracic Surgery Patients Less Than 7 Years of Age (RISE-7).

Hypertension after cardiothoracic surgery is common, often requiring pharmacologic management. The recommended first-line antihypertensives in pediatrics are angiotensin converting enzyme inhibitors. Captopril and enalapril are approved for infants and children; however, lisinopril is only approved for > 7 years of age. This study evaluated safety and efficacy of converting from captopril to lisinopril in patients utilizing a pre-defined conversion of 3 mg captopril to 1 mg lisinopril. This was a single center, retrospective study including patients less than 7 years of age admitted for cardiothoracic surgery who received both captopril and lisinopril from 01/01/2017 to 06/01/2022.The primary outcome was mean change in systolic blood pressure (SBP) from baseline for 72 h after conversion of captopril to lisinopril. A total of 99 patients were enrolled. There was a significant decrease in mean SBP (99.12 mmHg vs 94.86 mmHg; p = 0.007) with no difference in DBP (59.23 mmHg vs 61.95 mmHg; p = 0.07) after conversion to lisinopril. Of the 99 patients who were transitioned to lisinopril, 79 (80%) had controlled SBP, 20 (20%) remained hypertensive, 13 (13%) received an increase in their lisinopril dose, and 2 (2%) required an additional antihypertensive agent. There was a low overall rate of AKI (3%) and hyperkalemia (4%) respectively. This study demonstrates that utilizing lisinopril with a conversion rate of 3 mg of captopril to 1 mg of lisinopril was safe and effective for controlling hypertension in pediatric patients following cardiothoracic surgery.

Oral angiotensin-converting enzyme inhibitor captopril protects the heart from Porphyromonas gingivalis LPS-induced cardiac dysfunction in mice.

Although angiotensin converting enzyme (ACE) inhibitors are considered useful for the treatment of human heart failure, some experimental failing-heart models have shown little beneficial effect of ACE inhibitors in animals with poor oral health, particularly periodontitis. In this study, we examined the effects of the ACE inhibitor captopril (Cap; 0.1 mg/mL in drinking water) on cardiac dysfunction in mice treated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS) at a dose (0.8 mg/kg/day) equivalent to the circulating level in patients with periodontal disease. Mice were divided into four groups: 1) Control, 2) PG-LPS, 3) Cap, and 4) PG-LPS + Cap. After1 week, we evaluated cardiac function by echocardiography. The left ventricular ejection fraction was significantly decreased in PG-LPS-treated mice compared to the control (from 66 ± 1.8 to 59 ± 2.5%), while Cap ameliorated the dysfunction (63 ± 1.1%). The area of cardiac fibrosis was significantly increased (approximately 2.9-fold) and the number of apoptotic myocytes was significantly increased (approximately 5.6-fold) in the heart of PG-LPS-treated group versus the control, and these changes were suppressed by Cap. The impairment of cardiac function in PG-LPS-treated mice was associated with protein kinase C δ phosphorylation (Tyr-311), leading to upregulation of NADPH oxidase 4 and xanthine oxidase, and calmodulin kinase II phosphorylation (Thr-286) with increased phospholamban phosphorylation (Thr-17). These changes were also suppressed by Cap. Our results suggest that the renin-angiotensin system might play an important role in the development of cardiac diseases induced by PG-LPS.

Clinical Value of the Combination Detection of Captopril Renal Scintigraphy and Plasma Renin Activity in the Diagnosis of Renal Hypertension.

OBJECTIVE: This study aimed to investigate the clinical value of the combination detection of captopril renal scintigraphy (CRS) and plasma renin activity (PRA) in the diagnosis of renal hypertension (RHR). METHODS: Retrospective analysis was conducted on the clinical data of 163 patients with suspected RHR admitted to our hospital from March 2019 to March 2021, and all patients underwent blood pressure, CRS and digital subtraction angiography (DSA). The patients were divided into the positive group (n = 100) and the negative group (n = 63) in accordance with the results of DSA examination. PRA, angiotensin II and aldosterone levels of the two groups were detected and compared. The receiver operating characteristic curve was used to analyse the CRS, PRA and combined diagnostic performance. RESULTS: The uptake ratio value after captopril intervention in the positive group was 36.71% ± 8.79%, which was significantly lower than that in the negative group (56.79% ± 10.09%, p < 0.05). The serum PRA level of the positive group was 4.70 ± 1.67 ng/mLꞏh, which was distinctly higher than that of the negative group (2.12 ± 1.03 ng/mLꞏh, p < 0.05). The sensitivity and Youden index under the combination detection (area under the curve (AUC) = 0.956, p < 0.001) were all higher than those under single detection. CONCLUSION: The combined detection of PRA and CRS can provide considerable evidence for the early diagnosis and treatment of RHR, which has a certain clinical value.

Interventions for chronic kidney disease in people with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017. OBJECTIVES: To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination. SEARCH METHODS: We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE). MAIN RESULTS: We included three RCTs with 385 participants. We rated the certainty of the evidence as low to very low across different outcomes according to GRADE methodology, downgrading for risk of bias concerns, indirectness, and imprecision. Hydroxyurea versus placebo One RCT published in 2011 compared hydroxyurea to placebo in 193 children aged nine to 18 months. We are unsure if hydroxyurea compared to placebo reduces or prevents progression of kidney disease assessed by change in glomerular filtration rate (mean difference (MD) 0.58 mL/min /1.73 m2, 95% confidence interval (CI) -14.60 to 15.76; 142 participants; very low certainty). Hydroxyurea compared to placebo may improve the ability to concentrate urine (MD 42.23 mOsm/kg, 95% CI 12.14 to 72.32; 178 participants; low certainty), and may make little or no difference to SCD-related serious adverse events, including acute chest syndrome (risk ratio (RR) 0.39, 99% CI 0.13 to 1.16; 193 participants; low certainty), painful crisis (RR 0.68, 99% CI 0.45 to 1.02; 193 participants; low certainty); and hospitalisations (RR 0.83, 99% CI 0.68 to 1.01; 193 participants; low certainty). No deaths occurred in either trial arm and the RCT did not report quality of life. Angiotensin-converting enzyme inhibitors versus placebo One RCT published in 1998 compared an ACEI (captopril) to placebo in 22 adults with normal blood pressure and microalbuminuria. We are unsure if captopril compared to placebo reduces proteinuria (MD -49.00 mg/day, 95% CI -124.10 to 26.10; 22 participants; very low certainty). We are unsure if captopril reduces or prevents kidney disease as measured by creatinine clearance; the trial authors stated that creatinine clearance remained constant over six months in both groups, but provided no comparative data (very low certainty). The RCT did not report serious adverse events, all-cause mortality, or quality of life. Angiotensin-converting enzyme inhibitors versus vitamin C One RCT published in 2020 compared an ACEI (lisinopril) with vitamin C in 170 children aged one to 18 years with normal blood pressure and microalbuminuria. It reported no data we could analyse. We are unsure if lisinopril compared to vitamin C reduces proteinuria in this population: the large drop in microalbuminuria in both arms of the trial after only one month on treatment may have been due to an overestimation of microalbuminuria at baseline rather than a true effect. The RCT did not report serious adverse events, all-cause mortality, or quality of life. AUTHORS' CONCLUSIONS: We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.

Antihypertensive, antioxidant, and renal protective impact of integrated GJD with captopril in spontaneously hypertensive rats.

Hypertension is the most prevalent chronic disease World-wide, and the leading preventable risk factor for cardiovascular disease (CVD). Few patients accomplish the objective of decreasing blood pressure and avoiding hypertensive target organ damage after treatments with antihypertensive agents which opens the door for other treatments, such as herbal-and antihypertensive combination therapy. Captopril (CAP), as a-pril which inhibits angiotensin converting enzyme has long been used in the management of hypertension and CVD. Gedan Jiangya Decoction (GJD) is known for antihypertensive effects in prior studies. The research is aimed to determine whether GJD in combination with captopril has antihypertensive, kidney protective, antioxidant, and vasoactive effects in spontaneously hypertensive rats (SHR). Regular measurements of systolic and diastolic blood pressure (SBP and DBP), and body weight were monitored weekly. H&E staining was utilized to examine histopathology. The combined effects were studied using ELISA, immunohistochemistry, and qRT-PCR. Significant reductions in SBP, DBP, aortic wall thickness, and improvement in renal tissue were observed following GJD + CAP treatment, with increased serum levels of NO, SOD, GSH-Px, and CAT and decreases in Ang II, ET-1, and MDA. Similarly, GJD + CAP treatment of SHR's significantly decreased ET-1 and AGTR1 mRNA and protein expression while increasing eNOS mRNA and protein expression in thoracic aorta and kidney tissue. In conclusion, the present investigation found that GJD + CAP treatment decreases SHR blood pressure, improves aorta remodeling and renal protection, and that this effect could be attributable, in part, due to antioxidant and vascular tone improvement.

Oral administration of the herbal oligonucleotide XKC-sRNA-h3 prevents angiotensin II-induced hypertension in mice.

Hypertension has become a growing public health concern worldwide. In fact, hypertension is commonly associated with increased morbidity and mortality. Currently, oligonucleotide drugs have proven to be promising therapeutic agents for various diseases. In the present study, we aimed to demonstrate that a herbal small RNA (sRNA), XKC-sRNA-h3 (B55710460, F221. I000082.B11), exhibits potent antihypertensive effects by targeting angiotensin-converting enzyme (ACE) in mice. When compared with captopril, oral administration of the sphingosine (d18:1)-XKC-sRNA-h3 bencaosome more effectively prevented angiotensin II-induced hypertensive cardiac damage and alleviated kidney injury in mice. Such findings indicated that XKC-sRNA-h3 may be a novel orally available ACE inhibitor type oligonucleotide drug for hypertension.

Topical captopril: a promising treatment for secondary lymphedema.

Transforming growth factor-beta 1 (TGF-ß1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-ß1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-ß1 signaling, and inhibition of Ang II production using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic efficacy in some pathological settings. Therefore, we analyzed the expression of ACE and Ang II in clinical lymphedema biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL) and mouse models, and found that cutaneous ACE expression is increased in lymphedematous tissues. Furthermore, topical captopril decreases fibrosis, activation of intracellular TGF-ß1 signaling pathways, inflammation, and swelling in mouse models of lymphedema. Captopril treatment also improves lymphatic function and immune cell trafficking by increasing collecting lymphatic pumping. Our results show that the renin-angiotensin system in the skin plays an important role in the regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may hold merit for treating lymphedema.

Application of a physiologically based pharmacokinetic model in predicting captopril disposition in children with chronic kidney disease.

Over the last several decades, angiotensin-converting enzyme inhibitors (ACEIs) have been a staple in the treatment of hypertension and renovascular disorders in children. One of the ACEIs, captopril, is projected to have all the benefits of traditional vasodilators. However, conducting clinical trials for determining the pharmacokinetics (PK) of a drug is challenging, particularly in pediatrics. As a result, modeling and simulation methods have been developed to identify the safe and effective dosages of drugs. The physiologically based pharmacokinetic (PBPK) modeling is a well-established method that permits extrapolation from adult to juvenile populations. By using SIMCYP simulator, as a modeling platform, a previously developed PBPK drug-disease model of captopril was scaled to renally impaired pediatrics population for predicting captopril PK. The visual predictive checks, predicted/observed ratios (ratiopred/obs), and the average fold error of PK parameters were used for model evaluation. The model predictions were comparable with the reported PK data of captopril in mild and severe chronic kidney disease (CKD) patients, as the mean ratiopred/obs Cmax and AUC0-t were 1.44 (95% CI 1.07 - 1.80) and 1.26 (95% CI 0.93 - 1.59), respectively. The successfully developed captopril-CKD pediatric model can be used in suggesting drug dosing in children diagnosed with different stages of CKD.

COVID-19: Understanding the impact of anti-hypertensive drugs and hydroxychloroquine on the ACE1 and ACE2 in lung and adipose tissue in SHR and WKY rats.

Hypertensive individuals taking anti-hypertensive drugs from renin-angiotensin system inhibitors may exhibit a more severe evolution of the disease when contracting the SARS-CoV-2 virus (COVID-19 disease) due to potential increases in ACE2 expression. The study investigated ACE1 and ACE2 axes and hydroxychloroquine in the lungs and adipose tissue of male and female normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). SHRs were treated with losartan (10 mg/kg/day) or captopril (10 mg/kg/day) for 14 days or 7 days with hydroxychloroquine (200 mg/kg/day) in drinking water. WKY rats were also treated for 7 days with hydroxychloroquine. Blood pressure (BP), protein, and mRNA expression of ACE1 and ACE2 were analyzed in serum, adipose, and lung tissues. Losartan and captopril reduced BP in both sexes in SHR, whereas hydroxychloroquine increased BP in WKY rats. Losartan reduced ACE2 in serum and lungs in both sexes and in adipose tissue of male SHRs. Captopril decreased ACE2 protein in the lung of females and in adipose tissue in both sexes of SHRs. Hydroxychloroquine decreased ACE1 and ACE2 proteins in the lungs in both sexes and adipose tissue in male SHRs. In female WKY rats, ACE2 protein was lower only in the lungs and adipose tissue. Losartan effectively inhibited ACE2 in male and captopril in female SHRs. Hydroxychloroquine inhibited ACE2 in male SHRs and female WKY rats. These results further our understanding of the ACE2 mechanism in patients under renin-angiotensin anti-hypertensive therapy and in many trials using hydroxychloroquine for COVID-19 treatment and potential sex differences in response to drug treatment.

Prevention of Radiation-Induced Bladder Injury: A Murine Study Using Captopril.

PURPOSE: Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury. METHODS AND MATERIALS: C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30 Gy or 3 fractions of 8 Gy (8 Gy × 3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, as well as an assessment of systemic changes in inflammatory-mediated circulating immune cells. RESULTS: SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with nonirradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (P = .0428) and negatively correlated with number of voids (P = .028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. CONCLUSIONS: This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed.

Angiotensin converting enzyme (ACE) inhibitors as radiation countermeasures for long-duration space flights.

Angiotensin converting enzyme (ACE) inhibitors are effective countermeasures to chronic radiation injuries in rodent models, and there is evidence for similar effects in humans. In rodent models ACE inhibitors are effective mitigators of radiation injury to kidney, lung, central nervous system (CNS) and skin, even when started weeks after irradiation. In humans, the best data for their efficacy as radiation countermeasures comes from retrospective studies of injuries in radiotherapy patients. We propose that ACE inhibitors, at doses approved for human use for other indications, could be used to reduce the risk of chronic radiation injuries from deep-space exploration. Because of the potential interaction of ACE inhibitors and microgravity (due to effects of ACE inhibitors on fluid balance) use might be restricted to post-exposure when/if radiation exposures reached a danger level. A major unresolved issue for this approach is the sparse evidence for the efficacy of ACE inhibitors after low-dose-rate exposure and/or for high-LET radiations (as would occur on long-duration space flights). A second issue is that the lack of a clear mechanism of action of the ACE inhibitors as mitigators makes obtaining an appropriate label under the Food and Drug Administration Animal Rule difficult.

Randomized, double-blinded, controlled clinical trial of the effect of captopril, telmisartan and their combination on systemic inflammation of patients on hemodialysis.

To evaluate individual and combined effect of captopril and telmisartan on systemic inflammation markers of hemodialysis (HD) patients. Randomized, double-blinded, controlled clinical trial. Patients on HD at least 2 months, with arteriovenous fistula, were randomly allocated to groups: (1) captopril/placebo (N 13); (2) telmisartan/placebo (N 13); (3) captopril + telmisartan (N 12); or (4) placebo/placebo (N 12). During 3 months, patients received oral drugs as follows: captopril 50 mg/day, telmisartan 80 mg/day or placebo. Patients excluded if they had conditions or were on drugs potentially influencing on inflammation. Clinical and biochemical evaluations were performed monthly. Serum tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), and C-reactive protein (CRP) were measured at 0, 1 and 3 months. Baseline, demographic, clinical and biochemical variables were comparable between groups. Baseline versus final inflammatory markers were: captopril/placebo TNFα, 2.47 (0.1-4.5) versus 1.73 (0.3-3.8) pg/ml; IL-6, 17.03 (7.2-23) versus 7.90 (0.7-19) pg/ml; CRP, 4.21 (1.6-18) versus 5.9 (3.0-28) mg/l; telmisartan/placebo TNFα, 3.03 (2.3-4.6) versus 1.70 (1.2-2.0) pg/ml; IL-6, 14.10 (5.5-23) versus 9.85 (6.2-13) pg/ml; CRP, 5.74 (2.1-13) versus 10.60 (1.5-27) mg/l; captopril + telmisartan TNFα, 1.43 (0.7-5.4) versus 0.40 (0.1-2.1) pg/ml; IL-6, 10.05 (4.9-23) versus 4.00 (0.7-7.7) pg/ml (p < 0.05); CRP, 3.26 (0.7-12) versus 2.83 (0.6-6.5) mg/l; placebo/placebo TNFα, 3.13 (1.6-5.6) versus 1.64 (1.6-2.3) pg/ml; IL-6, 8.12 (5.4-16) versus 7.60 (2.4-15) pg/ml; CRP, 5.23 (1.9-16) versus 3.13 (1.5-18) mg/l. Monotherapy with captopril or telmisartan display a trend, but their combined treatment significantly decreased serum levels of IL-6. No remarkable changes on TNFα and CRP were observed.

Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis.

Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3-C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 µg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice.

GJD Modulates Cardiac/Vascular Inflammation and Decreases Blood Pressure in Hypertensive Rats.

Gedan Jiangya decoction (GJD) (aqueous ethanol extract), a traditional Chinese medicine formula which contain six botanical drugs (Uncaria rhynchophylla (Miq.) Miq., Salvia miltiorrhiza Bunge, Pueraria lobata (Willd.) Ohwi, Eucommia ulmoides Oliv., Prunella vulgaris L., and Achyranthes bidentata Blume) was designed to treat hypertension; however, the underlying mechanism of action is unclear. This study aimed to determine the mechanisms of action of GJD in the treatment of hypertension in spontaneously hypertensive rats (SHR). Male SHRs were randomly divided into five groups: GJD doses were low (1.36 g/kg/d), medium (2.72 g/kg/d), and high (5.44 g/kg/d), captopril (13.5 mg/kg/d), and SHR groups, with Wistar-Kyoto rats (WKY) serving as the control. Every rat was gavaged once a day. The ALC-NIBP, a noninvasive blood pressure device, measured systolic (SBP) and diastolic (DBP) blood pressures. Six weeks following treatment, all rats were anesthetized. The blood samples were obtained from the abdominal aorta and then serum isolated to assess endothelin-1 and angiotensin II, interleukin-1beta, interleukin-6, and TNF-alpha. The left ventricular and thoracic aortas were taken for HE staining, immunohistochemistry, RT-qPCR, and western blot examination. Following GJD therapy, SBP and DBP were significantly lowered, as were serum levels of endothelin-1 and angiotensin II. The thickness of the left ventricular and thoracic aorta walls reduced, as did type I collagen, type III collagen, and alpha-SMA expression in the left ventricular and aortic tissues. The GJD treatment significantly reduced serum levels of the inflammatory markers interleukin-1beta, interleukin-6, and TNF-alpha. Furthermore, interleukin-1 beta, interleukin-6, TNF-alpha, TAK1, and NF-κB/p65 levels were significantly reduced in left ventricular and aortic tissues, whereas IkB-alpha levels were significantly elevated. GJD has a dose-dependent effect on all parameters. In conclusion, GJD has been shown to lower blood pressure, improve cardiovascular remodeling, and reduce inflammation via regulating NF-κB in SHRs.

Anti-Hypertensive Effects of Anthocyanins from Hibiscus sabdarifa Calyx on the Renin-Angiotensin-Aldoslestrone System in Wistar Rats.

Hibiscus sabdariffa (HS) has gained attention as an anti-hypertensive agent. In the present study, we hypothesized that anthocyanins from HS may attenuate salt-induced hypertension in rats by suppressing the components of renin-angiotensin-aldoslestrone system (RAAS). Hypertension was induced in the rats by adding 8% NaCl in their diet for six weeks. Wistar rats (n=5 each) were randomly divided into seven groups. Group 1 was the normentensive control group and was fed with normal rat chew and water ad libitum; groups 2 and 3 served as hypertensive control (negative untreated and positive treated with captopril 30mg/kg respectively); groups 4, 5, and 6 served as treatment groups and were administered with graded doses of anthocyanins( 50, 100, 200mg/kg respectively) while group 7 received both 100mg anthocyanins and 30mg captopril per day for 4 weeks. Using HPLC, anthocyanins were isolated from HS calyx following standard protocol. Anthocyanins significantly (p<0.05) reduced blood pressure and heart rate in hypertensive rats in a dose dependent manner. The blood pressure reduction by anthocyanins was associated with a reduction in serum ACE and plasma aldosterone in the hypertensive rats. The effects of anthocyanins on blood pressure and on biomarkers of RAAS were similar to those of captopril, a reference anti-hypertensive drug. The results suggest that anthocyanins exerts a significant (p<0.05) anti-hypertensive potency on rats, probably mediated by the reduction in components of the RAAS. Keywords: hypertension, anthocyanins, renin, aldosterone, rats.