The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Revisiting the dipeptidyl carboxypeptidase inhibitor captopril as a source of pan anti-trypanosomatid agents.

The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 µM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.

Ho(III)-coordination Complex: Fluorescence Performances and Combined with Captopril-Hydrogels against Glioma.

In this study, a novel dinuclear lanthanide complex, denoted as [Ho2(L)2(acac)2(CH3OH)2]·CH3OH (1) (where H2L is 2-[((4-methyl)-2-(carboxyl)-imino)]methyl]-8-hydroxyquinoline, and Hacac is acetylacetonate), was successfully synthesized and characterized using single-crystal and elemental analysis, with the auxiliary ligand ß-diketonate and the 8-hydroxyquinoline Schiff base derivative serving as the foundation. Through ligand-to-metal charge transfer, Compound 1 demonstrated remarkable green fluorescence properties, showcasing potential applications in green fluorescence materials and fluorescence sensing. Additionally, Hyaluronic Acid (HA)/Carboxymethyl Chitosan (CMCS) hydrogels were synthesized through a chemical method. Utilizing captopril as a drug model, a novel metal gel granule of captopril was developed and assessed for its inhibitory activity against glioma cells. Molecular docking simulations revealed that only the methanol group in the Ho complex could contribute a polar atom for the formation of binding interactions.

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.

Development of a "turn off" fluorescent molecularly imprinted nanoparticle-based sensor for selective captopril quantification in synthetic urine and wastewater samples.

The combination of silica nanoparticles with fluorescent molecularly imprinted polymers (Si-FMIPs) prepared by a one-pot sol-gel synthesis method to act as chemical sensors for the selective and sensitive determination of captopril is described. Several analytical parameters were optimized, including reagent ratio, solvent, concentration of Si-FMIP solutions, and contact time. Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), and the ninhydrin assay were used for characterization. The selectivity was evaluated against molecules belonging to other drug classes, such as fluoroquinolones, nonacid nonopioids, benzothiadiazine, alpha amino acids, and nitroimidazoles. Under optimized conditions, the Si-FMIP-based sensor exhibited a working range of 1-15 µM, with a limit of detection (LOD) of 0.7 µM, repeatability of 6.4% (n = 10), and suitable recovery values at three concentration levels (98.5% (1.5 µM), 99.9% (3.5 µM), and 99.2% (7.5 µM)) for wastewater samples. The sensor provided a working range of 0.5-15 µM for synthetic urine samples, with an LOD of 0.4 µM and a repeatability of 7.4% (n = 10) and recovery values of 93.7%, 92.9%, and 98.0% for 1.0 µM, 3.5 µM, and 10 µM, respectively. In conclusion, our single-vessel synthesis approach for Si-FMIPs proved to be highly effective for the selective determination of captopril in wastewater and synthetic urine samples.

The role of confirmatory tests in the diagnosis of primary aldosteronism.

Confirmatory tests for diagnosis of primary aldosteronism (PA) play an important role in sparing patients with a false-positive aldosterone-to-renin ratio (ARR) screening test from undergoing invasive subtyping procedures. We recommend that patients with a positive ARR test should undergo at least one confirmatory test to confirm or exclude the diagnosis of PA before directly proceeding to subtype studies, except for patients with significant PA phenotypes, including spontaneous hypokalemia, plasma aldosterone concentration >20 ng/dL plus plasma renin activity below a detectable level. Although a gold standard confirmatory test has not been identified, we recommend that saline infusion test and captopril challenge test, which were widely used in Taiwan. Patients with PA have been reported to have a higher prevalence of concurrent autonomous cortisol secretion (ACS). ACS is a biochemical condition of mild cortisol overproduction from adrenal lesions, but without the typical clinical features of overt Cushing's syndrome. Concurrent ACS may result in incorrect interpretation of adrenal venous sampling (AVS) and may lead to adrenal insufficiency after adrenalectomy. We recommend screening for ACS in patients with PA scheduled for AVS examinations as well as for adrenalectomy. We recommend the 1-mg overnight dexamethasone suppression test as screening method to detect ACS.

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Angiotensinergic neurotransmission in the bed nucleus of the stria terminalis is involved in cardiovascular responses to acute restraint stress in rats.

The brain angiotensin II acting via AT1 receptors is a prominent mechanism involved in physiological and behavioral responses during aversive situations. The AT2 receptor has also been implicated in stress responses, but its role was less explored. Despite these pieces of evidence, the brain sites related to control of the changes during aversive threats by the brain renin-angiotensin system (RAS) are poorly understood. The bed nucleus of the stria terminalis (BNST) is a limbic structure related to the cardiovascular responses by stress, and components of the RAS system were identified in this forebrain region. Therefore, we investigated the role of angiotensinergic neurotransmission present within the BNST acting via local AT1 and AT2 receptors in cardiovascular responses evoked by an acute session of restraint stress in rats. For this, rats were subjected to bilateral microinjection of either the angiotensin-converting enzyme inhibitor captopril, the selective AT1 receptor antagonist losartan, or the selective AT2 receptor antagonist PD123319 before they underwent the restraint stress session. We observed that BNST treatment with captopril reduced the decrease in tail skin temperature evoked by restraint stress, without affecting the pressor and tachycardic responses. Local AT2 receptor antagonism within the BNST reduced both the tachycardia and the drop in tail skin temperature during restraint. Bilateral microinjection of losartan into the BNST did not affect the restraint-evoked cardiovascular changes. Taken together, these data indicate an involvement of BNST angiotensinergic neurotransmission acting via local AT2 receptors in cardiovascular responses during stressful situations.

Magnetic molecularly imprinted polymer based on dynamically established metal-mediated binding sites for the determination of trace captopril in rat plasma.

Therapeutic drug monitoring of captopril, which is a commonly used antihypertensive agent in clinical practice, is necessary. However, matrix effect-induced pretreatment is the bottleneck for determination. Metal-mediated molecularly imprinted polymers, an essential branch of molecularly imprinted polymers with better specificity and selectivity, have been used to separate/enrich analytes from complex matrices. In this work, Cu2+ was introduced to dynamically establish the binding sites of metal-mediated molecularly imprinted polymer towards captopril. All evidence demonstrated that the metal-mediated molecularly imprinted polymer based on Cu2+ coordination obtained a higher adsorption capacity (81.23 mg/g), faster adsorption rate (adsorption equilibrium within 50 min), and better selectivity (with the unrecognized analog). Subsequently, the Cu2+ -mediated molecularly imprinted polymer was used as dispersive molecularly imprinted solid-phase extraction to successfully establish an analytical platform for the determination of trace captopril in rat plasma. The enrichment factor was up to 20, the detection limit was as low as 0.16 µg/ml, and the average recovery was in the range of 87.51%-98.28% with a relative standard deviation of less than 3.29%. This study provides a promising reference for the preparation of selective adsorbents to improve pretreatment.

LC-MS/MS bioanalytical method for the quantitative analysis of nifedipine, bisoprolol, and captopril in human plasma: Application to pharmacokinetic studies.

In this study, the development and validation of an accurate and highly sensitive LC-MS/MS method were performed for the estimation of nifedipine, bisoprolol and captopril in real human plasma. Liquid-liquid extraction using tert-butyl methyl ether was efficiently applied for extraction of the analytes from plasma samples. The chromatographic separation was carried out using an isocratic elution mode on the X-terra MS C18 column (4.6 × 50 mm, 3.5 µm). The mobile phase consisted of methanol-0.1% formic acid (95:5, v/v) for determination of nifedipine and bisoprolol and acetonitrile-0.1% formic acid (70:30, v/v) for determination of captopril with a flow rate of 0.5 ml/min. Acceptable results regarding the different validation characteristics of the analytes were obtained in accordance with US Food and Drug Administration recommendations for bioanalytical methods. The developed approach was linear over concentration ranges of 0.5-130.0, 50.0-4,500.0 and 0.3-30.0 ng/ml for nifedipine, captopril and bisoprolol, respectively. The method revealed a sufficient lower limit of quantification in the range of 0.3-50.0 ng/ml, as well as high recovery percentages, indicating high bioanalytical applicability. The proposed method was efficiently applied to a pharmacokinetic evaluation of a fixed-dose combination of the analytes in healthy male volunteers.

Synthesis of magnetic molecular imprinted polymer with a new functional monomer for dispersive micro solid phase extraction of captopril from wastewater and biological samples and determination by UV-Vis spectrophotometry.

A magnetic molecularly imprinted polymer (MMIP) was fabricated for captopril by surface polymerization of Fe3O4@SiO2 nanoparticles using a new functional monomer of N-(allylcarbamothioyl)-2-chlorobenzamide. It was then employed as a selective nanosorbent for dispersive magnetic micro solid phase extraction (DM-µ-SPE) of captopril from biological and wastewater samples. To characterize the physicochemical properties of the MMIP, different analytical methods such as the vibrating sample magnetometer, field emission scanning electron microscopy, Brunauer-Emmett-Teller, and Fourier transform infrared spectroscopy were utilized. To gain the maximum extraction recovery of captopril, the influence of various operating conditions was investigated and experimental settings optimized. After the extraction step, the concentration of captopril was measured by UV-Vis spectrophotometer at 245 nm. The assessments demonstrated that the MMIP provides higher extraction efficiency in comparison to magnetic non-imprinted polymer, suggesting the establishment of selective recognition binding sites at the MMIP surface. The method depicted desirable figures of merit of a low detection limit of 0.16 µg L-1, a limit of quantification of 0.50 µg L-1, a linear dynamic range of 0.50-22.0 µg L-1, and an acceptable preconcentration factor of 333. The magnetic MIP was successfully employed for preconcentration and extraction of trace amounts of captopril in real samples, such as human blood serum, urine, and wastewater samples, with recoveries in the range 95.7 to 102.6% and relative standard deviations < 5%.

Performance of Zr-Based Metal-Organic Framework Materials as In Vitro Systems for the Oral Delivery of Captopril and Ibuprofen.

Zr-based metal-organic framework materials (Zr-MOFs) with increased specific surface area and pore volume were obtained using chemical (two materials, Zr-MOF1 and Zr-MOF3) and solvothermal (Zr-MOF2) synthesis methods and investigated via FT-IR spectroscopy, TGA, SANS, PXRD, and SEM methods. The difference between Zr-MOF1 and Zr-MOF3 lies in the addition of reactants during synthesis. Nitrogen porosimetry data indicated the presence of pores with average dimensions of ~4 nm; using SANS, the average size of the Zr-MOF nanocrystals was suggested to be approximately 30 nm. The patterns obtained through PXRD were characterized by similar features that point to well-crystallized phases specific for the UIO-66 type materials; SEM also revealed that the materials were composed of small and agglomerate crystals. Thermogravimetric analysis revealed that both materials had approximately two linker deficiencies per Zr6 formula unit. Captopril and ibuprofen loading and release experiments in different buffered solutions were performed using the obtained Zr-based metal-organic frameworks as drug carriers envisaged for controlled drug release. The carriers demonstrated enhanced drug-loading capacity and showed relatively good results in drug delivery. The cumulative percentage of drug release in phosphate-buffered solution at pH 7.4 was higher than that in buffered solution at pH 1.2. The release rate could be controlled by changing the pH of the releasing solution. Different captopril release behaviors were observed when the experiments were performed using a permeable dialysis membrane.

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.

Captopril exhibits protective effects through anti-inflammatory and anti-apoptotic pathways against hydrogen peroxide-induced oxidative stress in C6 glioma cells.

Recent studies have shown that angiotensin-converting enzyme (ACE) inhibitors have reduced oxidative damage in the central nervous system (CNS). Accumulating evidence have also demonstrated that captopril, an ACE inhibitor, has protective effects on the CNS. However, its effects on hydrogen peroxide (H2O2)-induced oxidative damage in glial cells and interaction with the inflammatory system are still uncertain. Therefore, this study was aimed to investigate the protective effect of captopril on glial cell damage after H2O2-induced oxidative stress involved in the inflammatory and apoptotic pathways. The control group was without any treatment, and the H2O2 group was treated with 0.5 mM H2O2 for 24 h. The captopril group was treated with various concentrations of captopril for 24 h. The captopril + H2O2 group was pre-treated with captopril for 1 h and then exposed to 0.5 mM H2O2 for 24 h. In the captopril + H2O2 group, captopril at all concentrations significantly increased the cell viability in C6 cells. It also significantly increased the TAS and decreased the TOS levels which are an indicator of oxidative stress. Moreover, captopril significantly reduced the inflammation markers including NF-kB, IL-1 ß, COX-1, and COX-2 levels. Flow cytometry results also exhibited that captopril pretreatment significantly decreased the apoptosis rate. Besides, captopril significantly reduced apoptotic Bax and raised anti-apoptotic Bcl-2 protein levels. In conclusion, captopril has protective effects on C6 cells after H2O2-induced oxidative damage by inhibiting oxidative stress, inflammation, and apoptosis. However, further studies need to be conducted to evaluate the potential of captopril as a neuroprotective agent.

Captopril inhibits matrix metalloproteinase activity and improves dentin bonding durability.

OBJECTIVES: We investigated the inhibitory effects of captopril on matrix metalloproteinases (MMPs) and its effect as a primer on dentin bonding durability. MATERIALS AND METHODS: One hundred fifty human third molars were selected. Flat surfaces of the middle dentin were exposed, etched 15 s, and followed by pretreatment with a primer for 60 s, including distilled water (control, the negative control primer), 2% chlorhexidine digluconate (CHD, the positive control primer), and captopril solution. Inhibitory effects of primers on MMPs were evaluated by hydroxyproline and gelatinase activity tests. All primers were applied on dentin followed by bonding. Some of the samples were sliced into slabs, placed in a fluorescent solution containing gelatin, and incubated for in situ zymography. Some were cut into sticks, and after aging for 1 day, 12 months, or 24 months, microtensile bonding strength was tested. Some were cut into slabs, aged for 1 day, 12 months, or 24 months, and taken out for nanoleakage tests to reveal interface defects. RESULTS: Hydroxyproline and gelatinase activity analyses showed that captopril exerted better inhibitory effects on MMPs, relative to 2% CHD (p < 0.05). A 0.2% captopril aqueous solution (0.2% CapW) was chosen to apply to the dentin. In situ zymography showed that inhibitory effects of captopril on gelatinase were significantly higher compared to 2% CHD (p < 0.01). Microtensile strength revealed that the bonding effects of the 0.2% CapW group lasted longer, compared to the control and 2% CHD groups (p < 0.05). Interface defects, detected by nanoleakage, were significantly reduced in the 0.2% CapW group, compared to the control and 2% CHD groups (p < 0.05). CONCLUSIONS: Captopril inhibits dentin MMP activities and effectively improves dentin bonding durability. CLINICAL RELEVANCE: Captopril is a promising dentin bonding primer for improving bonding durability.

Beneficial Effects of Dietary Nitrite on a Model of Nonalcoholic Steatohepatitis Induced by High-Fat/High-Cholesterol Diets in SHRSP5/Dmcr Rats: A Preliminary Study.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. Endothelial dysfunction caused by hepatic lipotoxicity is an underlying NASH pathology observed in the liver and the cardiovascular system. Here, we evaluated the effect of dietary nitrite on a rat NASH model. Stroke-prone, spontaneously hypertensive 5/Dmcr rats were fed a high-fat/high-cholesterol diet to develop the NASH model, with nitrite or captopril (100 mg/L, each) supplementation in drinking water for 8 weeks. The effects of nitrite and captopril were evaluated using immunohistochemical analyses of the liver and heart tissues. Dietary nitrite suppressed liver fibrosis in the rats by reducing oxidative stress, as measured using the protein levels of nicotinamide adenine dinucleotide phosphate oxidase components and inflammatory cell accumulation in the liver. Nitrite lowered the blood pressure in hypertensive NASH rats and suppressed left ventricular chamber enlargement. Similar therapeutic effects were observed in a captopril-treated rat NASH model, suggesting the possibility of a common signaling pathway through which nitrite and captopril improve NASH pathology. In conclusion, dietary nitrite attenuates the development of NASH with cardiovascular involvement in rats and provides an alternative NASH therapeutic strategy.

Catechin Reduces Blood Pressure in Spontaneously Hypertensive Rats through Modulation of Arachidonic Acid Metabolism.

(1) Background: hypertension affects approximately half of the adults in the United States (roughly 116 million). The cytochrome P450 (CYP)-mediated metabolism of arachidonic acid (AA) in the kidney has been found to play a major role in the pathogenesis of hypertension. This study examines the anti-hypertensive effect of the natural polyphenolic compound catechin (CAT) and investigates if it impacts the metabolism of AA in the kidney in comparison to captopril (CAP): a commonly used antihypertensive drug. (2) Methods: spontaneously hypertensive rats (SHR) were randomly divided into five groups. The treatment groups were administered CAT in drinking water at doses of 10 and 50 mg/kg. A positive control group received CAP at a dose of 10 mg/kg in the drinking water, and one group received both CAP and CAT at doses of 10 mg/kg and 50 mg/kg, respectively. Blood pressure was monitored weekly for five weeks. The activity of the two major enzymes involved in AA metabolism in the kidney, namely CYP4A and soluble epoxide hydrolase (sEH), were analyzed. (3) Results: CAP monotherapy was found to reduce blood pressure compared to the control untreated rats but did not demonstrate any effect on AA metabolism. Low- and high-dose CAT resisted the rise in blood pressure observed in the untreated SHR and significantly lowered blood pressure compared to the control group, respectively. Only rats treated with high CAT doses demonstrated significant inhibition of CYP4A and sEH enzyme activities. The coadministration of CAP and a high dose of CAT resulted in more pronounced blood pressure-lowering effects, but no more significant effects on AA metabolism were found compared to a high dose of CAT alone. (4) Conclusion: the modulation of AA metabolism in the kidney contributes, at least partially, to the blood pressure-lowering effect of CAT in SHR rats.

Resveratrol Supplants Captopril's Protective Effect on Cardiac Remodeling in a Hypertension Model Elicited by Renal Artery Stenosis.

Background: Renovascular hypertension elicits cardiac damage and remodeling. Two-kidney, one-clip (2K1C) is an experimental model used to study hypertension pathophysiology. In this model, the renin-angiotensin-system (RAS) is overactive due to renal artery stenosis, leading to cardiac remodeling. Redox mechanisms underlying RAS activation mediate hypertension-induced cardiovascular damage. Preclinical studies and clinical trials demonstrated resveratrol's protective effects in cardiovascular diseases, mainly attributed to its antioxidant properties. We hypothesized resveratrol alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor would be beneficial against cardiac damage caused by renovascular hypertension. Objective: We investigated the benefits of resveratrol against cardiac remodeling in 2K1C rats compared with captopril. Methods: Male Wistar rats underwent unilateral renal stenosis - 2K1C Goldblatt model of hypertension. Systolic Blood Pressure (SBP) was measured before and 6 weeks after surgery. Hypertensive 2K1C rats presented SBP≥160 mmHg. From the 6th week after the surgery, the animals received oral resveratrol (20 mg/kg), captopril (12 mg/kg), or their combination for 3 times per week for 3 weeks. Whole heart hypertrophy was evaluated. Histological assays assessed left ventricle hypertrophy and fibrosis. Results: Renovascular hypertension caused cardiac hypertrophy, accompanied by increased myocyte diameter and collagen deposition. Resveratrol reduced 2K1C rats' SBP and whole heart hypertrophy, independently of captopril. Resveratrol caused a higher reduction in ventricular hypertrophy than captopril. Collagen deposition was greater reduced by 2K1C treated only with resveratrol than with captopril alone or combined with resveratrol. Conclusion: Independent of captopril, resveratrol prompts cardioprotective effects on cardiomyocyte remodeling and fibrosis resulting from renovascular hypertension in 2K1C rats.

Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors.

ß-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-ß-lactamase 1 (NDM-1) is able to hydrolyze nearly all ß-lactam antibiotics and even clinically used serine-ß-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.