Action Of Glycosides Research Articles

The significant role of glycosides in Leukemia: Mechanistic and Clinical prospects

Leukemia is a type of cancer that affects the lymphatic system and bone marrow. It is a heterogeneous disorder with two main types: acute and chronic leukemia. Acute leukemia is more aggressive and severe in children, whereas chronic leukemia mainly affects adults and is comparatively less aggressive. If left untreated, both types can lead to serious illness and even death. Although there are treatment options available such as chemotherapy, radiation therapy, immunotherapy, and the popular CART therapy, leukemia remains a challenging disease worldwide. These existing strategies have limitations, including frequent relapses and toxicity, which highlights the need to explore alternative therapeutic approaches. Glycosides, which are secondary metabolites found in plants, show promise as potential solutions. These substances have a wide range of therapeutic applications, high bioavailability, and low toxicity. They can be used to treat various diseases, both communicable and non-communicable, making them an intriguing class of drugs. However, further research is necessary to uncover their potential value in treating cancer, particularly leukemia. This study aims to investigate the mechanisms of action, effectiveness, and utilization of different glycosides in the treatment of leukemia, while considering the current limitations of existing therapies.

Sulfated Triterpene Glycosides from the Far Eastern Sea Cucumber Cucumaria djakonovi: Djakonoviosides C1, D1, E1, and F1; Cytotoxicity against Human Breast Cancer Cell Lines; Quantitative Structure-Activity Relationships.

Four new mono- and trisulfated triterpene penta- and tetraosides, djakonoviosides C1 (1), D1 (2), E1 (3), and F1 (4) were isolated from the Far Eastern sea cucumber Cucumaria djakonovi (Cucumariidae, Dendrochirotida), along with six known glycosides found earlier in other Cucumaria species. The structures of unreported compounds were established on the basis of extensive analysis of 1D and 2D NMR spectra as well as by HR-ESI-MS data. The set of compounds contains six different types of carbohydrate chains including two new ones. Thus, djakonovioside C1 (1) is characterized by xylose as the second residue, that was a branchpoint in the pentasaccharide chain. Meanwhile, only quinovose and rarely glucose have been found earlier in pentasaccharide chains branched at C-2 of the second sugar unit. Djakonovioside E1 (3) is characterized by a tetrasaccharide trisulfated chain, with glucose as the second residue. So, in the series of isolated glycosides, three types of sugars in the second position were presented: the most common, quinovose-in six compounds; glucose-in three substances; and the rare xylose-in one glycoside. The set of aglycones was composed of holostane- and non-holostane-type polycyclic systems; the latter comprised normal and reduced side chains. Noticeably, isokoreoside A (9), isolated from C. djakonovi, was a single glycoside having a 9(11)-double bond, indicating two oxidosqualenecyclases are operating in the process of the biosynthesis of aglycones. Some of the glycosides from C. djakonovi, which were characterized by pentasaccharide branched chains containing one to three sulfate groups, are chemotaxonomic features of the representatives of the genus Cucumaria. The assortment of sugar parts of Cucumaria's glycosides was broadened with previously undescribed penta- and tetrasaccharide moieties. The metabolic network of sugar parts and aglycones is constructed based on biogenetic relationships. The cytotoxic action of compounds 1-10, isolated from C. djakonovi, against human breast cancer cell lines was investigated along with the hemolytic activity. Erythrocytes were, as usual, more sensitive to the membranolytic action of the glycosides than cancer cells. The triple-negative breast cancer MDA-MB-231 cell line was more vulnerable to the action of glycosides in comparison with the other tested cancer cells, while the MCF-7 cell line was less susceptible to cytotoxic action. Djakonovioside E1 (3) demonstrated selective action against ER-positive MCF-7 and triple-negative MDA-MB-231 cell lines, while the toxic effect in relation to normal mammary epithelial cells (MCF-10A) was absent. Cucumarioside A2-5 (6) inhibited the formation and growth of colonies of cancer cells to 44% and tumor cell migration to 85% of the control. Quantitative structure-activity relationships (QSAR) were calculated on the basis of the correlational analysis of the physicochemical properties and structural features of the glycosidic molecules and their membranolytic activity. QSAR revealed the extremely complex nature of such relationships, but these calculations correlated well with the observed SAR.

Identification of pyrrolizidine alkaloids and flavonoid glycosides through HR-LCMS/MS analysis, biological screening, DFT and molecular docking studies on Heliotropium dasycarpum Ledeb.

The current study was carried out to reveal the chemical profile and biological screening of Heliotropium dasycarpum Ledeb, as well as the feasibility of its industrial application. Therefore, the methanolic extract (HdM) of H. dasycarpum was divided into n-hexane (HdH), ethyl acetate (HdE) and water (HdW) soluble fractions. All the fractions were inactive against acetylcholinesterase (AChE) enzyme, 3T3 and HeLa cell lines, but showed immunomodulatory effect up to 37 %. HdE fraction further displayed significant anti-urease activity with IC50 value of 74.072 ± 0.002, while HdM was found moderate inhibitor (63 %). Thus HdE was subjected to HR-LCMS/MS analysis in positive and negative ionization modes, and a qualitative analytical method with a data mining strategy was utilized. The secondary metabolites were identified by dereplication strategy using molecular networking as a bioinformatics tool, which disclosed the presence of 08 known alkaloids of heliotrine-type (1, 3, 5–10), and 05 (12–16) known flavonoids and flavonoid glycosides along with 03 new (2, 4 and 11) putative pyrrolizidine analogues. DFT simulations of identified compounds were performed using multiple quantum chemical and geometrical descriptors in order to determine their quantitative structure activity relationship. These secondary metabolites were docked against the enzyme urease which substantiated the inhibitory action of pyrrolizidine alkaloids and flavonoid glycosides. Furthermore, ADME analysis provided the base for the use of these compounds for further studies as drug leads and to unveil industrial application of H. dasycarpum in formulating products against gastritis, peptic ulcer and gastric cancer.

Investigation of the In Vivo Metabolism of Sibirioside A and Angoroside C in Rats by HPLC-ESI-IT-TOF-MSn.

Sibirioside A and angoroside C are two important phenylpropanoid glycosides of the traditional Chinese medicine Scrophulariae Radix. High performance liquid chromatography, coupled with an ion trap time-of-flight multistage mass spectrometry equipped with electrospray ionization source (HPLC-ESI-IT-TOF-MSn), was applied to the profile and we identified the metabolites of sibirioside A and angoroside C in vivo in rats. A total of four metabolites of sibirioside A were identified: SM1, SM2 and SM3 which were known as new compounds. A total of 25 metabolites were detected for angoroside C: AM4, AM5, AM6, AM7, AM16, AM17, AM20, AM21, AM22, AM23 and AM25 which were identified to be new compounds. The main metabolic reactions were hydrolysis, reduction, hydroxylation, methylation, sulfation, and gluconylation. The prototype of sibirioside A was widely distributed in tissues found in the heart, liver, spleen, lung, kidney, stomach and small intestine of rats, and mainly distributed in the stomach, small intestine, kidney and liver. But for angoroside C, nothing was found in the viscera except the stomach and small intestine. The metabolites of sibirioside A were mainly eliminated from feces, while it was urine for the metabolites of angoroside C. Furthermore, 19 metabolites were likely to have bioactivities based on the ‘PharmMapper’ analysis, which roughly matched the known pharmacological activities of Scrophulariae Radix (SR) and the prototypes. One of the main pharmacological activities of SR in traditional Chinese medicine is anti-diabetes, and the predicted results showed that SM1, SM2, SM3, AM2, AM4, AM5, AM6, AM9, AM10, AM11, AM12, AM13, AM15, AM18, AM19, AM24, and AM25 might be used to cure diabetes. These findings provide a reference for studying the metabolism, distribution and pharmacological actions of phenylpropanoid glycosides in vivo.

Characteristics of Eliciting Effects of Furostanol Glycosides on Cultured Yam Cells

To unravel mechanisms of elicitor action of furostanol glycosides (FGs), the formation of superoxide anion after the addition of FGs to a suspension culture of yam (Dioscorea deltoidea Wall. ex Griseb) cells was studied. The substantial increase in superoxide level, evaluated by nitroblue tetrazolium (NBT) reduction to formazan, was found at the exponential phase of cell growth. The involvement of NADPH oxidase in the superoxide generation was revealed by means of inhibitory analysis. Diphenyliodonium chloride (DPI), the inhibitor of NADPH oxidase, compromised the action of FGs. Meanwhile, the elimination of apoplastic peroxidase did not affect the accumulation of formazan, which suggests the involvement of NADPH oxidase but not peroxidase in the superoxide generation. In addition to NBT-test, the superoxide formation was judged by changes in activity of superoxide dismutase (SOD). Exogenous FGs activated the enzyme due to the increased production of superoxide anion. In this case, DPI decreased SOD activity that conforms to the NADPH oxidase involvement in the superoxide generation. The analysis of antioxidant activity of FGs by inhibition of radicals of 2,2-diphenyl-1-picrylhydrazyl showed that FGs are weak reductants in comparison with ascorbic acid. The results of the work allow for the suggestion that, supposing a weak reducing capacity of FGs, the special feature of their exogenous action on cultured yam cells is the increase in the level of superoxide anion radical mainly produced by NADPH oxidase.

IMPROVEMENT OF SEED PRODUCTIVITY IN PARENTAL LINES OF F1 HYBRYD IN HEAD CABBAGE UNDER AN EFFECT OF STEROID GLYCOSIDES

Development of F1 cabbage hybrids is concerned to difficulties of artificial pollination, low ability to developovary leading to low seed productivity in parental lines. The aim of the study is to improve the seed productivity of self-pollinated parental line 3/14C for F1 cabbage hybrid ‘Krasotka’. Secondary plant metabolites such as steroid glycosides can help overcome these difficulties and increase the seed productivity (Blandinskaya et al., 2013). 3/14C-line was propagated by backcrossing flowers in bud stage with artificial self-pollination, using water solutions of steroid glycosides ‘Moldstim’ and ‘Melongozid’ (in concentrations 0.1%, 0.01%, 0.001% and 0.0001%). Seed productivity was evaluated according to methods that were elaborated earlier (Bukharov A.F. et al., 2011, 2013). It was established that all parameters of seed formation and development were increased significantly under treatment of steroid glycosides ‘Moldstim’ and ‘Melongozid’ in mentioned concentration. Differences were significant at the 5%-level of significance. Concentration of 0.001% was more effective than other both preparations. These preparations stimulated all phases of seed development. Number of fruits was increased by 16-39%, a number of seeds per one the pod was also increased by 17-38%, mass of 1000 seeds was increased by 9-12%. Thus, the seed productivity of parental line 3/14C F1cabbage hybrid named ‘Krasotka’ was increased by 44 to 105% as result of the action of steroid glycosides. Thus, ‘Moldstim’ and ‘Melongozid’ in concentration of 0.001% can be recommend as physiological stimulators to improve seed productivity in parental lines necessary for development of F1 cabbage hybrids.

In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides.

The purpose of this study was to analyze the inhibitory action of quercetin glycosides by computational docking studies. For this, natural metabolite quercetin glycosides isolated from buckwheat and onions were used as ligand for molecular interaction. The crystallographic structure of molecular target angiotensin-converting enzyme (ACE) (peptidyl-dipeptidase A) was obtained from PDB database (PDB ID: 1O86). Enalapril, a well-known brand of ACE inhibitor was taken as the standard for comparative analysis. Computational docking analysis was performed using PyRx, AutoDock Vina option based on scoring functions. The quercetin showed optimum binding affinity with a molecular target (angiotensin-converting-enzyme) with the binding energy of −8.5 kcal/mol as compared to the standard (−7.0 kcal/mol). These results indicated that quercetin glycosides could be one of the potential ligands to treat hypertension, myocardial infarction, and congestive heart failure.

Pregnane glycosides interfere with steroidogenic enzymes to down‐regulate corticosteroid production in human adrenocortical H295R cells

A group of bioactive steroidal glycosides (pregnanes) with anorectic activity in animals was isolated from several genera of milkweeds including Hoodia and Asclepias. In this study, we investigated the effects, structure-activity relationships, and mechanism of action of pregnane glycosides on steroidogenesis in human adrenocortical H295R cells. Administration of pregnane glycosides for 24 h suppressed the basal and forskolin-stimulated release of androstenedione, corticosterone, and cortisone from H295R cells. The conversion of progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to either androstenedione or 11-deoxycortisol was most strongly affected, with 12-cinnamoyl-, benzoyl-, and tigloyl-containing pregnanes showing the highest activity. Incubation of pregnane glycosides for 24 h had no effect on mRNA transcripts of CYP11A1, CYP21A1, CYP11B1 cytochrome enzymes and steroidogenic acute regulatory protein (StaR) protein, yet resulted in twofold decrease in HSD3B1 mRNA levels. At the same time, pregnane glycosides had no effect on the CYP1, 2, or 3 drug and steroid metabolism enzymes and showed weak Na(+) /K(+) ATPase and glucocorticoid receptor binding. Taken together, these data suggest that pregnane glycosides specifically suppress steroidogenesis through strong inhibition of 11β-hydroxylase and steroid 17-alpha-monooxygenase, and weak inhibition of cytochrome P450 side chain cleavage enzyme and 21β-hydroxylase, but not 3β-hydroxysteroid dehydrogenase/isomerase.

Severity of the cardiac impairment determines whether digitalis prolongs or reduces survival of rats with heart failure due to myocardial infarction

BackgroundThe aim of the present study was to evaluate if the influence of digitalis on survival depends on the severity of cardiac dysfunction in heart failure (HF). Methods and resultsDoppler echocardiogram (DE) parameters were analyzed in 84 Wistar control (C) and 80 Wistar rats treated with 0.1mg/100g/day of digitoxin (D) five days after coronary occlusion. The DE variables correlated with the survival of the animals were: myocardial infarction size, left chamber dimensions, fractional area change and E/A ratio. The animals were observed for up to 280days. Mortality was worsened in rats in the D group with a myocardial infarction (MI)<37% and with better DE predictors of survival. Digitoxin was found to prolong survival in rats with an MI≥37% and worse DE predictors. ConclusionFor the first time our study has shown experimentally that the action of digitalis glycosides can positively or negatively influence survival during treatment of HF. It prolongs survival of those in advanced state and compromises survival when there is less severity of the disease. In fact, the greater benefits occur when digitoxin was used in heightened ventricular dilatations and worse ventricular performance.

Cytotoxic Action of Triterpene Glycosides from Sea Cucumbers from the genus Cucumaria on Mouse Spleen Lymphocytes. Inhibition of Nonspecific Esterase

Four triterpene glycosides from sea cucumbers belonging to the genus Cucumaria, okhotoside A(1)-1 (1), cucumarioside A(0)-1 (2), frondoside A (3) and cucumarioside A(2)-2 (4) inhibit the activity of nonspecific esterase of mouse spleen lymphocytes. The dependence of the inhibitory activity of the glycosides on their structure is similar to that for hemolytic activity. The absence of inhibitory activity for the preparation Cumaside, which is a complex of cucumarioside A(2)-2 and related compounds with cholesterol, shows a cholesterol-dependent character of the inhibitory action of the glycosides. The effective inhibitory concentrations of frondoside A and cucumarioside A(2)-2 are significantly higher than the immunomodulatory doses of these glycosides.

Antitumor activity and mechanisms of action of total glycosides from aerial part of Cimicifuga dahurica targeted against hepatoma

BackgroundMedicinal plant is a main source of cancer drug development. Some of the cycloartane triterpenoids isolated from the aerial part of Cimicifuga dahurica showed cytotoxicity in several cancer cell lines. It is of great interest to examine the antiproliferative activity and mechanisms of total triterpenoid glycosides of C. dahurica and therefore might eventually be useful in the prevention or treatment of Hepatoma.MethodsThe total glycosides from the aerial part (TGA) was extracted and its cytotoxicity was evaluated in HepG2 cells and primary cultured normal mouse hepatocytes by an MTT assay. Morphology observation, Annexin V-FITC/PI staining, cell cycle analysis and western blot were used to further elucidate the cytotoxic mechanism of TGA. Implanted mouse H22 hepatoma model was used to demonstrate the tumor growth inhibitory activity of TGA in vivo.ResultsThe IC50 values of TGA in HepG2 and primary cultured normal mouse hepatocytes were 21 and 105 μg/ml, respectively. TGA induced G0/G1 cell cycle arrest at lower concentration (25 μg/ml), and triggered G2/M arrest and apoptosis at higher concentrations (50 and 100 μg/ml respectively). An increase in the ratio of Bax/Bcl-2 was implicated in TGA-induced apoptosis. In addition, TGA inhibited the growth of the implanted mouse H22 tumor in a dose-dependent manner.ConclusionTGA may potentially find use as a new therapy for the treatment of hepatoma.

Central nervous system depressant action of flavonoid glycosides

The pharmacological effects on the central nervous system (CNS) of a range of available flavonoid glycosides were explored and compared to those of the glycosides 2 S-hesperidin and linarin, recently isolated from valeriana. The glycosides 2 S-neohesperidin, 2 S-naringin, diosmin, gossipyn and rutin exerted a depressant action on the CNS of mice following i.p. injection, similar to that found with 2 S-hesperidin and linarin. We demonstrate in this work that these behavioural actions, as measured in the hole board, thiopental induced sleeping time and locomotor activity tests, are unlikely to involve a direct action on γ-aminobutyric acid type A (GABA A) receptors. The corresponding aglycones were inactive, pointing to the importance of the sugar moieties in the glycosides in their CNS depressant action following systemic administration. The pharmacological properties of the flavonoid glycosides studied here, in addition to our previous results with hesperidin and linarin, opens a promising new avenue of research in the field.

Comparative Study of Effects of Various Sterols and Triterpenoids on Permeability of Model Lipid Membranes

Using permeability to labeled glucose as a criterion of stability for liposomal membranes, a comparative study on stabilizing properties of different sterols and triterpenes in phospholipid bilayer has been carried out as well as on structural peculiarities of sterols responsible for membranolytic properties of cucumarioside G1 from the cucumaria Eupentacta fraudatris. Stabilizing action of the studied sterols and triterpenoides incorporated in the bilayer decreases in the following order: cholesterol sulfate > cholesterol > Δ 5-sterols > β-sitosterol > ergosterols > Δ 7-sterols > epicholesterol > pregnane > androstane > coprosterol > 14α-methylcholest-9(11)-en-3β-ol > 4α, 14α-dimethylcholest-9(11)-en-3β-ol > holothurinogenin A1 > glucoside of cholesterol > β-xylosidase of Δ 7-sterols > betulin > protopanaxatriol > phosphatidylcholine liposomes without sterol > protopanaxadiol > oleanolic acid. Sterol-dependent membranolytic cucumarioside G1 practically loses its ability to increase permeability of phospholipid membranes containing sterols obtained from this holothuria as well as coprosterol, epicholestrol, sulfated and glycosylated forms of sterols. The obtained results confirm the “sterol” hypothesis of the mechanism of membranotropic action of holothuria glycosides and of resistance to them of holothuria cell membranes.

Myocardial Na,K-ATPase: the molecular basis for the hemodynamic effect of digoxin therapy in congestive heart failure.

Congestive heart failure may be deemed the epidemic of cardiology in the 21st century in the industrialized part of the world. Although new therapies improving morbidity and mortality from chronic heart failure have emerged it is likely that there is a growing role for digoxin. Thus, digoxin treatment is known to control symptoms of congestive heart failure when added to standard therapy. In this setting, we review the prevailing knowledge of the Na,K-ATPase, the cellular receptor for the inotropic action of digitalis glycosides, in relation to the hemodynamic effect of digoxin. It is concluded that if improvement of hemodynamics is needed in congestive heart failure, this knowledge should be taken into account and in many cases digoxin should be added to standard therapy. Digoxin is still the only safe inotropic drug for oral use that improves hemodynamics. Digoxin should be used to heart failure patients in sinus rhythm when they after institution of mortality reducing treatment still have heart failure symptoms, and to patients intolerant to heart failure mortality reducing drugs. Digoxin should probably in heart failure patients with sinus rhythm be given in the lowest possible dose that relieves symptoms sufficiently.

Activation of cardiac ryanodine receptors by cardiac glycosides.

This study investigated the effects of cardiac glycosides on single-channel activity of the cardiac sarcoplasmic reticulum (SR) Ca2+ release channels or ryanodine receptor (RyR2) channels and how this action might contribute to their inotropic and/or toxic actions. Heavy SR vesicles isolated from canine left ventricle were fused with artificial planar lipid bilayers to measure single RyR2 channel activity. Digoxin and actodigin increased single-channel activity at low concentrations normally associated with therapeutic plasma levels, yielding a 50% of maximal effect of approximately 0.2 nM for each agent. Channel activation by glycosides did not require MgATP and occurred only when digoxin was applied to the cytoplasmic side of the channel. Similar results were obtained in human RyR2 channels; however, neither the crude skeletal nor the purified cardiac channel was activated by glycosides. Channel activation was dependent on [Ca2+] on the luminal side of the bilayer with maximal stimulation occurring between 0.3 and 10 mM. Rat RyR2 channels were activated by digoxin only at 1 microM, consistent with the lower sensitivity to glycosides in rat heart. These results suggest a model in which RyR2 channel activation by digoxin occurs only when luminal [Ca2+] was increased above 300 microM (in the physiological range). Consequently, increasing SR load (by Na+ pump inhibition) serves to amplify SR release by promoting direct RyR2 channel activation via a luminal Ca2+-sensitive mechanism. This high-affinity effect of glycosides could contribute to increased SR Ca2+ release and might play a role in the inotropic and/or toxic actions of glycosides in vivo.

The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides.

The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na+-Ca2+ exchange activity secondary to Na+ pump inhibition. However, proof of this model is lacking and alternative mechanisms have been proposed. We directly tested the role of the Na+-Ca2+ exchanger in the action of the glycoside ouabain using Na+-Ca2+ exchanger knockout mice. Ablation of the exchanger is embryonic lethal, but contractility can be studied in embryonic heart tubes at day 9.5 postcoitum. Heart tubes isolated from homozygous Na+-Ca2+ exchanger knockout mice (NCX-/-) display surprisingly normal Ca2+ transients. Removal of extracellular Na+ induces Ca2+ overload in wild-type heart tubes but does not alter the Ca2+ transients of NCX-/- heart tubes. Similarly, ouabain, at levels causing Ca2+ overload in wild-type heart tubes, has no effect on NCX-/- heart tubes. We conclude that in embryonic mouse myocytes the Na+-Ca2+ exchanger is absolutely required for the effect of cardiac glycosides on Ca2+(i).

Hypotensive action of coumarin glycosides from Daucus carota.

Daucus carota (carrot) has been used in traditional medicine to treat hypertension. Activity-directed fractionation of aerial parts of D. carota resulted in the isolation of two cumarin glycosides coded as DC-2 and DC-3. Intravenous administration of these compounds caused a dose-dependent (1-10 mg/kg) fall in arterial blood pressure in normotensive anaesthetised rats. In the in vitro studies, both compounds caused a dose-dependent (10-200 microg/ml) inhibitory effect on spontaneously beating guinea pig atria as well as on the K+ -induced contractions of rabbit aorta at similar concentrations. These results indicate that DC-2 and DC-3 may be acting through blockade of calcium channels and this effect may be responsible for the blood pressure lowering effect of the compounds observed in the in vivo studies.

Application of Morphological Trends of Evolution to Phylogenetic Interpretation of Chemotaxonomic Data

Data on the membranotropic action of triterpene glycosides from sea cucumbers ( Holothurioidea, Echindermata) are used as a model for studying the evolution of biochemical adaptations. Conceptions such as the theory of modes of organogenesis, and the theory of phylembryogeneses developed by the Russian school of evolutionary morphology, and other morphological trends of evolutionary transformations of anatomical structures are applicable to the phylogenetic interpretation of chemotaxonomic data. The processes of ontogenesis and biosynthesis of secondary metabolites are compared within the framework of the theory of phylembryogeneses. The deep inner similarity of these processes are shown. Concurrence of the modes of phyembryogenesis noted by Severtsov and the principles of micromolecular evolution noted by Gottlieb and Harborne are also shown. The biological significance of presence or absence of substances, (or some features of these substances) for the whole organism that produced them is the main criterion we propose as an approach for polarization of a biochemical phylogenetic series. The application of methods of comparative anatomy to the molecular level for purposes of investigation on evolution of biomolecules and their functions could be called “chemical morphology”.

Influence of cycloartanes from plants of the genusAstragalus and their synthetic analogs on the contractive function of the myocardium and the activity of Na,K-ATPase

An evaluation has been mde of the cardiotonic activities of cycloartane methylsteroids isolated from plants of the genusAstragalus and their synthetic analogs. It has been established that the compounds investigated exhibit a positive inotropic effect expressed to different degrees. The mechanism of the realization of the positive inotropic action of cycloartane glycosides differs from that of cardiosteroid drugs.

The effects of the purinergic system on digitalis-induced epileptiform activity.

It has been suggested that endogenous chemical substances, such as adenosine, released during a seizure attack, may act as anticonvulsants in vivo. We have investigated electrophysiologically the effects of purinoceptor agonists and antagonists on the epileptiform activity induced by intracortical digitalis in anesthetized rats. Intracortical injections of 1, 2, or 4 micrograms digitalis (desacetyl lanatocid C) caused an epileptiform electrocorticogram (ECoG). The application of adenosine (25 or 100 microM) or adenosine triphosphate (ATP) (3 mM) after desacetyl lanatocid C blocked the epileptiform activity. beta, gamma-Methylene ATP (0.1-0.8 mM), a stable analog of ATP, produced inhibition and then death. The epileptogenic effect of desacetyl lanatocid C was enhanced by theophylline (1 mM); however, suramin (1 mM) changed the pattern of epilepsy. These results indicate that the purinergic system may be involved in the mechanism of action of digitalis glycosides.