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Hypertension drives the development of concentric left ventricular hypertrophy (LVH). However, the relative contribution of pentraxin-3 (PTX-3), a novel marker for inflammatory cardiovascular disease, in the hypertrophic response to pressure overload has not been adequately elucidated. We investigated the role of PTX-3 in the development of LVH in spontaneously hypertensive rats (SHR), untreated and treated with either captopril (an ACE inhibitor) or hydralazine (a non-specific vasodilator). Three-month-old SHR received either 20 mg/kg/day hydralazine (SHR + H, n = 6), 40 mg/kg/day captopril (SHR + C, n = 6), or plain gelatine cubes (untreated SHR, n = 7) orally for 4 months. Wistar Kyoto rats (WKY, n = 7) were used as the normotensive controls. Blood pressure (BP) was measured using the tail-cuff method. Cardiac geometry and function were determined using M-mode echocardiography. Circulating concentrations of inflammatory markers were measured in plasma by ELISA. LV fibrosis and cardiomyocyte width were assessed by histology. Relative mRNA expression of PTX-3 was determined in the LV by RT-PCR. Untreated SHR exhibited greater systolic BP and relative wall thickness (RWT) compared to WKY. Captopril and hydralazine normalized BP but only captopril reversed RWT in SHR. Circulating PTX-3 and VCAM-1 levels were elevated in untreated SHR and reduced with captopril and hydralazine. Circulating PTX-3 was positively associated with systolic BP but lacked independent relations with indices of LVH. LV relative mRNA expression of PTX-3 was similar between the groups. PTX-3 may not be involved in the development of LVH in SHR, but plausibly reflects the localized inflammatory milieu associated with hypertension., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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 Akr1b7 CreERT2/+ ; R26R mTmG/+ 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 Akr1b7 CreERT2/+ ;Ren1 cFl/- ;R26R mTmG/+ 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 Akr1b7 CreERT2 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, Akr1b7 CreERT2 , 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.

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., (© 2024. The Author(s).)

Human induced pluripotent stem cell (hiPSC)-derived cardiac organoids (COs) have shown great potential in modelling human heart development and cardiovascular diseases, a leading cause of global death. However, several limitations such as low reproducibility, limited vascularization and difficulty in formation of cardiac chamber were yet to be overcome. We established a new method for robust generation of COs, via combination of methodologies of hiPSC-derived vascular spheres and directly differentiated cardiomyocytes from hiPSCs, and investigated the potential application of human COs in cardiac injury modelling and drug evaluation. The human COs we built displayed a vascularized and chamber-like structure, and hence were named vaschamcardioids (vcCOs). These vcCOs exhibited approximately 90% spontaneous beating ratio. Single-cell transcriptomics identified a total of six cell types in the vcCOs, including cardiomyocytes, cardiac precursor cells, endothelial cells, fibroblasts, etc. We successfully recaptured the processes of cardiac injury and fibrosis in vivo on vcCOs, and showed that the FDA-approved medication captopril significantly attenuated cardiac injury-induced fibrosis and functional disorders. In addition, the human vcCOs exhibited an obvious drug toxicity reaction to doxorubicin in a dose-dependent manner. We developed a three-step method for robust generation of chamber-like and vascularized complex vcCOs, and our data suggested that vcCOs might become a useful model for understanding pathophysiological mechanisms of cardiovascular diseases, developing intervention strategies and screening drugs., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

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 (CL tot ) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t 1/2 ) and volume of distribution at steady state (V dss ) 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., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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 ( 60 Co 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.

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin-angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients' parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM.

Purpose: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy., Methods: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8 + T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism., Results: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays., Conclusion: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future., (© 2024. The Author(s).)

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., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Introduction: Chronic hypertension increases the risk of vascular cognitive impairment (VCI) by ∼60%; however, how hypertension affects the vasculature of the hippocampus remains unclear but could contribute to VCI., Methods: Memory, hippocampal perfusion, and hippocampal arteriole (HA) function were investigated in male Wistar rats or spontaneously hypertensive rats (SHR) in early (4 to 5 months old), mid (8 to 9 months old), or late adulthood (14 to 15 months old). SHR in late adulthood were chronically treated with captopril (angiotensin converting enzyme inhibitor) or apocynin (antioxidant) to investigate the mechanisms by which hypertension contributes to VCI., Results: Impaired memory in SHR in late adulthood was associated with HA endothelial dysfunction, hyperconstriction, and ∼50% reduction in hippocampal blood flow. Captopril, but not apocynin, improved HA function, restored perfusion, and rescued memory function in aged SHR., Discussion: Hippocampal vascular dysfunction contributes to hypertension-induced memory decline through angiotensin II signaling, highlighting the therapeutic potential of HAs in protecting neurocognitive health later in life., Highlights: Vascular dysfunction in the hippocampus contributes to vascular cognitive impairment. Memory declines with age during chronic hypertension. Angiotensin II causes endothelial dysfunction in the hippocampus in hypertension. Angiotensin II-mediated hippocampal arteriole dysfunction reduces blood flow. Vascular dysfunction in the hippocampus impairs perfusion and memory function., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Mitochondrial dysfunction is a recent emerging research scope that proved to be involved in many cardiovascular diseases culminating in chronic heart failure (CHF), which remains one of the primary causes of morbidity and mortality. This study investigated the added cardio-protective effects of exogenous melatonin administration to conventional captopril therapy in isoproterenol (ISO) exposed rats with CHF. Five groups of Wistar rats were recruited; (I): Control group, (II): (ISO group), (III): (ISO + captopril group), (IV): (ISO + melatonin group) and (V): (ISO + melatonin/captopril group). Cardiac function parameters and some oxidant, inflammatory and fibrotic markers were investigated. Moreover; mRNA expression of mitochondrial mitophagy [parkin & PTEN induced kinase 1 (PINK1)], biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)], fusion [mitofusin 2 (Mfn2)] and fission [dynamin-related protein 1 (DRP-1)] parameters in rat's myocardium were evaluated. Rats' myocardium was histo-pathologically and immunohistochemically evaluated for Beclin1 and Sirt3 expression. The present study revealed that captopril and melatonin ameliorated cardiac injury, oxidative stress biomarkers, and pro-inflammatory cytokines in ISO-exposed rats. These protective effects could be attributed to mitochondrial dynamic proteins control (i.e. enhanced the mRNA expression of parkin, PINK1, PGC-1α and Mfn2, while reduced DRP-1 mRNA expression). Also, Beclin1 and Sirt3 cardiac immunoreactivity were improved. Combined captopril and melatonin therapy showed a better response than either agent alone. Melatonin enhanced myocardial mitochondrial dynamics and Sirt3 expression in CHF rats and may represent a promising upcoming therapy added to conventional heart failure treatment., (© 2024. The Author(s).)

T1D can be associated with metabolic disorders and several impaired pathways, including insulin signaling, and development of insulin resistance through the renin-angiotensin system (RAS). The main precursor of RAS is angiotensinogen (Agt) and this system is often linked to autophagy dysregulation. Dysregulated autophagy has been described in T1D and linked to impairments in both glucose metabolism, and leukotrienes (LTs) production. Here, we have investigated the role of RAS and LTs in both muscle and liver from T1D mice, and its effects on insulin and autophagy pathways. We have chemically induced T1D in 129sve and 129sve 5LO -/- mice (lacking LTs) with streptozotocin (STZ). To further inhibit ACE activity, mice were treated with captopril (Cap). In muscle of T1D mice, treatment with Cap increased the expression of RAS (angiotensinogen and angiotensin II receptor), insulin signaling, and autophagy markers, regardless of the genotype. In the liver of T1D mice, the treatment with Cap increased the expression of RAS and insulin signaling markers, mostly when LTs were absent. 5LO -/- T1D mice showed increased insulin sensitivity, and decreased NEFA, after the Cap treatment. Cap treatment impacted both insulin signaling and autophagy pathways at the mRNA levels in muscle and liver, indicating the potential role of ACE inhibition on insulin sensitivity and autophagy in T1D., (© 2023. The Author(s).)

Although angiotensin converting enzyme (ACE) inhibitors are considered useful for the treatment of human heart failure, some experimental failing-heart models have shown little beneficial effect of ACE inhibitors in animals with poor oral health, particularly periodontitis. In this study, we examined the effects of the ACE inhibitor captopril (Cap; 0.1 mg/mL in drinking water) on cardiac dysfunction in mice treated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS) at a dose (0.8 mg/kg/day) equivalent to the circulating level in patients with periodontal disease. Mice were divided into four groups: 1) Control, 2) PG-LPS, 3) Cap, and 4) PG-LPS + Cap. After1 week, we evaluated cardiac function by echocardiography. The left ventricular ejection fraction was significantly decreased in PG-LPS-treated mice compared to the control (from 66 ± 1.8 to 59 ± 2.5%), while Cap ameliorated the dysfunction (63 ± 1.1%). The area of cardiac fibrosis was significantly increased (approximately 2.9-fold) and the number of apoptotic myocytes was significantly increased (approximately 5.6-fold) in the heart of PG-LPS-treated group versus the control, and these changes were suppressed by Cap. The impairment of cardiac function in PG-LPS-treated mice was associated with protein kinase C δ phosphorylation (Tyr-311), leading to upregulation of NADPH oxidase 4 and xanthine oxidase, and calmodulin kinase II phosphorylation (Thr-286) with increased phospholamban phosphorylation (Thr-17). These changes were also suppressed by Cap. Our results suggest that the renin-angiotensin system might play an important role in the development of cardiac diseases induced by PG-LPS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kiyomoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Occlusal disharmony is known to affect not only the oral cavity environment, but also the autonomic nervous system in the heart. Since the renin-angiotensin system (RAS) inhibitor captopril (Cap) is one of the first-line drugs for preventing cardiac remodeling in patients with heart failure, we hypothesized that Cap might prevent cardiac dysfunction induced by occlusal disharmony. Here, to test this idea, we used our bite-opening (BO) mouse model, which was developed by cementing a suitable appliance onto the mandibular incisor. Mice were divided into four groups: (1) Control, (2) BO, (3) Cap, and (4) BO + Cap. After 2 weeks, we evaluated cardiac function by echocardiography and confirmed that cardiac function was significantly decreased in the BO group compared to the control, while Cap ameliorated the dysfunction. Cardiac fibrosis, myocyte apoptosis and oxidative stress-induced myocardial damage in the BO group were significantly increased versus the control, and these increases were suppressed by Cap. Cardiac dysfunction induced by BO was associated with dual phosphorylation on PKCδ (Tyr-311/Thr-505), leading to activation of CaMKII with increased phosphorylation of RyR2 and phospholamban. Our results suggest that the RAS might play an important role in the development of cardiac diseases induced by occlusal anomalies., (© 2023. The Author(s).)

It has been suggested that the neuro-visceral integration works asymmetrically and that this asymmetry is dynamic and modifiable by physio-pathological influences. Aminopeptidases of the renin-angiotensin system (angiotensinases) have been shown to be modifiable under such conditions. This article analyzes the interactions of these angiotensinases between the left or right frontal cortex (FC) and the same enzymes in the hypothalamus (HT), pituitary (PT), adrenal (AD) axis (HPA) in control spontaneously hypertensive rats (SHR), in SHR treated with a hypotensive agent in the form of captopril (an angiotensin-converting enzyme inhibitor), and in SHR treated with a hypertensive agent in the form of the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). In the control SHR, there were significant negative correlations between the right FC with HPA and positive correlations between the left FC and HPA. In the captopril group, the predominance of negative correlations between the right FC and HPA and positive correlations between the HPA and left FC was maintained. In the L-NAME group, a radical change in all types of interactions was observed; particularly, there was an inversion in the predominance of negative correlations between the HPA and left FC. These results indicated a better balance of neuro-visceral interactions after captopril treatment and an increase in these interactions in the hypertensive animals, especially in those treated with L-NAME.

Background: Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H 2 S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN)., Results: Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H 2 S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H 2 S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect., Conclusions: Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H 2 S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling., (© 2023. Sociedad de Biologia de Chile.)

Hypertension has become a growing public health concern worldwide. In fact, hypertension is commonly associated with increased morbidity and mortality. Currently, oligonucleotide drugs have proven to be promising therapeutic agents for various diseases. In the present study, we aimed to demonstrate that a herbal small RNA (sRNA), XKC-sRNA-h3 (B55710460, F221. I000082.B11), exhibits potent antihypertensive effects by targeting angiotensin-converting enzyme (ACE) in mice. When compared with captopril, oral administration of the sphingosine (d18:1)-XKC-sRNA-h3 bencaosome more effectively prevented angiotensin II-induced hypertensive cardiac damage and alleviated kidney injury in mice. Such findings indicated that XKC-sRNA-h3 may be a novel orally available ACE inhibitor type oligonucleotide drug for hypertension., (© 2023. Science China Press.)

Endothelial dysfunction represents a major cardiovascular risk factor for hypertension. Sp1 and Sp3 belong to the specificity protein and Krüppel-like transcription factor families. They are ubiquitously expressed and closely associated with cardiovascular development. We investigate the role of Sp1 and Sp3 in endothelial cells in vivo and evaluate whether captopril, an angiotensin-converting enzyme inhibitor (ACEI), targets Sp1/Sp3 to exert its effects. Inducible endothelial-specific Sp1/Sp3 knockout mice are generated to elucidate their role in endothelial cells. Tamoxifen-induced deletion of endothelial Sp1 and Sp3 in male mice decreases the serum nitrite/nitrate level, impairs endothelium-dependent vasodilation, and causes hypertension and cardiac remodeling. The beneficial actions of captopril are abolished by endothelial-specific deletion of Sp1/Sp3, indicating that they may be targets for ACEIs. Captopril increases Sp1/Sp3 protein levels by recruiting histone deacetylase 1, which elevates deacetylation and suppressed degradation of Sp1/Sp3. Sp1/Sp3 represents innovative therapeutic target for captopril to prevent cardiovascular diseases., (© 2023. Springer Nature Limited.)

Hypertension is the most prevalent chronic disease World-wide, and the leading preventable risk factor for cardiovascular disease (CVD). Few patients accomplish the objective of decreasing blood pressure and avoiding hypertensive target organ damage after treatments with antihypertensive agents which opens the door for other treatments, such as herbal-and antihypertensive combination therapy. Captopril (CAP), as a-pril which inhibits angiotensin converting enzyme has long been used in the management of hypertension and CVD. Gedan Jiangya Decoction (GJD) is known for antihypertensive effects in prior studies. The research is aimed to determine whether GJD in combination with captopril has antihypertensive, kidney protective, antioxidant, and vasoactive effects in spontaneously hypertensive rats (SHR). Regular measurements of systolic and diastolic blood pressure (SBP and DBP), and body weight were monitored weekly. H&E staining was utilized to examine histopathology. The combined effects were studied using ELISA, immunohistochemistry, and qRT-PCR. Significant reductions in SBP, DBP, aortic wall thickness, and improvement in renal tissue were observed following GJD + CAP treatment, with increased serum levels of NO, SOD, GSH-Px, and CAT and decreases in Ang II, ET-1, and MDA. Similarly, GJD + CAP treatment of SHR's significantly decreased ET-1 and AGTR1 mRNA and protein expression while increasing eNOS mRNA and protein expression in thoracic aorta and kidney tissue. In conclusion, the present investigation found that GJD + CAP treatment decreases SHR blood pressure, improves aorta remodeling and renal protection, and that this effect could be attributable, in part, due to antioxidant and vascular tone improvement., (© 2023. The Author(s).)

Background: Angiotensin-converting enzyme inhibitor (ACEi) inhibits the catalysis of angiotensin I to angiotensin II and the degradation of substance P (SP) and bradykinin (BK). While the possible relationship between ACEi and SP in nociceptive mice was recently suggested, the effect of ACEi on signal transduction in astrocytes remains unclear., Objectives: This study examined whether ACE inhibition with captopril or enalapril modulates the levels of SP and BK in primary cultured astrocytes and whether this change modulates PKC isoforms (PKCα, PKCβI, and PKCε) expression in cultured astrocytes., Methods: Immunocytochemistry and Western blot analysis were performed to examine the changes in the levels of SP and BK and the expression of the PKC isoforms in primary cultured astrocytes, respectively., Results: The treatment of captopril or enalapril increased the immunoreactivity of SP and BK significantly in glial fibrillary acidic protein-positive cultured astrocytes. These increases were suppressed by a pretreatment with an angiotensin-converting enzyme. In addition, treatment with captopril increased the expression of the PKCβI isoform in cultured astrocytes, while there were no changes in the expression of the PKCα and PKCε isoforms after the captopril treatment. The captopril-induced increased expression of the PKCβI isoform was inhibited by a pretreatment with the neurokinin-1 receptor antagonist, L-733,060, the BK B 1 receptor antagonist, R 715, or the BK B 2 receptor antagonist, HOE 140., Conclusions: These results suggest that ACE inhibition with captopril or enalapril increases the levels of SP and BK in cultured astrocytes and that the activation of SP and BK receptors mediates the captopril-induced increase in the expression of the PKCβI isoform., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Korean Society of Veterinary Science.)

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Prior investigation shows an increase in the activity of both hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin system (RAS) in diabetic patients. Moreover, activation of angiotensin-II type 1 receptor (AT 1 ) has been associated with adrenal steroidogenesis. This study investigates the role of RAS on the overproduction of corticosterone in diabetic mice. Diabetes was induced by intravenous injection of alloxan into fasted Swiss-webster mice. Captopril (angiotensin-converting enzyme inhibitor), Olmesartan (AT 1 receptor antagonist), CGP42112A (AT 2 receptor agonist) or PD123319 (AT 2 receptor antagonist) were administered daily for 14 consecutive days, starting 7 days post-alloxan. Plasma corticosterone was evaluated by ELISA, while adrenal gland expressions of AT 1 receptor, AT 2 receptor, adrenocorticotropic hormone receptor MC2R, pro-steroidogenic enzymes steroidogenic acute regulatory protein (StAR), and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) were assessed using immunohistochemistry or western blot. Diabetic mice showed adrenal gland overexpression of AT 1 receptor, MC2R, StAR, and 11βHSD1 without altering AT 2 receptor levels, all of which were sensitive to Captopril or Olmesartan treatment. In addition, PD123319 blocked the ability of Olmesartan to reduce plasma corticosterone levels in diabetic mice. Furthermore, CGP42112A significantly decreased circulating corticosterone levels in diabetic mice, without altering the overexpression of MC2R and StAR in the adrenal glands. Our findings revealed that inhibition of both angiotensin synthesis and AT 1 receptor activity reduced the high production of corticosterone in diabetic mice via the reduction of MC2R signaling expression in the adrenal gland. Furthermore, the protective effect of Olmesartan on the overproduction of corticosterone by adrenals in diabetic mice depends on both AT 1 receptor blockade and AT 2 receptor activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaves, Magalhães, Insuela, Silva, Martins and Carvalho.)

Impaired metabolic functions underlie the pathophysiology of diabetes and obesity. The renin-angiotensin system (RAS) is one pathway related to the pathophysiology of both diseases. RAS activation in metabolically active tissues exerts pro-inflammatory effects via angiotensin II (Ang II), linked to dysfunction in cellular processes such as autophagy, which is associated with obesity and diabetes. Here, we determined whether RAS is involved in metabolic dysregulations in a Type 1 Diabetes (T1D) mouse model, treated with captopril, and in an obesity mouse model (Agt-Tg) that overexpresses angiotensinogen (Agt) in adipose tissue. T1D mice had lower plasma leptin, resistin and higher non-esterified fatty acids (NEFA) compared to wild type (Wt) mice, even under captopril treatment. Further, mRNA levels for Agt, At1, Insr, and Beclin1 were upregulated in muscle and liver of T1D mice with captopril compared to Wt. Moreover, autophagy markers LC3 and p62 proteins were decreased, regardless of captopril treatment in the liver from T1D mice. In obese Wt mice, captopril increased muscle Irs1 gene levels. Further, captopril reduced mRNA levels of At1, Insr, Ampk, Beclin1, Atg12, and Lc3 in the liver from both Wt and Agt-Tg mice, while Agt, At1, Insr, and Atg12 expression was reduced in Agt-Tg mice without captopril treatment. Irs1 expression was decreased in the liver from obese Wt mice treated with captopril. Our results suggest that captopril treatment upregulates components of RAS, insulin signaling, and autophagy in both muscle and liver, indicating potential utility of captopril in targeting both insulin sensitivity and autophagy in diabetes and obesity., (Copyright © 2022. Published by Elsevier B.V.)

Gedan Jiangya decoction (GJD) (aqueous ethanol extract), a traditional Chinese medicine formula which contain six botanical drugs (Uncaria rhynchophylla (Miq.) Miq., Salvia miltiorrhiza Bunge, Pueraria lobata (Willd.) Ohwi, Eucommia ulmoides Oliv., Prunella vulgaris L., and Achyranthes bidentata Blume) was designed to treat hypertension; however, the underlying mechanism of action is unclear. This study aimed to determine the mechanisms of action of GJD in the treatment of hypertension in spontaneously hypertensive rats (SHR). Male SHRs were randomly divided into five groups: GJD doses were low (1.36 g/kg/d), medium (2.72 g/kg/d), and high (5.44 g/kg/d), captopril (13.5 mg/kg/d), and SHR groups, with Wistar-Kyoto rats (WKY) serving as the control. Every rat was gavaged once a day. The ALC-NIBP, a noninvasive blood pressure device, measured systolic (SBP) and diastolic (DBP) blood pressures. Six weeks following treatment, all rats were anesthetized. The blood samples were obtained from the abdominal aorta and then serum isolated to assess endothelin-1 and angiotensin II, interleukin-1beta, interleukin-6, and TNF-alpha. The left ventricular and thoracic aortas were taken for HE staining, immunohistochemistry, RT-qPCR, and western blot examination. Following GJD therapy, SBP and DBP were significantly lowered, as were serum levels of endothelin-1 and angiotensin II. The thickness of the left ventricular and thoracic aorta walls reduced, as did type I collagen, type III collagen, and alpha-SMA expression in the left ventricular and aortic tissues. The GJD treatment significantly reduced serum levels of the inflammatory markers interleukin-1beta, interleukin-6, and TNF-alpha. Furthermore, interleukin-1 beta, interleukin-6, TNF-alpha, TAK1, and NF- κ B/p65 levels were significantly reduced in left ventricular and aortic tissues, whereas IkB-alpha levels were significantly elevated. GJD has a dose-dependent effect on all parameters. In conclusion, GJD has been shown to lower blood pressure, improve cardiovascular remodeling, and reduce inflammation via regulating NF- κ B in SHRs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Shadi A. D. Mohammed et al.)

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., (© 2022. The Author(s).)

Background: Hypotension that is resistant to phenylephrine is a complication that occurs in anesthetized patients treated with angiotensin converting enzyme (ACE) inhibitors. We tested the hypothesis that Ang 1-7 and the endothelial Mas receptor contribute to vasodilation produced by propofol in the presence of captopril., Methods: The internal diameters of human adipose resistance arterioles were measured before and after administration of phenylephrine (10 -9 to 10 -5  M) in the presence and absence of propofol (10 -6  M; added 10 min before the phenylephrine) or the Mas receptor antagonist A779 (10 -5  M; added 30 min before phenylephrine) in separate experimental groups. Additional groups of arterioles were incubated for 16 to 20 h with captopril (10 -2  M) or Ang 1-7 (10 -9  M) before experimentation with phenylephrine, propofol, and A779., Results: Propofol blunted phenylephrine-induced vasoconstriction in normal vessels. Captopril pretreatment alone did not affect vasoconstriction, but the addition of propofol markedly attenuated the vasomotor response to phenylephrine. A779 alone did not affect vasoconstriction in normal vessels, but it restored vasoreactivity in arterioles pretreated with captopril and exposed to propofol. Ang 1-7 reduced the vasoconstriction in response to phenylephrine. Addition of propofol to Ang 1-7-pretreated vessels further depressed phenylephrine-induced vasoconstriction to an equivalent degree as the combination of captopril and propofol, but A779 partially reversed this effect., Conclusions: Mas receptor activation by Ang 1-7 contributes to phenylephrine-resistant vasodilation in resistance arterioles pretreated with captopril and exposed to propofol. These data suggest an alternative mechanism by which refractory hypotension may occur in anesthetized patients treated with ACE inhibitors., (© 2022. The Author(s).)

Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis-induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.

Background: Parkinson disease (PD) and Alzheimer's disease (AD) are progressive neurodegenerative disorders characterized by loss of selective neurons in discreet part of the brain. The peptide angiotensin II (Ang II) plays significant role in hippocampal and striatal neurons degeneration through the generation of reactive oxygen species. Blockade of the angiotensin converting enzyme or ATI receptors provides protection in animal models of neurodegenerative diseases. In the present study, the neuroprotective effect of captopril was investigated in Drosophila melanogaster model using the UAS-GAL4 system to express the synuclein and Aβ42 peptide in the flies' neurons., Methods: The disease causing human Aβ42 peptide or α-syn was expressed pan-neuronally (elav-GAL4) or dopamine neuron (DDC-GAL4) using the UAS-GAL4 system. Flies were either grown in food media with or without captopril (1, 5, or 10µM). This was followed by fecundity, larva motility, negative geotaxis assay (climbing) and lifespan as a measure of neurodegeneration., Results: Elav-Gal4

Background: In previous studies, angiotensin-converting enzyme inhibitor (ACEI) use was associated with increased bone loss, while an angiotensin II type I receptor blocker had no effect on bone loss in elder subjects, which suggested that the effect of ACEI on bone loss was not mediated through the classical renin-angiotensin system. In this study, we set to investigate whether the effect of ACEI on bone deterioration was mediated via the kinin-kallikrein system., Methods: Six-month-old male and female spontaneously hypertensive rats were used. The effect of captopril on blood pressure, serum Ang II, and bradykinin concentration was measured in intact rats. Ovariectomy and orchidectomy were performed to establish an osteoporosis model in female and male rats, respectively. Captopril and the bradykinin receptor blocker icatibant (HOE140) were administered after operation for 12 weeks. Serum Ang II and bradykinin concentration, bone turnover markers, bone mineral density (BMD), and bone microarchitecture were evaluated. Femur samples were subjected to a mechanical test., Results: Captopril decreased blood pressure and serum Ang II concentration and increased serum bradykinin concentration in intact rats ( P < 0.05). After castration, captopril decreased serum Ang II concentration ( P < 0.05); in female rats, icatibant increased serum Ang II concentration ( P < 0.05). Captopril increased serum bradykinin concentration ( P < 0.05); in male rats, icatibant decreased serum bradykinin concentration ( P < 0.05). Captopril increased the rat urine deoxypyridinoline-creatinine ratio (DPD/Cr) and serum osteocalcin concentration ( P < 0.05). Icatibant decreased urine DPD/Cr in male rats ( P < 0.05) and increased osteocalcin concentration in female rats ( P < 0.05). Captopril increased cancellous BMD in castrated hypertensive rats ( P < 0.05), and icatibant further increased cancellous BMD ( P < 0.05), which was due to the increased trabecular bone number. In mechanical testing, ACEI increased bone strength ( P < 0.05), and icatibant further improved it ( P < 0.05)., Conclusion: ACEI decreased bone deterioration in both male and female hypertensive rats, and the bradykinin receptor blocker further decreased bone deterioration., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Na Zhang et al.)

(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin−angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi p < 0.05, CD11b+Ly6CLo p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM.

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 6 th 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., (Copyright ©2022, Yale Journal of Biology and Medicine.)

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.

Current hypertension guidelines suggest various strategies to reduce blood pressure levels, thereby reducing cardiovascular events: combinations of drugs with different mechanisms of action, such as an angiotensin converting enzyme inhibitors (ACEIs) and a diuretic, are the cornerstone of the modern treatment of hypertension, also as initial therapy. Among ACEIs, zofenopril has been shown to be effective in the management of hypertension both as monotherapy and in combination with a diuretic: zofenopril/hydrochlorothiazide fixed dose combination is particularly useful to improve treatment adherence through simplification of treatment regimen. Moreover, thanks to the sulfhydryl group, zofenopril has some peculiar properties (higher lipophilicity and tissue penetration, lower bradykinin-dependent effect, higher affinity for, and more persistent binding to, tissue ACE, significant antioxidant effect), which may account for the cardioprotective effects of the drug demonstrated in both pre-clinical studies and randomized clinical trials. The positive impact of zofenopril on clinical outcomes has been extensively documented by the SMILE program, including several clinical trials in patients with different conditions of myocardial ischemia treated with zofenopril: the results of the SMILE program, demonstrating the benefits of zofenopril vs. placebo and other ACEIs, emphasize the importance of a differentiated approach to patients with ischemic heart disease, based on a careful choice of the adopted agent, in order to improve the overall impact of pharmacological treatment on clinical outcomes.

Hypertension is a chronic disease associated with chronic inflammation involving activated macrophages. Antihypertensive drugs (for example, angiotensin-converting enzyme inhibitors-ACEIs) used in the treatment of hypertension have immunomodulatory properties. On the other hand, the immunological effect of diuretics and combined drugs (diuretics + ACEI) is unclear. Therefore, we examined the influence of diuretics and combination drugs (ACEI + diuretic) on cellular response (contact hypersensitivity), production of reactive oxygen intermediates (ROIs), and nitric oxide (NO), and the secretion of interleukin-12 (IL-12). CBA mice were administered i.p. captopril (5 mg/kg) with or without hydrochlorothiazide (10 mg/kg) or furosemide (5 mg/kg) for 8 days. On the third day, the mice were administered i.p. mineral oil, and macrophages were collected 5 days later. In the presented results, we show that diuretics administered alone or with captopril increase the generation of ROIs and reduce the formation of NO by macrophages. Moreover, tested drugs inhibit the secretion of IL-12. Diuretics and combined drugs reduce the activity of contact hypersensitivity (both activation and induction phases). Our research shows that the tested drugs modulate the cellular response by influencing the function of macrophages, which is important in assessing the safety of antihypertensive therapy.

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)-1β, 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/β-catenin. These results demonstrated the mechanism of captopril as well as the role of the NF-kappaB or wnt3α/β-catenin on HSC-T6 activation induced by HG.

Hypertension is accompanied by the over-activation of macrophages. Diuretics administered alone or in combination with hypotensive drugs may have immunomodulatory effects. Thus, the influence of tested drugs on mouse macrophage-mediated humoral immunity was investigated. Mice were treated intraperitoneally with captopril (5 mg/kg) with or without hydrochlorothiazide (10 mg/kg) or furosemide (5 mg/kg) by 8 days. Mineral oil-induced peritoneal macrophages were harvested to assess the generation of cytokines in ELISA, and the expression of surface markers was analyzed cytometrically. Macrophages were also pulsed with sheep red blood cells (SRBC) and transferred to naive mice for evaluation of their ability to induce a humoral immune response. Tested drugs increase the expression of surface markers important for the antigen phagocytosis and presentation. SRBC-pulsed macrophages from mice treated with captopril combined with diuretics increased the secretion of antigen-specific antibodies by recipient B cells, while macrophages of mice treated with hydrochlorothiazide or furosemide with captopril increased the number of antigen-specific B cells. Tested drugs alter the macrophage secretory profile in favor of anti-inflammatory cytokines. Our results showed that diuretics with or without captopril modulate the humoral response by affecting the function of macrophages, which has significant translational potential in assessing the safety of antihypertensive therapy.

Our laboratory has demonstrated that captopril, an angiotensin converting enzyme inhibitor, mitigates hematopoietic injury following total body irradiation in mice. Improved survival in mice is correlated with improved recovery of mature blood cells and bone marrow, reduction of radiation-induced inflammation, and suppression of radiation coagulopathy. Here we investigated the effects of captopril treatment against radiation injuries in the Göttingen mini pig model of Hematopoietic-Acute Radiation Syndrome (H-ARS). Minipigs were given captopril orally (0.96 mg/kg) twice daily for 12 days following total body irradiation (60Co 1.79 Gy, 0.42-0.48 Gy/min). Blood was drawn over a time course following irradiation, and tissue samples were collected at euthanasia (32-35 days post-irradiation). We observed improved survival with captopril treatment, with survival rates of 62.5% in vehicle treated and 87.5% in captopril treated group. Additionally, captopril significantly improved recovery of peripheral blood mononuclear cells, and a trend toward improvement in recovery of red blood cells and platelets. Captopril significantly reduced radiation-induced expression of cytokines erythropoietin and granulocyte-macrophage colony-stimulating factor and suppressed radiation-induced acute-phase inflammatory response cytokine serum amyloid protein A. Using quantitative-RT-PCR to monitor bone marrow recovery, we observed significant suppression of radiation-induced expression of redox stress genes and improved hematopoietic cytokine expression. Our findings suggest that captopril activities in the Göttingen minipig model of hematopoietic-acute radiation syndrome reflect findings in the murine model., Competing Interests: KOG is currently employed by Leidos Biomedical Research Inc. KOG was not employed by Leidos Biomedical Research Inc at the time this study was conducted. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-β-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR.

Cisplatin (Cis) is an effective cancer therapy commonly employed in many therapeutic regimens. However, treatment regimens that contain either a high dose or cumulative doses of Cis could trigger liver damage. A unique study demonstrated that captopril (Cap) protects against Cis-induced liver toxicity, but only some liver function enzymes and some antioxidant enzymes were investigated in that study. Our study aims to elucidate the protective mechanism of Cap against Cis liver toxicity. Acute liver toxicity was induced in rats by injecting a single Cis dose (7.5 mg/kg) in three groups (n = 6). Two groups were pre-treated with low (50 mg/kg) and high (100 mg/kg) Cap doses for one week before Cis injection, and the third group was injected with Cis only. The high Cap dose significantly improved liver function markers (ALT, AST, and ALP) and hepatic tissue pathology. The low Cap dose significantly improved ALP and, to a lesser extent, hepatic tissue pathology. Both Cap doses significantly decreased liver contents of MDA, IL-1β, and cleaved caspase-3; and liver protein expression of TNF-α, Bax, and caspase-3. The high Cap dose significantly increased liver contents of GSH, GPx, CAT, and SOD, and the liver protein expression of Bcl2. Moreover, only the high Cap dose significantly decreased liver IL-6 content and cytochrome C protein expression. Cap did not inhibit the antitumor impact of Cis against HCT116 cancer cells. Therefore, Cap restricts Cis-induced liver toxicity by reducing inflammation and apoptosis and augmenting the antioxidant system., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

[Figure: see text].

Background: Captopril, an angiotensin-converting enzyme inhibitor, and losartan, an angiotensin II receptor blocker, are used for the treatment of hypertension, but their effects on cardiac stereology are unknown. This study, therefore, aimed to examine their effects on cardiac stereology in rats with renovascular hypertension., Methods: This study was conducted at Histomorphometry and Stereology Research Centre, and Cardiovascular Pharmacology Research Lab, Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, in August 2015 to August 2016. Fourty-eight rats were allocated to six groups (n=8 per each group): a sham group, which received a vehicle (distilled water) and five renal artery-clipped groups, which received the vehicle, captopril (50 or 100 mg/ kg/day), or losartan (25 or 50 mg/kg/day). After four weeks, the animals' systolic blood pressures (mm Hg) were measured, and the total volumes of their heart, myocardium, endocardium, matrix, and myocardial vessels (mm 3 ), as well as the number of their cardiomyocytes, and Purkinje fibers were determined. Data were analyzed using one-way analysis of variance (ANOVA) followed by least significant difference (LSD) test. P value of equal to or less than 0.05 was considered significant., Results: The renal artery-clipped rats receiving the vehicle had a significantly higher systolic blood pressure (P<0.001); heart weight (g) (P<0.001); and total volume of the heart (P<0.001), myocardium (P=0.020), endocardium (P=0.009), and myocardial vessels (P=0.008); as well as a significantly lower number of cardiomyocytes (P=0.010) and Purkinje cells (P=0.005), than did the rats in the sham group. The renal artery-clipped rats receiving captopril or losartan had a significantly lower systolic blood pressure (P<0.001), heart weight (P=0.007), and total volume of the heart (P<0.001), myocardium (P<0.001), endocardium (P=0.027), and myocardial vessels (P=0.004) than did the renal artery-clipped rats receiving the vehicle. Neither captopril nor losartan prevented a reduction in the number of Purkinje cells, but captopril at the higher dose attenuated cardiomyocyte loss (P=0.010)., Conclusion: Captopril and losartan lowered the systolic blood pressure and cardiac hypertrophy but failed to prevent Purkinje cell loss. Captopril only at the higher dose prevented cardiomyocyte loss. Captopril exerted a greater inhibitory effect on cardiac stereology, which warrants further research., (Copyright: © Iranian Journal of Medical Sciences.)

The lung is sensitive to radiation and exhibits several phases of injury, with an initial phase of radiation-induced pneumonitis followed by delayed and irreversible fibrosis. The angiotensin-converting enzyme inhibitor captopril has been demonstrated to mitigate radiation lung injury and to improve survival in animal models of thoracic irradiation, but the mechanism remains poorly understood. Here we investigated the effect of captopril on early inflammatory events in the lung in female CBA/J mice exposed to thoracic X-ray irradiation of 17-17.9 Gy (0.5-0.745 Gy min-1). For whole-body + thoracic irradiation, mice were exposed to 7.5 Gy (0.6 Gy min-1) total-body 60Co irradiation and 9.5 Gy thoracic irradiation. Captopril was administered orally (110 mg kg-1 day-1) in the drinking water, initiated 4 h through to150 days post-irradiation. Captopril treatment increased survival from thoracic irradiation to 75% at 150 days compared with 0% survival in vehicle-treated animals. Survival was characterized by a significant decrease in radiation-induced pneumonitis and fibrosis. Investigation of early inflammatory events showed that captopril significantly attenuated macrophage accumulation and decreased the synthesis of radiation-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines in the lungs of irradiated mice. Suppression of IL-1β and TNF-α correlated with an increase of the anti-inflammatory cytokine IL-10 in the spleen with captopril treatment. We also found that captopril decreased markers for radiation-induced accelerated senescence in the lung tissue. Our data suggest that suppression of inflammation and senescence markers, combined with an increase of anti-inflammatory factors, are a part of the mechanism for captopril-induced survival in thoracic irradiated mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Angiotensin converting enzyme inhibitors, among them captopril, improve survival following myocardial infarction (MI). The mechanisms of captopril action remain inadequately understood due to its diverse effects on multiple signalling pathways at different time periods following MI. Here we aimed to establish the role of captopril in late-stage post-MI remodelling. Left anterior descending artery (LAD) ligation or sham surgery was carried out in male C57BL/6J mice. Seven days post-surgery LAD ligated mice were allocated to daily vehicle or captopril treatment continued over four weeks. To provide comprehensive characterization of the changes in mouse heart following MI a 3D light sheet imaging method was established together with automated image analysis workflow. The combination of echocardiography and light sheet imaging enabled to assess cardiac function and the underlying morphological changes. We show that delayed captopril treatment does not affect infarct size but prevents left ventricle dilation and hypertrophy, resulting in improved ejection fraction. Quantification of lectin perfused blood vessels showed improved vascular density in the infarct border zone in captopril treated mice in comparison to vehicle dosed control mice. These results validate the applicability of combined echocardiographic and light sheet assessment of drug mode of action in preclinical cardiovascular research.

Valsartan belongs to angiotensin II type 1 (AT1) receptor blockers (ARB) used in cardiovascular diseases like heart failure and hypertension. Except for its AT1-antagonism, another mechanism of drug action has been suggested in recent research. One of the supposed actions refers to the positive impact on redox balance and reducing protein glycation. Our study is aimed at assessing the antiglycooxidant properties of valsartan in an in vitro model of oxidized bovine serum albumin (BSA). Glucose, fructose, ribose, glyoxal (GO), methylglyoxal (MGO), and chloramine T were used as glycation or oxidation agents. Protein oxidation products (total thiols, protein carbonyls (PC), and advanced oxidation protein products (AOPP)), glycooxidation products (tryptophan, kynurenine, N-formylkynurenine, and dityrosine), glycation products (amyloid- β structure, fructosamine, and advanced glycation end products (AGE)), and albumin antioxidant activity (total antioxidant capacity (TAC), DPPH assay, and ferric reducing antioxidant power (FRAP)) were measured in each sample. In the presence of valsartan, concentrations of protein oxidation and glycation products were significantly lower comparing to control. Moreover, albumin antioxidant activity was significantly higher in those samples. The drug's action was comparable to renowned antiglycation agents and antioxidants, e.g., aminoguanidine, metformin, Trolox, N-acetylcysteine, or alpha-lipoic acid. The conducted experiment proves that valsartan can ameliorate protein glycation and oxidation in vitro in various conditions. Available animal and clinical studies uphold this statement, but further research is needed to confirm it, as reduction of protein oxidation and glycation may prevent cardiovascular disease development., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Kacper Maksymilian Mil et al.)

Wine lees (WL) are by-products generated in the winemaking process. The aim of this study was to investigate the angiotensin-converting enzyme inhibitory (ACEi) activity, and the blood pressure (BP) lowering effect of WL from individual grape varieties. The relationship among their activities and phenolic profiles was also studied. Three WL, from Cabernet, Mazuela, and Garnacha grape varieties, were firstly selected based on their ACEi properties. Their phenolic profiles were fully characterized by UHPLC-ESI-Q-TOF-MS. Then, their potential antihypertensive effects were evaluated in spontaneously hypertensive rats (SHR). BP was recorded before and after their oral administrations (2, 4, 6, 8, 24, and 48 h) at a dose of 5 mL/kg bw. Cabernet WL (CWL) exhibited a potent antihypertensive activity, similar to that obtained with the drug Captopril. This BP-lowering effect was related to the high amount of anthocyanins and flavanols present in these lees. In addition, a potential hypotensive effect of CWL was discarded in normotensive Wistar-Kyoto rats. Finally, the ACEi and antihypertensive activities of CWL coming from a different harvest were confirmed. Our results suggest the potential of CWL for controlling arterial BP, opening the door to commercial use within the wine industry.

Brain radiation can occur from treatment of brain tumors or accidental exposures. Brain radiation has been rarely considered, though, as a possible tool to alter protein levels involved in neurodegenerative disorders. We analyzed possible molecular and neuropathology changes of phosphorylated-Tau (pTau), all-Tau forms, β-tubulin, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA-1), myelin basic protein (MBP), and GAP43 in Frontal Cortex (FC), Hippocampus (H) and Cerebellum (CRB) of swine brains following total-body low-dose radiation (1.79 Gy). Our data show that radiated-animals had lower levels of pTau in FC and H, APP in H and CRB, GAP43 in CRB, and higher level of GFAP in H versus sham-animals. These molecular changes were not accompanied by obvious neurohistological changes, except for astrogliosis in the H. These findings are novel, and might open new perspectives on brain radiation as a potential tool to interfere with the accumulation of specific proteins linked to the pathogenesis of various neurodegenerative disorders.

Background: Angiotensin-converting enzyme (ACE) inhibitors have been shown to promote endothelial progenitor cell (EPC) function. However, the efficacies of different ACE inhibitors in improving the migratory capabilities of ECPs in coronary artery disease (CAD) patients is unclear. This study compared the effectiveness of captopril, lisinopril, and ramipril toward the migration capability of impaired EPCs from CAD patients. Methods: We isolated peripheral blood mononuclear cells (PBMCs), separated EPCs from PBMCs, and divided them into an untreated group (control) and treated groups of captopril, lisinopril, and ramipril at doses of 1mM, 10mM, and 100mM. EPC migration was evaluated using the Boyden chamber assay. Analysis of variance (ANOVA) was performed using SPSS 25.0. Results: This study showed that treatment with captopril, lisinopril, and ramipril starting at the lowest dose (1 mM) increased EPC migration (65,250 ± 6,750 cells; 60,750± 5,030 cells; and 49,500 ± 8,400 cells, respectively) compared to control (43,714 ± 7,216 cells). Increased migration of EPCs was observed by increasing the treatment dose to 10 mM with captopril, lisinopril, and ramipril (90,000 ± 16,837 cells; 79,071 ± 2,043 cells; and 64,285 ± 11,824 cells, respectively). The highest EPC migration was shown for lisinopril 100 mM (150,750 ± 16,380 cells), compared to captopril and ramipril at the same dose (105,750 ± 8112 cells and 86,625 ± 5,845 cells, respectively). Conclusions: Captopril, ramipril, and lisinopril were shown to increase EPC migration in a dose-dependent manner. Low-dose (1 mM) and medium-dose (10 mM) captopril had a larger effect on ECP migration than lisinopril and ramipril. Meanwhile, high-dose lisinopril (100mM) had the highest migration effect, suggesting it may be preferable for promoting EPC migration in CAD patients., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Oktaviono YH et al.)

Context: HuoxueJiangtang decoction (ZY) is a traditional Chinese medicine for the treatment of diabetes., Objective: The protective effect of ZY on renal injury in diabetic nephropathy rats was investigated in this study., Materials and Methods: Fifty 4-week-old SPF Wistar male rats were selected to construct diabetic nephropathy model rats (DN) group by continuous high-fat feeding for 4 weeks, followed by a tail vein injection of 30 mg/kg streptozotocin for 1 week. The experimental rats were divided into six groups of 10 rats: normal (control), DN, DN + ZY, DN + metformin, DN + metformin + ZY, and DN + metformin + captopril (positive control) groups. Among the groups, 6.25 g/kg ZY, 250 mg/kg metformin, and 17.5 mg/kg captopril were given to the rats by gavage once a day for 16 weeks. Blood glucose, dietary behaviour, biochemical indicators, and gene expression changes were measured in each group., Results: Metformin + ZY treatment significantly lowered blood glucose, water intake, urine total protein, urine albumin, urine volume, serum triglyceride, and serum cholesterol levels in the DN group. The pathological changes of kidney tissue showed that the DN + metformin + ZY group had a protective effect on kidney tissue damage. And ZY and metformin + ZY treatments repaired the expression of genes in the DN group., Discussion and Conclusion: The ZY and metformin combined treatment showed a clear therapeutic effect on kidney damage in DN. This study provides a potential mechanism for the treatment of diabetic nephropathy with ZY combined with metformin.