Action Of Calcium Antagonists Research Articles

Inhibition of Acetylcholinesterase with Novel 1, 3, 4, Oxadiazole Derivatives: A Kinetic, In Silico, and In Vitro Approach.

Alzheimer's disease (AD) is a neurological disease that disturbs the memory, thinking skills, and behavior of the affected person. AD is a complex disease caused by the breakdown of acetylcholine via acetylcholinesterase (AChE). The present study aimed to assess the synthetic inhibitors of AChE that could be used to treat AD. For this purpose, synthetic compounds of oxadiazole derivatives (15-35) were evaluated and identified as promising inhibitors of AChE, exhibiting IC50 varying between 41.87 ± 0.67 and 1580.25 ± 0.7 μM. The kinetic parameters indicated that all the studied compounds bind to the allosteric site and decrease the efficiency of the AChE enzyme. In silico docking analysis showed that the majority of the compounds interact with the anionic subsite and Per-Arnt-Sim domain of AChE and are stabilized by various bonds including π-π and hydrogen bonding. The stability of the most potent compounds 16 and 17 with AChE interaction was confirmed by molecular dynamics simulations. Moreover, all compounds exhibited concentration-dependent calcium (Ca2+) antagonistic and spasmolytic activities. Among the whole series of oxadiazole derivatives, compounds 16 and 17 displayed the highest activities on spontaneous and potassium (K+)-induced contraction. Therefore, the AChE inhibitory potential, cytotoxicity safe profile, and Ca2+ antagonistic ability of these compounds make them potential therapeutic agents against AD and its associated problems in the future.

Ethnopharmacological basis and pharmacodynamics prospectives for folkloric claims of Rosa webbiana wall. Ex. Royle in diarrhea and asthma via In vitro, In vivo and In silico techniques

Ethnopharmacological relevanceRosa webbiana (Family: Rosaceae) is used by South Asian herbalists to treat gastrointestinal and respiratory disorders. Aim of the studyThis research aimed at multiple targets to verify R. webbiana for treating diarrhea and asthma. In vitro, in vivo, and in silico experiments were planned to demonstrate the antispasmodic and bronchodilator potential of R. webbiana. Materials and methodsThe bioactive compounds of R. webbiana were identified and quantified through LC ESI-MS/MS and HPLC. These compounds were predicted for muti-mechanisms of bronchodilator and antispasmodic potential in network pharmacology and molecular docking. In vitro methods (isolated rabbit trachea, bladder, and jejunum tissues) confirmed these multi-mechanisms for antispasmodic and bronchodilator effects. Antiperistalsis, antidiarrheal, and antisecretory experiments were conducted in in-vivo experiments. ResultsThe phytochemical analysis indicates the presence of rutin (742.91 μg/g), kaempferol (726.32 μg/g), and quercitrin (688.20 μg/g) in Rw. EtOH. These bioactive compounds in network pharmacology interfere with the pathogenic genes of diarrhea and asthma, which are the members of calcium-mediated signaling pathways and showed the stronger binding affinity towards voltage-gated L-type calcium channels, myosin light chain-kinase, Calcium calmodulin-dependent-kinase, Phosphodiesterase-4, and phosphoinositide phospholipase-C in molecular docking. Rw. EtOH elicited a spasmolytic response in isolated jejunum, trachea, and urine preparations by relaxing K+ (80 mM) and CCh (1 μM) spastic contractions. Additionally, it suppressed calcium concentration-response curves to the right, like verapamil. Like dicyclomine, it caused a rightward parallel shift of the CCh curves, followed by a non-parallel shift at higher concentrations with suppression of the maximal response. Like papaverine, it also caused isoprenaline-induced inhibitory CRCs to shift to the left. Verapamil did not potentiate isoprenaline-induced inhibitory CRCs, although it was more efficacious against K+ (80 mM) than CCh (1 μM)-induced contractions. R. webbiana EtOH extract exhibited complete antiperistalsis (21.55%), antidiarrheal (80.33%), and antisecretory (82.59±0.60) activities in vivo experiments at the dose of 300 mg/kg. ConclusionThus, Rw. EtOH modulated multiple pathways, produced calcium antagonistic, anticholinergic, and phosphodiesterase inhibitory actions, and had antidiarrheal and bronchodilator effects.

The calcium-antagonist activity of the material released by olive pollen (PMR), tested on Ca2+-cytosolic of PE/CA-PJ15 cells

Inhalation of olive pollen (Olea europaea L.) is one of the main causes of allergy in Mediterranean countries and some areas of North America. The response to allergens consists in the production of inflammatory cytokines which is mediated by the deregulation of Ca2+ signals. In this study, the biological activity of the material released in olive pollen hydration (PMR) was tested on Ca2+ cytosolic of PE/CA-PJ15 cells (PJ-15). Ca2+ cytosolic was determined by fluorometric assay with the cell line PE/CA-PJ15 (PJ-15) labeled with the fluorescent probe FURA 2 AM. The material released in olive pollen hydration (PMR) was analyzed by HPLC for the determination of phenolic acids. PMR was subjected to fractionation by gel filtration, and the fractions with Ca2+-chelating activity were tested with SDS-PAGE and the single bands characterized by proteomic analysis. PMR showed high Ca2+-chelating activity and is able of blocking the increase Ca2+-cytosolic produced by thapsigargin (TG). PMR then restored Ca2+ homeostasis in PJ-15 cells deregulated by the endoplasmic reticulum Ca2+-ATPases inhibitor. It is therefore possible that PMR can antagonize the effects of allergens on Ca2+ cytosolic. The analytical characterization of the material released by the pollen highlighted in the pollen allergen Ole e 3 and in the p-coumaric acid the possible culprits of the Ca2+-antagonist activity of PMR. Furthermore, the sequence of Ole e 3 could provide information for the possible construction of a synthetic peptide to be used in an allergy-targeted Ca2+-antagonist therapy.

Design, synthesis and biological evaluation of new dihydropyridine derivatives as PD-L1 degraders for enhancing antitumor immunity

Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4-induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy.

The effect of fixed oil extracts of Nigella sativa on sickle cells: An in-vitro study in Khartoum state -Sudan

In Sudan, sickle cell anemia (SCA) is one of the most common inherited disorders of hemoglobin that has complications and becomes world problem. Nigella sativa NS (black seed) has been reported to have calcium antagonist and antioxidant activities, both of which play a role in the management of sickle cell anemia. The aim of the current study was to evaluate of the anti-sickling activity of the NS extracts, forty patients with sickle cell anemia were recruited for the study. A total of 3ml of venous blood was collected from each patient after obtaining the consent and the ethical approval, the blood was treated with Nigella sativa (NS) extract, and sickling test was performed. Descriptive study and p-values were used, and the correlation was evaluated, data was analyzed by SPSS. Recent study found that the sickling test after treating blood with Nigella sativa extract showed a negative result in 75% of patients and a 25% of patients showed persistently positive sickling test result. The anti-sickling effect in relation to various hemoglobin concentration, gender and age group showed p values of 0.007, 0.672 and 0.853 respectively indicating significant relationship with Hb concentration. Our study concluded that the fixed oil extract from Nigella sativa has an in-vitro anti-sickling activity on patients with SCA and this finding could indicate the use of this extract in treatment.

Identification of Chemical Markers for the Discrimination of Radix Angelica sinensis Grown in Geoherb and Non-Geoherb Regions Using UHPLC-QTOF-MS/MS Based Metabolomics.

This research aimed to discover chemical markers for discriminating radix Angelica sinensis (RAS) from different regions and to explore the differences of RAS in the content of four active compounds and anti-inflammatory activities on lipopolysacchride (LPS)-induced RAW264.7 cells and calcium antagonists on the HEK 293T cells of RAS. Nine compounds were selected as characteristic chemical markers by ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS), based on metabolomics, in order to rapidly discriminate RAS from geoherb and non-geoherb regions. The contents of senkyunolide I and butylidenephthalide in geoherb samples were higher than those in non-geoherb samples, but the contents of ferulic acid and levistolide A were lower in the geoherb samples. Furthermore, the geoherbs showed better nitric oxide (NO) inhibitory and calcium antagonistic activities than the non-geoherbs. These results demonstrate the diversity in quality of RAS between geoherbs and non-geoherbs.

Searching for calcium antagonists for hypertension disease therapy from Moutan Cortex, using bioactivity integrated UHPLC-QTOF-MS.

Calcium channel blockers (CCBs) are currently the most commonly used drugs for the treatment of hypertension. Moutan Cortex (MC), a traditional Chinese herb, has been found to have an anti-hypertensive effect. However, its potential mechanisms in the regulation of intracellular calcium concentration ([Ca2+ ]i ) remain poorly understood. The main objective of this work was to identify the potential calcium antagonists from MC and study their molecular mechanisms. Ultra-high performance liquid chromatography-quadrupole-time-of-fight-mass spectrometry (UHPLC-QTOF-MS) analysis combined with a dual-luciferase reporter assay was utilised to systematically screen the calcium antagonistic active ingredients in the methanol extract of MC. Additionally, the molecular mechanism of these compounds was further studied using live-cell imaging analysis with the calcium ion (Ca2+ ) probe dye fluo-4/AM to monitor changes in [Ca2+ ]i . Three monoterpenoids (paeoniflorin, benzoylpaeoniflorin and mudanpioside C), one phenolic acid (paeonol) and one gallotannin (1,2,3,4,6-O-pentagalloylglucose) were screened out as potential calcium antagonists in MC. Among them, the calcium antagonistic activity of benzoylpaeoniflorin, mudanpioside C and 1,2,3,4,6-O-pentagalloylglucose is first reported. Additionally, paeoniflorin, benzoylpaeoniflorin, mudanpioside C and paeonol can effectively block voltage-operated Ca2+ channels (VOCCs) to exert calcium antagonism, while 1,2,3,4,6-O-pentagalloylglucose plays a role in blocking inositol 1,4,5-trisphosphate receptors (IP3Rs). This work indicated that the anti-hypertensive efficacy of MC acted through multiple components selectively antagonising multiple cell signalling pathways to regulate [Ca2+ ]i . Furthermore, they could be considered as a reference standard for controlling the quality of Chinese medicinal materials.

Applications of calcium channel blockers in psychiatry: pharmacokinetic and pharmacodynamic aspects of treatment of bipolar disorder

ABSTRACTIntroduction: Calcium channel blockers (CCBs) comprise a heterogeneous group of medications that reduce calcium influx and attenuate cellular hyperactivity. Evidence of hyperactive intracellular calcium ion signaling in multiple peripheral cells of patients with bipolar disorder, calcium antagonist actions of established mood stabilizers, and a relative dearth of treatments have prompted research into potential uses of CCBs for this common and disabling condition.Areas covered: This review provides a comprehensive overview of intracellular calcium signaling in bipolar disorder, structure and function of calcium channels, pharmacology of CCBs, evidence of efficacy of CCBs in bipolar disorder, clinical applications, and directions for future research.Expert opinion: Despite mixed evidence of efficacy, CCBs are a promising novel approach to a demonstrated cellular abnormality in both poles of bipolar disorder. Potential advantages include low potential for sedation and weight gain, and possible usefulness for pregnant and neurologically impaired patients. Further research should focus on markers of a preferential response, studies in specific bipolar subtypes, development of CCBs acting preferentially in the central nervous system and on calcium channels that are primarily involved in neuronal signaling and plasticity.

Searching for synergistic calcium antagonists and novel therapeutic regimens for coronary heart disease therapy from a Traditional Chinese Medicine, Suxiao Jiuxin Pill

Coronary heart disease is a vital cause of morbidity and mortality worldwide, and calcium channel blockers (CCBs) are important drugs that can be used to treat cardiovascular diseases. Suxiao Jiuxin Pill (SX), a traditional Chinese medicine, is widely used as an emergency drug for coronary heart disease therapy. However, understanding its potential mechanism in intracellular calcium concentration ([Ca2+]i) modulation remains a challenge. To identify the active pharmacological ingredients (APIs) and reveal a novel combination therapy for ameliorating cardiovascular diseases, the ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) combined with a dual-luciferase reporter [Ca2+]i assay system was applied. Ligustrazine, ferulic acid, senkyunolide I, senkyunolide A and ligustilide were identified as potential calcium antagonists in SX, and the combination of ligustrazine and senkyunolide A showed synergetic calcium antagonistic activity. Additionally, the synergetic mechanism was further investigated by live-imaging analysis with the Ca2+ indicator fluo-4/AM by monitoring fluorescence changes. Our results indicated that ligustrazine can block voltage-operated Ca2+ channels (VDCCs) effectively and senkyunolide A can exert an inhibition effect mostly on ryanodine receptors (RYRs) and partly on VDCCs. Finally, an arterial ring assay showed that the combination of ligustrazine and senkyunolide A exerted a better vasodilatation function than using any components alone. In this study, we first revealed that a pair of natural APIs in combination acting on VDCCs and RYRs was more effective on vasodilatation by regulating [Ca2+]i.

Synthesis of novel unsymmetrical coumarinyl-1,4-dihydropyridines

ABSTRACTThe novel unsymmetrical 3,5-dialkoxycarbonyl-2,6-dimethyl-4-(7′,8′-dimethoxycoumarin-4′-yl)-1,4-dihydropyridines and 5-acetyl-3-alkoxycarbonyl-2,6-dimethyl-4-(7′,8′-dimethoxycoumarin-4′-yl)-1,4-dihydropyridines (coumarinyl-1,4-dihydropyridines) have been synthesized by Knoevenagel condensation of 4-formyl-7,8-dimethoxycoumarin with alkyl acetoacetates in the presence of AlCl3 followed by cyclization of the resulted Knoevenagel product with other alkyl acetoacetate or acetyl acetone and ammonium acetate. The structure of the intermediate Knoevenagel product and the cyclized unsymmetrical coumarinyl-1,4-dihydropyridines has been established on the basis of their spectral data analysis and single-crystal X-ray diffraction analysis. The observed conformation of the coumarinyl-1,4-dihydropyridines holds the key to promising calcium antagonistic activity of the synthesized coumarinyl-1,4-dihydropyridines.

Roles of magnesium ions in vascular relaxation via calcium channel and cyclooxygenase pathway in isolated rat aorta

The impact of magnesium (Mg) on vascular tone is mainly due to its calcium antagonist activity resulting in smooth muscle relaxation. The present study was designed to determine the roles of nitric oxide and calcium ions in magnesium -induced vasorelaxation in rats aortic rings. In this study, the aorta contracted with NE (3x10-6M), pre-incubated with cyclooxygenase (COX) and epoxygenase inhibitors, then dose response curve(DRC) made to magnesium sulfate (MgSO4 ) served as a control. On the other hand, the aorta incubated with L-NAME (10 mM) ,nifedipine (10-5M) , indomethacin (10-5M) and clotrimazole (30 mM) for 20 minutes then contracted by nor-epinephrine (NE) and relaxed by MgSO4 doses. Interestingly, L-NAME shifted the DRC of MgSO4 to the left and elevated Emax significantly. Furthermore, p IC50 tended to increase in L-NAME pre-incubated aortic rings. Also, aortic rings that are pre-contracted with 10-6M NE in the absence of calcium ions shifted the DRC to the left but it significantly reduced pIC50. Furthermore, calcium channel blocker (Nifedipine) significantly reduced the relaxatory effects of magnesium ions and it markedly decreased Emax with altering pIC50 values significantly. The present results revealed that indomethacin pre-incubation slightly shifted the curve of MgSO4 to the right, while p IC50 was significantly increased and Emax did not significantly change in clotrimazole pre-incubation. In conclusions, the results of this study suggested that magnesium ions can probably relax aortic smooth muscles , and this is may be returned to in part to nitric oxide ,COX and epoxygenase enzyme pathways.

Evaluation of Usefulness of Propiverine Hydrochloride in Poor Responders to Previous Anticholinergics.

In recent years, some patients have been unresponsive to anticholinergics used in the treatment of pollakisuria/urinary incontinence. It has been suggested that propiverine hydrochloride, which has not only anticholinergic activity, but also calcium antagonistic activity, may be useful in poor responders to other anticholinergics. In this study, a specific drug use-results survey was conducted in poor responders to other anticholinergics to evaluate the usefulness of propiverine hydrochloride. In this survey, propiverine hydrochloride was administered for 12 weeks to poor responders to previous anticholinergics, and its usefulness was evaluated by the overactive bladder symptom score (OABSS). A total of 3851 subjects at 680 institutions were enrolled in the survey. Of the 3624 subjects included in the safety evaluation (male 1899, female 1725, mean age 73.4 years), 2932 were included in the efficacy evaluation (male 1610, female 1322, mean age 73.8 years). Propiverine hydrochloride significantly improved the OABSS without any safety concerns in poor responders to previous anticholinergics (OABSS, 8.22 at baseline, 6.50 at Week 4, 5.87 at Week 8, and 5.57 at Week 12, P < 0.001). The present findings indicate that propiverine hydrochloride may be a useful therapeutic option for poor responders to previous anticholinergics.

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

Synthesis, Evaluation of Pharmacological Activity, and Molecular Docking of 1,4-Dihydropyridines as Calcium Antagonists.

1,4-Dihydropyridine (DHP) is an important class of calcium antagonist. It inhibits the influx of extracellular Ca(2+) through L-type voltage-dependent calcium channels. Two series of nifedipine analogues were synthesized and evaluated as calcium antagonists. The ortho-nitrophenyl ring of nifedipine was replaced with an ortho- or a meta-chlorophenyl substituent. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution with groups of suitable bulkiness, such as ethyl ester, at the 3- and 5-positions of the DHP ring gave 3h, which is approximately three-fold more active than nifedipine as a calcium antagonist. A docking study with the DHP receptor model was performed to interpret the differences in calcium antagonist activities. The molecular docking study demonstrated that the lipophilicity of the substituted phenyl group at the 4-position of the DHP ring is an important factor that could increase the activity of the calcium antagonist taking the steric factor into consideration. Bulky groups interfere with ring-to-ring hydrophobic interaction with Tyr(1460) and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increase activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring may ensure strong binding to the receptor and hence stabilization of the closed-channel conformation.

Mechanism of Action, Efficacy, and Adverse Events of Calcium Antagonists in Hypertrophic Scars and Keloids: A Systematic Review.

Pathological scars often cause major cosmetic and functional consequences, which make effective treatment important. Intralesional therapies are widely used, with corticosteroid injection considered to be first choice. An emerging and promising treatment option is the calcium antagonist verapamil. To provide a comprehensive evidence-based review of current evidence on mechanism of action, efficacy, and adverse events of calcium antagonists in treatment of hypertrophic scars and keloids. A Cochrane Library and PubMed search was performed for the literature pertaining to treatment with calcium antagonists in pathological scars. Articles were categorized into two groups: mechanism of action or efficacy and adverse events. Six in vitro studies were included in the first subgroup. Calcium antagonists have been found to reduce extra cellular matrix production, induce procollagenase synthesis, and inhibit interleukin-6, vascular endothelial growth factor, and proliferation of fibroblasts. Eight studies with a median level of evidence of 3.5 (range: 2-4) were included in the second category. A good efficacy with no major side effects was reported for calcium antagonists. Important methodological shortcomings of the available literature were identified. Interesting results have been reported, but further large scale, high-quality studies are needed to optimally evaluate efficacy of treatment with calcium antagonists.

The Effect of Eqoul, a Metabolite of Isoflavone, on Endothelial Cell-independent Vasodilatation of Human Uterine Artery In Vitro.

BackgroundThe purpose of this study is to investigate 1) whether equol has the direct modulation on vascular tone of endothelium-denuded human uterine artery, and 2) if present, whether this equol-induced modulation of vascular tone is mediated by intracellular calcium modulation through Ca2+ & K+ channels on vascular smooth muscle cell membrane.MethodsThe uterine arteries were obtained at the time of hysterectomy from 15 women. The uterine smooth muscles were pretreated with phenylephrine, 10-5 M & high KCl solution 70 mM. The equol at 6 different concentrations from 10-11 to 10-6 M were used for the evaluation of modulatory action of equol on precontracted vascular smooth. The cumulative concentration-response for equol were determined on phenylephrine-induced contractions and compared with the results without pretreatment.ResultsEquol 10-11 to 10-6 M in concentration showed relaxation effect on vascular smooth muscle contraction which was induced by phenylephrine 10-5 M. This relaxation effect of equol was dose-dependent. Equol in same concentrations showed no significant effects on vascular smooth muscle contraction induced by high KCI solution. Phenylephrine-induced contraction was markedly reduced from 10-7 to 10-4 M in concentration by pretreatment of equol, but high KCI-induced contraction was not affected by pretreatment of equol.ConclusionsThis vasodilatation effect of equol may be induced by calcium antagonistic action, which was mediated through antagonistic action for receptor-dependent Ca2+ channel, but not for voltage-dependent Ca2+ channel. As far as we know, this is the first report of phytoestrogen equol on vascular reactivity of human vessels.

El papel del clevidipino en el tratamiento antihipertensivo: resultados clínicos

The prevalence of hypertension in general population is from 30% to 45%. Anesthesiologists frequently deal with the challenge of maintaining adequate control of perioperative blood pressure. On sudden elevations, a precise control is required to prevent end-organ damage. Recently, clevidipine, an ultra-short acting calcium antagonist has been approved by the FDA (www.accessdata.fda.gov), as a strategy for the intravenous treatment of hypertension; and by the Spanish Agency of Medicines and Medical Devices (www.aemps.gob.es) for the rapid reduction of arterial blood pressure in the perioperative setting. This medication has shown to have a rapid onset, easy titratability, and to exert a precise control of blood pressure. In addition, clevidipine has shown to be highly effective as monotherapy, and to have an excellent transition to oral antihypertensive therapy.For this article, an online search of the Medline literature was conducted up to February 2014 and «clevidipine» and «hypertension» used as keywords in order to analyze pharmacokinetics and pharmacodynamics of clevidipine. There are also clinical studies that provide evidence of the rapid and effective control that clevidipine has on blood pressure, especially in acute perioperative and emergency settings.

Total Synthesis of Marine Cyclopeptide Scytonemin A

Scytonemin A, a 34-membered cyclic undecapeptide with potent calcium-antagonistic activity, was isolated from a Scytonema sp. (strain U-3 – 3) by Moore and coworkers in 1988. The structure of the scytonemin A was determined by interpretation of spectral data, chemical degradation, and evaluation of the amino acids obtained by acid hydrolysis. However, the absolute configuration of one of the stereogenic centers presented within the side chain was not assigned. Both scytonemin A and its C-9 epimer were synthesized. The absolute stereochemistry of C9 of scytoenmin A was then assigned by extensive NMR studies of the two synthetic samples. The absolution configuration of scytoenmin A was also confirmed by further Chiral HPLC studies of the two synthetic materials along with the authentic sample. Detailed synthetic studies and stereochemical assignment/confirmation will be presented.

Calcium Channel Blocking Activity in Desmostachya bipinnata (L.) Explains its use in Gut and Airways Disorders

Desmostachya bipinnata, despite of its popular medicinal uses, has not been widely studied for its effect in diarrhea, indigestion, and asthma. The aim of the present investigation was to provide scientific rationale for these applications. The crude aqueous-methanolic extract of D. bipinnata (Db.Cr) was evaluated through in vivo and in vitro experiments. Db.Cr (100-500 mg/kg) protected mice against castor oil-induced diarrhea, similar to loperamide. When tested on gut preparations, Db.Cr produced an atropine-sensitive spasmogenic effect in rabbit jejunum up to 5 mg/mL, followed by a partial relaxation at 10 mg/mL. With atropine preincubation, a verapamil-like inhibitory effect was evident against spontaneous and high K(+) (80 mM)-induced contractions. The maximum stimulant effect was comparable with the acetylcholine-induced maximum contraction and was similarly reproducible in guinea pig ileum. Db.Cr inhibited carbachol (1 μM)-induced contraction in rabbit trachea but caused an atropine-sensitive accentuation of high K(+) -induced contraction at 0.003-0.3 mg/mL followed by inhibition at 1-5 mg/mL. On activity-directed fractionation, inhibitory effect was concentrated on organic and stimulant effect in aqueous fraction. This study, suggesting the presence of calcium antagonist activity, possibly underlying its medicinal effect in hyperactive gut and respiratory disorders, and cholinergic activity, possibly underlying its digestive effect, provides rationale for these therapeutic uses of D. bipinnata.

Action of calcium antagonists and agonists on isolated human thoracic arteries used for coronary artery bypass grafting

BackgroundThe goal of this study was to investigate the modulation of the contraction-relaxation effects in isolated human thoracic artery samples of three calcium-channel antagonists, amlodipine (CAS [88150-42-9]), cerebrocrast (CAS [118790-71-9]) and diltiazem (CAS [42399-41-7]), and two calcium-channel agonists, CGP 28392 (CAS [89289-93-0]) and benzimidazole derivative. To estimate the endothelial function of the artery samples, carbachol, an agonist of muscarinic receptors, was used. MethodsThe experiments were conducted on isolated human thoracic artery samples, and their isometric contractions were recorded using an i-FOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10−7 to 10−4M) were established. ResultsCarbachol at concentrations of 10−7 to 10−6M did not cause any relaxation of artery rings precontracted by 10−4M phenylephrine, and at concentrations of 10−5 and 10−4M, isometric contractions increased by 7% and 20%, respectively. In response to amlodipine, cerebrocrast and CGP28392, the contraction of artery samples increased significantly, whereas diltiazem and benzimidazole derivative caused their relaxation by ~55%. ConclusionThe obtained data indicate that the endothelium of the thoracic artery, which is used for coronary artery bypass grafting, is damaged by and may have some influence on the inadequate response of 1,4-dihydropyrine type calcium-channel antagonists.