Surrogate endpoint meta-regression: Useful statistics for regulators and trialists.

OBJECTIVES: The main purpose of using a surrogate endpoint is to estimate the treatment effect on the true endpoint sooner than with a true endpoint. Based on a meta-regression of historical randomized trials with surrogate and true endpoints, we discuss statistics for applying and evaluating surrogate endpoints. METHODS: We computed statistics from two types of linear meta-regressions for trial-level data: simple random effects and novel random effects with correlations among estimated treatment effects in trials with more than 2 arms. A key statistic is the estimated intercept of the meta-regression line. An intercept that is small or not statistically significant increases confidence when extrapolating to a new treatment because of consistency with a single causal pathway and invariance to labeling of treatments as controls. For a regulator applying the meta-regression to a new treatment, a useful statistic is the 95% prediction interval. For a clinical trialist planning a trial of a new treatment, useful statistics are the surrogate threshold effect proportion, the sample size multiplier adjusted for dropouts, and the novel true endpoint advantage. RESULTS: We illustrate these statistics with surrogate endpoint meta-regressions involving anti-hypertension treatment, breast cancer screening, and colorectal cancer treatment. CONCLUSION: Regulators and trialists should consider using these statistics when applying and evaluating surrogate endpoints.

Psiguanol, a novel α-pyrone derivative from Psidium guajava leaves and vasorelaxant activity in rat aorta cells through intracellular cGMP-dependent opening of calcium-activated potassium channels.

The phytochemical investigation of Psidium guajava leaves led to the isolation of total nineteen compounds which belongs to meroterpenoids, flavonoid, phenolics, and triterpenoids. The compounds were isolated using extensive chromatography techniques and identified as psiguanol (4), as new compound along with guajadial (1), psidial A (2), ß-caryophyllene (3), quercetin (5), avicularin (6), guaijaverin (7), hyperin (8), rutin (9), ursolic acid (10), corosolic acid (11), asiatic acid (12), ß-sitosterol (13), ß-sitosterol-D-glucoside (14), ellagic acid (15), 3,3',4'-trimethylellagic acid 4-O-glucoside (16), protocatechuic acid (17), gallic acid (18), and tricosanoic acid (19) as known molecules. The compound 16 was isolated for the first time from this plant. The isolated compounds were evaluated for vasorelaxation activity in rat aorta cells and it was observed that compound 4 exhibited the most potent vasorelaxation response in the ex-vivo model in isolated rat aorta cells. Mechanistically, the vasorelaxation activity of 4 was mediated through cGMP-dependent BKCa channel opening.

Peptide derived C. striata albumin as a natural angiotensin-converting enzyme inhibitor.

As one of the most popular sources for fish albumin, Channa striata has been considered as a promising substitute for human albumin. However, scientific information regarding its genomic and proteomic is very limited, making its identification rather complicated. In this study, we aimed to isolate, characterize, and examine the bioactivity of protein and peptide derivatives of C. striata albumin. Fractionation of albumin from C. striata extract was conducted using Cohn Process and the yield was evaluated. The peptides were further produced by enzymatic hydrolysis. All these proteins were studied using tricine-SDS PAGE and tested for in vitro ACE inhibition. Dry weights of the Fraction-5, where the albumin was more abundant and purer, was 3.8 ± 2.1%. Based on tricine-SDS PAGE analysis, two bands of protein, e.g., approximately 10 and 13 kDa, were detected with highest intensity found in Fraction-5, which might be albumin of C. striata. An increasing trend of ACE inhibition by the fractions was observed, ranging from 7.09 to 22.99%. The highest ACEI activity was found in peptides from alcalase hydrolysis with molecular size <3 kDa (56.65 ± 2.32%, IC50 36.93 µg/mL). This value was also statistically significant compared with the non-hydrolyzed Fraction-5 and Parental Fraction, which were 23.48 ± 3.11% (P < 0.05) and 13.02 ± 0.68% (P < 0.01), respectively. Taken together, these findings suggest a promising potential of peptide-derived C. striata albumin for natural antihypertensive agents.

Optimization and In Vitro Characterization of Telmisartan Loaded Sodium Alginate Beads and Its In Vivo Efficacy Investigation in Hypertensive Induced Animal Model.

BACKGROUND: Antihypertensive drug telmisartan (TEL) belongs to BCS class II, which is characterized by low water solubility and, consequently, low oral bioavailability. Gastroretentive systems may overcome the problems associated with low solubility of TEL and incomplete absorption by localizing the drug release in the stomach. The purpose of this study was to prepare TEL-loaded, oil-entrapped, floating alginate beads with the intent of enhancing the oral bioavailability of TEL for the treatment of hypertension. METHODS: For the formulation and optimization of seventeen formulations of TEL-loaded oil-entrapped floating alginate beads, a central composite design was utilized. The concentration of sodium alginate (X1), the concentration of cross-linker (X2), and the concentration of sesame oil (X3) served as independent variables, whereas the entrapment efficiency (Y1), in vitro buoyancy (Y2), and drug release Q6h (Y3) served as dependent variables. Using the emulsion gelation method and calcium chloride as the cross-linking agent, different formulations of TEL alginate beads were produced. All formulations were evaluated for their entrapment efficiency percentage, in vitro buoyancy, and in vitro drug release. The optimal formulation of TEL alginate beads was prepared with and without oil and evaluated for entrapment efficiency percentage, in vitro buoyancy, swelling ratio, average size, and in vitro drug release. Using scanning electron microscopes, the surface morphology was determined. Using IR spectroscopy, the compatibility between the ingredients was determined. In vivo evaluation of the optimized formulation in comparison to the free TEL was done in hypertension-induced rats, and the systolic blood pressure and all pharmacokinetic parameters were measured. RESULTS: The prepared beads exhibited a high entrapment efficiency percentage, in vitro buoyancy, and prolonged drug release. TEL was compatible with other ingredients, as approved by IR spectroscopy. The prepared TEL beads were spherical, as shown by the SEM. The relative bioavailability of TEL-loaded oil-entrapped beads was 222.52%, which was higher than that of the pure TEL suspension. The prepared TEL beads formulation exhibited a higher antihypertensive effect for a prolonged time compared to pure TEL suspension. CONCLUSIONS: It can be concluded that this innovative delivery method of TEL-loaded oil-entrapped beads is a promising tool for enhancing drug solubility and, thus, oral bioavailability and therapeutic efficacy, resulting in enhanced patient compliance. Furthermore, the in vivo study confirmed the formulation's extended anti-hypertensive activity in animal models.

ACE inhibitory activities of two peptides derived from Volutharpa ampullacea perryi hydrolysate and their protective effects on H2O2 induced HUVECs injury.

The purpose of this study is to explore the effects of IVTNWDDMEK and VGPAGPRG, two angiotensin I-converting enzyme (ACE) inhibitory peptides purified from Volutharpa ampullacea perryi, on ACE's two domains and on nitric oxide (NO), endothelin-1(ET-1) production in human vascular endothelial cells (HUVECs). In addition, we sought to investigate the effects of these two peptides on HUVECs injury induced by H2O2. The results indicated that the inhibition of the ACE C-domain was significantly higher than that of the ACE N-domain by these two peptides. Molecular dynamics (MD) analysis revealed that the hydrogen bonds interactions between ACE and two peptides, the chelation between peptides and Zn2+ both play important role, which might contribute significantly to the ACE inhibitory activity. Two peptides significantly increase NO and ET-1 production in a dose-dependent manner and protects against hydrogen peroxide-induced HUVEC cell injury. The reported results also show that two peptides up-regulated the expression of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1), and reduce the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA). Our study indicated that IVTNWDDMEK and VGPAGPRG could be potent ACE inhibitors and Volutharpa ampullacea perryi is a good source of bioactive peptides, which provided a theoretical basis for the broad application of two selected peptides as functional food with anti-hypertensive activity.

Improvement on blood pressure and skin using roselle drink: A clinical trial.

Roselle (Hibiscus sabdariffa L.) is an increasingly attractive plant for its health and pharmaceutical, beverage, and cosmetic applications. The purpose of this study was to investigate the clinical effects of roselle drink on antioxidant activity, blood pressure, and skin condition. Roselle drink used in this study contained rich phenolics (1.96 g of gallic acid equivalent/100 ml) and anthocyanins (1.65 g of cyanidin-3-glucoside equivalent/100 ml). In a randomized, cross-over, double-blind, placebo-controlled clinical study, 39 healthy adults received drank 200 ml of roselle drink or placebo-control drink for 6 months. A significant reduction in the blood pressure was observed in the roselle drink treated group when compared with preintervention values. After 6 months of treatment with roselle drink, serum phenolics contents, the levels of Trolox equivalent antioxidant capacity (TEAC), glutathione, superoxide dismutase (SOD), glucose-6-phosphate dehydrogenase (G-6-PDH), glutathione peroxidase (GSH-Px), and glutathione reductase (GSH-Rd) were significantly increased in healthy subjects. However, a significant increment in skin redness and skin moisture was observed in the facial skin of roselle drink-treated participants. Oral administration of roselle drink for 6 months significantly lowered the blood pressure, improved antioxidation level, and positively regulated skin redness as well as moisture. Phenolics and anthocyanins in roselle could be the major potential contributors to such health effects. PRACTICAL APPLICATIONS: Roselle is a typical plant. Continuous administration of roselle drink clearly improved antioxidation levels, reduced blood pressure and positively regulated skin redness and moisture. Phenloics and anthocyanins in roselle could be the major potentila contributors of such health benefits.

New paeonol derivative C302 reduces hypertension in spontaneously hypertensive rats through endothelium-dependent and endothelium-independent vasodilation.

Hypertension is a major risk factor for cardiovascular disease and Chinese herb monomers could provide new structural skeletons for anti-hypertension new drug development. Paeonol is a Chinese herbal monomer extracted from Cortex moutan, exhibited some anti-hypertensive activity. The study focused on the structural optimization of paeonol to provide promising lead compounds for anti-hypertension new drug development. Herein, twelve new paeonol derivatives (PD) were designed and synthesized and their vasodilation activity was evaluated by in vitro vasodilation drug screening platform based on Myograph. Its anti-hypertension activity, PD-C302 (2-hydroxy-4-methoxyvalerophenone) as a representative with the optimal vasodilation activity, was determined by its response to blood pressure in spontaneously hypertensive rats (SHR) in vivo. Moreover, its molecular mechanism was probed by the vasodilation activity of rat superior mesenteric artery rings with or without endothelium pre-contracted by potassium chloride (KCl) or phenylephrine hydrochloride (PE). It was indicated that PD-C302 significantly reduced the blood pressure in SHR, which would involve in PD-C302-induced vasodilation. Furthermore, endothelium-dependent pathways and endothelium-independent pathways both contributed importantly to PD-C302-induced vasodilation at low concentration of PD-C302. Endothelium-independent pathways (vascular smooth muscle cell-mediated vasodilation), were mainly responsible for the PD-C302-induced vasodilation at high concentration of PD-C302, which involved in opening multiple K+ channels to restrain Ca2+ channels, and then triggered vasodilation to reduce blood pressure. PD-C302 has a simple structure and favorable anti-hypertensive activity in vivo, which could be a promising lead compound for anti-hypertension new drug development.

Soy protein degradation drives diversity of amino-containing compounds via Bacillus subtilis natto fermentation.

Food fermentation has been playing an important role in producing bioactive components (e.g., peptides), which exert many healthy effects. In this study, it was observed that natto possessed significantly higher angiotensin I-converting enzyme (ACE) inhibitory effect than soybean. Meanwhile, a total of 246 amino-containing compounds were identified via LC-Q-TOF-MS/MS, including amino acids, dipeptides, tripeptides, O-methyl-peptide, and biogenic amines, 187 of them were only detected in natto. Of the list, dipeptides, with ACE inhibitory abilities or potentials, were found to be the most significantly up-regulated class and positively correlated with significantly increased ACE inhibitory activity of natto. Moreover, dynamic profiling elucidated the increased dipeptides were generated from water soluble and insoluble protein via Bacillus subtilis natto fermentation. Taken together, this study enriches the chemical diversity of natto and provides an in-depth insight into the degradation mechanism of soy protein during natto fermentation, which can be extended to other functional foods.

Antihypertensive drug-related genes polymorphisms in hypertensive patients at a certain hospital / 中国热带医学

@#Abstract: Objective　By analyzing the frequency distribution of antihypertensive drug-related genotypes in hypertensionpatients treated in our hospital, so as to provide a clinical basis for individualized treatment of hypertension patients. Methods　A total of 72 hypertensive patients treated in Hainan Hospital of PLA General Hospital from June 2021 to April 2022 were collected. PCR-melting curve method was used to detect CYP2D6*10 (c.100 C>T), CYP2C9*3 (c.1075 A>C), ADRB1 (c.1165 G>C), AGTR1 (c.1166 A>C), ACE (I/D), NPPA (T2238C) and CYP3A5*3 (A6986G), and the relationship between different genotypes and biochemical indexes was analyzed. Results　According to the statistics of the gene and genotype frequency of each point in 72 patients, the gene frequencies of 7 sites all conformed to Hardy Weinberg equilibrium. There were gender differences in ADRB1 genotypes (χ2 = 5.878, P<0.05). There were statistical differences in triglycerides [AA: 1.4 (1.0, 2.0)mmol/L; AC: 2.2 (1.5, 2.5)mmol/L; P=0.038], total cholesterol [AA: 4.0 (3.1, 4.9) mmol/L; AC: 4.8 (4.0, 5.3) mmol/L; P=0.040] and low-density lipoprotein cholesterol [(AA: 2.4 (1.8, 3.3) mmol/L; AC: 3.2 (2.5, 3.5) mmol/L; P=0.035] among patients with different genotypes of AGTR1 locus. The patients with different genotypes of CYP2C9 locus had significant differences in their alanine transferase (ALT) [AA:16.9 (11.4,30.2) mmol/L; AC:10.4 (9.4, 18.2) mmol/L; P=0.040]. Aftergene-directed individualized therapy, different genotypes of CYP3A5 andAGTR1 affected the heart rate [CYP3A5: AA: (79.3±7.0) beats/min; AG： (69.8±6.8) beats/min; GG： (68.8±7.3) beats/min; P=0.010], systolic blood pressure [AGTR1: AA: (131.3±16.7) mmHg; AC: (140.6±11.8) mmHg; P=0.014] and diastolic blood pressure [CYP3A5: AA: (90.0±8.3) mmHg; AG: (78.7±10.8) mmHg; GG: (74.9±10.7) mmHg; P=0.025; AGTR1: AA: (75.3±10.2) mmHg; AC: (86.3±10.6) mmHg; P=0.001] of patients. Conclusions　The related gene loci of antihypertensive drugs are an important basis for guiding the diversification and individualization of clinical medication. Clinicians need to consider the impact of related genes on drug efficacy and adverse reactions when prescribing.

Investigating the Role of EPA and DHA on Cellular Oxidative Stress; Profiling Antidiabetic and Antihypertensive Potential.

Background: Polyunsaturated fatty acids (PUFAs) remain part of the diet and are essential for growth and development. Furthermore, omega - 3 fatty acids boost various cardiovascular disease risk factors as well as lower blood pressure and cholesterol levels. The effects of PUFAs on glycemia in type 2 diabetes patients are unclear. In the present study, the anti-diabetic and anti-hypertensive potential of eicosapentenoic acid (EPA) and docosahexaenoic acid (DHA)-two polyunsaturated fatty acids-were examined. Material and Methods: Using 3T3-L1 pre-adipocyte cells fed with PUFAs, the antioxidant capacity of EPA and DHA was assessed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay/test. The DPPH activity of EPA and DHA was 49.72 and 50.51%, respectively, indicating a reduction in oxidative stress. The number, size, and total lipid content of adipocytes in adipose tissue were used to study the anti-diabetic effect of EPA and DHA. Both PUFAs were revealed to have a much lower capacity for cell lysis of 3T3-L1 pre-adipocytes when compared to propylene glycol monomethyl ether acetate (PMA). In 3T3-L1 pre-adipocyte cells that had been treated with EPA and DHA, the gene expression profiles for ATP synthase 6 were examined. Results: The results demonstrated a similar trend of reducing total lipid content in 3T3-L1 pre-adipocyte cells treated with EPA and DHA. The amount of cell lysis was then examined for 3T3-L1 pre-adipocyte cells exposed to DHA and EPA, and the results showed 38.45% and 41.26%, respectively. In the 3T3-L1 pre-adipocyte cells, treatment with PUFAs, EPA, and DHA dramatically lowered total lipid content after 48 hours. The study also revealed that exposing 3T3-L1 pre-adipocyte cells to EPA at 90 g/ml for 48 hours reduced the total lipid content by a significant amount. Conclusion: According to the findings, EPA and DHA therapy reversed oxidative stress in mitochondria and upregulated the ATP synthase 6 gene. This discovery shows how EPA and DHA have anti-diabetic and hypertension properties.

The antihypertensive potential of flavonoids from Chinese Herbal Medicine: A review.

With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.

Chronic Intermittent Hypobaric Hypoxia Decreases High Blood Pressure by Stabilizing the Vascular Renin-Angiotensin System in Spontaneously Hypertensive Rats.

BACKGROUND AND AIMS: Previous studies have demonstrated the anti-hypertensive effect of chronic intermittent hypobaric hypoxia (CIHH) in hypertensive rats. The present study investigated the anti-hypertensive effect of CIHH in spontaneously hypertensive rats (SHR) and the role of the renin-angiotensin system (RAS) in anti-hypertensive effect of CIHH. METHODS: Fifteen-week-old male SHR and WKY rats were divided into four groups: the SHR without CIHH treatment (SHR-CON), the SHR with CIHH treatment (SHR-CIHH), the WKY without CIHH treatment (WKY-CON), and the WKY with CIHH treatment (WKY-CIHH) groups. The SHR-CIHH and WKY-CIHH rats underwent 35-days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h per day. Arterial blood pressure and heart rate were recorded by biotelemetry, and angiotensin (Ang) II, Ang1-7, interleukin (IL)-6, tumor necrosis factor-alpha (TNF)-α, and IL-10 in serum and the mesenteric arteries were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The microvessel tension recording technique was used to determine the contraction and relaxation of the mesenteric arteries. Hematoxylin and eosin and Masson's staining were used to observe vascular morphology and fibrosis. Western blot was employed to detect the expression of the angiotensin-converting enzyme (ACE), ACE2, AT1, and Mas proteins in the mesenteric artery. RESULTS: The biotelemetry result showed that CIHH decreased arterial blood pressure in SHR for 3-4 weeks (P < 0.01). The ELISA and immunohistochemistry results showed that CIHH decreased Ang II, but increased Ang1-7 in serum and the mesenteric arteries of SHR. In the CIHH-treated SHR, IL-6 and TNF-α decreased in serum and the mesenteric arteries, and IL-10 increased in serum (P < 0.05-0.01). The microvessel tension results revealed that CIHH inhibited vascular contraction with decreased Ang1-7 in the mesenteric arteries of SHR (P < 0.05-0.01). The staining results revealed that CIHH significantly improved vascular remodeling and fibrosis in SHR. The western blot results demonstrated that CIHH upregulated expression of the ACE2 and Mas proteins, and downregulated expression of the ACE and AT1 proteins (P < 0.05-0.01). CONCLUSION: CIHH decreased high blood pressure in SHR, possibly by inhibiting RAS activity, downregulating the ACE-Ang II-AT1 axis and upregulating the ACE2-(Ang1-7)-Mas axis, which resulted in antagonized vascular remodeling and fibrosis, reduced inflammation, and enhanced vascular relaxation.

Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect.

BACKGROUND: Carvedilol, the anti-hypertensive drug, has poor bioavailability when administered orally. Ethosomes-mediated transdermal delivery is considered a potential route of administration to increase the bioavailability of carvedilol. The central composite design could be used as a tool to optimize ethosomal formulation. Thus, this study aims to optimize carvedilol-loaded ethosomes using central composite design, followed by incorporation of synthesized ethosomes into hydrogels for transdermal delivery of carvedilol. RESULTS: The optimized carvedilol-loaded ethosomes were spherical in shape. The optimized ethosomes had mean particle size of 130 ± 1.72 nm, entrapment efficiency of 99.12 ± 2.96%, cumulative drug release of 97.89 ± 3.7%, zeta potential of - 31 ± 1.8 mV, and polydispersity index of 0.230 ± 0.03. The in-vitro drug release showed sustained release of carvedilol from ethosomes and ethosomal hydrogel. Compared to free carvedilol-loaded hydrogel, the ethosomal gel showed increased penetration of carvedilol through the skin. Moreover, ethosomal hydrogels showed a gradual reduction in blood pressure for 24 h in rats. CONCLUSIONS: Taken together, central composite design can be used for successful optimization of carvedilol-loaded ethosomes formulation, which can serve as the promising transdermal delivery system for carvedilol. Moreover the carvedilol-loaded ethosomal gel can extend the anti-hypertensive effect of carvedilol for a longer time, as compared to free carvedilol, suggesting its therapeutic potential in future clinics.

Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects.

Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target-ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 µM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 µM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development.

Anti-Hypertensive Effects of Peptides Derived from Rice Bran Protein.

Hypertension is one of the major risk factors for arteriosclerosis. Anti-hypertensive peptides derived from animal proteins, such as milk, eggs and fish, are well studied. Anti-hypertensive peptides have also been identified from plant proteins such as soybeans. Rice bran, a byproduct of white rice polishing, is rich in protein and its high protein efficiency ratio is well known. This review discusses the anti-hypertensive peptides identified from rice bran protein and their mechanisms. In addition, we describe protease-digested rice bran from which functional peptides have not been isolated.

Design, synthesis and biological evaluation of novel fluoro-substituted benzimidazole derivatives with anti-hypertension activities.

A series of new fluoro-substituted benzimidazole derivatives were designed, synthesized and pharmacologically evaluated. All the target compounds were characterized by 1HNMR, 13CNMR, mass spectra and elemental analysis. The biological evaluation showed that most of the synthesized compounds displayed nanomolar affinity to the angiotensin II type 1 (AT1) receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. The maximal response of mean blood pressure (MBP) lowered 74.5 ± 3.5 mmHg (1g) and 69.2 ± 0.9 mmHg (2a) at 10 g/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than both losartan and telmisartan. So, compounds 1g and 2a may be considered as potential antihypertension drug candidates.

Telmisartan and Rosuvastatin Synergistically Ameliorate Dementia and Cognitive Impairment in Older Hypertensive Patients With Apolipoprotein E Genotype.

Objective: To investigate the effect of telmisartan, rosuvastatin, or their combination on dementia and to understand the impact of apolipoprotein E (APOE) genotype on the effect of the medications in older patients with hypertension. Methods: This is a double-blind, randomized, and placebo-controlled trial using a 2 × 2 factorial design. Between April 2008 and November 2010, 1,244 hypertensive patients aged ≥60 years without cognitive impairment were recruited from communities in six cities in Shandong area, China. Patients were randomized into telmisartan and rosuvastatin administration after a 2-week washout period. APOE genotype was identified at the baseline. Possible dementia was determined using the combination of the global cognitive function and Assessment of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Results: Over an average follow-up of 7 [interquartile range (IQR): 6.7-7.2] years, telmisartan and rosuvastatin significantly reduced the cognitive impairment progression and the incidence of dementia. There was a synergistic interaction between telmisartan and rosuvastatin to reduce the cognitive impairment and the incidence of dementia (P adjusted < 0.001). The cognitive impairment progression and the risk of dementia were higher in the hypertensive patients with APOE ε4 allele than in those without APOE ε4 allele. Rosuvastatin medication significantly alleviated the cognitive impairment progression and the risks of dementia in patients with APOE ε4 allele. Conclusion: The combination of telmisartan and rosuvastatin might be an effective prevention and/or treatment strategy for cognitive impairment and dementia, especially in hypertensive patients with the APOE ε4 allele. Clinical Trial Registration: www.ClinicalTrials.gov, ChiCTR.org.cn, identifier ChiCTR-IOR-17013557. Registered on April 12, 2017 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=23121.

Comprehensive characterisation of phenolics from Nitraria sibirica leaf extracts by UHPLC-quadrupole-orbitrap- MS and evaluation of their anti-hypertensive activity.

ETHNOPHARMACOLOGICAL RELEVANCE: For more than ten scores years, the leaves and fruits of Nitraria sibirica have been used as a natural remedy for indigestion, irregular manes, and hypertension in the Middle East and Central Asia, especially, are recommended for hypertension treatment in the northwest region, China. AIM OF THE STUDY: we aimed to support the traditional usage of N. sibirica leaves as pharmaceuticals or dietary supplements in treatment of hypertension by investigating their chemical constituents and anti-hypertensive activity. METHODS: We identified the chemical composition of N. sibirica leaves ethanolic purified extract (NSL-EPE) using UHPLC-quadrupole-orbitrap-MS, and quantified the main chemical constituents by an analytical method established and validated. We also evaluated anti-hypertensive activity of NSL-EPE using spontaneously hypertensive rats (SHR): blood pressure was measured weekly by non-invasive blood pressure (NIBP) measurements; hemodynamic parameters, biochemical and clinical chemistry variables in plasma, serum and kidney tissue were measured after 10 weeks of treatment with NSL-EPE as well. RESULTS: UHPLC-quadrupole-orbitrap-MS analysis identified 52 compounds, of which 40 compounds were reported for the first time in N. sibirica. 11 phenolic compounds further quantitatively analyzed, among which the most abundant compound was found to be clovin (8.8%). Systolic blood pressure decreased progressively from the second treatment week compared to that in non-treated SHRs. The plasma endothelin, aldosterone, angiotensin II levels were significantly increased, while the level of NOX was significantly decreased; glutathione to oxidized glutathione ratio, superoxide dismutase and total catalase levels in the kidney tissue were markedly accelerated, while malondialdehyde level was significantly reduced in NSL-EPE treated SHRs. Moreover, the serum cholesterol, triglyceride, blood uria nitrogen and creatinine were attenuated in NSL-EPE treated SHRs (P < 0.05), but in sharp contrast to those values in the water-treated SHRs. CONCLUSION: This study screened out leading compounds from N. sibirica and offered a new understanding of the antihypertensive properties of N. sibirica leaves, by which inhibit oxidative stress-induced endothelial dysfunction and improve lipid profiles.

Camel Hemorphins Exhibit a More Potent Angiotensin-I Converting Enzyme Inhibitory Activity than Other Mammalian Hemorphins: An In Silico and In Vitro Study.

Angiotensin-I converting enzyme (ACE) is a zinc metallopeptidase that has an important role in regulating the renin-angiotensin-aldosterone system (RAAS). It is also an important drug target for the management of cardiovascular diseases. Hemorphins are endogenous peptides that are produced by proteolytic cleavage of beta hemoglobin. A number of studies have reported various therapeutic activities of hemorphins. Previous reports have shown antihypertensive action of hemorphins via the inhibition of ACE. The sequence of hemorphins is highly conserved among mammals, except in camels, which harbors a unique Q>R variation in the peptide. Here, we studied the ACE inhibitory activity of camel hemorphins (LVVYPWTRRF and YPWTRRF) and non-camel hemorphins (LVVYPWTQRF and YPWTQRF). Computational methods were used to determine the most likely binding pose and binding affinity of both camel and non-camel hemorphins within the active site of ACE. Molecular dynamics simulations showed that the peptides interacted with critical residues in the active site of ACE. Notably, camel hemorphins showed higher binding affinity and sustained interactions with all three subsites of the ACE active site. An in vitro ACE inhibition assay showed that the IC50 of camel hemorphins were significantly lower than the IC50 of non-camel hemorphins.

Left ventricular hypertrophy and hypertension.

Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease (CVD) morbidity and mortality. The left ventricle (LV) is a primary target for HTN end-organ damage. In addition to being a marker of HTN, LV geometrical changes: concentric remodeling, concentric or eccentric LV hypertrophy (LVH) are major independent risk factors for not only CVD morbidity and mortality but also for all-cause mortality and neurological pathologies. Blood pressure control with lifestyle changes and antihypertensive agents has been demonstrated to prevent and regress LVH. Herein, we provide a comprehensive review of literature on the relationship between HTN and LV geometry abnormalities with a focus on diagnosis, prognosis, pathophysiological mechanisms, and treatment approaches.