Injectable, reversibly thermoresponsive captopril-laden hydrogel for the local treatment of sensory loss in diabetic neuropathy.

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.

Correlation of ACE insertion/deletion gene polymorphism with captopril effectiveness in Indonesian hypertensive patients.

Background: Hypertension is a prevalent health concern in Indonesia, with a high percentage of patients unresponsive to ACE inhibitor treatment. Methods: This multicenter case-control study investigated the correlation between ACE I/D and captopril effectiveness in Indonesian hypertensive patients. Hypertensive patients were divided into control (n = 69) and case (n = 73) groups. ACE I/D was identified using PCR and electrophoresis.Results: No significant differences in genotype frequencies or allele distribution were observed. The difference of blood pressure reduction among the three genotypes also lacked statistical significance.Conclusion:  ACE I/D is not significantly associated with blood pressure reduction following captopril therapy in Indonesian hypertensive patients. These results underscore the limited predictive utility of ACE I/D in managing hypertension with captopril.

[Box: see text].

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.

Comparison of four confirmatory tests for the diagnosis of primary aldosteronism: Bayesian analysis in the absence of a gold standard.

BACKGROUND: Captopril challenge test (CCT), seated saline infusion test (SSIT), oral sodium loading test (OSLT) and fludrocortisone suppression test (FST) are widely used diagnostic tests for primary aldosteronism (PA). These tests differ in terms of safety and complexity. Whether the simpler tests (CCT and SSIT) are comparable in diagnostic performance to the more complex ones (FST and OSLT) is unclear. PURPOSE: To compare the diagnostic accuracy of the four tests. METHODS: This is a retrospective study of hypertensive patients who were screened for PA and completed at least one confirmatory test. The patients were divided into two cohorts: one including those who completed one to three tests was used for the estimation of sensitivity and specificity. The other including those who completed four tests was used for the comparison of accuracy. Bayesian method was used to obtain the sensitivity, specificity, and Youden index of each test. RESULTS: The study included 1011 hypertensive patients. Among them, 895 patients completed one to three tests (including 889 CCT, 605 FST, 611 SSIT and 69 OSLT), and 116 patients completed four tests. SSIT had the highest sensitivity of 0.82(95% CI 0.78-0.86) but the lowest specificity of 0.76(0.70-0.80). OSLT had the lowest sensitivity of 0.65(0.56-0.75) but the highest specificity of 0.91(0.82-0.96). The sensitivity and specificity were 0.78 (95% CI, 0.75-0.82), 0.82 (95% CI, 0.78-0.85), for CCT, and 0.77 (95% CI, 0.73-0.81), 0.87 (95% CI, 0.82-0.91) for FST, respectively. The Youden index was not significantly different among the four tests[0.60(0.55-0.65) for CCT; 0.58(0.51-0.64) for SSIT; (0.64(0.57-0.69) for FST; 0.56(0.43-0.67) for OSLT]. CONCLUSION: The accuracy of simpler tests is comparable to the more complex ones. Considering the safety and simplicity of CCT, it may be a reasonable first choice when confirming the diagnosis of PA.

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic-pharmacodynamic analyses.

This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.

Diets containing phytobiotics, l-arginine, vitamin E and captopril modulate ascites syndrome-related genes expression in broiler chickens exposed to low ambient temperature.

BACKGROUND: Our hypothesis centred on the potential to mitigate ascites outbreaks in birds exposed to cold stress by inhibiting pulmonary artery contraction through dietary intervention. OBJECTIVE: This study aimed to evaluate the effect of natural and synthetic medications on growth performance, ascites-related parameters and the expression of ascites-related genes in the lung tissue of broiler chickens under low ambient temperature. METHODS: We randomly assigned 450 one-day-old male Ross 308 chicks to six dietary treatments across five replicate pens, each containing 15 chicks. The treatments included a basal diet (control), and the basal diet was supplemented with hydroalcoholic extracts of sumac (HES, 200 mg/kg), Syrian mesquite (HEM, 200 mg/kg), l-arginine (40% above requirement), captopril (15 mg/kg) and vitamin E (100 mg/kg). RESULTS: Diets containing HEM, l-arginine and vitamin E resulted in increased average daily gain on days 8-14 and 0-28, whereas HES showed a similar effect only during days 8-14 compared to the control diet (p < 0.05). Additionally, feed additives decreased packed cell volume, left and right ventricle volumes and systolic blood pressure (p < 0.05). Moreover, chickens fed the control and l-arginine diets exhibited higher levels of angiotensin converting enzyme (ACE) mRNA in lung tissue compared to those fed HES, HEM and captopril (p < 0.05). Meanwhile, supplementation with HEM and l-arginine increased the expression of inducible nitric oxide synthase (iNOS) mRNA in lung tissue compared to other treatments (p < 0.05). Regarding Cu/Zn-superoxide dismutase (Cu/Zn-SOD) expression, feed additives increased mRNA level in lung tissue, except for captopril (p < 0.05). CONCLUSIONS: This study demonstrates that the plant extracts may reduce the incidence of ascites syndrome not only through their antioxidant properties but also by modulating the expression of ACE, iNOS and Cu/Zn-SOD genes.

An efficient inducible model for the control of gene expression in renin cells.

Fate mapping and genetic manipulation of renin cells have relied on either noninducible Cre lines that can introduce the developmental effects of gene deletion or bacterial artificial chromosome transgene-based inducible models that may be prone to spurious and/or ectopic gene expression. To circumvent these problems, we generated an inducible mouse model in which CreERT2 is under the control of the endogenous Akr1b7 gene, an independent marker of renin cells that is expressed in a few extrarenal tissues. We confirmed the proper expression of Cre using Akr1b7CreERT2/+;R26RmTmG/+ mice in which Akr1b7+/renin+ cells become green fluorescent protein (GFP)+ upon tamoxifen administration. In embryos and neonates, GFP was found in juxtaglomerular cells, along the arterioles, and in the mesangium, and in adults, GFP was present mainly in juxtaglomerular cells. In mice treated with captopril and a low-salt diet to induce recruitment of renin cells, GFP extended along the afferent arterioles and in the mesangium. We generated Akr1b7CreERT2/+;Ren1cFl/-;R26RmTmG/+ mice to conditionally delete renin in adult mice and found a marked reduction in kidney renin mRNA and protein and mean arterial pressure in mutant animals. When subjected to a homeostatic threat, mutant mice were unable to recruit renin+ cells. Most importantly, these mice developed concentric vascular hypertrophy ruling out potential developmental effects on the vasculature due to the lack of renin. We conclude that Akr1b7CreERT2 mice constitute an excellent model for the fate mapping of renin cells and for the spatial and temporal control of gene expression in renin cells.NEW & NOTEWORTHY Fate mapping and genetic manipulation are important tools to study the identity of renin cells. Here, we report on a novel Cre mouse model, Akr1b7CreERT2, for the spatial and temporal regulation of gene expression in renin cells. Cre is properly expressed in renin cells during development and in the adult under basal conditions and under physiological stress. Moreover, renin can be efficiently deleted in the adult, leading to the development of concentric vascular hypertrophy.

Mitigating Viral Impact on the Radiation Response of the Lung.

Inflammation is a key factor in both influenza and radiation-induced lung pathophysiology. This implies a commonality of response to pulmonary damage from these insults and suggests exacerbated pathology may occur after combined exposure. We therefore tested the hypothesis that past inflammation from viral infection alters the lung microenvironment and lowers tolerance for radiation injury. Mice were inoculated with influenza A virus (IAV) and three weeks later, after virus clearance, mice received total-body irradiation (TBI). Survival as well as systemic and local lung inflammation were assessed, and strategies to mitigate pulmonary injury were investigated. After IAV infection alone, body condition recovered within 3 weeks, however inflammatory pathways remained active for 15 weeks. IAV infection exacerbated subsequent TBI responses, evident by increased lethality, enhanced histologically evident lung injury and an altered lung macrophage phenotype. To mitigate this enhanced sensitivity, captopril [an angiotensin converting enzyme inhibitor (ACEi)] was administered to limit tissue inflammation, or inflammatory monocyte-derived macrophage recruitment was blocked with a C-C chemokine receptor type 2 (CCR2) inhibitor. Both treatments abrogated the changes in circulating immune cells observed 4 weeks after TBI, and attenuated pro-inflammatory phenotypes in lung alveolar macrophages, appearing to shift immune cell dynamics towards recovery. Histologically apparent lung injury was not improved by either treatment. We show that latent lung injury from viral infection exacerbates radiation morbidity and mortality. Although strategies that attenuate proinflammatory immune cell phenotypes can normalize macrophage dynamics, this does not fully mitigate lung injury. Recognizing that past viral infections can enhance lung radiosensitivity is of critical importance for patients receiving TBI, as it could increase the incidence of adverse outcomes.

The multi-dimensional impact of captopril modification on human serum albumin.

Captopril is a thiol drug, widely used for the management of hypertension and cardiovascular diseases. Reactive thiols are found to covalently modify the cysteines of plasma proteins and affect their structure and function. Human serum albumin (HSA) is prone to undergo modification by various low molecular weight compounds, including drugs. Cysteine34 (Cys34) in HSA has a free thiol group with antioxidant properties, considered to be the most redox-sensitive amino acid in plasma. Through mass-spectrometric analysis, we demonstrate for the first time that captopril forms a disulfide adduct at Cys34 residue and increases the protease susceptibility of HSA to trypsin. As evidenced by our biophysical and electron microscopy studies, HSA undergoes structural alteration, aggregation and morphological changes when treated with different captopril concentrations. Molecular dynamics studies further revealed the regions of secondary structural changes in HSA due to disulfide adduct formation by captopril at Cys34. It also elucidated the residues involved in the noncovalent interactions with captopril. It is envisaged that structural change in HSA may influence the efficacy of drug delivery as well as its own biological function. These findings may thus provide significant insights into the field of pharmacology intriguing further investigation into the effects of long-term captopril treatment.

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.

A novel robust hydrogel-assisted paper-based sensor based on fluorescence UiO-66-NH2@ZIF-8 for the dual-channel detection of captopril.

Captopril (CP) is commonly used as an active enzyme inhibitor for the treatment of coronary heart disease, hypertension and angina pectoris. The development of sensitive and efficient method for CP analysis is of great importance in biomedical research. Herein, we fabricated a sensitive and robust hydrogel-assisted paper-based sensor based on fluorescence UiO-66-NH2@ZIF-8 and Co, N-doped carbon nanozymes with oxidase-mimicking activity for accurate monitoring of captopril. The hydrogel-assisted paper-based sensor appeared a visible pink signal due to the catalytic oxidation of colorless N,N-diethyl-p-phenylenediamine (DPD) to oxDPD by Co, N-doped carbon-based nanozymes, and resulted in the fluorescence quenching of UiO-66-NH2@ZIF-8. In the presence of captopril, the oxidation of chromogenic substrate DPD by Co, N-doped nanozymes in the hydrogel-assisted paper-based sensor was hindered and accompanied by a change in the visible color, leading to recovery of the fluorescence of UiO-66-NH2@ZIF-8, and the change in the fluorescence color could also be observed. Therefore, the quantitative detection of captopril is achieved by taking a smartphone photograph and converting the image parameters into data information using ImageJ software. The portable hydrogel-assisted paper sensor provided sensitive detection of captopril in two modes based on visible color change as well as fluorescence color change with limits of detection of 0.45 µM and 0.47 µM, respectively. This hydrogel-assisted paper-based sensor has been successfully applied to the accurate monitoring of captopril in human serum, providing a potential avenue for in situ detection of captopril.

Repeated doses of captopril induce airway hyperresponsiveness by modulating the TRPV1 receptor in rats.

Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways.

The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation.

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1ß, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.

Captopril's influence on Danio rerio embryonic development: Unveiling significant toxic outcomes at environmentally relevant concentrations.

Anticipating a global increase in cardiovascular diseases, there is an expected surge in the use of angiotensin-converting enzyme inhibitors, notably captopril (CAP). This heightened usage raises significant environmental apprehensions, mainly due to limited knowledge regarding CAP's toxic effects on aquatic species. In response to these concerns, the current study aimed to tackle this knowledge gap by evaluating the potential influence of nominal concentrations of CAP (0.2-2000 µg/L) on the embryonic development of Danio rerio. The findings revealed that CAP at all concentrations, even at concentrations considered environmentally significant (0.2 and 2 µg/L), induced various malformations in the embryos, ultimately leading to their mortality. Main malformations included pericardial edema, craniofacial malformation, scoliosis, tail deformation, and yolk sac deformation. In addition, CAP significantly altered the antioxidant activity of superoxide dismutase and catalase across all concentrations. Simultaneously, it elevated lipid peroxidation levels, hydroperoxides, and carbonylic proteins in the embryos, eliciting a substantial oxidative stress response. Likewise, CAP, at all concentrations, exerted significant modulatory effects on the expression of genes associated with apoptosis (bax, bcl2, p53, and casp3), organogenesis (tbx2a, tbx2b, and irx3b), and ion exchange (slc12a1 and kcnj1) in Danio rerio embryos. Both augmentation and reduction in the expression levels of these genes characterized this modulation. The Pearson correlation analysis indicated a close association between oxidative damage biomarkers and the expression patterns of all examined genes with the elevated incidence of malformations and mortality in the embryos. In summary, it can be deduced that CAP poses a threat to aquatic species. Nevertheless, further research is imperative to enhance our understanding of the environmental implications of this pharmaceutical compound.

Rosmarinic acid alleviates septic acute respiratory distress syndrome in mice by suppressing the bronchial epithelial RAS-mediated ferroptosis.

Activating angiotensin-converting enzyme 2 (ACE2) is an important player in the pathogenesis of septic-related acute respiratory distress syndrome (ARDS). Rosmarinic acid (RA) as a prominent polyphenolic secondary metabolite derived from Rosmarinus officinalis modulates ACE2 in sepsis remains unclear, although its impact on ACE inhibition and septic-associated lung injury has been explored. The study investigated the ACE2 expression in lipopolysaccharide (LPS)-induced lungs in mice and BEAS2B cells. Additionally, molecular docking, protein-protein interaction (PPI) network analysis, and western blotting were employed to predict and evaluate the molecular mechanism of RA on LPS-induced ferroptosis in vivo and in vitro. LPS-induced glutathione peroxidase 4 (GPX4) downregulation, ACE/ACE2 imbalance, and alteration of frequency of breathing (BPM), minute volume (MV), and the expiratory flow at 50% expired volume (EF50) were reversed by captopril pretreatment in vitro and in vivo. RA notably inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of GPX4 and ACE2 proteins, lung function improvement, and decreased inflammatory cytokines levels and ER stress in LPS-induced ARDS in mice. Molecular docking showed RA was able to interact with ACE and ACE2. Moreover, combined with different pharmacological inhibitors to block ACE and ferroptosis, RA still significantly inhibited inflammatory cytokines Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and C-X-C motif chemokine 2 (CXCL2) levels, as well as improved lung function, and enhanced GPX4 expression. Particularly, the anti-ferroptosis effect of RA in LPS-induced septic ARDS is RAS-dependent.

Design and fabrication of 3D-printed gastric floating tablets of captopril: effect of geometry and thermal crosslinking of polymer on floating behavior and drug release.

The present study aims to investigate the potential of the 3D printing technique to design gastroretentive floating tablets (GFTs) for modifying the drug release profile of an immediate-release tablet. A 3D-printed floating shell enclosing a captopril tablet was designed having varying number of drug-release windows. The impact of geometrical changes in the design of delivery system and thermal cross-linking of polymers were evaluated to observe the influence on floating ability and drug release. Water uptake, water insolubilization, Differential Scanning Calorimetry (DSC), and Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) were performed to assess the degree of thermal cross-linking of polyvinyl alcohol (PVA) filament. The 3D-printed GFT9 was considered the optimized gastric floating tablet that exhibited >12 h of total floating time with zero floating lag time and successfully accomplished modified-drug release by exhibiting >80% of drug release in 8 h. The zero-order release model, with an r2 value of 0.9923, best fitted the drug release kinetic data of the GFT9, which followed a super case II drug transport mechanism with an n value of 0.95. The optimized gastric floating device (GFT9) also exhibited the highest MDT values (238.55), representing slow drug release from the system due to thermal crosslinking and the presence of a single drug-releasing window in the device.

Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs.

BACKGROUND AND PURPOSE: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. EXPERIMENTAL APPROACH: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. KEY RESULTS: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. CONCLUSIONS AND IMPLICATIONS: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.

Chronic inhibition of angiotensin converting enzyme lowers blood pressure in spontaneously hypertensive rats by attenuation of sympathetic tone: The role of enhanced baroreflex sensitivity.

Spontaneously hypertensive rats (SHR) are characterized by sympathetic hyperactivity and insufficient parasympathetic activity, and their high blood pressure (BP) can be lowered by long-term inhibition of the renin-angiotensin system. The aim of our study was to determine the influence of chronic inhibition of angiotensin converting enzyme (ACE) by captopril on cardiovascular regulation by the sympathetic and parasympathetic nervous system. Implanted radiotelemetric probes or arterial cannulas were used to measure mean arterial pressure (MAP), heart rate (HR), and arterial baroreflex in adult SHR and Wistar-Kyoto (WKY) rats under basal or stress conditions. MAP and the low-frequency component of systolic blood pressure variability (LF-SBPV, marker of sympathetic activity) were greater in SHR than in WKY rats. Under basal conditions chronic captopril treatment reduced both parameters more effectively in SHR, and the same was true during acute restraint stress. HR was similar in control rats of both strains, but WKY rats showed greater heart rate variability (HRV), indicating higher parasympathetic activity. Captopril administration increased HR in both strains, whereas HRV was decreased only in WKY. Chronic captopril treatment improved the impaired baroreflex-HR control in SHR by increasing the sensitivity but not the capacity of vagal arm of arterial baroreflex. Captopril treatment attenuated BP changes elicited by dimethylphenylpiperazinium (DMPP, agonist of nicotinic acetylcholine receptors), especially in SHR, indicating that sympathetic nerve transmission is facilitated by angiotensin II more in hypertensive than in normotensive animals. Thus, chronic ACE inhibition improves baroreflex sensitivity and lowers BP through both central and peripheral attenuation of sympathetic tone.

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.

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.