Development Of Antihypertensive Drugs Research Articles

Precision Hypertension.

Hypertension affects >1 billion people worldwide. Complications of hypertension include stroke, renal failure, cardiac hypertrophy, myocardial infarction, and cardiac failure. Despite the development of various antihypertensive drugs, the number of people with uncontrolled hypertension continues to rise. While the lack of compliance associated with frequent side effects to medication is a contributory issue, there has been a failure to consider the diverse nature of hypertensive populations. Instead, we propose that hypertension can only be truly managed by precision. A precision medicine approach would consider each patient's unique factors. In this review, we discuss the progress toward precision medicine for hypertension with more predictiveness and individualization of treatment. We will highlight the advances in data science, omics (genomics, metabolomics, proteomics, etc), artificial intelligence, gene therapy, and gene editing and their application to precision hypertension.

Phytochemical characterization, antioxidant activity and antihypertensive evaluation of Ocimum basilicum L. in l-NAME induced hypertensive rats and its correlation analysis

Ocimum basilicum Linn. (basil) is an aromatic culinary herb that has shown a great potential in therapeutic world. It has many promising pharmacological activities that make it centre for investigations for many researchers. Current study has been planned to determine chemical constituents of basil leaves extracts and their in-vitro and ex-vivo antioxidant and in-vivo antihypertensive potential. GC-MS studies of non-polar extracts showed presence of 75 compounds including monoterpenes, hydrocarbons, sesquiterpenes, triterpenes, phyto-sterols and phthalates. Higher percentages of fatty acids were also identified. The major compounds include linalool (7.65%), terpineol (1.42%), tau-cadinol (13.55%), methyl palmitate (14.24%), palmitic acid (14.31%), linolenic acid (1.30%) and methyl linolenate (17.72%). Electron spray ionization mass spectrometry ESI-HRMS/MS of the polar extracts revealed the presence of alkaloids, phenolic acid, amino acid, coumarin, lignin, flavanoid and terpene derivative. Total phenolic content and total flavonoid content were determined using spectrophotometric technique and calculated as gallic acid equivalents GAE/g dry weight and rutin equivalent RE/g of dry weight respectively. The highest phenolic content and flavonoid content were found in ethyl acetate extract 9.40 mg GAE/g and 15.9 mg RE/g of dry weight. All the extracts showed significant antioxidant activity in DPPH and ABTS cation decolorization assays. Dichloromethane extract possess the highest DPPH scavenging activity, i.e., 64.12% ± 0.23 at concentration of 4 mg/ml. Moreover in ex-vivo studies all the extracts showed prominent effect by inhibiting AAPS induce oxidation in Human erythrocytes being 69.24% ± 0.18 in dichloromethane extract, 64.44% ± 0.04 in ethyl acetate and 53.33% ± 0.09 in acetone extract. The methanol extract of O. basilicum exhibited significant decrease in systolic blood pressure in l-Name induced hypertensive rats at the dose of 50 mg/kg for 28 days. Total phenolic content had a higher linear correlation (r = 0.678) with antihypertensive activity, with a level of significance 95% showing that phenolic compounds in the leaves of the plant has important role in inhibiting l –NAME induced hypertension while flavonoid compounds may play a key role in the antioxidant activities of the plant, through synergism. Conclusively, O. basilicum leaves with bioactive metabolites are a potential source for the development of antihypertensive drugs.

A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension.

Genetic variants in the third intron of the PRDM6 gene have been associated with BP traits in multiple GWAS. By combining fine mapping, massively parallel reporter assays, and gene editing, we identified super enhancers that drive the expression of PRDM6 and are partly regulated by STAT1 as the causal variants for hypertension. The heterozygous disruption of Prdm6 in mice expressing Cre recombinase under the control of mouse smooth muscle cell protein 22-α promoter (Prdm6fl/+ SM22-Cre) exhibited a markedly higher number of renin-producing cells in the kidneys at E18.5 compared with WT littermates and developed salt-induced systemic hypertension that was completely responsive to the renin inhibitor aliskiren. Strikingly, RNA-Seq analysis of the mouse aortas identified a network of PRDM6-regulated genes that are located in GWAS-associated loci for blood pressure, most notably Sox6, which modulates renin expression in the kidney. Accordingly, the smooth muscle cell-specific disruption of Sox6 in Prdm6fl/+ SM22-Cre mice resulted in a dramatic reduction of renin. Fate mapping and histological studies also showed increased numbers of neural crest-derived cells accompanied by increased collagen deposition in the kidneys of Prdm6fl/+ Wnt1Cre-ZsGreen1Cre mice compared with WT mice. These findings establish the role of PRDM6 as a regulator of renin-producing cell differentiation into smooth muscle cells and as an attractive target for the development of antihypertensive drugs.

Method Development and Validation of Anti Diabetic and Antihypertensive Drugs by using- RP HPLC

Writing research reveals that there is no thorough explanatory approach for the examination of selected pharmaceuticals Nebivolol and Hydrochlorothaizide, ALSK and Amlodipine, and ATNL and BCTM by synchronous estimation using Bio pertinent media in RP-HPLC using Bio pertinent media. HPLC, HPTLC and spectrophotometer are scientific methods that may be used to analyse mixtures either alone or in combination with other procedures. As a result, it was decided that a new logical strategy innovation was required for the simultaneous estimation of Nebivolol and Hydrochlorothaizide, ALSK and Amlodipine, ATNL and BCTM in pharmaceutical dosage frames and their estimate in bioapplicable medium. RP-HPLC for synchronous examination of Nebivolol and Hydrochlorothaizide, ALSK and Amlodipine, and ATNL and BCTM is being developed to establish another fundamental, rapid and accurate, prolific and repeatable RP-HPLC technology. By adhering to ICH regulations, the method will be accepted.

Design, synthesis, and biological evaluation of novel NO-releasing 4-chromanone derivatives as potential vasodilator agents.

The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway is an effective mechanism involved in the treatment of hypertension. In our search for potential antihypertensive agents, a series of novel NO-donor derivatives of the 4-chromanone skeleton were designed and synthesized by coupling furoxans or nitrooxy NO-donor moieties. All derivatives showed enhanced nitric oxide releasing capacity and vasodilator activity with EC50 values ranging from 0.0215 μM to 1.46 μM, obviously superior to those of precursor 3. These biological evaluations indicated that all compounds displayed an important vasorelaxant effect, and several compounds (9c, 14b, 14c, 14d) presented good vasodilator activity, with 14c being the best. Furthermore, molecular modeling studies revealed that compound 14c occupied the pocket well with the phosphodiesterase 5 domain in a favorable conformation. In conclusion, we observed that these novel compounds can act as structural templates for the design and subsequent development of new vasodilators and antihypertensive drugs.

Vietnamese Dalbergia tonkinensis: A Promising Source of Mono- and Bifunctional Vasodilators.

Hypertension is a risk factor for cardiovascular diseases, which are the main cause of morbidity and mortality in the world. In the search for new molecules capable of targeting KCa1.1 and CaV1.2 channels, the expression of which is altered in hypertension, the in vitro vascular effects of a series of flavonoids extracted from the heartwoods, roots, and leaves of Dalbergia tonkinensis Prain, widely used in traditional medicine, were assessed. Rat aorta rings, tail artery myocytes, and docking and molecular dynamics simulations were used to analyse their effect on these channels. Formononetin, orobol, pinocembrin, and biochanin A showed a marked myorelaxant activity, particularly in rings stimulated by moderate rather than high KCl concentrations. Ba2+ currents through CaV1.2 channels (IBa1.2) were blocked in a concentration-dependent manner by sativanone, 3′-O-methylviolanone, pinocembrin, and biochanin A, while it was stimulated by ambocin. Sativanone, dalsissooside, and eriodictyol inhibited, while tectorigenin 7-O-[β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside], ambocin, butin, and biochanin A increased IKCa1.1. In silico analyses showed that biochanin A, sativanone, and pinocembrin bound with high affinity in target-sensing regions of both channels, providing insight into their potential mechanism of action. In conclusion, Dalbergia tonkinensis is a valuable source of mono- and bifunctional, vasoactive scaffolds for the development of novel antihypertensive drugs.

High-Throughput Identification of Antihypertensive Peptides (AHTPs) and Characterization of AHTP-Derived Genes in the Lined Seahorse (Hippocampus erectus)

Recently, the prevalence of hypertension has become a global challenge. Therefore, tremendous efforts have been made to identify and purify antihypertensive peptides (AHTPs) from food-derived proteins to aid the discovery of new hypotensive drugs with fewer side effects. In this study, we performed high-throughput prediction of AHTPs based on multi-omics data, providing an overview of AHTPs in the lined seahorse proteins and suggesting their potential application as bioactive agents to lower blood pressure. We identified 14,695 AHTP-derived genes in the lined seahorse, and most of them were supported by transcriptomic evidence, whereas only 495 genes were further detected by proteome sequencing. Among these predicted AHTP-derived genes, the longest titin had the most hits with 104 AHTPs, some of which were clustered in exon 158, 194, and 204. Another AHTP-rich group was in the collagen family, and four AHTP-rich collagens exhibited much higher transcription in the pouch than in other examined tissues, including brain, testis, and embryos. Additionally, antihypertensive triplets, comprised of the permutations of Gly, Pro, and Lys, prevailed in all collagen sequences due to the representative XaaYaaGly repeat units. In summary, our present findings provide a solid basis for understanding the abundance of various AHTPs in the lined seahorse as well as shed light on the development of antihypertensive products and drugs using seahorses as an important resource.

Death-Associated Protein Kinase 3 Inhibitors Identified by Virtual Screening for Drug Discovery in Cancer and Hypertension.

Death-associated protein kinase 3 (DAPK3) is a serine/threonine protein kinase that regulates apoptosis, autophagy, transcription, and actin cytoskeleton reorganization. DAPK3 induces morphological alterations in apoptosis when overexpressed, and it is considered a potential drug target in antihypertensive and anticancer drug development. In this article, we report new findings from a structure-guided virtual screening for discovery of phytochemicals that could modulate the elevated expression of DAPK3, and with an eye to anticancer drug discovery. We used the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), a curated database, as part of the methodology. The potential initial hits were identified based on their physicochemical properties and binding affinity toward DAPK3. Subsequently, various filters for drug likeness followed by interaction analysis and molecular dynamics (MD) simulations for 100 nsec were performed to explore the conformational sampling and stability of DAPK3 with the candidate molecules. Notably, the data from all-atom MD simulations and principal component analysis suggested that DAPK3 forms stable complexes with ketanserin and rotenone. In conclusion, this study supports the idea that ketanserin and rotenone bind to DAPK3, and show stability, which can be further explored as promising scaffolds in drug development and therapeutics innovation in clinical contexts such as hypertension and various types of cancer.

Effect of Flavonoid Rich Fraction of Coriandrum sativum Leaf on Lipid Profile, Nitric Oxide, Ang II and Cardio Histopathology in L-NAME Intoxicated Experimental Rats

Coriandrum sativum has been used in traditional medicines as an anti-inflammatory, analgesic, and antibacterial agent. It is recently been shown to have antioxidant activities. This study evaluated the effects of Flavonoid Rich Fraction of Coriandrum sativum Leaf (FRFCSL) on Lipid Profile, Nitric Oxide, Ang II and Cardio Histopathology in L-NAME intoxicated Experimental Rats. Standard analytical method and DPPH radical scavenging activity were employed for the phytochemicals and antioxidant analysis respectively. The acute toxicity study showed the extract and flavonoids fraction are nontoxic at 5000mg/kg body weight. Thirty rats were divided into five groups of six (6) rats each. Group 1 was administered water and feed only, Group 2 was administered 40mg/kg N-Nitro-L-Arginine Methyl Ester (L-NAME) without treatment, Group 3 through 5 were administered 40mg/kg N-Nitro-L-Arginine Methyl Ester (L-NAME) with concomitant administration of Captopril (20mg/kg b.w), FRFCSL (200mg/kg b.w) and FRFCSL (400mg/kg b.w) respectively for 21 days. In phytochemical screening, presence of flavonoids, saponins, tannins, alkaloids, cardiac glycosides, steroids were confirmed as part of secondary metabolites in the extract. The flavonoid fraction showed increase % DPPH radical inhibition in concentration-dependent manner. FRFCSL treatment significantly (p<0.05) and dose-dependently lowered low density lipoprotein and triglycerides. Also It significantly (p<0.05) prevented L-NAME induced decrease in serum angiotensin II, high density lipoprotein and serum nitric oxide concentrations compared to the untreated rats. The Flavonoid Rich Fraction of Coriandrum Sativum Leaf showed great potential as antihypertensive, antihyperlipidemic and cardioprotective agent in rats thus confirming its usefulness in traditional health therapy and potential for antihypertensive drug development.

Simultaneous fluorescence imaging of Golgi O2•− and Golgi H2O2 in mice with hypertension

Hypertensive cardiovascular disease is a persistent threat to public health. Elucidating the pathogenesis of hypertension is expected to provide more highly targeted therapies for patients. To date, reactive oxygen species (ROS) induced endothelial nitric oxide synthase (eNOS) uncoupling are generally considered to be common phenomena in hypertension. However, the critical factor contribute to persistent eNOS uncoupling remains poorly understood. Herein, we established a fluorescence probe, GolROS, for the multicolored and simultaneous detection of Golgi O2•− and H2O2 in situ. We successfully detected increases in Golgi ROS levels in hypertensive mice and evaluated the pharmaceutical effects of various antihypertensive drugs. More importantly, we identified the ROS post-transcriptional modification sites on dihydrofolate reductase (DHFR). Altogether, we propose a novel therapeutic target for hypertension, which will promote the development of new antihypertensive drugs, and also developed an ideal fluorescence probe to study in situ Golgi O2•− and H2O2 changes in various biochemical processes.

Preparation of antihypertensive peptides from quinoa via fermentation with Lactobacillus paracasei

AbstractQuinoa is a pseudo‐cereal that is rich in protein and an ideal source of antihypertensive peptides. In this study, quinoa flour was fermented with Lactobacillus paracasei CICC 20241 via solid fermentation to produce antihypertensive peptides. The peptides were isolated and purified by ultrafiltration and gel chromatography, and then identified by liquid chromatography−tandem mass spectrometry. A total of 91 peptides were identified. In addition, five potential angiotensin‐converting enzyme (ACE) inhibitory peptides were synthesized with reference to in silico analysis. Among them, NIFRPFAPEL and AALEAPRILNL had the greatest inhibitory effect, with an IC50 of 49.02 and 79.72 µM, respectively. Inhibition dynamics and molecular docking indicated that NIFRPFAPEL formed eight hydrogen bonds with ACE residues Tyr523, Arg522, Glu384, Glu143, Glu123, Thr92, Tyr62, and Trp59. NIFRPFAPEL exerted a competitive inhibitory effect by interacting with residues Tyr523 and Glu384 of pocket S1. AALEAPRILNL exerted a noncompetitive inhibitory effect by forming eight hydrogen bonds with the inactive ACE site residues Ser516, Glu403, Ser355, Glu143, ARG124, and Asn70. These results confirmed that quinoa is a potential material for antihypertensive functional foods, while NIFRPFAPEL and AALEAPRILNL could be used for the development of antihypertensive functional foods or drugs.

Synthesis, quantum chemical, and molecular modeling investigations of 1,2,3‐triazole fused dicarboxylate bioorganic derivative as angiotensin‐converting enzyme inhibitor

AbstractIn this present work, we report structural and computational studies of 1,2,3‐triazole fused dicarboxylate derivative (TMND), which is investigated as an angiotensin‐converting enzyme (ACE) inhibitor for antihypertension treatment. The crystal structure of TMND is solved by single‐crystal XRD method and correlated with density functional B3LYP/6–311++ method. We performed Hirshfeld surface analysis to examine the strength of hydrogen bonds and to measure the intercontacts and enrichment ratio. The enrichment ratio of OH contact in TMND crystal validates (EOH = 1.20) that the OC and O═C bonds produce four weak hydrogen bonds of the type O…HC as evident in the supramolecular crystal packing. The enrichment ratio of CH contacts (ECH = 1.02) represent CH…π interactions with aromatic rings present in TMND crystal structure similar to XRD data. By using density functional theory (DFT/B3LYP/6–311++) method, frontier molecular orbital and molecular electrostatic potential map were computed and reactive regions were identified. In silico ACE inhibition nature of the TMND compound was evaluated using molecular docking method and followed by molecular dynamics simulation. Results reveals superior ACE inhibition ability of TMND compound over the native ligand and standard Food and Drug Administration approved antihypertensive drug lisinopril. Hence, it is concluded that our compound TMND could be considered for the antihypertensive drug design and development process.

A new wave of the innovation and development of novel antihypertensive drugs

尽管已有多种不同作用机制的降压药物，但仍有许多患者血压控制不达标，仍需进一步研发降压药物。目前降压药物的研发主要有两个方向，一个是单片复方降压制剂，尤其是血管紧张素转化酶抑制剂或血管紧张素Ⅱ受体阻滞剂与钙通道阻滞剂、噻嗪类利尿剂组成的三药复方，另一个则是新靶点降压药物，包括利钠肽系统相关的脑啡肽酶/血管紧张素Ⅱ受体双重抑制剂、内皮素受体拮抗剂以及高选择性醛固酮受体拮抗剂等。.

A bio-inspired plasmonic nanosensor for angiotensin-converting enzyme through peptide-mediated assembly of gold nanoparticles

Angiotensin-converting enzyme (ACE) can indicate blood pressure that relates to human health such as the cardiovascular disease. However, current methods are not competent to detect the ACE activity in a rapid and straightforward way. Plasmonic biosensors built on the modulation of metallic nanomaterials have emerged as novel tools for the detection of biomarkers. In this work, we report a bio-inspired strategy for the plasmonic detection of ACE in a rapid, sensitive, and selective way through peptide-mediated assembly of gold nanoparticles (AuNPs). In this biosensor, cysteine-angiotensin I-cysteine can assemble and aggregate AuNPs due to the Au–S bond. The presence of ACE can specifically catalyze the hydrolysis of angiotensin I, thus dissociating the cysteine-cysteine structure of the peptide that results in the disassembly and dispersion of AuNPs. This bio-inspired plasmonic nanosensor enables naked-eyed readout of ACE detection with great selectivity and high sensitivity with a LOD of 0.40 mU/mL. It also allows for the screening of ACE inhibitors and inhibitory peptides for the development of antihypertensive drugs or food. The biosensing technique developed in this work provides a new plasmonic approach that holds great promise as a point-of-care platform for biomedical diagnostics and the food industry.

ROBUSTNESS EVALUATION OF HPLC DETERMINATION OF ATORVASTATIN AND LISINOPRIL ON COLUMN PUROSPHER C8 STAR IN PHARMACEUTICALS

Introduction. Innovative pharmaceutical development of various antihypertensive drugs with statins and the creation of domestic fixed-dose combinations of drugs with different effects is an urgent task of modern pharmacy, which will help attract more patients to the treatment and prevention of cardiovascular disease. Pharmaceutical development of atorvastatin and lisinopril by our scientific group proposes for using the ratio of (1/1) for lisinopril (10 mg) and atorvastatin (10 mg). HPLC (High-Performance Liquid Chromatography) technique is adopted as it is considered as the most common technique in realm of quality control analysis.
 The aim of the study – to evaluate the robustness of HPLC (High-Performance Liquid Chromatography) method for the quantitation of lisinopril and atorvastatin and determine the analytical parameters that present greater influence in the final results of the analysis.
 Research Methods. An efficient method to assess the robustness of analytical methods is by Youden’s test, by means of an experiment design which involves seven analytical parameters combined in eight tests. In the recent studies, we assessed the robustness of a chromatographic method to quantify lisinopril and atorvastatin in tablets using Youden’s test.
 Results and Discussion. By using the criteria of Youden’s test, HPLC method proved to be greatly robust regarding content of lisinopril and atorvastatin, when variations in seven analytical parameters were introduced. The most variation in effects of the analytical parameters in retention time (Rt) for lisinopril and atorvastatin HPLC quantitation was when used column supplier. Purospher C8 STAR (55 mm x 4mm, 5 μm) is based on high purity silica and an almost complete surface coverage. Purospher C8 STAR provides excellent peak symmetry for acidic, basic and even chelating compounds, highest column efficiency in terms of the number of theoretical plates, and exceptional stability from pH 1.5 to 10.5.
 Conclusion. Youden’s test can be applied successfully for the ro­bustness evaluation in validation process of analytical methods and results ontained in our work should be interest to the scientific population dealing with pharmaceutical analytical chemistry.

Mdivi-1, a mitochondrial fission inhibitor, reduces angiotensin-II- induced hypertension by mediating VSMC phenotypic switch

Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension.

Discovery of trans-3,4,4′-trihydroxystilbene as new lead vasorelaxant agent for antihypertensive drug development

AimsThe structure-vasorelaxant activity relationships (SARs) assessment in previous study has found that trans-3,4,4′-trihydroxystilbene (344OH) could potentially act as a vasorelaxing agent with demonstration of over 2-fold maximal relaxation (Rmax) compared to its analogue, resveratrol. The present study focuses on the mechanism of actions and pathways employed by 344OH and compared to its analogue to further speculate the SAR of stilbenoids towards vasorelaxation. Materials and methodsThe 344OH employed in present study was synthesized based on the protocol in previous study. The vascular responses towards the cumulative addition of 344OH were evaluated using in vitro rat aortic rings assays. Key findingsThe pEC50 and Rmax values were found to be 4.33 ± 0.05 and 106 ± 3.99%, respectively. Results showed that the vasorelaxation of 344OH were predominated by G-protein-coupled muscarinic- (M3) and β2-adrenergic receptors, followed by PGI2/AC/cAMP- and NO/sGC/cGMP-dependent pathways. It was also identified that 344OH employed voltage-activated- (Kv), calcium-activated- (Kca) and inwardly-rectifying (Kir) potassium channels and act as an antagonist for both VOCC and IP3R while regulating the action potential in the vasculature. SignificanceThe different position of hydroxyl substituent located in A-ring of the stilbenoid backbone in 344OH compared to resveratrol resulted in a significant difference in mechanistic actions that lead to 344OH's fast-acting and less time-dependent vasorelaxation behaviour. This has substantially increased the potential of 344OH to be developed as an effective antihypertensive drug in future. Present findings further strengthen our inferences where the SARs study approach should be carried out as the mainstream methodology in future drug development research.

A novel approach for the treatment of hypertension with the soluble guanylate cyclase stimulating drug

ABSTRACT Introduction Despite the significant progress in the development of safe and effective antihypertensive drugs, the control of blood pressure (BP) is still not satisfactory. The current antihypertensive drugs reduce the BP by increasing sodium and water excretion (diuretics), by blocking the action of the sympathetic system, by blocking the calcium entry into vascular smooth muscle cells, or by blocking the action of the renin-angiotensin-aldosterone system. Areas Covered There is a need for the development of new antihypertensive drugs with a different mechanism of action. This new class of drugs are the soluble guanylate cyclase (sGC) stimulators and decrease the BP through arterial vasodilation by stimulating the sGC and increasing the production of cyclic-guanosine-monophosphate (cGMP), a potent vasodilator, independently of the endogenous nitric oxide. However, there is limited research on their antihypertensive action. For further knowledge of the antihypertensive effects and safety of these drugs, a focused Medline search of the English language literature was conducted between 2010 and 2020 and 27 studies with pertinent information were selected. Expert Opinion The analysis of data from these demonstrated that these drugs are safe and have beneficial antihypertensive and metabolic effects and they will be useful for hypertensive patients with diabetes and dyslipidemia.

APATINIB-INDUCED HYPERTENSION ASSOCIATED WITH BETTER PROGNOSIS IN PATIENT WITH SOLID TUMOR

Objective: To investigate the incidence of apatinib-induced hypertension (HTN) in the treatment of patients with solid tumor in real world and to determine whether apatinib-induced HTN is associated with its anti-tumor efficacy. Design and method: We retrospectively collected the medical records of patients with solid tumor treated with apatinib in Lanzhou University Second Hospital and Gansu Provincial Cancer Hospital, from Oct 1st 2014 to Jun 30st 2019. The patients were then prospectively followed to determine the disease state, time of disease progression and death, as well as whether or not have newly initiated HTN. The mean follow-up was 16.5month, with the longest follow-up of 48 months. The apatinib-induced HTN was defined as either newly initiated HTN in patients with normal blood pressure or increases of antihypertensive intensity in patients with pre-existed HTN. The prognosis of patients was estimated with progression-free survival (PFS) and overall survival (OS). Results: A total of 400 patients were enrolled, of whom 136 (34%) were diagnosed with HTN induced by apatinib. The primary tumor in 40% of the patients were gastrointestinal cancer, followed by hepatobiliary cancer (14.5%) and lung cancer (13.3%). Patients in HTN group were older (p = 0.03), more frequently with proteinuria (p = 0.035) and higher dosage of apatinib (p = 0.024). The survival analysis showed that apatinib-induced HTN was associated with significantly longer PFS, as well as OS (both p < 0.01), the differences existed both in univariate and multivariate analyses. The subgroup analyses were performed in patients with gastrointestinal cancer, hepatobiliary cancer, and lung cancer, all showed consistent results. Conclusions: HTN is one of the most common side effects of apatinib in the treatment of solid tumors, with an incidence of as high as 34% in real world. Apatinib-induced HTN is significantly associated with better anti-tumor efficacy in patients with solid tumors. Given that there is still no effective predictive biomarker for apatinib, drug-induced HTN may be used as an surrogate one. The development of new antihypertensive drugs with better antihypertensive effects while no influences on antitumor activity, is in urgent need.

KCNQ5 Potassium Channel Activation Underlies Vasodilation by Tea

Background/Aims:Tea, produced from the evergreen Camellia sinensis, has reported therapeutic properties against multiple pathologies, including hypertension. Although some studies validate the health benefits of tea, few have investigated the molecular mechanisms of action. The KCNQ5 voltage-gated potassium channel contributes to vascular smooth muscle tone and neuronal M-current regulation.Methods:We applied electrophysiology, myography, mass spectrometry and in silico docking to determine effects and their underlying molecular mechanisms of tea and its components on KCNQ channels and arterial tone.Results:A 1% green tea extract (GTE) hyperpolarized cells by augmenting KCNQ5 activity >20-fold at resting potential; similar effects of black tea were inhibited by milk. In contrast, GTE had lesser effects on KCNQ2/Q3 and inhibited KCNQ1/E1. Tea polyphenols epicatechin gallate (ECG) and epigallocatechin-3-gallate (EGCG), but not epicatechin or epigallocatechin, isoform-selectively hyperpolarized KCNQ5 activation voltage dependence. In silico docking and mutagenesis revealed that activation by ECG requires KCNQ5-R212, at the voltage sensor foot. Strikingly, ECG and EGCG but not epicatechin KCNQ-dependently relaxed rat mesenteric arteries.Conclusion:KCNQ5 activation contributes to vasodilation by tea; ECG and EGCG are candidates for future anti-hypertensive drug development.