Antihypertensive Effect Research Articles

Co-delivery of novel valsartan and hydrochlorothiazide pH-responsive electrospun polymeric nanofibers for improved oral delivery

Valsartan (VAL) and Hydrochlorothiazide (HCTZ) as a fixed-dose combination are widely used for the management of hypertension. To enhance the dissolution and oral delivery of VAL (BCS class II drug) and HCTZ (BCS class IV drug), nanofibers containing both drugs were prepared using an electrospinning technique. VAL/HCTZ-loaded NFs were prepared using Eudragit L100-55 (EUD L100-55) and Poly (ethyne oxide) (PEO) polymer mixture and the formulation process was optimized through three process variables of polymer composition, polymer concentration, and spinning voltage. VAL/HCTZ-loaded NFs were characterized for their size, surface morphology, entrapment efficiency (%EE), drug-polymer interaction, in vitro drug release, ex-vivo permeation, and in vivo studies. Smooth, beadles and uniform drug-loaded NFs were successfully fabricated using optimum polymer composition (EUD L100-55/PEO 3:1), concentration (12 % w/v), and applied voltage (30 KV). The optimum formula (F9) showed a low average nanosize of 300 nm and a high drug loading of > 90 % was achieved. In vitro, release results showed a pH-dependent drug release, with minimum drug released at pH lower than 4.5, but a significant and complete release of both drugs was achieved at pH 6.5. The EUD L100-55/PEO improved the dissolution of VAL and HCTZ compared to free drugs at the intestinal site of absorption. Differential Scanning calorimetry and Fourier Transform Infra-Red studies showed both drugs’ amorphization and compatibility between drugs and polymers. Permeability behavior for the VAL/HCTZ-loaded NFs was found to be significantly higher than free drug suspensions of both drugs which indicated the improvement of VAL and HCTZ permeability through the intestinal membrane. The in vivo study proved the enhanced oral anti-hypertensive action of drugs-loaded NFs compared to free drug suspensions. The superior in vitro release, ex-vivo permeation, and in vivo anti-hypertensive effect indicate that drug-loaded nanofibers have the potential to improve the biological activity and hence oral delivery of the fixed-drug combination.

Chronic cannabidiol treatment induces cardiovascular improvement in renovascular hypertensive rats.

Cannabidiol (CBD) is increasingly studied for its therapeutic potential in neurodegenerative diseases. Previous research on acute CBD administration has demonstrated cardiovascular benefits in hypertensive rats, including reduced mean blood pressure and oxidative stress. To investigate the long-term cardiovascular effects of chronic CBD treatment in renovascular hypertension induced by the 2-kidney-1-clip (2K1C) model. Male Wistar rats (180-200 g, 8 weeks old) underwent 2K1C or SHAM surgery. Six weeks later, rats received chronic CBD treatment (20 mg/kg, twice daily for 14 days). A combination of ex vivo, in vitro, and in vivo methods was used to assess CBD's cardiovascular effects in 2K1C hypertensive rats. Chronic CBD treatment significantly reduced blood pressure and the depressor response to hexamethonium (a ganglionic blocker). It also normalized variability in low-frequency (LF) power and LF/high-frequency (HF) ratio. CBD enhanced vasodilation and reduced vasoconstriction in the mesenteric artery of 2K1C rats, accompanied by decreased expression of aortic reactive oxygen species (ROS). Our findings suggest that chronic CBD treatment exerts antihypertensive effects by improving baroreflex sensitivity and vascular function while decreasing arterial ROS levels and sympathetic nerve activity. These results underscore CBD's potential therapeutic role in managing cardiovascular complications associated with renovascular hypertension.

In vivo and in silico antihypertensive, anti-inflammatory, and analgesic activities of Vernonia amygdalina Del. leaf extracts

Vernonia amygdalina (VA) leaves contain many potential active ingredients and exhibit diverse pharmacological activities. The antihypertensive, anti-inflammatory, and analgesic effects of VA crude and fraction extracts were carried out using Swiss albino mice models. VAE is considered safe to be administered due to LD50 being greater than 10,000 mg/kg body weight. A dose-dependent increase in antihypertensive, anti-inflammatory, and analgesic activities was observed in both VAE and fractions, similar to the reference drugs. The antihypertensive effect of the VAE 2.0 (2000 mg/kg, SBP: ↓26.05 %, DBP: ↓34.51 %) was nearly equivalent to Captopril (100 mg/kg, SBP: ↓30.28 %, DBP: ↓40.71 %) with no statistically significant difference (p > 0.05). The VAE 1.0 (1000 mg/kg), and EA 30 (30 mg/kg) showed potent anti-inflammatory activity when reducing the total edematous paw volume significantly (p < 0.01) by ↓65.58 %, and ↓69.34 %, respectively, similar to Ibuprofen (7.5 mg/kg, ↓67.03 %). Besides, VAE (>500 mg/kg), and W 400 (water, 400 mg/kg) fraction extracts showed a potent analgesic effect equivalent to Para 50 (paracetamol 50 mg/kg) for the highest protection (>65 %) against the acetic acid-induced writhing after 35 min. Moreover, cepharanthine, cynaroside, and vernoniosides of VA leaf extract exhibited the highest affinity (>10 kcal/mol) in anti-inflammatory and analgesic targets (iNOS and COX-2) and antihypertensive targets (ACE and β1 adrenoreceptor). Therefore, the crude and fraction extracts of VA leaves from the percolation method and bioactive metabolites are a potential source that can be developed into antihypertensive, anti-inflammatory, and analgesic agents in herbal medicine.

Spironolactone in modern cardiology: from many years of experience to the latest evidence of effectiveness (literature review)

Spironolactone is a drug that plays an important role in the treatment of various diseases, especially in the field of cardiology and endocrinology. First synthesized in 1957, spironolactone gained widespread recognition due to its unique ability to block the action of aldosterone, a hormone that plays an important role in the pathogenesis of many cardiovascular diseases and increases the risk of severe cardiovascular complications. Spironolactone is included in the list of essential medicines of the World Health Organization. In cardiology, it is one of the universal remedies, because it is prescribed for resistant or secondary hypertension, heart failure, as part of hormonal therapy and in a number of other clinical conditions and situations. Resistant hypertension is a complex and serious medical problem, which is a significant challenge for doctors and patients, as it requires a specialized and individualized approach to treatment. Clinical studies found that spironolactone was the most effective adjunctive drug for the management of resistant hypertension, and this superiority of spironolactone confirmed the central role of sodium retention in the development of treatment resistance. Studies have shown that the addition of spironolactone to initial combination therapy resulted in a more potent antihypertensive effect compared to the addition of doxazosin or bisoprolol. The proportion of patients in whom spironolactone was the optimal blood pressure-lowering drug appeared to be the largest, according to the analysis on the prediction of the effect of each drug on the blood pressure level using plasma renin and the probability that different drugs will be best at different points of renin distribution in the blood plasma. Spironolactone has been used in modern cardiology for a long time to treat patients with heart failure and atrial fibrillation, but in this article, we have focused on another very important site for spironolactone administration, namely hypertension, especially in its resistant forms.

Antimicrobial activities of Diltiazem Hydrochloride: drug repurposing approach

Background The growing concern of antibiotic-resistant microbial strains worldwide has prompted the need for alternative methods to combat microbial resistance. Biofilm formation poses a significant challenge to antibiotic efficiency due to the difficulty of penetrating antibiotics through the sticky microbial aggregates. Drug repurposing is an innovative technique that aims to expand the use of non-antibiotic medications to address this issue. The primary objective of this study was to evaluate the antimicrobial properties of Diltiazem HCl, a 1,5-benzothiazepine Ca2+ channel blocker commonly used as an antihypertensive agent, against four pathogenic bacteria and three pathogenic yeasts, as well as its antiviral activity against the Coxsackie B4 virus (CoxB4). Methods To assess the antifungal and antibacterial activities of Diltiazem HCl, the well diffusion method was employed, while crystal violet staining was used to determine the anti-biofilm activity. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay was utilized to evaluate the antiviral activity of Diltiazem HCl against the CoxB4 virus. Results This study revealed that Diltiazem HCl exhibited noticeable antimicrobial properties against Gram-positive bacteria, demonstrating the highest inhibition of Staphylococcus epidermidis, followed by Staphylococcus aureus. It effectively reduced the formation of biofilms by 95.1% and 90.7% for S. epidermidis, and S. aureus, respectively. Additionally, the antiviral activity of Diltiazem HCl was found to be potent against the CoxB4 virus, with an IC50 of 35.8 ± 0.54 μg mL−1 compared to the reference antiviral Acyclovir (IC50 42.71 ± 0.43 μg mL−1). Conclusion This study suggests that Diltiazem HCl, in addition to its antihypertensive effect, may also be a potential treatment option for infections caused by Gram-positive bacteria and the CoxB4 viruses, providing an additional off-target effect for Diltiazem HCl.

Nanocarrier-Based Delivery Approaches of Mangiferin: An Updated Review on Leveraging Biopharmaceutical Characteristics of the Bioactive.

In recent years, bioactive constituents from plants have been investigated as an alternative to synthetic approaches of therapeutics. Mangiferin (MGF) is a xanthone glycoside extracted from Mangifera indica and has shown numerous medicinal properties, such as antimicrobial, anti-diarrhoeal, antiviral, anti-inflammatory, antihypertensive, anti-tumours, and anti-diabetic effects. However, there are numerous challenges to its effective therapeutic usage, including its low water solubility, limited absorption, and poor bioavailability. Nano formulation approaches in recent years exhibited potential for the delivery of phytoconstituents with key benefits of high entrapment, sustained release, enhanced solubility, stability, improved pharmacokinetics, and site-specific drug delivery. Numerous techniques have been employed for the fabrication of MGF-loaded Nano formulations, and each technique has its advantages and limitations. The nanocarriers that have been employed to fabricate MGF nanoformulations for various therapeutic purposes include; polymeric nanoparticles, nanostructure, lipid carriers, polymeric micelles, Nano emulsions, microemulsion & self-microemulsifying drug delivery system, solid lipid nanoparticles, gold nanoparticles, carbon nanotubes, transfersomes, nanoliposomes, ethosomes & transethosomes, and glycethosomes. Different biopharmaceutical characteristics (size, shape, entrapment efficiency, zeta potential, in vitro drug release, ex vivo drug permeation,, and in vivo studies) of the mentioned MGF-loaded nanocarriers have been methodically discussed. Patent reports are also included to further strengthen the potential of MGF in the management of diseases.

Mechanism Actions of Coniferyl Alcohol in Improving Cardiac Dysfunction in Renovascular Hypertension Studied by Experimental Verification and Network Pharmacology.

Renovascular hypertension (RH), a secondary hypertension, can significantly impact heart health, resulting in heart damage and dysfunction, thereby elevating the risk of cardiovascular diseases. Coniferol (CA), which has vascular relaxation properties, is expected to be able to treat hypertension-related diseases. However, its potential effects on cardiac function after RH remain unclear. In this study, in combination with network pharmacology, the antihypertensive and cardioprotective effects of CA in a two-kidney, one-clip (2K1C) mice model and its ability to mitigate angiotensin II (Ang II)-induced hypertrophy in H9C2 cells were investigated. The findings revealed that CA effectively reduced blood pressure, myocardial tissue damage, and inflammation after RH. The possible targets of CA for RH treatment were screened by network pharmacology. The interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathways were identified using a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The inflammatory response was identified using a Gene Ontology (GO) enrichment analysis. Western blot analysis confirmed that CA reduced the expression of IL-17, matrix metallopeptidase 9 (MMP9), cyclooxygenase 2 (COX2), and TNF α in heart tissues and the H9C2 cells. In summary, CA inhibited cardiac inflammation and fibrohypertrophy following RH. This effect was closely linked to the expression of MMP9/COX2/TNF α/IL-17. This study sheds light on the therapeutic potential of CA for treating RH-induced myocardial hypertrophy and provides insights into its underlying mechanisms, positioning CA as a promising candidate for future drug development.

Walnut peptide relieves hypertension and associated kidney and heart injury by regulating the renin-angiotensin-aldosterone system and intestinal microbiota.

Hypertension is a chronic disease with high morbidity and mortality. Previously, we screened a walnut meal peptide FDWLR (PEP) with significant angiotensin-converting enzyme inhibitory activity. The present study further investigated the anti-hypertensive effects of PEP in vivo using spontaneously hypertensive rats. The results indicated that PEP reduced blood pressure and the indices in the renin-angiotensin-aldosterone system (RAAS) including angiotensin-converting enzyme (ACE) (decreased by 15.36%), angiotensin II (Ang II) (decreased by 31.56%), angiotensinogen (AGT) (decreased by 58.84%) and aldosterone (ALD) (decreased by 18.27%), whereas NO levels increased by 54.96%. The pathological analysis showed that PEP relieved cardiac and renal damage. PEP also alleviated oxidative stress, inflammation and fibrosis in the heart and kidney. Mechanistically, PEP mitigated cardiac and renal damage by simultaneously regulating ACE-Ang II-AT1R and the ACE2-Ang (1-7)-MAS axis. Additionally, PEP increased the levels of short chain fatty acids by 224.16% and improved gut microbiota by increasing the abundance of Prevotella, Phascolarctobacterium, Clostridium_sensu_stricto and Bifidobacterium, at the same time as decreasing Bacteroides and Alistipes abundances. This study indicated that PEP prevented hypertension and associated heart and kidney damage by modulating the RAAS system and gut microbiota, which is valuable in guiding future development and optimal utilization of walnut meal. © 2024 Society of Chemical Industry.

Antihypertensive mechanism of the medicine food homology compound solution with high ACE inhibition rate based on network pharmacology and molecular docking

Certain instances of medicine food homology (MFH) have an antihypertensive effect, which has a therapeutic effect on hypertension, but their mechanism in treating hypertension and improving blood pressure is still unclear. The objective of this study is to analyze the potential bioactive substances and the hypotensive mechanism by which the MFH compound solution (Hawthorn:Lycium barbarum:Cassia = 4:1:1) with a high angiotensin-converting enzyme (ACE) inhibition rate. This will be achieved through the use of network pharmacology and molecular docking techniques, which will be further validated through experimental testing. The key components in the MFH compound solution were obtained by constructing the component-disease target network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to explore the pathways of the MFH compound solution participating in anti-hypertension. The content of the main active ingredients in the MFH compound solution was identified by high-performance liquid chromatography (HPLC). The main active components were quercetin, beta-sitosterol, stigmasterol, kaempferol, and isorhamnetin, while the identified core genes were AKT1 and TP53. Through pathway analysis, the mechanisms of the MFH compound solution against hypertension may be Lipid and atherosclerosis, Calcium signaling pathway, PI3K-AKT signaling pathway, etc. Moreover, the molecular docking of five key compounds and the top five targets verified the reliability of network pharmacology results. HPLC analysis revealed that these five active substances were detected in the MFH compound solution, where kaempferol was the most abundant. This study revealed that the MFH compound exerted a hypotensive effect through multiple targets and pathways.

Mineralocorticoid Receptor Blocker Prevents Mineralocorticoid Receptor-Mediated Inflammation by Modulating Transcriptional Activity of Mineralocorticoid Receptor-p65-Signal Transducer and Activator of Transcription 3 Complex.

Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanizedat either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. Invitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.

Plasma renin activity as a marker for predicting the antihypertensive effect of switching to sacubitril/valsartan in treated hypertensive patients: Usefulness in daily clinical practice.

The authors investigated the antihypertensive effect of sacubitril/valsartan (Sac/Val) when switching from other drugs and assessed whether brain natriuretic peptide (BNP) or plasma renin activity (PRA) before drug switching was a predictor of blood pressure lowering after switching to Sac/Val. In 92 patients with treated hypertension, clinic blood pressure, plasma BNP, and PRA were examined before and after switching to Sac/Val. Clinic systolic and diastolic blood pressures significantly decreased after drug switching to Sac/Val (p<.0001, respectively). The level before drug switching of BNP had no correlation with the change in systolic blood pressure (Δ-SBP) before and after switching to Sac/Val, but that of PRA was significantly correlated with Δ-SBP (r=.3807, p=.0002). A multiple regression analysis revealed that PRA before drug switching was an independent determinant of Δ-SBP. Our findings suggest that low PRA may become a useful marker to predict the antihypertensive effect of switching to Sac/Val in treated hypertensive patients.

Antihypertensive Effects of Lindera erythrocarpa Makino via NO/cGMP Pathway and Ca2+ and K+ Channels.

Studies have demonstrated the therapeutic effects of Lindera plants. This study was undertaken to reveal the antihypertensive properties of Lindera erythrocarpa leaf ethanolic extract (LEL). Aorta segments of Sprague-Dawley rats were used to study the vasodilatory effect of LEL, and the mechanisms involved were evaluated by treating specific inhibitors or activators that affect the contractility of blood vessels. Our results revealed that LEL promotes a vasorelaxant effect through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, blocking the Ca2+ channels, opening the K+ channels, and inhibiting the vasoconstrictive action of angiotensin II. In addition, the effects of LEL on blood pressure were investigated in spontaneously hypertensive rats by the tail-cuff method. LEL (300 or 1000 mg/kg) was orally administered to the rats, and 1000 mg/kg of LEL significantly lowered the blood pressure. Systolic blood pressure decreased by -20.06 ± 4.87%, and diastolic blood pressure also lowered by -30.58 ± 5.92% at 4 h in the 1000 mg/kg LEL group. Overall, our results suggest that LEL may be useful to treat hypertensive diseases, considering its vasorelaxing and hypotensive effects.

Bioconversion of agriculture by-products with functionally enhanced Streptomyces sp. SCUT-3: Fish skin as a model

With the global population continuously rising, efficient bioconversion of inedible agricultural by-products is crucial for human food and energy sustainability. We here propose solid-state fermentation approaches to efficiently convert biopolymers into oligomers/monomers by accelerating the natural degradation process of the versatile Streptomyces sp. strain SCUT-3. Using fish skin as a representative by-product, 54.3 g amino acids and 14.7 g peptides (91 % < 2500 Da) were recovered from 89.0 g protein in 100 g tilapia skin sample by collagenase-overexpressed SCUT-3 for seven days at a 1:4 substrate:liquid ratio. Fish skin collagen hydrolysates exhibited excellent anti-oxidation, anti-hypertension, scratch-repairing, anti-aging, anti-ultraviolet radiation, and anti-inflammation effects on human skin fibroblasts In vitro and zebrafish larvae in vivo, indicating their potential applications in healthcare/skincare and anti-atopic dermatitis. As Laozi said, the divine law follows nature. This study underscores the efficacy of genetically engineered SCUT-3 according to its natural biomass utilization laws in large-scale biopolymer conversion.

O54 THE EFFECT OF SACUBITRIL/VALSARTAN TREATMENT ON HYPERTENSIVE PATIENTS

Background and Objective: Sacubitril/Valsartan was approved in Japan in 2020 for the treatment of heart failure and subsequently for the treatment of hypertension. It is a drug with a novel mechanism of action that inhibits both angiotensin receptors and neprilysin. Besides its cardioprotective and antihypertensive effects, a subanalysis of previous clinical trials in heart failure patients has shown that it tends to slow the rate of decline in renal function, and is expected to have therapeutic effects against CKD. However, its effect on renal function in hypertensive patients is unknown. In this study, we examined renal prognosis in patients with essential hypertension. Methods: 166 consecutive patients who received an initial dose of ARNI(Sacubitril/Valsartan) (N=104) or ARB (Azilsartan) (N=42) and had blood tests performed before and within 3 months after the first dose at Osaka University Hospital from June 2020 to April 2023 were analyzed retrospectively. Results: ARNI tended to be administered to elderly patients and patients with impaired renal function in both male and female patients. eGFR did not decrease in the ARNI group at either 3 or 12 months post-dose. eGFR decreased over time in the ARB group at 3 and 12 months post-dose. 5 patients on ARNI had drug discontinuations that were thought to be due to adverse drug events (hypotension in 2, numbness in 1, dizziness in 1, syncope in 1 patient). Conclusions: In this study, ARNI tended to be administered in more elderly hypertensive patients. Although there were a few treatment interruptions due to adverse drug events, the adverse effects on renal function were rather minor compared to ARBs, and under careful management, ARNI may be a useful antihypertensive treatment modality even in elderly patients and patients with impaired renal function.

New 2,4-diphenylaminopyrimidinothiophene derivatives: Synthesis, Spectroscopic analysis, X-ray, DFT calculation, ADMET prediction, and biological activity

Pyrimidine derivatives have garnered significant attention due to their wide range of biological activities, including anticancer, antimicrobial, and antihypertensive effects. Leveraging the diverse pharmacological potential of pyrimidines, we designed and synthesized a series of novel 2,4-diphenylaminopyrimidinothiophene derivatives. The structures of these target compounds 2a-2h were confirmed using NMR and HRMS techniques, with compound 2 g further characterized by single-crystal X-ray diffraction and FT-IR analysis. Additionally, Density Functional Theory (DFT) calculations for compound 2g were conducted at the B3LYP/6–311++G(d,p) level. Focal adhesion kinase (FAK) inhibitory activity and in vitro antitumor efficacy of compounds 2a-2h against U87-MG cell lines were assessed, revealing that certain compounds exhibited significant antitumor activity. Molecular docking studies indicated that compound 2g effectively occupies the ATP binding site of FAK. Furthermore, the ADMET properties of compounds 2a-2h were predicted, providing valuable insights into their pharmacokinetic profiles. These findings lay a foundation for further exploration of compound 2g as a potential FAK inhibitor.

Xeroderris stuhlmannii (Taub.) Mendonça & E.P.Sousa (Fabaceae): Evidence of the antihypertensive and antioxidant activities of its leaf aqueous extract in cadmium chloride hypertensive rats

Xeroderris stuhlmannii (Fabaceae) is a medicinal reported in Cameroonian herbal medicine to treat hypertension. The aim of the study was to assess the antihypertensive and antioxidant activities of X. stuhlmannii aqueous leaf extract (AEXS) on cadmium chloride-induced hypertensive rats. The in vitro antioxidant activities of AEXS were investigated for their radical scavenging potency using 2,2-diphenyl-1-picrylhydrazyl (DPPH), Ferric reducing antioxidant power (FRAP), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS), Nitric oxide (NO) and OH- assays completed with oxidative stress markers analyses. Antihypertensive activity of AEXS (35, 100, and 300 mg/kg) was assessed in CdCl2 induced-hypertensive rats. Antihypertensive activities performed include systolic (SBP), diastolic blood pressure (DBP) and heart rate (HR) variation, followed by evaluation of selected biochemical parameters in urine, blood (Alanine aminotransferase (ALT), aspartate aminotransferase (AST)), creatinine, urea and total protein) and histological examination of tissue samples (aorta, heart, kidneys and liver). The amount of the phenols of the leaf extract was estimated in mg gallic acid equivalent and identification of some compounds was done by UPLC-UV-ESI-TOF-MS. Accordingly, the identified phenols were stuhlmannione A (1), formononetin (2), stuhlmarotenoid A (3), 9-methoxymaackiain (4), 4-hydroxymaackiain (5) and 7-hydroxy-3′,4′-methylenedioxy-isoflavone (6). The extract exhibited a significant (P < 0.05–0.001) decrease of SBP, DBP and HR when compare to control. AEXS also reduced (P < 0.05) serum rates of ALT, AST, and urea. The extract showed beneficial effects on alterations observed in the histological structures of the aorta, heart, kidneys and liver. AEXS highlighted high level of phenols (26.48 ± 2.89 mg GAE/g) and a strong antiradical activity on DPPH, ABTS+, OH− and NO with IC50 of 148.8 μg/mL, 27.83 μg/mL, 22.29 μg/mL, 29.84 μg/mL respectively. An optical density of 1.79 nm was obtained with FRAP test. Thus, X. stuhlmannii leaf extract has in vitro antioxidant and antihypertensive effects that may support its use against hypertension.

House cricket protein hydrolysates alleviate hypertension, vascular dysfunction, and oxidative stress in nitric oxide-deficient hypertensive rats.

Edible insects with high protein content and bioactive peptides with health promotion against chronic disease. Deficiency of nitric oxide (NO) contributes to hypertension, a leading cause of cardiovascular diseases and death worldwide. This study assessed the antihypertensive effects of house cricket protein hydrolysates (HCPH) in NO-deficient hypertensive rats. Male Sprague-Dawley rats (n = 12/group) were hypertensive after the administration of Nω-nitro-L-arginine methyl ester (L-NAME) at a dose of 50 mg/kg body weight (BW)/day in drinking water for 7 weeks. The animals were then treated with HCPH (250 or 500 mg/kg BW/day) or lisinopril (Lis) (1 mg/kg BW/day) for the last 4 weeks of L-NAME administration. Blood pressure (BP), vascular function, and structural changes, endothelial NO synthase (eNOS), and p47phox nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression in aortic tissues, plasma nitrate/nitrite, plasma angiotensin-converting enzyme (ACE) activity, and oxidative stress markers in blood and tissues were evaluated. Induction of hypertension resulted in significantly elevated BP, decreased plasma nitrate/nitrite concentration, abolished vascular function, and increased vascular wall thickness. Overproduction of carotid and mesenteric superoxide, increased plasma, heart, and kidney malondialdehyde, and protein carbonyl levels, and increased plasma ACE activity were observed. Down-expression of eNOS with overexpression of p47phox NADPH oxidase subunit was also found in L-NAME hypertensive rats. Oral treatment with HCPH, particularly at a dose of 500 mg/kg BW/day, significantly alleviated these alterations in a manner comparable to that of Lis. HCPH improved vascular function and exerted antihypertensive effects, mainly due to the improvement of NO bioavailability, reduction of oxidative stress, and inhibition of ACE.

P178 CENTRAL OR PERIPHERAL INJECTION OF A FORMULATION CONTAINING THE ANGIOTENSINERGIC DIPEPTIDE ASP-ARG REDUCES ARTERIAL PRESSURE AND CARDIAC INOTROPY IN HYPERTENSIVE RATS

Background and objective: Acute injection of Angiotensin 1-2 [Ang-(1-2)] reduced arterial pressure and heart rate, and improved coronary perfusion in normotensive and hypertensive rats. Formulations that confer stability and protection against proteolysis are requisites to the feasibility peptides. Next, we evaluated in rats the cardiovascular effects of peripheral or central injections of a complex containing Ang-(1-2) surrounded by a cyclodextrin. Methods: Ethics committee approval by CEUA-FOAr/UNESP 15/2022. We used male Holtzman rats that underwent 2 kidneys, 1 clip (2K1C) hypertension or sham surgery. Six weeks later, rats were separated in different experimental sets (n=4-6 per group) and were instrumented for intracerebroventricular (i.c.v.) and intravenous (i.v.) injections while recording arterial and cardiac left ventricular pressures. The dipeptide was injected i.c.v. (1, 25, 50 and 250pmol/2 μL) or i.v. (25mmol/0.1 mL). Results: dipeptide i.c.v. (25, 50 or 250pmol) reduced arterial pressure of normotensive rats (Δ=-20±3, -20±1 and -18±7mmHg respectively, P&lt;0.05 vs. baseline). In 2K1C, the antihypertensive effect was observed at all doses (Δ=-19±4, -26±5, -19±3 and -17±1mmHg respectively, P&lt;0.05 vs. baseline). I.v. injection of the dipeptide evoked slight increase in arterial pressure (Δ=7±3mmHg; P&lt;0.05 vs. baseline) that was accompanied by a positive inotropic effect (Δ=524±159mmHg/s; P&lt;0.05 vs. baseline). In 2K1C, this same injection reduced arterial and ventricular pressures (Δ=-14±4 and -20±1mmHg respectively, P&lt;0.05 vs. baseline), and caused negative inotropy (ΔLVdP/dtmax=-1140±170mmHg/s; P&lt;0.05 vs. baseline). I.c.v. injection of dipeptide in anesthetized normotensive rats discretely increased arterial and ventricular pressures, while in 2K1C group it reduced arterial and ventricular pressures (Δ=-17±3 and -18±4mmHg respectively, P&lt;0.05 vs. baseline). The ratio between the variations in contractility and mean arterial pressure revealed afterload-independent inotropic effects, i.e, the dipeptide directly affects heart performance of 2K1C. Conclusions: The formulation containing Asp1-Arg2 reduces arterial pressure and modulates cardiac function during hypertension. Whether Ang-(1-2) acts through some antagonism on Angiotensin II receptors or other paths remain to be investigated. Support: CONFAP-FAPESP/FAPEG 2019/24154-3, PROPe-UNESP 13/2022, CNPq-404079/2021-0 and FAPEG-202310267000206.

Quercetin Protects Against Hypertensive Renal Injury by Attenuating Apoptosis: An Integrated Approach Using Network Pharmacology and RNA Sequencing.

Quercetin is known for its antihypertensive effects. However, its role on hypertensive renal injury has not been fully elucidated. In this study, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and Annexin V staining were used to assess the pathological changes and cell apoptosis in the renal tissues of angiotensin II (Ang II)-infused mice and Ang II-stimulated renal tubular epithelial cell line (NRK-52E). A variety of technologies, including network pharmacology, RNA-sequencing, immunohistochemistry, and Western blotting, were performed to investigate its underlying mechanisms. Network pharmacology analysis identified multiple potential candidate targets (including TP53, Bcl-2, and Bax) and enriched signaling pathways (including apoptosis and p53 signaling pathway). Quercetin treatment significantly alleviated the pathological changes in renal tissues of Ang II-infused mice and reversed 464 differentially expressed transcripts, as well as enriched several signaling pathways, including those related apoptosis and p53 pathway. Furthermore, quercetin treatment significantly inhibited the cell apoptosis in renal tissues of Ang II-infused mice and Ang II-stimulated NRK-52E cells. In addition, quercetin treatment inhibited the upregulation of p53, Bax, cleaved-caspase-9, and cleaved-caspase-3 protein expression and the downregulation of Bcl-2 protein expression in both renal tissue of Ang II-infused mice and Ang II-stimulated NRK-52E cells. Moreover, the molecular docking results indicated a potential binding interaction between quercetin and TP53. Quercetin treatment significantly attenuated hypertensive renal injury and cell apoptosis in renal tissues of Ang II-infused mice and Ang II-stimulated NRK-52E cells and by targeting p53 may be one of the potential underlying mechanisms.

Abstract 03: Glomerular Hyperfiltration Promotes Chronic Kidney Disease through Interleukin 17A-Mediated Inflammation

Impaired renal autoregulation in obesity, diabetes and hypertension (HTN) causes elevated glomerular capillary pressure and glomerular hyperfiltration, initiating progressive glomerulosclerosis (GS), nephron loss and chronic kidney disease (CKD). Increased renal perfusion pressure drives renal T cell infiltration. T helper (Th) 17 cells promote vascular stiffening in HTN and renal interstitial fibrosis post AKI, but their roles in GS and CKD are poorly understood. We hypothesized that glomerular hyperfiltration promotes CKD through Th17-mediated GS and tested the hypothesis in 129S6 mice using the reduced kidney mass model (RKM) induced by uninephrectomy and partial renal artery ligation in the remaining kidney (functional renal mass reduced by ~ 5/6). BP (radiotelemetry) and GFR (FITC-sinistrin) of RKM mice were identical to sham controls at baseline (BL, n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. Mean BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p&lt;0.05, 2-way ANOVA) and remained elevated through week 12, exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, BUN and urinary albumin were significantly elevated after 5/6 ablation. In RKM mice, GFR gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic HTN and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Importantly, the early adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by a striking increase of renal interleukin (IL)-17A+ T cells, which preceded the late infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages, and T regulatory cells. Anti-IL17A antibodies (eBioMM17F3, 100 μg i.p. twice weekly) attenuated the early hyperfiltration, abolished aortic/renal inflammation, and prevented GFR decline and GS at week 8 in male but not female RKM mice, likely due to the anti-hypertensive and anti-inflammatory effects of IL-17A neutralization. We conclude that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis in CKD, at least in part, through IL-17A mediated renal inflammation.