Captopril inhibits thioacetamide-induced chronic liver injury associated with the suppression of inflammation / hypoxia- inducible factor 1-alpha / profibrogenic axis-mediated hepatotoxicity in rats / Captopril inhibe la lesión hepática crónica inducida por tioacetamida asociada con la supresión de la inflamación/factor 1-alfa inducible por hipoxia/hepatotoxicidad mediada por el eje profibrogénico en rata

SUMMARY: Liver transplantation is the only available method to treat liver failure induced by chronic liver injury. We sought to determine whether the angiotensin-converting enzyme inhibitor, captopril, can inhibit the development of chronic liver injury induced by the hepatotoxic agent thioacetamide (TAA) in association with the suppression of inflammation (hsCRP, TNF-α, and IL-6) / hypoxia- inducible factor 1-alpha (HIF-1α) / profibrosis (TIMP-1, MMP-9, and α-SMA) axis that mediates liver injury. Therefore, the model group of rats was injected for eight weeks with 200 mg/kg TAA starting at week two. The protective group was pretreated with 150 mg/ kg captopril daily for two weeks prior to TAA injections and continued receiving both capropril and TAA agents until being humanely scrificed at week 10. We observed a substantial damage to liver tissue in the model group as demonstrated by a significant (p<0.0001) increase in blood and hepatic tissue levels of high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-a (TNF-α), interleukin- 6 (L-6), HIF-1α, tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), alpha-smooth muscle actin (α-SMA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). All these parameters were significantly (p<0.0244) protected by captopril. Also, a significant (p<0.0001) positive correlation was observed between a-SMA (profibrosis) and the serum and tissue levels of hsCRP, TNF-α, HIF-1α, TIMP-1, MMP-9, and ALT. Thus, these findings suggest that the induction of chronic liver injury by the hepatotoxic compound, TAA is associated with the upregulation of inflammation/HIF-1α/profibrosis, with captopril exhibiting beneficial hepatic pleotropic effects.

El trasplante de hígado es el único método disponible para tratar la insuficiencia hepática inducida por una lesión hepática crónica. Buscamos determinar si el inhibidor de la enzima convertidora de angiotensina, captopril, puede inhibir el desarrollo de lesión hepática crónica inducida por el agente hepatotóxico tioacetamida (TAA) en asociación con la supresión de la inflamación (hsCRP, TNF-α e IL-6) / factor inducible por hipoxia 1-alfa (HIF-1α) / profibrosis (TIMP-1, MMP-9 y α- SMA) eje que media la lesión hepática. Por lo tanto, al grupo modelo de ratas se le inyectó durante ocho semanas 200 mg/kg de TAA a partir de la semana dos. El grupo protector fue pretratado con 150 mg/kg de captopril al día durante dos semanas antes de las inyecciones de TAA y continuó recibiendo capropril y agentes TAA hasta que fue sacrificado en la semana 10. Observamos un daño sustancial en el tejido hepático en el grupo modelo, como lo demuestra un aumento significativo (p<0,0001) de los niveles en sangre y tejido hepático de proteína C reactiva de alta sensibilidad (hsCRP), factor de necrosis tumoral-α (TNF-a), interleucina-6 (L-6), HIF-1α, inhibidor tisular de metaloproteinasas-1 (TIMP-1), metaloproteinasa de matriz-9 (MMP-9), actina de músculo liso alfa (α-SMA), alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Todos estos parámetros estaban significativamente (p<0,0244) protegidos por captopril. Además, se observó una correlación positiva significativa (p<0,0001) entre α-SMA (profibrosis) y los niveles séricos y tisulares de hsCRP, TNF-α, HIF-1α, TIMP- 1, MMP-9 y ALT. Por lo tanto, estos hallazgos sugieren que la inducción de daño hepático crónico por el compuesto hepatotóxico, TAA, está asociada con la regulación al alza de la inflamación/HIF-1α/profibrosis, con captopril exhibiendo efectos pleotrópicos hepáticos beneficiosos.

Hydrogen Sulphide Release via the Angiotensin Converting Enzyme Inhibitor Zofenopril Prevents Intimal Hyperplasia in Human Vein Segments and in a Mouse Model of Carotid Artery Stenosis.

OBJECTIVE: Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H2S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H2S. Here, it was hypothesised that zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia. METHODS: Spontaneously hypertensive male Cx40 deleted mice (Cx40-/-) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. RESULTS: Compared with control animals (intima/media thickness 2.3 ± 0.33 µm), enalapril reduced IH in Cx40-/- hypertensive mice by 30% (1.7 ± 0.35 µm; p = .037), while zofenopril abrogated IH (0.4 ± 0.16 µm; p < .002 vs. control and p > .99 vs. sham operated Cx40-/- mice). In WT normotensive mice, enalapril had no effect (0.9665 ± 0.2 µm in control vs. 1.140 ± 0.27 µm; p > .99), while zofenopril also abrogated IH (0.1623 ± 0.07 µm; p < .008 vs. control and p > .99 vs. sham operated WT mice). Zofenoprilat, but not enalaprilat, also prevented IH in human vein segments ex vivo. The effect of zofenopril on carotid and SMCs correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the mitogen activated protein kinase and mammalian target of rapamycin pathways in SMCs and human vein segments. CONCLUSION: Zofenopril provides extra beneficial effects compared with non-sulfhydryl ACEi in reducing SMC proliferation and re-stenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.

The angiotensin-converting enzyme inhibitor, captopril, suppressed hepatic stellate cell activation via NF-kappaB or wnt3α/ß-catenin pathway.

Activation of hepatic stellate cells (HSC) is associated with hepatic fibrogenesis, which is one of complications of diabetes mellitus. Captopril possesses potent anti-inflammation, oxidative stress and fibrosis effects. However, the specific molecular mechanism of captopril in high glucose (HG)-induced hepatic stellate cells has not been elucidated. Following the treatment of HG or captopril treatment for rat hepatic stellate cells (HSC-T6), cell activities were detected by Cell Counting Kit-8 (CCK8) assay. Reactive oxygen species (ROS) levels were determined by ROS staining. The expression of inflammation-related proteins (Interleukin (IL)-1ß, IL-6 and IL-8) and fibrosis-related proteins (fibronectin (FN), collagen I, collagen III, collagen IV, matrix metallopeptidase (MMP-2 and MMP-9) were determined by Western blot. Captopril significantly decreased HSC-T6 cell viability induced by HG in a dose-dependent manner, as well as decreased levels of malondialdehyde (MDA), ROS, pro-inflammatory markers and fibrosis-related proteins, while upregulated superoxide dismutase (SOD) activities. We further found that captopril decreased the ratio of p-IκBα/IκBα and the ratio of p-p65/p65. Intriguing, phorbol myristate acetate (PMA) or LiCl was able to significantly reverse the captopril-induced alteration of oxidative stress-, inflammation- and fibrosis-marker levels. In conclusion, in HG-stimulated HSC-T6 cells, captopril displayed a potent ability to inhibit oxidative stress, inflammation and hepatic fibrogenesis via NF-kappaB or wnt3α/ß-catenin. These results demonstrated the mechanism of captopril as well as the role of the NF-kappaB or wnt3α/ß-catenin on HSC-T6 activation induced by HG.

Physicochemical Characterization and Drug Release Properties of Methyl-Substituted Silica Xerogels Made Using Sol-Gel Process.

In this work, a multi-analytical approach involving nitrogen porosimetry, small angle neutron and X-ray scattering, Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies, X-ray diffraction, thermal analysis and electron microscopy was applied to organically modified silica-based xerogels obtained through the sol-gel process. Starting from a tetraethoxysilane (TEOS) precursor, methyltriethoxysilane (MTES) was added to the reaction mixture at two different pH values (2.0 and 4.5) producing hybrid xerogels with different TEOS/MTES molar ratios. Significant differences in the structure were revealed in terms of the chemical composition of the silica network, hydrophilic/hydrophobic profile, particle dimension, pore shape/size and surface characteristics. The combined use of structural characterization methods allowed us to reveal a relation between the cavity dimensions, the synthesis pH value and the grade of methyl substitution. The effect of the structural properties on the controlled Captopril release efficiency has also been tested. This knowledge facilitates tailoring the pore network for specific usage in biological/medical applications. Knowledge on structural aspects, as reported in this work, represents a key starting point for the production of high-performance silica-based hybrid materials showing enhanced efficacy compared to bare silica prepared using only TEOS.

Administration with Quinoa Protein Reduces the Blood Pressure in Spontaneously Hypertensive Rats and Modifies the Fecal Microbiota.

Despite the well-established role of quinoa protein as the source of antihypertensive peptides through in vitro enzymolysis, there is little evidence supporting the in vivo antihypertensive effect of intact quinoa protein. In this study, in vivo study on spontaneously hypertensive rats (SHRs) was conducted by administering quinoa protein for five weeks. Gastrointestinal content identification indicated that many promising precursors of bioactive peptides were released from quinoa protein under gastrointestinal processing. Quinoa protein administration on SHRs resulted in a significant decrease in blood pressure, a significant increase in alpha diversity, and microbial structure alternation towards that in non-hypertension rats. Furthermore, blood pressure was highly negatively correlated with the elevated abundance of genera in quinoa protein-treated SHRs, such as Turicibacter and Allobaculum. Interestingly, the fecal microbiota in quinoa protein-treated SHRs shared more features in the composition of genera with non-hypertension rats than that of the captopril-treated group. These results indicate that quinoa protein may serve as a potential candidate to lower blood pressure and ameliorate hypertension-related gut dysbiosis.

Inhibition of diabetes mellitus-induced knee joint injury in rats by a combination of metformin and captopril / Inhibición de la lesión de la articulación de la rodilla inducida por diabetes mellitus en ratas mediante una combinación de metformina y captopril

SUMMARY: Osteoarthritis (OA) is an inflammatory disease that damages the joints and affects millions of people worldwide. The potential inhibitory effects of the antidiabetic drug metformin combined with captopril, the angiotensin-converting enzyme inhibitor, on diabetes-induced damage to the knee joint articular cartilage associated with the inhibition of glycemia, dyslipidemia, and inflammation has not been investigated before. Therefore, we induced diabetes in rats using high carbohydrate and fat diets and a single injection of streptozotocin (50 mg/kg). The protective group of rats was pre-treated with combined daily doses of metformin (Met; 200 mg/kg body weight) and captopril (Cap; 150 mg/kg body weight) for 14 days before diabetic induction and continued on metformin and resveratrol until the end of the experiment at week 12. Harvested tissues obtained from knee joints were prepared for basic histology staining with haematoxylin and eosin (H&E) and examined under light microscopy. Representative H&E images showed that OA was developed in the diabetic rats as demonstrated by a profound damage to the knee joints such as irregular eroded and a sharp decrease in the thickness of the articular cartilage surface and abnormal remodeling of the subchondral bone that were substantially ameliorated by Met+Cap. Met+Cap also significantly (p< 0.05) reduced blood levels of glucose, glycated hemoglobin (HbA1c), dyslipidemia, and the inflammatory biomarkers, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) induced by diabetes. In addition, a significant (p≤ 0.0014) correlation between the articular cartilage thickness and the blood levels of glucose, HbA1c, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein- cholesterol (HDL-C), and hs-CRP were observed. Thus, we demonstrate that Met+Cap effectively protect the knee joint against injuries induced secondary to diabetes in rats, possibly due to the inhibition of glycemia, dyslipidemia, and biomarkers of inflammation.

RESUMEN: La osteoartritis (OA) es una enfermedad inflamatoria que daña las articulaciones y afecta a millones de per- sonas en todo el mundo. No se han investigado los posibles efectos inhibidores del fármaco antidiabético metformina combinado con captopril, el inhibidor de la enzima convertidora de angiotensina, sobre el daño inducido por la diabetes en el cartílago articular de la articulación de la rodilla asociado con la inhibición de la glucemia, dislipidemia e inflamación. En este estudio fue inducida la diabetes en ratas con dietas altas en carbohidratos y grasas y una sola inyección de estreptozotocina (50 mg / kg). El grupo protector de ratas se pretrató con dosis diarias combinadas de metformina (Met; 200 mg / kg de peso corporal) y captopril (Cap; 150 mg / kg de peso corporal) durante 14 días antes de la inducción diabética. El tratamiento se continuó con metformina y resveratrol hasta el final del experimento en la semana 12. Los tejidos obtenidos de las articulaciones de la rodilla se prepararon para la tinción de histología básica con hematoxilina y eosina (H&E) y se examinaron con microscopía óptica. Imágenes representativas de H&E mostraron que la OA se desarrolló en las ratas diabéticas, como lo evidencia un daño profundo en las articulaciones de la rodilla, como la erosión irregular y una fuerte disminución en el grosor de la superficie del cartílago articular y remodelación anor- mal del hueso subcondral que fueron mejorados sustancialmente por Met + Cap. Met + Cap. También redujo significativamente (p <0.05) los niveles sanguíneos de glucosa, hemoglobina glicosilada (HbA1c), dislipidemia y los biomarcadores inflamatorios, proteína C reactiva de alta sensibilidad (hs-CRP), interleucina-6 (IL-6), y factor de necrosis tumoral alfa (TNF-α) inducido por diabetes. Además, una correlación significativa (p≤ 0,0014) entre el grosor del cartílago articular y los niveles sanguíneos de glucosa, HbA1c, triglicéridos (TG), lipoproteínas-colesterol de baja densidad (LDL- C), lipoproteínas de alta densidad-colesterol (HDL-C) ) y hs-CRP. Así, demostramos que Met + Cap protege eficazmente la articulación de la rodilla contra lesiones inducidas por diabetes en ratas, posiblemente debido a la inhibición de la glicemia, dislipidemia y biomarcadores de inflamación.

Angiotensin-Converting Enzyme Inhibitor, Captopril, Improves Scar Healing in Hypertensive Rats.

Pathological cutaneous scars, with aberrant extracellular matrix accumulation, have multiple origins. Antihypertensive medications, such as calcium channel blockers, have been used to treat pathological scars. However, a relationship between angiotensin-converting enzyme (ACE) inhibitors, pathological scars, and blood pressure (BP) has never been reported. Here, we aimed to compare the differences in scar development and the effects of the administration of systemic ACE inhibitor on scar tissue in a normotensive rat, the Wistar Kyoto rat (WKY), a hypertensive rat, and the spontaneously hypertensive rat (SHR). Using an 8-mm punch, we created two full-thickness skin defects in a total of 32 rats (16 WKY and 16 SHR) to obtain a total of 64 wounds. We established control WKY (n = 16), captopril-treated WKY (n = 16), control SHR (n = 16), and captopril-treated SHR (n = 16) groups and started captopril (100 mg/g per day) treatment on day 21 in the appropriate groups. The BP of all groups was measured at 0, 3, and 5 weeks. The scar area was measured by histopathological examination, and scarring was expressed in terms of scar area and fibroblast and capillary counts. The expression of heat shock protein (HSP) 47, type I and III collagens, alpha-smooth muscle actin (α-SMA), Ki67, and vascular endothelial growth factor (VEGF) was investigated using immunohistochemistry. The scar area and fibroblast count were significantly higher in control SHR than in control WKY. The scar area, fibroblast count, and capillary count were significantly smaller in captopril-treated SHR than in control SHR. Immunostaining for α-SMA, Ki67, and VEGF also showed a noticeable decrease in scarring in the treated SHR compared with that in control SHR. Thus, BP affects scar development in a rat model, and an ACE inhibitor is more effective at reducing scars in hypertensive rats than in normotensive rats.

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19.

The key link between renin-angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity.

Combination of Captopril with Gliclazide Decreases Vascular and Renal Complications and Improves Glycemic Control in Rats with Streptozotocin- Induced Diabetes Mellitus.

BACKGROUND: The common antihypertensive angiotensin-converting enzyme (ACE) inhibitor captopril was reported to possess anti-oxidant and anti-inflammatory effects in different experimental models. Diabetic vascular complications arise from increased vascular endothelial inflammation and oxidative stress as well as decreased nitric oxide bioavailability in the vessel walls due to poor glycemic control. OBJECTIVE: This study aimed to evaluate the role of captopril and gliclazide in decreasing diabetes mellitus (DM) vascular complications caused by decreased cellular glucose uptake and impaired endothelial nitric oxide metabolism, as well as examine the effects of the combination on diabetic renal complication and plasma lipid profile. METHODS: Adult male Wister rats received captopril (25 mg/kg/day) and/or gliclazide (10 mg/kg/- day) by oral gavage daily for one month after induction of DM using streptozotocin (50 mg/kg, i.p., once). Serum glucose and insulin levels, inflammatory mediators like TNF-α, oxidative stress biomarkers like glutathione and nitric oxide, and plasma lipid profile were measured. Besides, histopathological examination of the thoracic aorta and kidney tissues, Western blot assessed the expression of nitric oxide synthase (NOS) subtypes in the thoracic aorta. RESULTS: Captopril significantly improved vascular architecture and oxidative stress and modulated nitric oxide synthesis via regulation of nitric oxide synthases, as well as decreased inflammation via down-regulating TNF-α, decreased systolic and diastolic blood pressure, and improved serum lipid profile in diabetic rats. Gliclazide increased serum insulin and decreased serum glucose, as well as its anti-oxidant and anti-inflammatory effects. CONCLUSION: Captopril showed a promising protective effect against DM vascular complications, at least via nitric oxide modulating effect, anti-oxidant effect, and anti-inflammatory activity that appeared in biochemical and histopathological findings, lipid profile, renal function, and architecture improvements. Combining gliclazide with captopril gives an additive effect through enhanced glycemic control and increased anti-oxidant and anti-inflammatory properties above captopril alone.

Antihypertensive effect of rapeseed peptides and their potential in improving the effectiveness of captopril.

BACKGROUND: The main objective of this study was to evaluate the safety and antihypertensive activity of rapeseed peptides and to investigate their potential synergy with captopril. RESULTS: The peptides were nontoxic with the maximum tolerated dose exceeding 25 g kg-1 BW d-1 for mice and they had angiotensin converting enzyme (ACE) inhibitory activity with IC50 value of 1.27 mg mL-1 . Rapeseed peptides did not have a synergistic effect with captopril on inhibiting ACE activity in simulated digestion tests in vitro. But in vivo they could synergistically augment the amplitude range of lowering blood pressure with captopril by approximately 9% and prolong the antihypertensive effect duration time by over 20% in antihypertension tests of spontaneously hypertensive rats. In addition, the inhibiting effect of rapeseed peptides on ACE activity was noticeable in some rat organs in vivo. Nevertheless, when compared to captopril group, the potential synergy of rapeseed peptides with captopril did not cause a further decrease in ACE activity in the organs but their synergy further improved levels of NO (12.7%) and endothelial nitric oxide synthase (74.1%) in rat serum. Further studies of some peptides identified from rapeseed peptides showed that some of the rapeseed peptides (Cys-Leu, Val-Ala-Pro) could markedly increase contents of NO and endothelial nitric oxide synthase. CONCLUSIONS: Rapeseed peptides have antihypertensive activity and they showed potential synergy with captopril in antihypertensive performance in vivo. The synergy was not from ACE inhibition but from other pathways, like improvement in endogenous vasodilator contents. © 2020 Society of Chemical Industry.

Effect of captopril, an angiotensin-converting enzyme inhibitor, on morphine analgesia and tolerance in rats, and elucidating the inflammation and endoplasmic reticulum stress pathway in this effect.

The purpose of current study was to examine the possible involvement of captopril, an angiotensin-converting enzyme inhibitor, on nociception, morphine analgesia and morphine tolerance development involving inflammation and ER-stress pathways in rats. In this study, thirty-six male Wistar rats were used. Animals were divided into six groups: Saline, 50 mg/kg captopril, 5 mg/kg morphine, morphine + captopril, morphine tolerance and morphine tolerance + captopril. The resulting analgesic effect was measured with hot plate and tail flick analgesia tests. The dorsal root ganglions (DRG) tissues were collected for inflammation parameters, endoplasmic reticulum (ER) stress and apoptosis proteins by using ELISA. Captopril showed anti-nociceptive effect when given alone (p < 0.05 to p < 0.01). In addition, captopril increased the analgesic effect of morphine (p < 0.05 to p < 0.001) and also decreased the tolerance to morphine at a significant level (p < 0.05 to p < 0.001). However, it decreased inflammation and ER-stress when applied with single-dose morphine and tolerance induction (p < 0.001). Moreover, captopril decreased apoptosis proteins after tolerance development (p < 0.001). In conclusion, captopril has antinociceptive properties, increasing analgesic effect of morphine, and preventing tolerance development. These effects may occur by suppressing inflammation and ER-stress pathways.

Comparison of the effects of losartan, captopril, angiotensin II type 2 receptor agonist compound 21, and MAS receptor agonist AVE 0991 on myocardial ischemia-reperfusion necrosis in rats.

Myocardial ischemia may occur as a result of pathophysiological and therapeutical applications such as atherosclerosis, thromboembolism, percutaneous transluminal coronary angioplasty, coronary artery bypass, and transplantation. In this study, we aimed to compare the effects of angiotensin (Ang) II type 2 (AT2 ) selective receptor agonist Compound 21 (C21), MAS receptor agonist AVE 0991, Ang II type 1 (AT1 ) selective receptor blocker losartan, and Ang-converting enzyme inhibitor captopril on haemodynamic parameters and infarct size on myocardial ischemia/reperfusion (MI/R)-induced necrosis in rats. To induce necrosis in the heart of rats, reperfusion for 2 h following ischemia for 30 min to the descending branch of the left main coronary artery was achieved. C21 (0.03 mg/kg), AVE 0991 (576 µg/kg), losartan (2 mg/kg), and captopril (3 mg/kg) were administered as an intravenous infusion at 10 min before and throughout the ischemia. Then, the infarct size and risk area were calculated from the heart. The percentage of myocardial infarct size to area at risk ratio (%IS/AR) of groups was Control (MI/R) group: 48.9 ± 8.8%; C21 group: 31.1 ± 7.8%; AVE 0991 group: 29.9 ± 4.8%; C21 + AVE 0991 group: 28.2 ± 3.3%; Losartan + AVE 0991 group: 30.8 ± 5.8%; Captopril + AVE 0991 group: 31.7 ± 7.7%. %IS/AR of the drug-treated groups decreased significantly when compared to the MI/R group (P < 0.05). Our results indicate that the importance of AT1 , AT2 , and MAS receptors in the MI/R injury. Inhibition of Ang II formation by captopril, blockade of AT1 receptor with losartan, and stimulation of AT2 receptor with C21 and MAS receptor with AVE 0991 showed beneficial effects by reducing infarct size.

Assessment of practices for suspended oral drugs by tablet crushing in pediatric units.

The aim of this study was to assess the impact of suspended drug by tablet crushing in our pediatric hospital in term of targeted dose and to identify parameters involved in the potential variability. Four usually crushed pediatric drug substances were selected: amiodarone, warfarin, hydrocortisone and captopril. Each tablet was crushed in a bag using a crusher device. Once crushed, a pre-determined volume of water was added using oral syringes before taking the necessary volume to obtain the targeted drug amount. For each drug, operators among pharmacy technicians and nurses investigated 2 targeted doses (high and low). Each suspension was assayed 3 times using the corresponding validated HPLC procedure. Statistical analysis was performed (GraphPad Prism®) to evaluate the impact of operators, the level of suction in bag, and actual drug doses. To investigate the impact of formulation change on syringe drug content, five generic drugs of amiodarone were selected. Syringes contents were compared using one-way ANOVA. Drug loss in syringe ranged from 8.1% to 54.1%. The drug loss represented 18.9% to 30.5% for amiodarone, 0.1% to 5.5% for captopril, 5.6% to 19.7% for warfarin and 5.0% to 30.7% for hydrocortisone. The comparison of level sampling of suspensions presented significant differences for amiodarone, hydrocortisone, and warfarin. Comparison of operators demonstrated significant difference between pharmacy technician and nurse (p = 0.0251). Finally, comparison of 5 generic drugs for amiodarone showed some statistical difference between the syringes content obtained when using the original medicine as compared to the generics. The physicochemical properties of each drug substance and the formulation of the drug product may both factor that should be considered. As a result, crushing tablets in water for oral administration needs a case by case assessment. Although appropriate pediatric formulations are lacking, suspend the crushed material in a given volume of water should be discouraged and not recommended because far from good practice.

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein-kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the in vivo effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi's may have potential for therapeutic use for systemic and NPSLE.

Self-Emulsifying Drug Delivery Systems: Hydrophobic Drug Polymer Complexes Provide a Sustained Release in Vitro.

The aim of this study was to develop hydrophobic ionic drug polymer complexes in order to provide sustained drug release from self-emulsifying drug delivery systems (SEDDS). Captopril (CTL) was used as an anionic model drug to form ionic complexes with the cationic polymers Eudragit RS, RL, and E. Complexes of polymer to CTL charge ratio 1:1, 2:1, and 4:1 were incorporated in two SEDDS, namely FA which was 40% Kolliphor RH 40, 20% Kolliphor EL, and 40% castor oil and FB, which was 40% Kolliphor RH 40, 30% glycerol, 15% Kolliphor EL, and 15% castor oil. Blank and complex loaded SEDDS were characterized regarding their droplet size, polydispersity index (PDI), and zeta potential. Resazurin assay was performed on Caco-2 cells to evaluate the biocompatibility of SEDDS. Release of CTL from SEDDS was determined in release medium containing 0.2 mg/mL of 5,5'-dithiobis(2-nitrobenzoic acid) (DNTB) allowing quantification of free drug released into solution via a thiol/disulfide exchange reaction between CTL and DNTB forming a yellow dye. The droplet size of SEDDS FA and SEDDS FB were in the range of 100 ± 20 nm and 40 ± 10 nm, respectively, with a PDI < 0.5. The zeta potential of SEDDS FA and SEDDS FB increased after the incorporation of complexes. Cell viability remained above 80% after incubation with SEDDS FA and SEDDS FB in a concentration of 1% and 3% for 4 h. Without any polymer, CTL was entirely released from both SEDDS within seconds. In contrast, the higher the cationic lipophilic polymer to CTL ratio in SEDDS, the more sustained was the release of CTL. Among the polymers which were evaluated, Eudragit RL provided the most sustained release. SEDDS FA containing Eudragit RL and CTL in a ratio of 1:1 released 64.78 ± 8.28% of CTL, whereas SEDDS FB containing the same complex showed a release of 91.85 ± 1.17% within 1 h. Due to the formation of lipophilic ionic polymer complexes a sustained drug release from oily droplets formed by SEDDS can be achieved. Taking into account that drugs are otherwise instantly released from SEDDS, results of this study might open the door for numerous additional applications of SEDDS for which a sustained drug release is essential.

Parameters of captopril challenge test can predict results of other confirmatory tests for primary aldosteronism and propose the next test to be done.

In Japan, primary aldosteronism (PA) is diagnosed if any one of the captopril challenge test (CCT), saline infusion test (SIT), furosemide-upright test (FUP), and oral salt-loading test (OST) is positive. The present study aimed to investigate if parameters of CCT, the safest confirmatory test, could predict decisions of other tests and propose the next test to diagnose PA in CCT-negative patients. In a cross-sectional design, 142 patients, who were referred to our hospital for the scrutiny of PA and underwent at least two confirmatory tests, were enrolled. While 123 patients underwent all of the CCT, SIT, and FUP, the OST was successfully done in only six patients and excluded from further analyses. CCT parameters showing correlations of higher degrees with SIT and FUP parameters were selected, and their powers to predict SIT and FUP decisions were investigated by receiver operating characteristic analyses. Proposals of the next test based on the CCT parameters were validated with SIT and FUP decisions in subsets of CCT-negative patients divided by cut-offs of the CCT parameters. The plasma aldosterone concentration and plasma renin activity 60 min after the load of CCT (CCT60-PAC and CCT60-PRA) were selected, and CCT60-PAC ≤59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h could predict negativities of SIT and FUP, respectively, with >95% specificities. Based on the validation, the present study suggested the SIT as the next test to be done if the CCT-negative patient belonged to the subset with CCT60-PAC >59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h, otherwise the FUP should be selected.

Maternal Treatment With Captopril Persistently Alters Gut-Brain Communication and Attenuates Hypertension of Male Offspring.

Maternal-fetal crosstalk has been implicated in long-term control of the health of offspring, including transgenerational hypertension. However, current knowledge is limited regarding maternal influences on the gut and its microbiome in blood pressure control in offspring. Therefore, the current study was designed to test the hypothesis that maternal factors influence the gut-brain axis impacting hypertension in offspring. We elected to use captopril, an antihypertensive angiotensin-converting enzyme inhibitor that possesses antibacterial properties, for the study. Pregnant female spontaneously hypertensive rats and normotensive Wistar Kyoto rats were treated with captopril water (100 mg/[kg·day]) or sterile water throughout pregnancy and lactation. At weaning, the pups from dams drinking sterile water were continued with sterile water until 12 weeks of age. The male pups from dams drinking captopril water were divided at weaning into 2 groups: offspring drinking captopril water and offspring withdrawn from captopril water, then drinking sterile water until 12 weeks of age. Captopril changed gut microbiota of spontaneously hypertensive rat dams, and some of these changes were reflected in their 12-week-old male offspring. These 12-week-old spontaneously hypertensive rat male offspring exposed to captopril via dams demonstrated persistently decreased systolic blood pressure, decreased number of activated microglia and neuroinflammation, as well as improvement of gut inflammation and permeability. Therefore, maternal captopril treatment improves the dysregulated gut-brain axis in spontaneously hypertensive rat male offspring, providing conceptual support that targeting the gut-brain axis via the mother may be a viable strategy for control of hypertension in the offspring.

Antihypertensive and renal protective effect of Shunaoxin pill combined with captopril on spontaneous hypertension rats.

INTRODUCTION: According to previous reports, hypertension has become the most common chronic disease in the world. Captopril, an angiotensin-converting enzyme inhibitor, has been widely used for the therapy of arterial hypertension and cardiovascular diseases therapy. Besides, Shunaoxin pill (SNX) as a traditional Chinese prescription showed antihypertensive effect in our previous research. OBJECTIVE: This study means to investigate whether SNX combining with captopril could show antihypertensive and renal protective effects on spontaneous hypertension rats (SHRs). METHODS: SHRs were randomly assigned to four treatment groups, including non-treated group, captopril, SNX, and captopril + SNX-treated groups. Their body weight and systolic blood pressure (SBP) were measured weekly. Histopathological examination was analyzed through Masson staining and hematoxylin and eosin staining. Biochemical analyses, ELISA, and western blot were used to analyze their combining mechanism. RESULTS: In this experiment, this combinatorial therapy significantly reduced aortic wall thickness, increased the content of NO, NOS and eNOS, decreased the content of bradykinin and endothelin 1(ET-1), and regulated the levels of TG, TC and HDLC back to normal, which suggested they could induce vasodilation and lower blood pressure. Meanwhile, histological examination alleviated that captopril + SNX remarkably inhibited renal injury, including tubular disorder, inflammatory cell infiltration and fibrosis. They down-regulated the serum levels of BUN and Cr, protein expression of IL-1ß, NF-κB, Bax, Cyt c, caspase 3, 8 and 9 in kidney tissues and significantly increased the levels of Bcl-2 in kidney tissues compared with monotherapy group. CONCLUSION: The combinatorial treatment of SNX and captopril lowered blood pressure through adjusting NO/NOS, ET-1 and dyslipidemia profile. Furthermore, this treatment alleviated the kidney damage via reducing the release of inflammatory factors and the expression of apoptotic markers. Therefore, these results provided a rationale for future clinical use of SNX combined with captopril in antihypertensive and protecting renal functions in hypertension.

Virgin olive oil (unfiltered) extract contains peptides and possesses ACE inhibitory and antihypertensive activity.

BACKGROUND & AIMS: The peptide and protein composition of olive oil is mostly unknown and the few studies available have not focused on the study of its low molecular weight peptides. We hypothesised that olive oil could naturally contain low molecular weight peptides with antihypertensive effect. METHODS: We produced virgin olive oil (unfiltered, var. Picual) and obtained a water-soluble peptide extract. We fractionated the peptide extract by FPLC and studied its angiotensin converting enzyme (ACE) inhibitory activity. We studied the antihypertensive effect of olive oil peptides on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) using an animal model of hypertension (spontaneously hypertensive rats, SHR). The animals were randomly distributed into 3 study groups (n = 8 per group) and received an oral dose of olive oil peptides (0.425 mg/kg of BW), or a dose of Captopril (50 mg/kg of BW) or water. SBP and DBP were registered in the rats before administration and a at 2, 4, 6, 8, 24 and 48 h post-administration of the corresponding dose. RESULTS: The peptide extract and FPLC purified fractions possessed angiotensin converting enzyme (ACE) inhibitory activity. Acute oral administration of olive oil water-soluble extract produced an average blood pressure reduction of 10 mmHg at 4 h (P < 0.01) and reached a maximum antihypertensive effect of 20 mmHg at 6 h, compared with baseline. CONCLUSION: Unfiltered virgin olive oil contains peptides and a water-soluble extract obtained from this oil possesses ACE inhibitory activity and in vivo antihypertensive effect.

Comparison of an angiotensin-I-converting enzyme inhibitory peptide from tilapia (Oreochromis niloticus) with captopril: inhibition kinetics, in vivo effect, simulated gastrointestinal digestion and a molecular docking study.

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.