Potent Antihypertensive Agent Research Articles

Computer-aided rational design and synthesis of new potential antihypertensive agents among 1,2,3-triazole-containing nifedipine analogs

1,2,3-Triazole-containing Nifedipine analogues offer the opportunity to increase biostability, bioavailability, efficacy and binding selectivity to target receptors. Here, we applied a computer-aided rational design for identifying new Nifedipine analogues containing a 1,2,3-triazole moiety. First, a new chemical library of 796 derivatives combining the DHP fragment and 1,2,3-triazole moiety was generated. Second, to reduce the library size, the library was pre-filtered using two 3D-pharmacophore models with different complexity, which allowed us to gradually reduce the chemical space, ending up with 26 hit candidates. Molecular docking calculations against the rCav1.1 receptor allowed the identification of eight derivatives 5a-h, characterized by the binding affinity towards the rCav1.1 receptor of the same level as approved Nifedipine-like drugs. Next, our molecular docking results were used to guide and optimize the retrosynthetic approaches for new analogues of Nifedipine as promising antihypertensive agents. So, a retrosynthetic approach for Nifedipine analogues with a 1,2,3-triazole ring in position 4 was proposed. Finally, eight analogues 5a-h determined by molecular docking calculations were synthesized using the suggested retrosynthetic approach. The aim of this study is to identify new Nifedipine analogues using a computer-aided drug design and a retrosynthetic approach. Materials and Methods. The organic synthesis of new Nifedipine analogues containing a 1,2,3-triazole moiety. Computer-aided drug design of new DHP derivatives using pharmacophore screening and molecular docking calculations. Results. Molecular docking of new Nifedipine analogues made it possible to estimate the binding affinity of new Nifedipine derivatives to the rCav1.1 receptor. Pharmacophore screening of a chemical library of analogues, consisting of 796 derivatives, allowed gradually reducing the chemical space and obtaining 26 candidates with high affinity to the rCav1.1 receptor. Using the method of molecular docking, eight hits 5a-h were identified, and the synthesis of the recommended compounds was proposed and performed. Conclusions. The results of molecular docking showed that Nifedipine analogues are characterized by binding affinity to the rCav1.1 receptor at the same level as approved Nifedipine-like drugs. Pharmacophore screening and molecular docking calculations indicate key features of the ligand-receptor interaction that can guide and optimize the synthesis of new Nifedipine analogues as promising new antihypertensive agents. A retrosynthetic approach was proposed, and the recommended compounds were synthesized

Fabrication, optimization, and evaluation of lyophilized lacidipine-loaded fatty-based nanovesicles as orally fast disintegrating sponge delivery system

Lacidipine (LCD) is a potent antihypertensive agent. Fatty-based nanovesicles (FNVs) were designed to improve LCD low solubility and bioavailability. LCD-FNVs were formulated according to different proportions of cetyl alcohol, cremophor®RH40, and oleic acid adopting Box-Behnken Design. The optimized LCD-FNVs, composed of cetyl alcohol 48.4 mg, cremophor®RH40 120 mg, and oleic acid 40 mg, showed minimum vesicle size (124.8 nm), maximum entrapment efficiency % (91.04 %) and zeta potential (-36.3 mV). The optimized FNVs were then used to formulate the lyophilized orally fast-disintegrating sponge (LY-OFDS). The LY-OFDS had a very short disintegration time (58 sec), remarkably high % drug release (100 % after 15 mins), and increased the drug transbuccal permeation by over 9.5-fold compared to the drug suspension. In-vivo evaluation of antihypertensive activity in rats showed that the LY-OFDS reduced blood pressure immediately after 5 min and reached normal blood pressure 4.5-fold faster than the marketed oral tablets. In the In-vivo pharmacokinetic study in rabbits, the LY-OFDS showed 4.7-fold higher bioavailability compared with the marketed oral tablet. In conclusion, the LY-OFDS loaded with LCD-FNVs is a safe, and non-invasive approach that can deliver LCD effectively to the blood circulation via the buccal mucosa giving superior immediate capabilities of lowering high blood pressure and increasing the drug bioavailability.

Characterization of four new cycloartane triterpenoids from Swietenia macrophylla and their angiotensin-I-converting enzyme inhibitory activity

Angiotensin I-converting enzyme (ACE) inhibition is currently a common method for the treatment and control of hypertension. In this study, four new (1–4) and one known (5) cycloartane triterpenoids were isolated from the leaves of Swietenia macrophylla by chromatographic techniques and identified by their spectroscopic data and a comprehensive comparison of published data. The triterpenoids were evaluated for their ACE inhibitory potential using in vitro inhibition assays and in silico methods. The inhibition assay and enzyme kinetics results showed that the most active triterpenoid, compound 4, inhibited ACE in a mixed-type manner with an IC50 value of 57.7 ± 6.07 μM. Computer simulations revealed that compound 4 reduces the catalytic efficiency of ACE by competitive insertion into the active pocket blocking the substrate, and the binding activity occurs mainly through hydrogen bonds and hydrophobic interactions. The study showed that S. macrophylla can be a source of bioactive material and the ACE inhibitory triterpenoid could be a potential antihypertensive agent.

In vitro evaluation of the anti-hypertensive potential of albumin and globulin hydrolysates from cocoa bean (Theobroma cacao L. var. Forastero)

According to reports from the World Health Organization (WHO), hypertension is considered the most common cardiovascular risk factor, affecting 25 to 30% of the world's population. One of the primary causes of hypertension is angiotensin-converting enzyme-I (ACE), which plays a crucial role in regulating blood pressure through the modulation of the renin-angiotensin-aldosterone system. Consequently, there is a wide range of drugs available that can inhibit ACE. However, these drugs can cause adverse side effects such as cough, headache, skin rash, altered taste, angioedema, nausea, and allergic reactions. For this reason, there is considerable interest in obtaining ACE inhibitors from natural sources that reduce side effects and dependence on drugs. Specifically, bioactive peptides present in enzymatic protein hydrolysates have shown anti-hypertensive properties by inhibiting ACE, making them a promising alternative in the prevention and treatment of hypertension. The objective of this study was to evaluate the ACE inhibitory activity (in vitro) of enzymatic hydrolysates obtained from cocoa bean proteins (albumin and globulin), with the purpose of considering them as a natural source of potential anti-hypertensive agents. The results demonstrated that the enzymatic treatment (with alcalase) of albumin and globulin from cocoa beans is a viable bioprocess for producing hydrolysates with ACE inhibitory activity. In particular, hydrolysates and peptide fractions (< 3000 Da) with greater ACE inhibitory capacity were generated from globulin, making them a suitable choice for designing functional foods.

Abstract 081: Transactivation Of Brain ADAM17 In Angiotensin II-Induced Hypertension Can Be Prevented By Kinin B1 Receptor Blockade

A disintegrin and metalloprotease 17 (ADAM17) has been implicated in mediating inflammation in several cardiovascular diseases. Targeting brain ADAM17 using siRNA revealed a reduction in blood pressure, confirming its role in hypertension. Previously, we reported that kinin B1 receptor (B1R) activation increases ADAM17 activity in primary hypothalamic neurons, while pretreatment with a B1R antagonist mitigated this effect. However, whether there is a direct interaction between ADAM17 and B1R in hypertension is unknown. In this study, we tested the hypothesis that B1R blockade will prevent the transactivation of ADAM17, thereby, preventing the development of angiotensin II-induced hypertension. Male and female C57BL/6NJ wild-type (WT) and B1R knockout mice (B1RKO) were administered Ang II (600 ng/kg/min; SC, 2 weeks) or saline via osmotic minipumps. Ang II infusion significantly increased mean arterial pressure (radiotelemetry) in WT mice (145 ±13 mmHg vs. 103 ±6, n=6, p<0.01), which was attenuated in B1RKO mice. Both male and female B1RKO mice showed similar attenuation of Ang II-induced hypertension. Ang II-infusion led to a significant upregulation of ADAM17 in the PVN of WT mice and was blunted in B1RKO mice (p<0.05, n=3). Proximity ligation assay (PLA) was used to examine close proximity (<40nm) interactions between two receptors. ADAM17-B1R interactions in the PVN of hypertensive mice were significantly increased (p<0.05, n=3). To further understand this correlation, primary neurons and microglia from the hypothalamus of neonatal WT mice were cultured and treated with Ang II (300 nM) for 24 hours. Ang II increased B1R and ADAM17 protein expression in both cell types and was prevented by a B1R antagonist SSR240612 (10 uM) (p<0.05, n=5). To supplement these findings, PLA was used on primary neurons and microglia and revealed an increase in ADAM17-B1R interactions following Ang II. Furthermore, B1R antagonism attenuated this ADAM17-B1R interaction in both neurons and microglia (p<0.05, n=5). Our data provides novel evidence that B1R blockade can attenuate Ang II-induced hypertension in the brain, possibly through a reduction in B1R-ADAM17 interactions, suggesting that B1R blockade may serve as a potential antihypertensive therapeutic agent.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers.

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a-c in acid medium (HCl) yielding pyrimidines 4a-c, which in turn were hydrolyzed to carboxylic acid derivatives 5a-c which were chlorinated by SOCl2 to give acyl chlorides 6a-c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a-c, 8a-c, and 9a-c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC50 measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure-activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents.

Latest Knowledge on the Role of Vitamin D in Hypertension.

Hypertension is the third leading cause of the global disease burden, and while populations live longer, adopt more sedentary lifestyles, and become less economically concerned, the prevalence of hypertension is expected to increase. Pathologically elevated blood pressure (BP) is the strongest risk factor for cardiovascular disease (CVD) and related disability, thus making it imperative to treat this disease. Effective standard pharmacological treatments, i.e., diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARBs), beta-adrenergic receptor blockers (BARBs), and calcium channel blockers (CCBs), are available. Vitamin D (vitD) is known best for its role in bone and mineral homeostasis. Studies with vitamin D receptor (VDR) knockout mice show an increased renin-angiotensin-aldosterone system (RAAS) activity and increased hypertension, suggesting a key role for vitD as a potential antihypertensive agent. Similar studies in humans displayed ambiguous and mixed results. No direct antihypertensive effect was shown, nor a significant impact on the human RAAS. Interestingly, human studies supplementing vitD with other antihypertensive agents reported more promising results. VitD is considered a safe supplement, proposing its great potential as antihypertensive supplement. The aim of this review is to examine the current knowledge about vitD and its role in the treatment of hypertension.

Antihypertensive effects of pentacyclic triterpenoid from Convolvulus pluricaulis and its plausible mechanism of action hypothesizing its selectivity targeting Mineralocorticoid receptor of RAAS.

BackgroundThe renin-angiotensin-aldosterone system (RAAS) is important in maintaining blood pressure and malfunction of this system leads to the main cause of hypertension. Though a variety of synthetic inhibitors have been used to treat hypertension and related disorders, chronic use of these inhibitors causes undesirable side effects. To eliminate this problem, several scientific studies have proved that plant based and food derived products could be used as an alternative strategy to treat high blood pressure. PurposeWe intend to isolate the major bioactive compound from the medicinal plant Convolvulus pluricaulis as it is reported to possess anti-hypertensive activity. We also aimed to address the mechanism of action of taraxerol and to hypothesize its selectivity targeting RAAS. Study designThe study was designed to isolate the phytoconstituent from C. pluricaulis and characterization by XRD, NMR, FT-IR, and UV–Vis. To further elucidate the activity of isolated molecules, we have designed a two-way approach using in-silico and in-vitro methodologies. MethodsThe roots of Convolvulus pluricaulis were dried, powdered and the extract was purified by repeated column chromatography. The purified compound was characterized by UV–Vis, IR, NMR, and single crystal X-ray diffraction. The high quality single crystal was grown from the mixture of hexane ethyl acetate. Molecular docking was done to identify the interaction pattern and binding efficacy of isolated compounds against various receptors of RAAS and the stability of the molecule was analyzed by molecular dynamic simulations. The cytotoxicity of the molecule was checked using the MTT assay and the IC50 value was also calculated against the AngII-induced cardiac hypertrophy in H9c2 cells. Tanimoto coefficient was calculated to check the similarity indices with the already reported antihypertensives from plants/herbs. ResultsThe crystal structure of taraxerol solved by crystallography has been deposited with the Cambridge Crystallographic Data Centre (CCDC: 2,180,265). Taraxerol had an IC50 at 20 μM concentration against AngII-induced cardiac hypertrophy in H9c2 cells, indicating that it suggestively increased the cell viability as compared to positive control. In-silico molecular docking analysis of taraxerol found that taraxerol binds to mineralocorticoid receptor with the binding energy of −11.03 kcal/mol. Molecular Dynamics (MD) simulations were further done to check the stability of MR-taraxerol complex to unravel the structure activity relationship of taraxerol. Furthermore, SAR studies show that taraxerol had the highest degree of molecular similarity (0.78% – 0.93%) with reported antihypertensive oleanane triterpenoids highlighting its efficacy. ConclusionOur findings corroborate taraxerol as a potential anti-hypertensive agent and leads to the hypothesis of its specificity towards Mineralocorticoid receptor than other receptors in RAAS.

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.

Updated review on benzimidazole derivatives as potential antihypertensive agents

A growing number of researchers in the field of medicinal chemistry are focused on nitrogenous heterocyclic compounds. Benzimidazole scaffolds appear often in this group of heterocyclic compounds. Benzimidazole derivatives are important chemotherapeutic drugs because of their isostructural pharmacophore of naturally occurring active biomolecules. Many benzimidazole derivatives have been produced in the recent few decades, and many of these compounds have shown high bioactivity against a wide range of diseases and have bioavailability, safety, and stability profiles that are among the best in the industry. Here, we've included data on the antihypertensive properties of benzimidazole derivatives that have appeared in recent studies (2010–2022), along with a structure-activity link for each. Human studies are underway for a number of intriguing therapeutic candidates, and some of them will be authorized for use in clinical settings. In order to gather the information on proposed topic all the scientific search engines and publisher sites were used such as Google scholar, Science direct, Bentham science, PubChem, PubMed, Tayler and Francis, Hindawi, Springer nature, and ACS websites. The present review provides a detailed insight of benzimidazole derivatives reported as antihypertensive agents.

Braylin induces a potent vasorelaxation, involving distinct mechanisms in superior mesenteric and iliac arteries of rats.

Arterial hypertension is a risk factor for various cardiovascular and renal diseases, representing a major public health challenge. Although a wide range of treatment options are available for blood pressure control, many hypertensive individuals remain with uncontrolled hypertension. Thus, the search for new substances with antihypertensive potential becomes necessary. Coumarins, a group of polyphenolic compounds derived from plants, have attracted intense interest due to their diverse pharmacological properties, like potent antihypertensive activities. Braylin (6-methoxyseselin) is a coumarin identified in the Zanthoxylum tingoassuiba species, described as a phosphodiesterase-4 (PDE4) inhibitor. Although different coumarin compounds have been described as potent antihypertensive agents, the activity of braylin on the cardiovascular system has yet to be investigated. To investigate the vasorelaxation properties of braylin and its possible mechanisms of action, we performed in vitro studies using superior mesenteric arteries and the iliac arteries isolated from rats. In this study, we demonstrated, for the first time, that braylin induces potent vasorelaxation, involving distinct mechanisms from two different arteries, isolated from rats. A possible inhibition of phosphodiesterase, altering the cyclic adenosine monophosphate (cAMP)/cAMP-dependent protein kinase (PKA) pathway, may be correlated with the biological action of braylin in the mesenteric vessel, while in the iliac artery, the biological action of braylin may be correlated with increase of cyclic guanosine monophosphate (cGMP), followed by BKCa, Kir, and Kv channel activation. Together, these results provide evidence that braylin can represent a potential therapeutic use in preventing and treating cardiovascular diseases.

The effects of oat ingredients on blood pressure in spontaneously hypertensive rats.

This study investigated the blood pressure (BP) lowering and cardioprotective effects of oat avenanthramide C and beta-glucan alone or in combination in spontaneously hypertensive rats (SHR). Five-weeks-old male SHR and Wistar-Kyoto rats received vehicle, avenanthramide C and beta-glucan alone or a combination of avenanthramide C and beta-glucan via gavage for 15weeks. BP was measured at 0, 10, and 15weeks of treatment. Echocardiography was performed at 15weeks of treatment. Oxidative stress and inflammation were also measured. Beta-glucan alone prevented the increase in systolic and diastolic BP in SHR, but avenanthramide C alone or the combination did not prevent the increase in systolic and diastolic BP. SHRs treated with beta-glucan and not avenanthramide C or the combination reduced isovolumetric relaxation time when compared to SHR treated with vehicle. Beta-glucan and avenanthramide C decreased the levels of malondialdehyde, a marker of oxidative stress in SHR. In conclusion, beta-glucan is a potential antihypertensive agent that may alleviate cardiovascular abnormalities. PRACTICAL APPLICATIONS: Oats products are believed to contain many bioactives that possess potential beneficial properties against chronic diseases. Specifically, oats beta-glucan has been well-established for its efficacy in positively modulating the risk factor for dyslipidemia. This preliminary in vivo study shows that beta-glucan is a potential antihypertensive agent that may alleviate cardiac dysfunction as well. In light of the current findings, further human studies may establish the efficacy of oats beta-glucan in hypertensive patients alongside the current antihypertensive medications. This novel attribute established via rigorous studies may provide an impetus for oats products and oats industry. Last but not least, it will also help improve the cardiovascular disease burden in a cost-effective way.

Blood pressure-lowering effects of a Bowman-Birk inhibitor and its derived peptides in normotensive and hypertensive rats

Bioactive plant peptides have received considerable interest as potential antihypertensive agents with potentially fewer side effects than antihypertensive drugs. Here, the blood pressure-lowering effects of the Bowman-Birk protease inhibitor, BTCI, and its derived peptides, PepChy and PepTry, were investigated using normotensive (Wistar-WR) and spontaneously hypertensive rats (SHR). BTCI inhibited the proteases trypsin and chymotrypsin, respectively, at 6 µM and 40 µM, a 10-fold greater inhibition than observed with PepTry (60 µM) and PepChy (400 µM). These molecules also inhibited angiotensin converting enzyme (ACE) with IC50 values of 54.6 ± 2.9; 24.7 ± 1.1; and 24.4 ± 1.1 µM, respectively, occluding its catalytic site, as indicated by molecular docking simulation, mainly for PepChy and PepTry. Gavage administration of BTCI and the peptides promoted a decrease of systolic and diastolic blood pressure and an increase of renal and aortic vascular conductance. These effects were more expressive in SHR than in WR. Additionally, BTCI, PepChy and PepTry promoted coronary vasodilation and negative inotropic effects in isolated perfused hearts. The nitric oxide synthase inhibitor blunted the BTCI and PepChy, with no cardiac effects on PepTry. The findings of this study indicate a therapeutic potential of BTCI and its related peptides in the treatment of hypertension.

Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension.

Growing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis. Recent preclinical investigations point arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with nonproteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed. We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolite levels were amplified in normotonic but not in hypertensive rats following the treatment. The data indicate that L-norvaline is a potential antihypertensive agent and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon BP regulation.

Antihypertensive Activity of Paullinia Pinnata Leaf Extract in Animal Models

Paullinia pinnta leaves are known for many medicinal properties. This study was undertaken to evaluate the antihypertensive activity of the aqueous and ethanolic extract of the leaves of Paullinia pinnata on an anaesthetized normotensive cat. Both extracts of P. pinnata leaves produced positive results for alkaloids, tannins, flavonoids, saponins, phenols, cardiac glycosides, terpenoids and steroids to the same extent in terms of concentration. The antihypertensive study involved the administration of equal volumes of varying concentrations of the aqueous and ethanolic extracts of P. pinnata leaves to the anaesthetized normotensive cat. The incremental concentration of both the ethanolic and aqueous extracts of P. pinnata leaves showed a positive ionotropic effect in the anaesthetized normotensive cat and is dose dependent and may involve any adrenergic receptor mediated action. The percentage reduction of the mean arterial blood pressures caused by the aqueous and ethanolic extracts are 0%, 11.86%, 0.13%, 6.52% and 5.66%, 0%, 14.82%, 47.17% respectively. One sample t test analysis with a test value of 100 gave mean values of (4.62 ± 2.85) and (16.91 ± 10.54) for aqueous extract and ethanolic extract respectively. This indicates that the ethanolic extract worked more effectively than the aqueous extract. This indicates that the ethanolic extract worked more effectively than the aqueous extract; and may be due to the presence of bioactive compounds which are of therapeutically potent antihypertensive agents. These findings show the potential antihypertensive activity of P. pinnata leaves to be use in treating or managing hypertension.

Synthesis, spectral properties, chemical descriptors and light harvesting studies of a new bioactive azo imidazole compound

The manuscript presents the synthesis and detailed spectral calculations of a new azoimidazole compound 1-[2-(2-hydroxy-3-methoxy-5-phenylazobenzaldeneamino) ethyl]-3-methyl-3H-imidazole (HMAI) and its further characterisations using different quantum mechanical and molecular modelling tools. The molecule was optimised using density functional theory formalism with D3LYP functional and 6–311++G (5D, 7 F) basis set. The computationally simulated and scaled IR and Raman spectra were compared with experimentally obtained spectral data, followed by detailed frequency assignments. Natural bond orbital (NBO) studies were used to analyse the various intramolecular hyperconjugative interactions. We are delighted to report that the molecule under study is an excellent material to be used as a non-linear optically active material from the hyperpolarizability studies and can be used an effective photosensitiser in dye sensitised solar cells (DSSC) from the light-harvesting efficiency (LHE) studies. Molecular docking studies indicate that this is an ideal molecule to be developed as a potential anti-hypertensive agent.

Sequence specific assignment and determination of OSR1 C-terminal domain structure by NMR

The binding of SPAK and OSR1 kinases to their upstream WNK kinases is mediated by the interaction of their highly conserved SPAK and OSR1 C-terminal domain (CTD) to RFx [V/I] peptide sequences from WNK kinases. A SPAK CTD knock-in mouse, where SPAK was unable to bind WNK kinases, exhibited low blood pressure. This highlighted the inhibition of SPAK and OSR1 kinases binding to their upstream WNK kinases as a plausible strategy in the discovery of new antihypertensive agents. To facilitate such endeavour, we herein report the optimisation and expression of isotopically labelled OSR1 CTD in E.coli and a structural model based on the sequence specific NMR assignments giving insights into the structure of apo OSR1 CTD. Additionally, we identified the OSR1 CTD amino acid residues that are important for the binding of an 18-mer RFQV peptide derived from human WNK4. Collectively, the NMR backbone assignments and the generated OSR1 CTD 3D model reported in this work will be a powerful resource for the NMR-based discovery of small molecule OSR1 (and SPAK) kinase inhibitors as potential antihypertensive agents.

Extract Stem Bark of Hymenaea Rubriflora D: A New Perspective of Vasorelaxant Agent

In this study, was investigated the action of the hydroalcoholic extract of the stem bark of Hymenaea rubriflora Ducke (HR-HAc) on the vascular reactivity of rats in vitro and administered in vivo. Cumulative doses of HR-HAc promoted dose-dependent relaxation aortic rings of Wistar rats with functional endothelium, which was inhibited in the presence of L-NAME. After, animals (n=5) were treated with 25, 50 and 100 mg / kg or saline for four weeks for determination of reactivity to acetylcholine, nitroprusside and phenylephrine. Was observed increased acetylcholine relaxing potency at all doses, with a greater effect on G50 (pD2 = 7.8 ± 0.1, Emax = 95.6 ± 1.1) and a decreased contractile potency to phenylephrine in G25 (pD2 = 6.9 ± 0.06, Emax = 61.5 ± 6.0%) and G50 (pD2 = 6.6 ± 0.06, Emax = 71.0 ± 8.5%) when compared to GC in the presence and absence of endothelium (pD2 = 6.4 ± 0.1, 6.4 ± 0.1 and 6.9 ± 0.1, respectively). Cumulative doses of nitroprusside resulted in increased relaxing potency in all supplemented groups and maintained Emax at 100%. Concludes that HR-HAc has vasorelaxant capacity and endothelium-dependent contractile inhibitor, either applied directly to aortic rings or after treatment with in vivo supplementation, which places this extract as a potential antihypertensive agent for future studies.

Puerarin Reduces Blood Pressure in Spontaneously Hypertensive Rats by Targeting eNOS.

Puerarin is an isoflavonoid isolated from the root of Pueraria lobata (Gegen in Chinese) that has been widely used to treat cardiovascular and cerebrovascular diseases in China. Here, we investigated the hypotensive effects and mechanisms of puerarin in spontaneously hypertensive rats. The qPCR array technique was used to determine the expression of hypertension-related genes. Then, the differentially expressed genes were analyzed using the STRING database. The systolic blood pressure and diastolic blood pressure of rats decreased after the administration of puerarin for nine weeks. Puerarin, but not losartan, also slowed the heart rate of rats. NO and cGMP levels were improved by puerarin. Eighteen differentially expressed hypertension-related genes were identified by comparing the model group with the control group and the high-dose puerarin group with the model group. NO and cGMP levels were increased by high-dose puerarin. High-dose puerarin increased the levels of the phosphorylated eNOS protein and decreased AT1 and Cav1 levels. Based on our results, eNOS was a key target in the mechanism by which puerarin reduced blood pressure, and puerarin represents a potential antihypertensive agent.

ENHANCEMENT OF THE SOLUBILITY AND THE DISSOLUTION RATE OF CANDESARTAN CILEXETIL USING MICROSPONGE TECHNOLOGY

Objective: The aim of the present study is to enhance the dissolution rate of candesartan cilexetil (CC) using microsponges. Candesartan is therapeutically a potent antihypertensive agent, but it suffers a major drawback of poor oral bioavailability, which is estimated to be 15% due to its low solubility in the gastrointestinal fluids and hepatic first-pass metabolism.Methods: Eudragit-based microsponges were prepared by quasi-emulsion solvent diffusion method using different drug–polymer ratios (1:1 to 1:6), stirring speeds (250–750 rpm), and emulsifier concentrations (polyvinyl alcohol) (0.05%–0.083% w/v). Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) study for CC, physical mixtures of drug–polymer, and selected formula were investigated to estimate compatibility of CC with other used ingredients. All formulations were evaluated for particle size, production yield, and loading efficiency. The in vitro drug release study of optimized formulation was performed in phosphate buffer pH 6.8.Results: The obtained results indicated that formula F3 which contains eudragit RS100 at drug:polymer ratio (6:1) was showed the smallest particle size with higher production yield and loading efficiency. DSC and FTIR study of the physical mixtures of drug and polymer revealed no drug–polymer interaction. The results clearly confirm that the percentage of CC released at 30 min from F3, CC powder, and self-made tablet was 54%, 20.325, and 38.9%, respectively.Conclusion: Microsponges technique was considered as a promising system to enhance the solubility and dissolution rate of poor-water soluble CC.