Antihypertensive effect and underlying mechanism of tripeptide NCW on spontaneously hypertensive rats using metabolomics analysis

Tripeptide NCW identified in our previous study displayed strong ACE inhibitory activity, whether it has the antihypertensive effect in vivo remains unknown. Thus, in this paper, we aimed to investigate...

Effect of nori, a combination of turmeric (Curcuma longa) and gotu kola (Centella Asiatica) on blood pressure, modulation of ACE, eNOS and iNOS gene expression in hypertensive rats

Hypertension is a major risk factor for causing life-threatening cardiovascular diseases such as myocardial infarction, coronary heart failure, kidney failure, and stroke. Its cases continue to increase worldwide and it is estimated that 1.56 billion adults would live with the condition in 2025. Therefore, this study aims to examine the antihypertensive effect of nori supplement prepared with a combination of turmeric (Curcuma longa) and gotu kola (Centella Asiatica) on L-NAME-induced and non-induced rats. It was conducted for 28 days on 25 wistar rats that were randomly assigned to the negative, positive, comparison, supplement, and test control groups. CODA was then used in measuring the blood pressure of the rats, while ECG and PPG sensors were utilized for arterial stiffness assessment, as well as for spatial QRS-T and heart rate analysis. Additionally, serum NO levels were measured using griess reagents by spectrophotometric λ540 nm. At the same time, the gel-based PCR semi-quantitative method was used in assessing the activity of ACE, including eNOS and iNOS gene expression. The results showed that nori preparations which contained a combination of 5% turmeric and gotu kola in a feed mixture, had an antihypertensive effect. The effect was characterized by a decrease in systolic, diastolic, and mean arterial blood pressure, as well as heart rate, arterial stiffness, and spatial QRS-T. Additionally, it occurred due to increased NO availability, which resulted from eNOS expression as well as a decrease in iNOS and ACE expression.

A network pharmacology-based approach to explore the active ingredients and molecular mechanism of Lei-gong-gen formula granule on a spontaneously hypertensive rat model

Background Lei-gong-gen formula granule (LFG) is a folk prescription derived from Zhuang nationality, the largest ethnic minority among 56 nationalities in China. It consists of three herbs, namely Eclipta prostrata (L.) L., Smilax glabra Roxb, and Centella asiatica (L.) Urb. It has been widely used as health protection tea for hundreds of years to prevent hypertension in Guangxi Zhuang Autonomous Region. The purpose of this study is to validate the antihypertensive effect of LFG on the spontaneously hypertensive rat (SHR) model, and to further identify the effective components and anti-hypertension mechanism of LFG. Methods The effects of LFG on blood pressure, body weight, and heart rate were investigated in vivo using the SHR model. The levels of NO, ANG II, and ET-1 in the serum were measured, and pathological changes in the heart were examined by H&E staining. The main active components of LFG, their corresponding targets, and hypertension associated pathways were discerned through network pharmacology analysis based on the Traditional Chinese Medicine Systems Pharmacology (TCMSP), Traditional Chinese Medicine Integrated Database (TCMID), and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Then the predicted results were further verified by molecular biology experiments such as RT-qPCR and western blot. Additionally, the potential active compounds were predicted by molecular docking technology, and the chemical constituents of LFG were analyzed and identified by UPLC-QTOF/MS technology. Finally, an in vitro assay was performed to investigate the protective effects of potential active compounds against hydrogen peroxide (H2O2) induced oxidative damage in human umbilical vein endothelial cells (HUVEC). Results LFG could effectively reduce blood pressure and increase serum NO content in SHR model. Histological results showed that LFG could ameliorate pathological changes such as cardiac hypertrophy and interstitial inflammation. From network pharmacology analysis, 53 candidate active compounds of LFG were collected, which linked to 765 potential targets, and 828 hypertension associated targets were retrieved, from which 12 overlapped targets both related to candidate active compounds from LFG and hypertension were screened and used as the potential targets of LFG on antihypertensive effect. The molecular biology experiments of the 12 overlapped targets showed that LFG could upregulate the mRNA and protein expressions of NOS3 and proto-oncogene tyrosine-protein kinase SRC (SRC) in the thoracic aorta. Pathway enrichment analysis showed that the PI3K-AKT signaling pathway was closely related to the expression of NOS3 and SRC. Moreover, western blot results showed that LFG significantly increased the protein expression levels of PI3K and phosphorylated AKT in SHR model, suggesting that LFG may active the PI3K-AKT signaling pathway to decrease hypertension. Molecular docking study further supported that p-hydroxybenzoic acid, cedar acid, shikimic acid, salicylic acid, nicotinic acid, linalool, and histidine can be well binding with NOS3, SRC, PI3K, and AKT. UPLC-QTOF/MS analysis confirmed that p-hydroxybenzoic acid, shikimic acid, salicylic acid, and nicotinic acid existed in LFG. Pre-treatment of HUVEC with nicotinic acid could alleviate the effect on cell viability induced by H2O2 and increase the NO level in cell supernatants. Conclusions LFG can reduce the blood pressure in SHR model, which might be attributed to increasing the NO level in serum for promoting vasodilation via upregulating SRC expression level and activating the PI3K-AKT-NOS3 signaling pathway. Nicotinic acid might be the potential compound for LFG antihypertensive effect.

ASSESSMENT OF THE SITUATION OF USE OF BLOOD PRESSURED DRUGS IN THE TREATMENT OF HIGH BLOOD PRESSURE FOR OUTCOME PATIENTS AT NAM DINH PROVINCIAL HOSPITAL IN JANUARY 2021

Hypertension is a disease that seriously affects the health and life expectancy of the community, playing a major etiological role in target organ damage. The selection of antihypertensive drugs to ensure reasonable safety and effectiveness is always a matter of concern of the medical industry. Applying the cross-sectional method on 2,640 patients being examined and treated for hypertension at Nam Dinh general hospital, it was found that 54.67% female patients accounted for the majority. The age of disease in both sexes is over 50 years old with a relatively high frequency of comorbidities. Most of them were prescribed drug combinations in treatment 77,9%. The group of ACE inhibitors + calcium blockers is the most common combination. ACE inhibitors are also the most commonly prescribed drugs in monotherapy. 11,4% of cases had adverse drug interactions, the most dangerous combination is UCMC + Potassium chloride and UCMC + Spironolactone causing hypokalemia. The most common interaction between beta-blockers and calcium blockers increases the antihypertensive effect.

The efficiency of dapagliflozin as add-on therapy in obese patients with resistant hypertension and chronic kidney disease

Background Obesity, insulin resistance, renal dysfunction, hyperuricemia are some of the most common causes of resistant hypertension (RH). A close relationship exists between RH and fluid retention. Currently, there is no consensus regarding pathogenetic therapy of RH and there are no studies on the effects of sodium–glucose cotransporter-2 (SGLT2) inhibitors in obese patients with RH and chronic kidney disease (CKD). The aim was to evaluate the effects of dapagliflozin (D) in obese P with RH and CKD stages 3a. Methods 45 obese P (mean body mass index (BMI) 34.2 kg/m2, waist circumference (WC) 104 cm) with true RH and CKD 3a (eGFR 45–59 mL/min/1.73m2) were included in the study under conventional therapy full doses of appropriate combinations (mean 3.7 antihypertensive drugs). The D at daily doses of 10 mg was added to previous treatment. The blood pressure (BP) was measured in the office and by ambulatory BP monitoring. Anthropometry, metabolic profile, including oral glucose tolerance test with insulin, homeostatic model assessment HOMA-R, hematocrit (Hct), uric acid, potassium (K), serum creatinine, calculated GFR were performed at baseline and after 12 weeks treatment. Results At baseline were excellent correlations between BMI and SBP (r=0.45, P<0.01), eGFR and DBP (r=−0.33, P<0.05), eGFR and Hct (r=0.31, P<0.05), BMI and HOMA-R (r=0.34, P<0.05). At baseline mean HOMA-R was 2,8±0.7, eGFR 53.50±3.26 ml/min/1.73 m2, uric acid 469±23 nmol/L, K 4,9±0.9 mmol/L. The asymptomatic hyperuricemia was observed in 57%, impaired glucose tolerance in the 37%. After 12 weeks administration of D, the mean 24 h ambulatory BP effectively decreased (−7.6/−4.3 mmHg; P<0.05 for both; respectively. Also, there were significant decreases in BMI (−2,1 kg/m2, P<0.01), WC (−4,8 cm, P<0.01), fasting glucose (−0,8 mmol/L, P<0.01) and uric acid (−42 nmol/L, P<0.01) without changes in insulin secretion and not significant improvement in HOMA-R (2,8±0.7 versus 2.4±0.4). Mean eGFR and K on D remained unchanged, however, the albumin/creatinine ratio decreased significantly (P<0.05). Also, the Hct significantly increased after start of D (P<0.01). By linear regression analysis, the independent associated factor for the change SBP was baseline BMI (P<0.05) and for the change DBP baseline eGFR (P<0.05). Conclusion Dapagliflozin shows an additional antihypertensive effect when added to the prior combination therapy in obese patients with RH and CKD 3a without risk of hyperkalemia. Dapagliflozin increase hematocrit, possibly due to its diuretic effects and hemoconcentration. So, positive antihypertensive effect D is due to natriuretic effect and decrease fluid retention. Furthermore, there is also a strong indication that the BP effect is also influenced by weight loss and dapagliflozin administration decreased body mass index, waist circumference, fasting glucose and uric acid, with a tendency to decrease the insulin resistance without changes in insulin secretion. FUNDunding Acknowledgement Type of funding sources: None.

Efficiency of brinzolamide and its combinations with timolol maleate in the treatment of primary open-angle glaucoma

PURPOSE. To evaluate the effectiveness of 1% brinzolamide solution (Brineks-M) and its combination with 0.5% timolol maleate solution (Brinarga) in the treatment of patients with primary open-angle glaucoma (POAG).METHODS. The study involved 56 patients (56 eyes) with initial or moderate POAG and normal or moderately increased intraocular pressure. Individually tolerated IOP, hydrodynamic parameters, hemodynamic parameters of the eye (by computer ophthalmoplethysmography), microcirculation (by OCT angiography of the optic nerve head) were determined during the study.RESULTS. The hypotensive effect of 1% brinzolamide solution (Brineks-M) in patients with the early stage of POAG (23 eyes) after 3 months was 22.5%. The antihypertensive effect of Brinarga in patients with early and moderate stages of POAG (33 eyes) was 31.3% and persisted for 3 months of observation.CONCLUSION. A decrease in IOP to an individually tolerable level was accompanied by an improvement in ocular hemodynamics and microhemocirculation of the optic nerve head, and stabilization of visual functions in patients with POAG.

Nanocrystalline Suspensions of Irbesartan Enhance Oral Bioavailability by Improving Drug Solubility and Leading Endocytosis Uptake into the Intestine

We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines.

Abstract P240: Role Of Acetic Acid Produced By Gut Microbiota In The Mechanism Of Reducing Blood Pressure By Saccharina Japonica In Renovascular Hypertensive Rats

In a previous study, we observed that Saccharina japonica (SJ) intake reduced blood pressure (BP) in 2-clip, 1-kidney renovascular hypertension model (2K1C) rats. However, the mechanism is not clear. Dietary fibers such as alginate, fucoidan and laminaran are components of SJ and have been reported to change gut microbiota and increase short-chain fatty acids (SCFAs) in normotensive rats. SCFAs have been reported to have an antihypertensive effect when intraperitoneally or intracolonically administered, although it was reported that 2K1C rats reduce SCFAs and bacteria which produce SCFAs compared to sham operated control model (SHAM) rats. To investigate whether acetic acid (AA), one of SCFAs, is involved in the mechanism of BP reduction by an ingestion of SJ, we observed AA, in 2K1C rats fed SJ. Under anesthesia, 2K1C and SHAM were induced to Sprague Dawley rats. Both models were allowed to ingest a standard diet (C group) or a 5% (5 of 100) SJ mixed diet (SJ group) for 7 weeks, to a drinking water freely. During the breeding period, the amount of intake, body weight, and systolic BP (SBP) of each group were observed. After that, rats were euthanized, the contents of cecum were collected, and the pH was measured. The amounts of AA were measured using a commercial kit. The SBP of 2K1C-C was significantly higher than that of SHAM-C throughout the feeding (146 ± 3 vs 131 ± 1 mmHg, p<0.05), the SBP of 2K1C-SJ was significantly lower than that of 2K1C-C (136 ± 5 vs 146 ± 3 mmHg, p<0.05). The pH of the cecal contents was significantly lowered in the SJ group rats in both SHAM and 2K1C. The amounts and concentrations of AA in the cecal contents were significantly increased in both SHAM ( 46 ± 8 vs 92 ± 9 mmol, p<0.05)and 2K1C (50 ± 3 vs 87 ± 5 mmol, p<0.05) in the SJ diet group compared with the C group. On the other hand, there was no significant difference in the amounts of AA between SHAM and 2K1C animal models. These results indicated that ingestion of SJ increased AA, and decreased pH in the cecal contents in both SHAM and 2K1C of the SJ group, which may be involved in the antihypertensive effect of SJ ingestion.

Effects of camel milk hydrolysate on blood pressure and biochemical parameters in fructose-induced hypertensive rats

Purpose This study aims to investigate the antihypertensive effect of camel milk hydrolysate in rats with fructose-induced hypertension. Design/methodology/approach The antihypertensive effect of fermented camel milk was determined using 6 groups comprising 36 Wistar male rats. Blood pressure of rats was altered via exposure to a 10% fructose (w/v) diet in drinking water for 3 weeks before conducting 21 days of treatment. The authors conducted the experiment for short and long term using different doses of 800 and 1,200 mg/kg body weight. Serum was used to assay total cholesterol (TC), triglyceride (TG), glucose and insulin levels using standard biochemical kits. Findings The group that received 1,200 mg hydrolysate camel milk (HM) has significantly (p = 0.003) reduced systolic and diastolic blood pressure after a short exposure time (4–8 h). These effects were significantly (p = 0.005) comparable to the nifedipine (NIF) drug group. Similar long-term (21 days) effects on blood pressure were observed in 1,200 mg HM and NIF groups. Angiotensin-converting enzyme (ACE) activity and levels were also reduced in a correlation with blood pressure reduction only in HM1200 and HM800 treated groups. The authors observed no significant effect on blood pressure in groups receiving the 800 mg HM or 1,200 mg unhydrolyzed camel milk (UM). Rats receiving the 10% fructose diet showed significant differences from control rats regarding their blood biochemistry, including TG, TC, blood glucose and insulin levels. Rats in groups NIF, HM1200 and HM800 showed a significant (p < 0.05) reduction in serum glucose, insulin, TG and TC levels toward the baseline level. Research limitations/implications Further mechanistic investigation on the HM antihypertensive activity is highly recommended before suggesting HM as a product to reduce blood pressure. While drug–food interaction between HM and antihypertensive drugs, especially ACE inhibitors, is probable, UM seems not to affect blood pressure or ACE activity and therefore is expected to have no or minimal effects on the activity of other antihypertensive drugs. Investigation of ACE expression from various organs including lungs and leukocytes is highly recommended in future works using sodium dodecyl-sulfate polyacrylamide gel electrophoresis and western blot analysis or reverse transcription polymerase chain reaction. Originality/value No previous studies have measured the antihypertensive activity of milk hydrolysate mediated by the reduction of ACE activity and levels in plasma. Mechanisms involved in attenuating the levels of ACE warrant further investigation.