Pharmacology of RG W-2938: a cardiotonic agent with vasodilator activity.

PubMed

Barrett, J A; Woltmann, R F; Swillo, R S; Kasiewski, C; Faith, W C; Campbell, H F; Perrone, M H

1990-10-01

The cardiovascular effects of RG W-2938, 6-[6-(3,4-dihydro-3-methyl-2(1H)-2-oxoquinazolinyl)]-4,5-dihydro-3 (2H-pyridazinone, a new nonglycoside, noncatecholamine cardiotonic/vasodilator agent were examined in vivo in anesthetized and conscious dogs and in vitro in isolated guinea pig hearts; in the latter, RG W-2938 5 nmol-5 mumol increased contractility in a dose-related fashion. RG W-2938 30-300 micrograms/kg administered intravenously (i.v.) to anesthetized dogs increased contractile force while decreasing arterial pressure and total peripheral resistance (TPR) in a dose-related manner. Heart rate (HR) was only slightly increased, and aortic flow was not appreciably altered. A single oral dose of RG W-2938 0.3 mg/kg administered to conscious chronically instrumented dogs produced a marked and sustained increase in contractility 15-240 min after treatment while only slightly increasing HR. The effects of RG W-2938 30-300 micrograms/kg, i.v. were studied in a mecamylamine-propranolol-induced model of heart failure. RG W-2938 effectively reversed the drug-induced heart failure by increasing myocardial contractility and decreasing arterial pressure while only slightly affecting HR. These studies show that RG W-2938 is an orally effective positive inotropic/vasodilator agent.

Specialized Functional Diversity and Interactions of the Na,K-ATPase

PubMed Central

Matchkov, Vladimir V.; Krivoi, Igor I.

2016-01-01

Na,K-ATPase is a protein ubiquitously expressed in the plasma membrane of all animal cells and vitally essential for their functions. A specialized functional diversity of the Na,K-ATPase isozymes is provided by molecular heterogeneity, distinct subcellular localizations, and functional interactions with molecular environment. Studies over the last decades clearly demonstrated complex and isoform-specific reciprocal functional interactions between the Na,K-ATPase and neighboring proteins and lipids. These interactions are enabled by a spatially restricted ion homeostasis, direct protein-protein/lipid interactions, and protein kinase signaling pathways. In addition to its “classical” function in ion translocation, the Na,K-ATPase is now considered as one of the most important signaling molecules in neuronal, epithelial, skeletal, cardiac and vascular tissues. Accordingly, the Na,K-ATPase forms specialized sub-cellular multimolecular microdomains which act as receptors to circulating endogenous cardiotonic steroids (CTS) triggering a number of signaling pathways. Changes in these endogenous cardiotonic steroid levels and initiated signaling responses have significant adaptive values for tissues and whole organisms under numerous physiological and pathophysiological conditions. This review discusses recent progress in the studies of functional interactions between the Na,K-ATPase and molecular microenvironment, the Na,K-ATPase-dependent signaling pathways and their significance for diversity of cell function. PMID:27252653

Antisolvent crystallization of a cardiotonic drug in ionic liquids: Effect of mixing on the crystal properties

NASA Astrophysics Data System (ADS)

de Azevedo Jacqueline, Resende; Fabienne, Espitalier; Jean-Jacques, Letourneau; Inês, Ré Maria

2017-08-01

LASSBio-294 (3,4-methylenedioxybenzoyl-2-thienylhydrazon) is a poorly soluble drug which has been proposed to have major advantages over other cardiotonic drugs. Poorly water soluble drugs present limited bioavailability due to their low solubility and dissolution rate. An antisolvent crystallization processing can improve the dissolution rate by decreasing the crystals particle size. However, LASSBio-294 is also poorly soluble in organic solvents and this operation is limited. In order to open new perspectives to improve dissolution rate, this work has investigated LASSBio-294 in terms of its antisolvent crystallization in 1-ethyl-3-methylimidazolium methyl phosphonate [emim][CH3O(H)PO2] as solvent and water as antisolvent. Two modes of mixing are tested in stirred vessel with different pre-mixers (Roughton or T-mixers) in order to investigate the mixing effect on the crystal properties (crystalline structure, particle size distribution, residual solvent and in vitro dissolution rate). Smaller drug particles with unchanged crystalline structure were obtained. Despite the decrease of the elementary particles size, the recrystallized particles did not achieve a better dissolution profile. However, this study was able to highlight a certain number of findings such as the impact of the hydrodynamic conditions on the crystals formation and the presence of a gel phase limiting the dissolution rate.

Phytochemical and pharmacological activity profile of Crataegus oxyacantha L. (hawthorn) - A cardiotonic herb.

PubMed

Orhan, Ilkay Erdogan

2016-09-18

Crataegus oxyacantha L. (syn. C. rhipidophylla Gand.) (Rosaceae) is one of two medicinally recognized hawthorn species in European Pharmacopeia. Standardization of the extract prepared from the berry and flowers of the plant is required according to its oligomeric procyanidins. C. oxyacantha is well-known for its use in the treatment of various heart problems particularly, including heart failure in cases of declining cardiac performance equivalent to stages I and II of the New York Heart Association classification, angina pectoris, hypertension with myocardial insufficiency, mild alterations of cardiac rhythm, and atherosclerosis. C. oxyacantha has been reported to exert several other pharmacological activities such as hypotensive, antihyperlipidemic, antihyperglycemic, anxiolytic, immunomodulatory, and antimutagenic. Oligomeric procyanidins and flavone/flavonol types of flavonoids, which are considered to be the chief groups of active substances, phenolic acids, triterpenes, fatty acids, and sterols are present in the plant. The present review aims mainly to outline cardiotonic effect of C. oxyacantha as well as its brief phytochemistry. Numerous experiments and clinical studies have underlined cardiovascular efficacy of the plant through various mechanisms including positive inotropic and negative chronotropic effects, escalation in coronary blood flow and exercise tolerance, inhibition of the enzymes such as angiotensin-converting enzyme (ACE) and phosphodiesterase, anti-inflammatory and antihyperlipidemic effects, improving status of antioxidant enzymes, etc., which support its cardioactive efficacy. The plant possesses several other bioactivities for human health usually concomitant to its rich polyphenolic content.

An updated review on the parasitic herb of Cuscuta reflexa Roxb.

PubMed

Patel, Satish; Sharma, Vikas; Chauhan, Nagendra S; Dixit, Vinod K

2012-03-01

Cuscuta reflexa Roxb. is a golden yellow, leafless, perennial, parasitic herb of the family Convolvulaceae. C. reflexa has been investigated for antispasmodic, hemodynamic, anticonvulsant, anti steroidogenic, antihypertensive, muscle relaxant, cardiotonic, antiviral, antibacterial, antioxidant, cholinergic, diuretic and hair growth activities. Many chemical constituents have been isolated from C. reflexa such as cuscutin, amarbelin, β-sitosterol, stigmasterol, kaempferol, dulcitol, myricetin, quercetin, coumarin and oleanolic acid. This review presents a detailed survey of the literature on pharmacognosy, phytochemistry and traditional and biological medicinal uses of C. reflexa.

Hellebrin and its aglycone form hellebrigenin display similar in vitro growth inhibitory effects in cancer cells and binding profiles to the alpha subunits of the Na+/K+-ATPase

PubMed Central

2013-01-01

Background Surface-expressed Na+/K+-ATPase (NaK) has been suggested to function as a non-canonical cardiotonic steroid-binding receptor that activates multiple signaling cascades, especially in cancer cells. By contrast, the current study establishes a clear correlation between the IC50in vitro growth inhibitory concentration in human cancer cells and the Ki for the inhibition of activity of purified human α1β1 NaK. Methods The in vitro growth inhibitory effects of seven cardiac glycosides including five cardenolides (ouabain, digoxin, digitoxin, gitoxin, uzarigenin-rhamnoside, and their respective aglycone forms) and two bufadienolides (gamabufotalin-rhamnoside and hellebrin, and their respective aglycone forms) were determined by means of the MTT colorimetric assay and hellebrigenin-induced cytotoxic effects were visualized by means of quantitative videomicroscopy. The binding affinity of ten of the 14 compounds under study was determined with respect to human α1β1, α2β1 and α3β1 NaK complexes. Lactate releases and oxygen consumption rates were also determined in cancer cells treated with these various cardiac glycosides. Results Although cardiotonic steroid aglycones usually display weaker binding affinity and in vitro anticancer activity than the corresponding glycoside, the current study demonstrates that the hellebrin / hellebrigenin pair is at odds with respect to this rule. In addition, while some cardiac steroid glycosides (e.g., digoxin), but not the aglycones, display a higher binding affinity for the α2β1 and α3β1 than for the α1β1 complex, both hellebrin and its aglycone hellebrigenin display ~2-fold higher binding affinity for α1β1 than for the α2β1 and α3β1 complexes. Finally, the current study highlights a common feature for all cardiotonic steroids analyzed here, namely a dramatic reduction in the oxygen consumption rate in cardenolide- and bufadienolide-treated cells, reflecting a direct impact on mitochondrial oxidative phosphorylation. Conclusions Altogether, these data show that the binding affinity of the bufadienolides and cardenolides under study is usually higher for the α2β1 and α3β1 than for the α1β1 NaK complex, excepted for hellebrin and its aglycone form, hellebrigenin, with hellebrigenin being as potent as hellebrin in inhibiting in vitro cancer cell growth. PMID:23621895

Cardiotonic steroid ouabain stimulates expression of blood-testis barrier proteins claudin-1 and -11 and formation of tight junctions in Sertoli cells.

PubMed

Dietze, Raimund; Shihan, Mazen; Stammler, Angelika; Konrad, Lutz; Scheiner-Bobis, Georgios

2015-04-15

The interaction of ouabain with the sodium pump induces signalling cascades resembling those triggered by hormone/receptor interactions. In the rat Sertoli cell line 93RS2, ouabain at low concentrations stimulates the c-Src/c-Raf/Erk1/2 signalling cascade via its interaction with the α4 isoform of the sodium pump expressed in these cells, leading to the activation of the transcription factor CREB. As a result of this signalling sequence, ouabain stimulates expression of claudin-1 and claudin-11, which are also controlled by a CRE promoter. Both of these proteins are known to be essential constituents of tight junctions (TJ) between Sertoli cells, and as a result of the ouabain-induced signalling TJ formation between neighbouring Sertoli cells is significantly enhanced by the steroid. Thus, ouabain-treated cell monolayers display higher transepithelial resistance and reduced free diffusion of FITC-coupled dextran in tracer diffusion assays. Taking into consideration that the formation of TJ is indispensable for the maintenance of the blood-testis barrier (BTB) and therefore for male fertility, the actions of ouabain described here and the fact that this and other related cardiotonic steroids (CTS) are produced endogenously suggest a direct influence of ouabain/sodium pump interactions on the maintenance of the BTB and thereby an effect on male fertility. Since claudin-1 and claudin-11 are also present in other blood-tissue barriers, one can speculate that ouabain and perhaps other CTS influence the dynamics of these barriers as well. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

PubMed Central

Sjögren, Benita; Parra, Sergio; Heath, Lauren J.; Atkins, Kevin B.; Xie, Zie-Jian

2012-01-01

Regulator of G protein signaling 2 (RGS2), a Gq-specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(−/−) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a β-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2- to 3-fold. Na+/K+-ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na+/K+-ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, Gq-dependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTS-induced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy. PMID:22695717

Electrophysiological effects of FK664, a new cardiotonic agent, on preparations from guinea pig ventricle and from rabbit sino-atrial node.

PubMed

Kodama, I; Anno, T; Sudo, Y; Satake, N; Shibata, S

1989-05-01

Effects of the cardiotonic agent FK664, 6-(3, 4-dimethoxy-phenyl)-1-ethyl-4-mesitylimino-3-methyl-3,4-dihydro-2 (1H)-pyrimidone, on isolated guinea pig ventricular muscles and rabbit sinus node pacemaker cells were studied using micro-electrode techniques. In ventricular muscles driven at 0.5-1.0 Hz, FK664 above 3 mumol.litre-1 caused an increase in contractile force and a shortening of time to peak tension. This positive inotropic effect of FK664 was accompanied by a slight elevation of the early plateau phase of the action potential, while other action potential variables were unaffected. The change in contractile force induced by FK664 was abolished in a low Ca2+ medium (0.12 mmol.litre-1) or by treatment with ryanodine (2 mumol.litre-1), whereas it was relatively well preserved in the preparations pretreated with nefedipine (1 mumol.litre-1). The slow action potentials induced by isoprenaline (0.3 mumol.litre-1) in high K+ medium (30 mmol.litre-1) and the slow inward current measured by single sucrose gap voltage clamp at a holding potential of -40 mV were unaffected by FK664. In sinus node pacemaker cells, FK664 (1-10 mumol.litre-1) caused a dose dependent acceleration of phase 4 depolarisation and a shortening of spontaneous firing cycle length. This positive chronotropic effect of FK664 was markedly inhibited in a low Ca2+ medium (0.3 mmol.litre-1). These findings suggest that FK664 has positive inotropic and chronotropic effects on the heart, due to an enhancement of transsarcolemmal calcium influx through the low threshold, dihydropyridine insensitive Ca2+ channel population.

Spin-labeled derivatives of cardiotonic steroids as tools for characterization of the extracellular entrance to the binding site on Na+ ,K+ -ATPase.

PubMed

Guo, Jin-Hua; Jiang, Ren-Wang; Andersen, Jacob Lauwring; Esmann, Mikael; Fedosova, Natalya U

2018-04-24

The information obtained from crystallized complexes of the Na + ,K + -ATPase with cardiotonic steroids (CTS) is not sufficient to explain differences in the inhibitory properties of CTS such as stereoselectivity of CTS binding or effect of glycosylation on the preference to enzyme isoforms. The uncertainty is related to the spatial organization of the hydrophilic cavity at the entrance of the CTS-binding site. Therefore, there is a need to supplement the crystallographic description with data obtained in aqueous solution, where molecules have significant degree of flexibility. This work addresses the applicability of the electron paramagnetic resonance (EPR) method for the purpose. We have designed and synthesized spin-labeled compounds based on the cinobufagin steroid core. The length of the spacer arms between the steroid core and the nitroxide group determines the position of the reporting group (N-O) confined to the binding site. High affinity to Na + ,K + -ATPase is inferred from their ability to inhibit enzymatic activity. The differences between the EPR spectra in the absence and presence of high ouabain concentrations identify the signature peaks originating from the fraction of the spin labels bound within the ouabain site. The degree of perturbations of the EPR spectra depends on the length of the spacer arm. Docking of the compounds into the CTS site suggests which elements of the protein structure might be responsible for interference with the spin label (e.g., steric clashes or immobilization). Thus, the method is suitable for gathering information on the cavity leading to the CTS-binding site in Na + ,K + -ATPase in all conformations with high affinity to CTS. © 2018 Federation of European Biochemical Societies.

AdE-1, a new inotropic Na(+) channel toxin from Aiptasia diaphana, is similar to, yet distinct from, known anemone Na(+) channel toxins.

PubMed

Nesher, Nir; Shapira, Eli; Sher, Daniel; Moran, Yehu; Tsveyer, Liora; Turchetti-Maia, Ana Luiza; Horowitz, Michal; Hochner, Binyamin; Zlotkin, Eliahu

2013-04-01

Heart failure is one of the most prevalent causes of death in the western world. Sea anemone contains a myriad of short peptide neurotoxins affecting many pharmacological targets, several of which possess cardiotonic activity. In the present study we describe the isolation and characterization of AdE-1 (ion channel modifier), a novel cardiotonic peptide from the sea anemone Aiptasia diaphana, which differs from other cnidarian toxins. Although AdE-1 has the same cysteine residue arrangement as sea anemone type 1 and 2 Na(+) channel toxins, its sequence contains many substitutions in conserved and essential sites and its overall homology to other toxins identified to date is low (<36%). Physiologically, AdE-1 increases the amplitude of cardiomyocyte contraction and slows the late phase of the twitch relaxation velocity with no induction of spontaneous twitching. It increases action potential duration of cardiomyocytes with no effect on its threshold and on the cell's resting potential. Similar to other sea anemone Na(+) channel toxins such as Av2 (Anemonia viridis toxin II), AdE-1 markedly inhibits Na(+) current inactivation with no significant effect on current activation, suggesting a similar mechanism of action. However, its effects on twitch relaxation velocity, action potential amplitude and on the time to peak suggest that this novel toxin affects cardiomyocyte function via a more complex mechanism. Additionally, Av2's characteristic delayed and early after-depolarizations were not observed. Despite its structural differences, AdE-1 physiologic effectiveness is comparable with Av2 with a similar ED(50) value to blowfly larvae. This finding raises questions regarding the extent of the universality of structure-function in sea anemone Na(+) channel toxins.

Femtosecond dynamics of a cardiotonic medicine (milrinone) in neutral water

NASA Astrophysics Data System (ADS)

Gil, M.; Douhal, A.

2006-09-01

Milrinone is a medicine used to attenuate heart attack disease. Understanding its interaction with water is of importance for the knowledge of its stability and related phenomena. This intimate information requires the unraveling of the dynamics under the physiological conditions. Here we report the first study of ultrafast processes of this medicine. We show that S 2 relaxation of the keto structure (K) occurs in ˜150 fs and the intramolecular-charge transfer reaction in less than 100 fs to produce a relaxed CT-K state. An observed ˜10 ps decay is assigned to vibrational relaxation/cooling and twisting in the formed CT-K.

Mangifera Indica (Mango)

PubMed Central

Shah, K. A.; Patel, M. B.; Patel, R. J.; Parmar, P. K.

2010-01-01

Mangifera indica, commonly used herb in ayurvedic medicine. Although review articles on this plant are already published, but this review article is presented to compile all the updated information on its phytochemical and pharmacological activities, which were performed widely by different methods. Studies indicate mango possesses antidiabetic, anti-oxidant, anti-viral, cardiotonic, hypotensive, anti-inflammatory properties. Various effects like antibacterial, anti fungal, anthelmintic, anti parasitic, anti tumor, anti HIV, antibone resorption, antispasmodic, antipyretic, antidiarrhoeal, antiallergic, immunomodulation, hypolipidemic, anti microbial, hepatoprotective, gastroprotective have also been studied. These studies are very encouraging and indicate this herb should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using mango for a variety of conditions should also be conducted. PMID:22228940

Cardiotonic steroids trigger non-classical testosterone signaling in Sertoli cells via the α4 isoform of the sodium pump.

PubMed

Konrad, Lutz; Dietze, Raimund; Kirch, Ulrike; Kirch, Herbert; Eva, Alexander; Scheiner-Bobis, Georgios

2011-12-01

The α4 isoform of the Na(+),K(+)-ATPase (sodium pump) is known to be expressed in spermatozoa and to be critical for their motility. In the investigation presented here, we find that the rat-derived Sertoli cell line 93RS2 also expresses considerable amounts of the α4 isoform in addition to the α1 isoform. Since Sertoli cells are not motile, one can assume that the function of the α4 isoform in these cells must differ from that in spermatozoa. Thus, we assessed a potential involvement of this isoform in signaling pathways that are activated by the cardiotonic steroid (CTS) ouabain, a highly specific sodium pump ligand. Treatment of 93RS2 cells with ouabain leads to activation of the c-Src/c-Raf/Erk1/2 signaling cascade. Furthermore, we show for the first time that the activation of this cascade by ouabain results in phosphorylation and activation of the transcription factor CREB. This signaling cascade is induced at low nanomolar concentrations of ouabain, consistent with the involvement of the α4 isoform. This is further supported by experiments involving siRNA: silencing of α4 expression entirely blocks ouabain-induced activation of Erk1/2 whereas silencing of α1 has no effect. The findings of this study unveil new aspects in CTS/sodium pump interactions by demonstrating for the first time ouabain-induced signaling through the α4 isoform. The c-Src/c-Raf/Erk1/2/CREB cascade activated by ouabain is identical to the so-called non-classical signaling cascade that is normally triggered in Sertoli cells by testosterone. Taking into consideration that CTS are produced endogenously, our results may help to gain new insights into the physiological mechanisms associated with male fertility and reproduction. Copyright © 2011 Elsevier B.V. All rights reserved.

Crataegus tanacetifolia leaf extract prevents L-NAME-induced hypertension in rats: a morphological study.

PubMed

Koçyildiz, Z Celebi; Birman, H; Olgaç, V; Akgün-Dar, K; Melikoğlu, G; Meriçli, A H

2006-01-01

Crataegus (hawthorn) has long been used as a folk medicine all around the world. Most of the studies with Crataegus species focus on effects on heart failure and cardiovascular disease. The pharmacological effects of Crataegus have been attributed mainly to the content of flavonoids, procyanidin, aromatic acid and cardiotonic amines. The present study investigated the blood pressure and the structure of the coronary arterial wall of L-NAME-induced hypertensive rats given an aqueous leaf extract of C. tanacetifolia (100 mg/kg), for 4 weeks via gavage. It was observed that C. tanacetifolia, especially the hyperoside fraction, prevented L-NAME-induced hypertension in rats and had beneficial effects on the cardiovascular system. Copyright 2006 John Wiley & Sons, Ltd.

Effect of lemongrass water extract supplementation on atherogenic index and antioxidant status in rats.

PubMed

Somparn, Nuntiya; Saenthaweeuk, Suphaket; Naowaboot, Jarinyaporn; Thaeomor, Atcharaporn; Kukongviriyapan, Veerapol

2018-06-01

Cymbopogon citratus (DC) Stapf., commonly known as lemongrass, possesses strong antioxidant and cardiotonic properties. Lemongrass water extract contains several polyphenolic compounds including gallic acid, isoquercetin, quercetin, rutin, catechin and tannic acid. Rutin, isoquercetin catechin and quercetin are the flavonoids most abundantly found in the extract. The extract significantly decreased total cholesterol, low-density lipoprotein and atherogenic index in rats after treatment (p < 0.05). Expression of genes and protein of sterol regulatory element binding protein-1c (SREBP1c) and HMG-CoA reductase (HMGR) was also lowered significantly in treated groups (p < 0.05). Moreover, serum antioxidant capacity increased in treated rats in comparison with untreated ones (p < 0.05) and was associated with decreased serum lipid peroxidation.

Cholinergic aspects of cyanide intoxication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Von Bredow, J.D.; Vick, J.A.

1993-05-13

The acute exposure of pentobarbital anesthetized dogs to cyanide leads to a rapid increase and sudden halt in respiration accompanied by cardiovascular irregularities and extreme bradycardia which ultimately lead to cardiac arrest and death. Cardiac irregularities and cardiac arrest in the presence of cyanide induced respiratory arrest are assumed to be due to anoxia and therefore unresponsive to cardiotonic agents. Pretreatment or treatment with atropine sulfate or methyl atropine nitrate provides a marked reduction in the cardiovascular irregularities, bradycardia and hypotension. The cyanide induced cardiovascular effect can also be prevented by bilateral vagotomy. An intramuscularly injected combination of 20 mg/kgmore » sodium nitrite and 1 mg/kg of atropine sulfate ensured recovery of pentobarbital anesthetized dogs exposed to lethal concentrations (2.5 mg/kg i.v.) of sodium cyanide.« less

Analysis of beat fluctuations and oxygen consumption in cardiomyocytes by scanning electrochemical microscopy.

PubMed

Hirano, Yu; Kodama, Mikie; Shibuya, Masahiro; Maki, Yoshiyuki; Komatsu, Yasuo

2014-02-15

The contractile behavior of cardiomyocytes can be monitored by measuring their action potentials, and the analysis is essential for screening the safety of potential drugs. However, immobilizing cardiac cells on a specific electrode is considerably complicated. In this study, we demonstrate that scanning electrochemical microscopy (SECM) can be used to analyze rapid topographic changes in beating cardiomyocytes in a standard culture dish. Various cardiomyocyte contraction parameters and oxygen consumption based on cell respiration could be determined from SECM data. We also confirmed that cellular changes induced by adding the cardiotonic agent digoxin were conveniently monitored by this SECM system. These results show that SECM can be a potentially powerful tool for use in drug development for cardiovascular diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

Preparative isolation of oligomeric procyanidins from Hawthorn (Crataegus spp.).

PubMed

Zumdick, S; Petereit, F; Luftmann, H; Hensel, A

2009-04-01

The oligomeric procyanidins (OPC) from Hawthorn leaves and flowers (Crataegi folium cum flore) are considered to be in part responsible for the cardiotonic clinical activity of the herbal material. Effective methods for rapid isolation of these heterogenous oligomeric clusters with defined molecular weight as reference compounds are not published until now. Therefore the water soluble fraction of an acetone/water (7 + 3) extract of Hawthorn leaves and flowers was fractionated by a combination of MPLC on RP-18 material and preparative HPLC using a diol stationary phase. This procedure resulted in the effective isolation of procyanidins with a distinct degree of polymerization (DP) from dimers DP2 up to tridecamers DP13. Exact mass measurements with negative ESI-TOF/MS were employed to confirm the respective structures of the isolated procyanidins.

Effect of the traditional Chinese medicines Chan Su, Lu-Shen-Wan, Dan Shen, and Asian ginseng on serum digoxin measurement by Tina-quant (Roche) and Synchron LX system (Beckman) digoxin immunoassays.

PubMed

Chow, Leonard; Johnson, Myrtle; Wells, Alice; Dasgupta, Amitava

2003-01-01

Chan Su, Lu-Shen-Wan, Dan Shen, and Asian ginseng are traditionally used to treat a number of conditions, including cardiovascular disease. All of these traditional Chinese medicines exhibit cardioactive properties. Digoxin is a cardioactive drug with a narrow therapeutic range (0.8-1.9 ng/mL). A patient taking digoxin may also take these Chinese medicines for their cardiotonic effects. Moreover, the active components of these medicines that are responsible for cardiotonic effects bear structural similarities to digoxin. Therefore, we studied the potential interference of these Chinese medicines with two digoxin immunoassays--the Tina-quant (Roche Diagnostics) and the Beckman (Synchron LX system)--and compared the values with the fluorescence polarization immunoassay (FPIA; Abbott Laboratories). When very small amounts (2-5 microL) of aqueous extract of Chan Su or Lu-Shen-Wan were added to drug-free serum, we observed high digoxin-like immunoreactivity with the FPIA. In contrast, when ethyl acetate extract of Dan Shen or microliter amounts of ginseng extract were added to drug-free serum, we observed modest digoxin-like immunoreactivity with the FPIA, but no apparent digoxin activity with the Roche and Beckman digoxin immunoassays. When aliquots of a digoxin pool prepared from patients receiving digoxin were supplemented with these Chinese medicines, we observed the most significant interference with the FPIA. The presence of endogenous digoxin-like immunoreactive substances can have additive effects with these Chinese medicines and falsely increase apparent digoxin levels by the FPIA. On the other hand, the Roche and Beckman assays were free from interference from DLIS but showed significant interference from Chan Su and Lu-Shen-Wan. We conclude that the FPIA showed the most significant interference from all four of the Chinese medicines we studied. However, the Roche and Beckman assays showed no interference from two (Dan Shen and Asian ginseng) of the four Chinese medicines we studied. Copyright 2003 Wiley-Liss, Inc.

Trichosanthes dioica Roxb.: An overview.

PubMed

Kumar, Nitin; Singh, Satyendra; Manvi; Gupta, Rajiv

2012-01-01

Trichosanthes, a genus of family Cucurbitaceae, is an annual or perennial herb distributed in tropical Asia and Australia. Pointed gourd (Trichosanthes dioica Roxb.) is known by a common name of parwal and is cultivated mainly as a vegetable. Juice of leaves of T. dioica is used as tonic, febrifuge, in edema, alopecia, and in subacute cases of enlargement of liver. In Charaka Samhita, leaves and fruits find mention for treating alcoholism and jaundice. A lot of pharmacological work has been scientifically carried out on various parts of T. dioica, but some other traditionally important therapeutical uses are also remaining to proof till now scientifically. According to Ayurveda, leaves of the plant are used as antipyretic, diuretic, cardiotonic, laxative, antiulcer, etc. The various chemical constituents present in T. dioica are vitamin A, vitamin C, tannins, saponins, alkaloids, mixture of noval peptides, proteins tetra and pentacyclic triterpenes, etc.

Phytopharmacological overview of Tribulus terrestris

PubMed Central

Chhatre, Saurabh; Nesari, Tanuja; Somani, Gauresh; Kanchan, Divya; Sathaye, Sadhana

2014-01-01

Tribulus terrestris (family Zygophyllaceae), commonly known as Gokshur or Gokharu or puncture vine, has been used for a long time in both the Indian and Chinese systems of medicine for treatment of various kinds of diseases. Its various parts contain a variety of chemical constituents which are medicinally important, such as flavonoids, flavonol glycosides, steroidal saponins, and alkaloids. It has diuretic, aphrodisiac, antiurolithic, immunomodulatory, antidiabetic, absorption enhancing, hypolipidemic, cardiotonic, central nervous system, hepatoprotective, anti-inflammatory, analgesic, antispasmodic, anticancer, antibacterial, anthelmintic, larvicidal, and anticariogenic activities. For the last few decades or so, extensive research work has been done to prove its biological activities and the pharmacology of its extracts. The aim of this review is to create a database for further investigations of the discovered phytochemical and pharmacological properties of this plant to promote research. This will help in confirmation of its traditional use along with its value-added utility, eventually leading to higher revenues from the plant. PMID:24600195

Recent developments in the field of arrow and dart poisons.

PubMed

Philippe, Geneviève; Angenot, Luc

2005-08-22

Arrow and dart poisons, considered as conventional natural sources for future drug discovery, have already provided numerous biologically active molecules used as drugs in therapeutic applications or in pharmacological research. Plants containing alkaloids or cardiotonic glycosides have generally been the main ingredients responsible for the efficacy of these poisons, although some animals, such as frogs, have also been employed. This paper, without being exhaustive, reports the greater strides made during the past 15 years in the understanding of the chemical nature and biological properties of arrow and dart poison constituents. Examples both of promising biological properties shown by these molecules and of crucial discoveries achieved by their use as pharmacological tools are given. Further studies of these toxic principles are likely to enable scientists to find new valuable lead compounds, useful in many fields of research, like oncology, inflammation and infectious diseases.

Trichosanthes dioica Roxb.: An overview

PubMed Central

Kumar, Nitin; Singh, Satyendra; Manvi; Gupta, Rajiv

2012-01-01

Trichosanthes, a genus of family Cucurbitaceae, is an annual or perennial herb distributed in tropical Asia and Australia. Pointed gourd (Trichosanthes dioica Roxb.) is known by a common name of parwal and is cultivated mainly as a vegetable. Juice of leaves of T. dioica is used as tonic, febrifuge, in edema, alopecia, and in subacute cases of enlargement of liver. In Charaka Samhita, leaves and fruits find mention for treating alcoholism and jaundice. A lot of pharmacological work has been scientifically carried out on various parts of T. dioica, but some other traditionally important therapeutical uses are also remaining to proof till now scientifically. According to Ayurveda, leaves of the plant are used as antipyretic, diuretic, cardiotonic, laxative, antiulcer, etc. The various chemical constituents present in T. dioica are vitamin A, vitamin C, tannins, saponins, alkaloids, mixture of noval peptides, proteins tetra and pentacyclic triterpenes, etc. PMID:22654406

Pretreatment with alcoholic extract of Crataegus oxycantha (AEC) activates mitochondrial protection during isoproterenol - induced myocardial infarction in rats.

PubMed

Jayalakshmi, R; Thirupurasundari, C J; Devaraj, S Niranjali

2006-11-01

Crataegus oxycantha (hawthorn) is used in herbal and homeopathic medicine as a cardiotonic. The present study was done to investigate the effect of the alcoholic extract of Crataegus oxycantha (AEC) on mitochondrial function during experimentally induced myocardial infarction in rat. AEC was administered orally to male albino rats (150-200 g), at a dosage of 0.5 ml/100 g body weight/day, for 30 days. At the end of the experimental period, the animals were administered isoproterenol (85 mg/kg body weight, s.c) for 2 days at an interval of 24 h. After 48 h, the rats were anaesthetized and sacrificed. The hearts were homogenized for biochemical and electron microscopic analysis. AEC pretreatment maintained mitochondrial antioxidant status, prevented mitochondrial lipid peroxidative damage and decrease in Kreb's cycle enzymes induced by isoproterenol in rat heart.

Health effects of hawthorn.

PubMed

Dahmer, Stephen; Scott, Emilie

2010-02-15

Hawthorn medicinal extract has long been a favored herbal remedy in Europe. The active components of this slow-acting cardiotonic agent are thought to be flavonoids and oligomeric procyanidins. The most studied hawthorn extracts are WS 1442 and LI 132. Reviews of placebo- controlled trials have reported both subjective and objective improvement in patients with mild forms of heart failure (New York Heart Association classes I through III). Other studies of hawthorn in patients with heart failure have revealed improvement in clinical symptoms, pressure-heart rate product, left ventricular ejection fraction, and patients' subjective sense of well-being. However, there is no evidence of a notable reduction in mortality or sudden death. Hawthorn is well tolerated; the most common adverse effects are vertigo and dizziness. Theoretic interactions exist with antiarrhythmics, antihypertensives, digoxin, and antihyperlipidemic agents. Proven conventional therapies for heart failure are still recommended until the safety and effectiveness of hawthorn has been proven in long-term studies.

Onosma L.: A review of phytochemistry and ethnopharmacology

PubMed Central

Kumar, Neeraj; Kumar, Rajnish; Kishore, Kamal

2013-01-01

The genus Onosma L. (Boraginaceae) includes about 150 species distributed world-wide in which only about 75 plants has been described for its morphology and less than 10 plants for their chemical constituents and clinical potential. The phytochemical reports of this genus revels that it comprise mainly aliphatic ketones, lipids, naphthazarins, alkaloids, phenolic compounds, naphthoquinones, flavones while most important are shikonins and onosmins. The plants are traditionally used as laxative, anthelmintic and for alexipharmic effects. The plants are also equally use in eye, blood diseases, bronchitis, abdominal pain, stangury, thirst, itch, lecoderma, fever, wounds, burns, piles and urinary calculi. The flowers of various plants are prescribed as stimulants, cardiotonic, in body swelling while leaves are used as purgative and in cutaneous eruptions. The roots are used for coloring food stuffs, oils and dying wool and in medicinal preparations. This review emphasizes the distribution, morphology, phytochemical constituents, ethnopharmacology, which may help in future research. PMID:24347922

Plant-derived cardiac glycosides: Role in heart ailments and cancer management.

PubMed

Patel, Seema

2016-12-01

Cardiac glycosides, the cardiotonic steroids such as digitalis have been in use as heart ailment remedy since ages. They manipulate the renin-angiotensin axis to improve cardiac output. However; their safety and efficacy have come under scrutiny in recent times, as poisoning and accidental mortalities have been observed. In order to better understand and exploit them as cardiac ionotropes, studies are being pursued using different cardiac glycosides such as digitoxin, digoxin, ouabain, oleandrin etc. Several cardiac glycosides as peruvoside have shown promise in cancer control, especially ovary cancer and leukemia. Functional variability of these glycosides has revealed that not all cardiac glycosides are alike. Apart from their specific affinity to sodium-potassium ATPase, their therapeutic dosage and behavior in poly-morbidity conditions needs to be considered. This review presents a concise account of the key findings in recent years with adequate elaboration of the mechanisms. This compilation is expected to contribute towards management of cardiac, cancer, even viral ailments. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Spectral and time-resolved properties of photoinduced hydroxyquinolines doped thin polymer films

NASA Astrophysics Data System (ADS)

Mehata, Mohan Singh

2018-01-01

Quinoline and its derivatives have a wide range of biological and pharmacological activities. Quinoline ring is used to design functional materials (quinoline derivatives) for OLEDs and field-induce electrooptics. It possesses antibacterial, antifungal, antimalarial, cardiotonic, anthelmintic, anti-inflammatory, anticonvulsant and analgesic activity. Here, we have examined photoexcitation dynamics of 6-hydroxyquinoline (6-HQ) doped in polymer films of polymethyl methacrylate (PMMA), polyvinyl alcohol (PVA) and cellulose acetate (CA) at atmospheric conditions. The absorption maximum of 6-HQ in polymer films was observed at 333 ± 1 nm, whereas fluorescence (FL) maximum fell in the range of 365-371 nm. In PVA film, in addition to the typical FL, a band maximum at 432 nm appeared as a result of an excited-state intermolecular proton transfer (ESIPT) reaction facilitated in the hydrogen-bonded complex formed in the ground state between 6-HQ:PVA. The multi-exponential decay behavior of 6-HQ in all the three polymer films indicates a nanoscale heterogeneity of the polymer environments.

Capillary electrophoretic analysis of flavonoids in single-styled hawthorn (Crataegus monogyna Jacq.) ethanolic extracts.

PubMed

Urbonaviciūte, A; Jakstas, V; Kornysova, O; Janulis, V; Maruska, A

2006-04-21

Flavonoids are an important group of natural compounds, which can prevent coronary heart disease and have antioxidant properties. Hawthorn is a well known and widely used medicinal plant due to its cardiotonic activity. Previous studies refer mostly to the HPLC analysis of the flavonoids: vitexin, quercetin, hyperoside, oligomeric procyanidins, which appear to be primarily responsible for the cardiac action of the plant. Aqueous ethanolic extracts of single-styled hawthorn (Crataegus monogyna Jacq., f.: Rosaceae Juss.) leaves and sprouts were analyzed by means of capillary zone electrophoresis (CZE). Influence of vegetation period on the extract qualitative composition and flavonoids quantities was evaluated. Sample preparation by extraction using different concentration of aqueous ethanol (40-96%, v/v) and the influence of extractant composition on the recovery of flavonoids are discussed in detail. The results obtained using CZE are compared to the results of spectrophotometric and HPLC analysis of the extracts. The effect of storage conditions of extracts (solar irradiation, temperature and duration) on degradation of flavonoids was investigated.

Antivenom potential of ethanolic extract of Cordia macleodii bark against Naja venom.

PubMed

Soni, Pranay; Bodakhe, Surendra H

2014-05-01

To evaluate the antivenom potential of ethanolic extract of bark of Cordia macleodii against Naja venom induced pharmacological effects such as lethality, hemorrhagic lesion, necrotizing lesion, edema, cardiotoxicity and neurotoxicity. Wistar strain rats were challenged with Naja venom and treated with the ethanolic extract of Cordia macleodii bark. The effectiveness of the extract to neutralize the lethalities of Naja venom was investigated as recommended by WHO. At the dose of 400 and 800 mg/kg ethanolic extract of Cordia macleodii bark significantly inhibited the Naja venom induced lethality, hemorrhagic lesion, necrotizing lesion and edema in rats. Ethanolic extract of Cordia macleodii bark was effective in neutralizing the coagulant and defibrinogenating activity of Naja venom. The cardiotoxic effects in isolated frog heart and neurotoxic activity studies on frog rectus abdominus muscle were also antagonized by ethanolic extract of Cordia macleodii bark. It is concluded that the protective effect of extract of Cordia macleodii against Naja venom poisoning may be mediated by the cardiotonic, proteolysin neutralization, anti-inflammatory, antiserotonic and antihistaminic activity. It is possible that the protective effect may also be due to precipitation of active venom constituents.

Effect of hawthorn (Crataegus oxycantha) crude extract and chromatographic fractions on multiple activities in a cultured cardiomyocyte assay.

PubMed

Long, S R; Carey, R A; Crofoot, K M; Proteau, P J; Filtz, T M

2006-11-01

Extracts of hawthorn (Crataegus oxycantha) have become popular herbal supplements for their well-recognized cardiotonic effects. Many commercial preparations have been used successfully in the treatment of congestive heart failure, although the active principles within these extracts have yet to be conclusively identified. Several hawthorn preparations were studied and found to have negative chronotropic effects in a cultured neonatal murine cardiomyocyte assay using unpaced cells. As compared to conventional cardiac drugs (i.e., epinephrine, milrinone, ouabain, or propranolol), hawthorn extract has a unique activity profile. Hawthorn extract appears to be anti-arrhythmic and capable of inducing rhythmicity in quiescent cardiomyocytes. Hawthorn extract does not cause beta-adrenergic receptor blockade at concentrations which cause negative chronotropic effects. Commercial hawthorn preparations, extracts prepared from dried leaves and those made from dried berries have similar chronotropic activities. When crude extracts are separated using size-exclusion chromatography, several fractions retain multiple cardiac activities. Assays with chromatographic fractions reveal that multiple dissimilar cardioactive components may exist within the extract, making the identification of individual active constituents more challenging.

Antivenom potential of ethanolic extract of Cordia macleodii bark against Naja venom

PubMed Central

Soni, Pranay; Bodakhe, Surendra H.

2014-01-01

Objective To evaluate the antivenom potential of ethanolic extract of bark of Cordia macleodii against Naja venom induced pharmacological effects such as lethality, hemorrhagic lesion, necrotizing lesion, edema, cardiotoxicity and neurotoxicity. Methods Wistar strain rats were challenged with Naja venom and treated with the ethanolic extract of Cordia macleodii bark. The effectiveness of the extract to neutralize the lethalities of Naja venom was investigated as recommended by WHO. Results At the dose of 400 and 800 mg/kg ethanolic extract of Cordia macleodii bark significantly inhibited the Naja venom induced lethality, hemorrhagic lesion, necrotizing lesion and edema in rats. Ethanolic extract of Cordia macleodii bark was effective in neutralizing the coagulant and defibrinogenating activity of Naja venom. The cardiotoxic effects in isolated frog heart and neurotoxic activity studies on frog rectus abdominus muscle were also antagonized by ethanolic extract of Cordia macleodii bark. Conclusions It is concluded that the protective effect of extract of Cordia macleodii against Naja venom poisoning may be mediated by the cardiotonic, proteolysin neutralization, anti-inflammatory, antiserotonic and antihistaminic activity. It is possible that the protective effect may also be due to precipitation of active venom constituents. PMID:25183127

Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes

NASA Astrophysics Data System (ADS)

Yuan, Jiani; Zhou, Xuanxuan; Cao, Wei; Bi, Linlin; Zhang, Yifang; Yang, Qian; Wang, Siwang

2017-11-01

Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method. Their mean particle sizes were 127.6 and 155.0 nm, mean zeta potentials were 2.24 and - 18.5 mV, and entrapment efficiencies were 76.31 and 78.40%, respectively. In vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that in bufalin-loaded liposomes. The cytotoxicity of blank liposomes has been found within acceptable range, whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity. In vivo pharmacokinetics indicated that bufalin-loaded PEGylated liposomes could extend or eliminate the half-life time of bufalin in plasma in rats. The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.

Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response.

PubMed

Inoue, Naoki; Hirouchi, Taisei; Kasai, Atsushi; Higashi, Shintaro; Hiraki, Natsumi; Tanaka, Shota; Nakazawa, Takanobu; Nunomura, Kazuto; Lin, Bangzhong; Omori, Akiko; Hayata-Takano, Atsuko; Kim, Yoon-Jeong; Doi, Takefumi; Baba, Akemichi; Hashimoto, Hitoshi; Shintani, Norihito

2018-01-08

We recently showed that a 13-kDa protein (p13), the homolog protein of formation of mitochondrial complex V assembly factor 1 in yeast, acts as a potential protective factor in pancreatic islets under diabetes. Here, we aimed to identify known compounds regulating p13 mRNA expression to obtain therapeutic insight into the cellular stress response. A luciferase reporter system was developed using the putative promoter region of the human p13 gene. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1α, a master player regulating mitochondrial metabolism, increased both reporter activity and p13 expression. Following unbiased screening with 2320 known compounds in HeLa cells, 12 pharmacological agents (including 8 cardiotonics and 2 anthracyclines) that elicited >2-fold changes in p13 mRNA expression were identified. Among them, four cardiac glycosides decreased p13 expression and concomitantly elevated cellular oxidative stress. Additional database analyses showed highest p13 expression in heart, with typically decreased expression in cardiac disease. Accordingly, our results illustrate the usefulness of unbiased compound screening as a method for identifying novel functional roles of unfamiliar genes. Our findings also highlight the importance of p13 in the cellular stress response in heart. Copyright © 2017. Published by Elsevier Inc.

Nationwide Survey of Palliative Care for Patients With Heart Failure in Japan.

PubMed

Kuragaichi, Takashi; Kurozumi, Yuma; Ohishi, Shogo; Sugano, Yasuo; Sakashita, Akihiro; Kotooka, Norihiko; Suzuki, Makoto; Higo, Taiki; Yumino, Dai; Takada, Yasuko; Maeda, Seiko; Yamabe, Saori; Washida, Koichi; Takahashi, Tomonori; Ohtani, Tomohito; Sakata, Yasushi; Sato, Yukihito

2018-04-25

Palliative care for heart failure (HF) patients is recommended in Western guidelines, so this study aimed to clarify the current status of palliative care for HF patients in Japan.Methods and Results:A survey was sent to all Japanese Circulation Society-authorized cardiology training hospitals (n=1,004) in August 2016. A total of 544 institutions (54%) returned the questionnaire. Of them, 527 (98%) answered that palliative care is necessary for patients with HF. A total of 227 (42%) institutions held a palliative care conference for patients with HF, and 79% of the institutions had <10 cases per year. Drug therapy as palliative care was administered at 403 (76%) institutions; morphine (87%) was most frequently used. Among sedatives, dexmedetomidine (33%) was administered more often than midazolam (29%) or propofol (20%). Regarding the timing of end-of-life care, most institutions (84%) reported having considered palliative care when a patient reached the terminal stage of HF. Most frequently, the reason for the decision at the terminal stage was "difficulty in discontinuing cardiotonics." A major impediment to the delivery of palliative care was "difficulty predicting an accurate prognosis." This large-scale survey showed the characteristics of palliative care for HF in Japan. The present findings may aid in the development of effective end-of-life care systems.

Tissue distribution study of periplocin and its two metabolites in rats by a validated LC-MS/MS method.

PubMed

Liu, Huaming; Zhang, Dandan; Tang, Zhidan; Sun, Mengjie; Azietaku, John Teye; Ouyang, Huizi; Chang, Yanxu; Wang, Meng; He, Jun; Gao, Xiumei

2018-05-29

Periplocin is a cardiac glycoside and has been used widely in the clinic for its cardiotonic, anti-inflammatory and anti-tumor effects. Though it was taken frequently by oral administration in clinic, there were no reports demonstrated that periplocin could be detected in vivo after an oral administration of periplocin, so it is badly need of searching the characteristic of periplocin in vivo after an oral administration. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to identify and quantify periplocin and its two metabolites in rat tissue after a single dosage of perplocin at 50 mg/kg. The results demonstrated that periplocin and its two metabolites were detected in all of the selected tissues, periplocin could be reach peak concentration quickly after administration, while periplocymarin and periplogenin reached maximum concentration more than 4.83 h after administration. The tissue distribution of analytes tended to be mostly in the liver, and higher analytes concentrations were found in the heart, liver, spleen, lung, kidney, but a small amount of chemical constituents were distributed into the brain. The consequences obtained using this method might provide a meaningful insight for the clinical investigations and applications. This article is protected by copyright. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miles, Andrew J.; Fedosova, Natalya U.; Hoffmann, Søren V.

Highlights: •Ouabain binding to pig and shark Na,K-ATPase enhances thermal stability. •Ouabain stabilises both membrane-bound and solubilised Na,K-ATPase. •Synchrotron radiation circular dichroism is used for structure determination. •Secondary structure in general is not affected by ouabain binding. •Stabilisation is due to re-arrangement of tertiary structure. -- Abstract: Cardiotonic steroids such as ouabain bind with high affinity to the membrane-bound cation-transporting P-type Na,K-ATPase, leading to complete inhibition of the enzyme. Using synchrotron radiation circular dichroism spectroscopy we show that the enzyme-ouabain complex is less susceptible to thermal denaturation (unfolding) than the ouabain-free enzyme, and this protection is observed with Na,K-ATPase purifiedmore » from pig kidney as well as from shark rectal glands. It is also shown that detergent-solubilised preparations of Na,K-ATPase are stabilised by ouabain, which could account for the successful crystallisation of Na,K-ATPase in the ouabain-bound form. The secondary structure is not significantly affected by the binding of ouabain. Ouabain appears however, to induce a reorganization of the tertiary structure towards a more compact protein structure which is less prone to unfolding; recent crystal structures of the two enzymes are consistent with this interpretation. These circular dichroism spectroscopic studies in solution therefore provide complementary information to that provided by crystallography.« less

Influence of aldosterone and salt or ouabain in a10 rat aorta smooth muscle cells.

PubMed

Schwerdt, Gerald; Frisch, Annett; Mildenberger, Sigrid; Hilgenfeld, Tim; Grossmann, Claudia; Gekle, Michael

2012-01-01

It is currently under debate whether aldosterone is able to induce fibrosis or whether it acts only as a cofactor under pathological conditions, e.g. as an elevated salt (NaCl) load. We tested the interaction of 10 nM aldosterone, 15 mM NaCl and 1 μM ouabain using rat aorta smooth muscle cells (A10) with respect to the following parameters: necrosis, apoptosis, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase activity, glutathione (GSH) content, collagen and fibronectin homeostasis and intracellular calcium distribution. Necrosis rates were increased after 48 h of incubation with aldosterone, salt or ouabain and in the combination of aldosterone and salt or ouabain. Apoptosis rates were decreased. A reduced defense capacity against oxidative stress was mirrored in the decreased G6PD activity and GSH content. Collagen III or fibronectin synthesis rates were unchanged, but gelatinase activity was increased resulting in a decreased media collagen III and fibronectin content. Calcium stores were increased by aldosterone in combination with ouabain. Aldosterone and salt per se can lead to cell injury that is aggravated in combination or with cardiotonic steroids. In cooperation with other vascular cells, this can generate a permissive milieu enabling aldosterone or salt to promote more extensive vascular injury. Copyright © 2012 S. Karger AG, Basel.

Valuable Nutrients and Functional Bioactives in Different Parts of Olive (Olea europaea L.)—A Review

PubMed Central

Ghanbari, Rahele; Anwar, Farooq; Alkharfy, Khalid M.; Gilani, Anwarul-Hassan; Saari, Nazamid

2012-01-01

The Olive tree (Olea europaea L.), a native of the Mediterranean basin and parts of Asia, is now widely cultivated in many other parts of the world for production of olive oil and table olives. Olive is a rich source of valuable nutrients and bioactives of medicinal and therapeutic interest. Olive fruit contains appreciable concentration, 1–3% of fresh pulp weight, of hydrophilic (phenolic acids, phenolic alchohols, flavonoids and secoiridoids) and lipophilic (cresols) phenolic compounds that are known to possess multiple biological activities such as antioxidant, anticarcinogenic, antiinflammatory, antimicrobial, antihypertensive, antidyslipidemic, cardiotonic, laxative, and antiplatelet. Other important compounds present in olive fruit are pectin, organic acids, and pigments. Virgin olive oil (VOO), extracted mechanically from the fruit, is also very popular for its nutritive and health-promoting potential, especially against cardiovascular disorders due to the presence of high levels of monounsaturates and other valuable minor components such as phenolics, phytosterols, tocopherols, carotenoids, chlorophyll and squalene. The cultivar, area of production, harvest time, and the processing techniques employed are some of the factors shown to influence the composition of olive fruit and olive oil. This review focuses comprehensively on the nutrients and high-value bioactives profile as well as medicinal and functional aspects of different parts of olives and its byproducts. Various factors affecting the composition of this food commodity of medicinal value are also discussed. PMID:22489153

The Sodium Pump α1 Subunit as a Potential Target to Combat Apoptosis-Resistant Glioblastomas1

PubMed Central

Lefranc, Florence; Kiss, Robert

2008-01-01

Purpose To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK α1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues. Design The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity, and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration. Results The natural ligands of the NaK are the cardiotonic steroids. A hemisynthetic derivative of 2″-oxovoruscharin (UNBS1450), a novel cardenolide, displays unique structural features, making its binding affinity to NaK α subunits (including α1) 10 to 100 times higher than that of other cardenolides. UNBS1450 markedly decreases intracellular ATP concentration in glioma cells, disorganizes the actin cytoskeleton, and leads to autophagic cell death in NaK α1 over-expressing glioma cells. Conclusions Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK α1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK α1 subunit. PMID:18323016

The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas.

PubMed

Lefranc, Florence; Kiss, Robert

2008-03-01

To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK alpha1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues. The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity,and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration. The natural ligands of the NaK are the cardiotonic steroids. A hemisynthetic derivative of 2"-oxovoruscharin (UNBS1450), a novel cardenolide, displays unique structural features, making its binding affinity to NaK alpha subunits (including alpha1) 10 to 100 times higher than that of other cardenolides. UNBS1450 markedly decreases intracellular ATP concentration in glioma cells, disorganizes the actin cytoskeleton, and leads to autophagic cell death in NaK alpha1 over-expressing glioma cells. Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK alpha1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK alpha1 subunit.

Digoxin Induces Cardiac Hypertrophy Without Negative Effects on Cardiac Function and Physical Performance in Trained Normotensive Rats.

PubMed

Neves, Claodete Hasselstrom; Tibana, Ramires Alsamir; Prestes, Jonato; Voltarelli, Fabricio Azevedo; Aguiar, Andreo Fernando; Ferreira Mota, Gustavo Augusto; de Sousa, Sergio Luiz Borges; Leopoldo, Andre Soares; Leopoldo, Ana Paula Lima; Mueller, Andre; Aguiar, Danilo Henrique; Navalta, James Wilfred; Sugizaki, Mario Mateus

2017-04-01

Cardiotonic drugs and exercise training promote cardiac inotropic effects, which may affect training-induced cardiac adaptations. This study investigated the effects of long-term administration of digoxin on heart structure and function, and physical performance of rats submitted to high-intensity interval training (HIIT). Male Wistar rats, 60 days old, were divided into control (C), digoxin (DIGO), trained (T), and trained with digoxin (TDIGO). Digoxin was administered by gavage (30 µg/kg/day) for 75 days. The HIIT program consisted of treadmill running 60 min/day (8 min at 80% of the maximum speed (MS) and 2 min at 20% of the MS), 5 days per week during 60 days. The main cardiac parameters were evaluated by echocardiograph and cardiomyocyte area was determined by histology. There were no group x time effects of digoxin, HIIT or interactions (digoxin and HIIT) on functional echocardiographic parameters (heart rate; ejection fraction) or in the maximum exercise test. There was a group x time interaction, as evidenced by observed cardiac hypertrophy in the TDIGO group evaluated by ratio of left ventricle weight to body weight (p<0.002) and cardiomyocyte area (p<0.000002). Long-term administration of digoxin promoted cardiac hypertrophy without affecting cardiac function and physical performance in rats submitted to HIIT. © Georg Thieme Verlag KG Stuttgart · New York.

[Secondary metabolites, lethality and antimicrobial activity of extracts from three corals and three marine mollusks from Sucre, Venezuela].

PubMed

Ordaz, Gabriel; D'Armas, Haydelba; Yáñez, Dayanis; Hernández, Juan; Camacho, Angel

2010-06-01

The study of biochemical activity of extracts obtained from marine organisms is gaining interest as some have proved to have efficient health or industrial applications. To evaluate lethality and antimicrobial activities, some chemical tests were performed on crude extracts of the octocorals Eunicea sp., Muricea sp. and Pseudopterogorgia acerosa and the mollusks Pteria colymbus, Phyllonotus pomum and Chicoreus brevifrons, collected in Venezuelan waters. The presence of secondary metabolites like alkaloids, unsaturated sterols and pentacyclic triterpenes in all invertebrates, was evidenced. Additionally, sesquiterpenlactones, saponins, tannins, cyanogenic and cardiotonic glycosides were also detected in some octocoral extracts, suggesting that biosynthesis of these metabolites is typical in this group. From the lethality bioassays, all extracts resulted lethal to Artemia salina (LC50<1000 microg/ml) with an increased of lethal activity with exposition time. P. pomum extract showed the highest lethality rate (LC50=46.8 microg/ml). Compared to the octocorals, mollusks extracts displayed more activity and a greater action spectrum against different bacterial strains, whereas octocorals also inhibited some fungi strains growth. Staphylococcus aureus was the most susceptible to the antimicrobial power of the extracts (66.7%), whereas Pseudomonas aeruginosa, Candida albicans and Aspergillus niger were not affected. The antibiosis shown by marine organisms extracts indicates that some of their biosynthesized metabolites are physiologically active, and may have possible cytotoxic potential or as a source of antibiotic components.

Repeated and chronic administration of Vardenafil or Sildenafil differentially affects emotional and socio-sexual behavior in mice.

PubMed

Dadomo, H; Parmigiani, S; Nicolini, Y; Freschini, S; Gioiosa, L; Patrelli, T S; Palanza, P; Volpi, R

2013-09-15

Selective phosphodiesterases (PDEs) inhibitors have been widely studied as therapeutic agents for treatment of various human diseases, including cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, antithrombotics, antiasthmatics, and agents for improving learning and memory. Although Sildenafil(®) and Vardenafil(®) have similar chemical formulae, the same target and interact with many of the same residues at the active site of phosphodiesterse-5 (PDE-5), they exhibit both in vitro and in vivo some important functional differences that could differentially affect behavior. Therefore we assessed whether repeated and chronic administration of Vardenafil and Sildenafil at a dose based upon human treatment can differentially affect aggressive, social, emotional and sexual behavior. To this aim, the effects of Sildenafil (10mg/kg) or Vardenafil (2mg/kg) (t.i.w., for 5 weeks) were observed in CD1 subordinate male mice in a low aggression and social subordination context. The results show that Sildenafil increased competitive aggression, environmental and social exploration, and reduced anxiety like behaviors as compared to controls, whereas Vardenafil had a significant major effect on appetitive and consummatory aspect of sexual behavior. This demonstrates that Sildenafil and Vardenafil, although being structurally and functionally similar, are characterized by different neuro-behavioral actions and can have differential therapeutic potentials. Copyright © 2013 Elsevier B.V. All rights reserved.

Probing the interaction of the phytochemical 6-gingerol from the spice ginger with DNA.

PubMed

Haris, Poovvathingal; Mary, Varughese; Sudarsanakumar, Chellappanpillai

2018-07-01

6-Gingerol [5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) decan-3-one], the bio-active ingredient of the popular Indian spice ginger (Zingiber officinale Roscoe), is well-known for its pharmacological and physiological actions. The potent antioxidant, antiemetic, antiulcer, antimicrobial, analgesic, hypoglycemic, antihypertensive, antihyperlipidemic, immunostimulant, anti-inflammatory, cardiotonic, and cancer prevention activities of 6-Gingerol has been investigated and explored. 6-Gingerol is a good candidate for the treatment of various cancers including prostrate, pancreatic, breast, skin, gastrointestinal, pulmonary, and renal cancer. In this study we report for the first time the molecular recognition of 6-Gingerol with calf thymus DNA (ctDNA) through experimental and molecular modeling techniques confirming a minor groove binding mode of 6-Gingerol with ctDNA. Fluorescence and UV-vis spectroscopic studies confirm the complex formation of 6-gingerol with ctDNA. The energetics and thermodynamics of the interaction of 6-Gingerol with ctDNA was explored by Isothermal Titration Calorimetry (ITC) and Differential Scanning Calorimetry (DSC). The ctDNA helix melting upon 6-Gingerol binding was examined by melting temperature T m analysis. Further the electrophoretic mobility shift assay confirms a possible groove binding of 6-Gingerol with ctDNA. Molecular docking and Molecular dynamics (MD) studies provide a detailed understanding on the interaction of 6-Gingerol binding in the minor groove of DNA which supports experimental results. Copyright © 2018. Published by Elsevier B.V.

Hypocalcemic rachitic cardiomyopathy in infants

PubMed Central

Elidrissy, Abdelwahab T.H.; Munawarah, Medinah; Alharbi, Khalid M.

2012-01-01

Hypocalcemic cardiomyopathy in infants is characterized by heart failure in a previously normal infant with hypocalcemia without organic cardiac lesion. Vitamin D deficiency rickets is increasing in Middle East. In a six month study 136 cases of rickets were diagnosed in the main Children’s Hospital in Almadinah but none of them showed evidence of cardiomyopathy. Concerned of missing this serious complication of rickets we searched pub med and present this review article. Results 61 cases of hypocalcemic cardiomyopathy were reported as case reports with two series of 16 and 15 cases from London and Delhi, respectively. The major features of these cases: the age ranged from one month to 15 months with a mean age of 5 months. All presented with heart failure and hypocalcemia. There was a minor feature of rickets in a few of the cases. All had high alkaline phosphatase. Echocardiology evidence of cardiomyopathy was found in all. Most of them responded to calcium, vitamin D and cardiotonic and diuretics. Discussion We concentrated on pathogenesis of this hypocalcemic cardiomyopathy and reviewed the literature. The evidence available supports that the most likely cause of cardiomyopathy is hypocalcemia. Hypovitamin D also contributes but hyperparathyroidism might have a protective role as we did not detect any evidence of cardiomyopathy with hyperparathyroidism and florid features of rickets. Conclusion We need to look out for cardiomyopathy among infants with hypocalcemia. For prevention maternal supplementation during pregnancy and lactation with up to 2000 units of vitamin D and 400 units for their infants. PMID:24174842

Taurine induces anti-anxiety by activating strychnine-sensitive glycine receptor in vivo.

PubMed

Zhang, Cheng Gao; Kim, Sung-Jin

2007-01-01

Taurine has a variety of actions in the body such as cardiotonic, host-defensive, radioprotective and glucose-regulatory effects. However, its action in the central nervous system remains to be characterized. In the present study, we tested to see whether taurine exerts anti-anxiety effects and to explore its mechanism of anti-anxiety activity in vivo. The staircase test and elevated plus maze test were performed to test the anti-anxiety action of taurine. Convulsions induced by strychnine, picrotoxin, yohimbine and isoniazid were tested to explore the mechanism of anti-anxiety activity of taurine. The Rotarod test was performed to test muscle relaxant activity and the passive avoidance test was carried out to test memory activity in response to taurine. Taurine (200 mg/kg, p.o.) significantly reduced rearing numbers in the staircase test while it increased the time spent in the open arms as well as the number of entries to the open arms in the elevated plus maze test, suggesting that it has a significant anti-anxiety activity. Taurine's action could be due to its binding to and activating of strychnine-sensitive glycine receptor in vivo as it inhibited convulsion caused by strychnine; however, it has little effect on picrotoxin-induced convulsion, suggesting its anti-anxiety activity may not be linked to GABA receptor. It did not alter memory function and muscle activity. Taken together, these results suggest that taurine could be beneficial for the control of anxiety in the clinical situations. Copyright (c) 2007 S. Karger AG, Basel.

Synthetic approach to the AB ring system of ouabain.

PubMed

Jung, Michael E; Piizzi, Grazia

2003-04-04

Several novel hydroxylated cis-decalin derivatives, potential intermediates for the synthesis of the AB ring system of the important cardiotonic steroid ouabain, have been synthesized from commercially available starting materials. The first step in the preparation of these highly functionalized intermediates is a Robinson annulation of the beta-keto ester 6 and the 4-silyl-3-buten-2-one 5 to furnish the octalone 4 with good diastereoselectivity in fair yield (due to competition with a novel silicon-to-carbon phenyl migration). Reduction of the epoxy alcohol 3 (derived from 4 in two high-yielding steps) with LiAlH(4) gave a mixture of the desired triol 11 along with the product of an unusual reductive opening at the tertiary carbon, namely the triol 12. A plausible mechanism for this unusual reduction is presented as are possible methods for avoiding it. In particular, reduction of the corrresponding epoxy ketone 15 with aluminum amalgam proceeded in good yield to give the hydroxy ketone 16. Also reduction of the epoxide ester having the inverted stereochemistry at C3 afforded the desired tertiary alcohol 33 in good yield. Another approach using the beta,gamma-unsaturated ketal 38 permitted the formation of the tertiary alcohol 40. Fleming oxidation of the related, very functionalized silane 39 afforded the desired 1beta-alcohol 41 in fair yield. Finally a novel rearrangement was observed when the epoxy alcohol 24 was treated with DIBAL to effect loss of the angular hydroxymethyl group to produce the tetrasubstitued alkene 29 in high yield.

Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury.

PubMed

Swaminathan, J K; Khan, M; Mohan, I K; Selvendiran, K; Niranjali Devaraj, S; Rivera, B K; Kuppusamy, P

2010-08-01

The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30min of global ischemia followed by 45min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1mg/ml/min for 10min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1alpha that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. 2010 Elsevier GmbH. All rights reserved.

Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury

PubMed Central

Swaminathan, Jayachandran Kesavan; Khan, Mahmood; Mohan, Iyappu K; Selvendiran, Karuppaiyah; Devaraj, S. Niranjali; Rivera, Brian K.; Kuppusamy, Periannan

2010-01-01

The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1 mg/ml/min for 10 min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1α that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. PMID:20171068

Crataegus special extract WS 1442 improves cardiac function and reduces infarct size in a rat model of prolonged coronary ischemia and reperfusion.

PubMed

Veveris, Maris; Koch, Egon; Chatterjee, Shyam S

2004-02-27

In Germany, hydroalcoholic extracts from hawthorn (Crataegus spp.) leaves with flowers are approved drugs for the treatment of mild forms of heart insufficiency. Besides cardiotonic effects these herbal remedies have been shown to possess cardioprotective properties. We now evaluated if treatment of rats with the Crataegus special extract WS 1442 also improves cardiac function and prevents myocardial infarction during prolonged ischemia and reperfusion lasting for 240 and 15 min, respectively. Oral administration of WS 1442 (10 or 100 mg x kg(-1) x day(-1)) for 7 days before ligation of the left coronary artery dose-dependently suppressed the decrease of the pressure rate product. WS 1442 treatment also attenuated the elevation of the ST-segment in the ECG, diminished the incidence of ventricular fibrillations (control: 67%; 10 mg x kg(-1): 64%; 100 mg x kg(-1): 27%) and reduced the mortality rate (control: 47%; 10 mg.kg(-1): 27%; 100 mg x kg(-1): 9%). Furthermore, the area of myocardial infarction within the ischemic zone was significantly smaller in treated rats (10 mg x kg(-1): 64.3 +/- 5.1%; 100 mg x kg(-1): 42.8 +/- 4.1%) when compared with controls (78.4 +/- 2.6%). It is suggested that these pharmacological effects are accounted for by the combined antioxidative, leukocyte elastase inhibiting and endothelial nitric oxide (NO) synthesis enhancing properties of WS 1442.

Cardiac glycoside ouabain induces activation of ATF-1 and StAR expression by interacting with the α4 isoform of the sodium pump in Sertoli cells.

PubMed

Dietze, Raimund; Konrad, Lutz; Shihan, Mazen; Kirch, Ulrike; Scheiner-Bobis, Georgios

2013-03-01

Sertoli cells express α1 and α4 isoforms of the catalytic subunit of Na(+),K(+)-ATPase (sodium pump). Our recent findings demonstrated that interactions of the α4 isoform with cardiotonic steroids (CTS) like ouabain induce signaling cascades that resemble the so-called non-classical testosterone pathway characterized by activation of the c-Src/c-Raf/Erk1/2/CREB signaling cascade. Here we investigate a possible physiological significance of the activated cascade. The results obtained in the current investigation show that the ouabain-induced signaling cascade also leads to the activation of the CREB-related activating transcription factor 1 (ATF-1) in the Sertoli cell line 93RS2 in a concentration- and time-dependent manner, as demonstrated by detection of ATF-1 phosphorylated on Ser63 in western blots. The ouabain-activated ATF-1 protein was found to localize to the cell nuclei. The sodium pump α4 isoform mediates this activation, as it is ablated when cells are incubated with siRNA to the α4 isoform. Ouabain also leads to increased expression of steroidogenic acute regulator (StAR) protein, which has been shown to be a downstream consequence of CREB/ATF-1 activation. Taking into consideration that CTS are most likely produced endogenously, the demonstrated induction of StAR expression by ouabain establishes a link between CTS, the α4 isoform of the sodium pump, and steroidogenesis crucial for male fertility and reproduction. Copyright © 2012 Elsevier B.V. All rights reserved.

E-1020, a water soluble imidazopyridine, has direct effects on Ca(2+)-dependent force and ATP hydrolysis of canine and bovine cardiac myofilaments.

PubMed

Powers, F M; Palmiter, K A; Solaro, R J

1996-01-01

E-1020 is a cardiotonic agent that acts as a cyclic-AMP phosphodiesterase inhibitor but also may have actions which alter myofilament response to Ca2+. To identify direct actions of E-1020 on cardiac contractile proteins, effects of E-1020 on myofibrillar Ca2+ dependent MgATPase and force generation in chemically skinned fiber bundles were measured. In bovine cardiac myofibrils, E-1020 (100 microM) significantly increased myofilament Ca2+ sensitivity and Ca(2+)-dependent ATPase activity at submaximal pCa values. At pCa 6.75, E-1020 significantly increased ATPase activity in bovine (10-100 microM) and canine (1-100 microM) cardiac myofibrils but had no effect on rat cardiac myofibrils. Moreover, in one population of canine ventricular fiber bundles, E-1020 (0.01-10 microM) significantly increased isometric tension at pCa 6.5 and 6.0, whereas in another population of bundles E-1020 had no effect on tension. In no case was resting (pCa 8.0) or maximal tension (pCa 4.5) increased by E-1020. Measurements of Ca2+ binding to canine ventricular skinned fiber preparations demonstrated that E-1020 does not alter the affinity of myofilament troponin C for Ca2+. We conclude that part of the mechanism by which E-1020 acts as an inotropic agent may involve alterations in the responsiveness of contractile proteins to Ca2+. The lack of effect of E-1020 on some preparations may be dependent on isoform populations of myofilament proteins.

The history of veterinary cardiology.

PubMed

Buchanan, James W

2013-03-01

Throughout civilization, animals have played a pivotal role in the advancement of science and medicine. From as early as 400 BC when Hippocrates recognized that diseases had natural causes, the steadfast advances made by biologists, scientists, physicians and scholars were fueled by timely and important facts and information- much of it gained through animal observations that contributed importantly to understanding anatomy, physiology, and pathology. There have been many breakthroughs and historic developments. For example, William Harvey in the 16th and 17th centuries clarified the importance of the circulatory system, aided by observations in dogs and pigs, which helped to clarify and confirm his concepts. The nineteenth century witnessed advances in physical examination techniques including auscultation and percussion. These helped create the basis for enhanced proficiency in clinical cardiology. An explosion of technologic advances that followed in the 20th century have made possible sophisticated, accurate, and non-invasive diagnostics. This permitted rapid patient assessment, effective monitoring, the development of new cardiotonic drugs, clinical trials to assess efficacy, and multi-therapy strategies. The latter 20th century has marshaled a dizzying array of advances in medical genetics and molecular science, expanding the frontiers of etiologies and disease mechanisms in man, with important implications for animal health. Veterinary medicine has evolved during the last half century, from a trade designed to serve agrarian cultures, to a diverse profession supporting an array of career opportunities ranging from private, specialty practice, to highly organized, specialized medicine and subspecialty academic training programs in cardiology and allied disciplines. Copyright © 2013 Elsevier B.V. All rights reserved.

Cardiovascular aspects of geriatric medicines in traditional Persian medicine; a review of phytochemistry and pharmacology.

PubMed

Zarshenas, Mohammad M; Jamshidi, Sahar; Zargaran, Arman

2016-10-15

Geriatrics are a group of patients over 65 years and with multiple comorbidities and different functional impairments. Apart from decline in body mass, presence of exhaustion and general fatigue, an aged person may also suffer from various disorders. Approximately, around 30% of geriatric subjects have significant cardiovascular ailments. Apart from the intensive management of cardiovascular aspects in elderly, monitoring of the complementary cardiac medicine in those people should be received more attention. There are many management lines for a cardio-geriatric condition in Traditional Persian Medicine (TPM). Accordingly, this paper aimed to deal with those medicaments as well as evidence-based clinical aspects and phytochemistry. By searching through main pharmaceutical manuscripts of Persian medicine during 10th-18th centuries (A.D.), concurrently, natural medicines for geriatrics and remedies for cardiovascular ailments were derived. On the other side, related phytochemical and pharmacological aspects of those remedies were highlighted. In all, 38 cardiovascular and 34 geriatric medicaments were found in those manuscripts. Antihyperlipidemic and cholesterol lowering activities of those medicines were the most reported activities in current medicine. However, other pharmacological reports were related to hypotensive, coagulant, cardio-protective and cardiotonic activities. In regard of the chemical composition, medicaments were mainly of polyphenols and flavonoids and also most of the employed extracts and fractions were yielded from polar or semi-polar solvents. With reference to these findings, flavonoid-rich medicaments from Persian medicine may be selected as considerable herbs for geriatrics with cardiovascular ailments. Copyright © 2016 Elsevier GmbH. All rights reserved.

The sea anemone toxin AdE-1 modifies both sodium and potassium currents of rat cardiomyocytes.

PubMed

Nesher, Nir; Zlotkin, Eliahu; Hochner, Binyamin

2014-07-01

AdE-1, a cardiotonic peptide recently isolated from the sea anemone Aiptasia diaphana, contains 44 amino acids and has a molecular mass of 4907 Da. It was previously found to resemble other sea anemone type 1 and 2 Na+ channel toxins, enhancing contractions of rat cardiomyocytes and slowing their twitch relaxation; however, it did not induce spontaneous twitches. AdE-1 increased the duration of the cardiomyocyte action potential and decreased its amplitude and its time-to-peak in a concentration-dependent manner, without affecting its threshold and cell resting potential. Nor did it generate the early and delayed after-depolarizations characteristic of sea anemone Na+ channel toxins. To further understand its mechanism of action we investigated the effect of AdE-1 on the major ion currents of rat cardiomyocytes. In the present study we show that AdE-1 markedly slowed inactivation of the Na+ current, enhancing and prolonging the current influx with no effect on current activation, possibly through direct interaction with the site 3 receptor of the Na+ channel. No significant effect of AdE-1 on the Ca2+ current was observed, but, unexpectedly, AdE-1 significantly increased the amplitude of the transient component of the K+ current, shifting the current threshold to more negative membrane potentials. This effect on the K+ current has not been found in any other sea anemone toxin and may explain the exclusive reduction in action potential amplitude and the absence of the action potential disorders found with other toxins, such as early and delayed after-depolarizations.

Influence of the extraction mode on the yield of hyperoside, vitexin and vitexin-2''-O-rhamnoside from Crataegus monogyna Jacq. (hawthorn).

PubMed

Martino, Emanuela; Collina, Simona; Rossi, Daniela; Bazzoni, Deborah; Gaggeri, Raffaella; Bracco, Francesco; Azzolina, Ornella

2008-01-01

The extract of Crataegus monogyna shows sedative, hypotensive, vasodilator and cardio-tonic actions. Although several papers dealing with the extraction of metabolites from Crataegus have been published, the plant productivity in terms of bioactive compounds is not easily understandable as yet. To investigate the influence of the extraction mode on the yield of bioactive compounds from Crataegus monogyna Jacq. in order to evaluate plant productivity. Samples were prepared by extraction of powdered material obtained from top branches, flowers and leaves. Soxhlet extraction, maceration and ultrasound- and microwave-assisted extraction at different experimental conditions were investigated for the exhaustive extraction of hyperoside, vitexin and vitexin-2''-O-rhamnoside. The phytocomponents were identified and quantified by HPLC-UV/PAD, comparing HPLC retention times and UV spectra of individual peaks with those of the standards analysed under the same conditions. An easy-to-use HPLC isocratic method suitable for the quantification of hyperoside, vitexin and vitexin-2''-O-rhamnoside in raw plant extracts was developed. The optimised HPLC methodology was applied to evaluate different extraction procedures. The ultrasound and microwave-assisted extraction protocols showed higher extraction efficiency than the others. In particular, the optimised microwave protocol gave rise to the highest extraction efficiency with high reproducibility. A microwave protocol combined with isocratic HPLC analysis is proposed for the rapid screening of plant materials collected in different environmental conditions in order to evaluate the productivity of Crataegus monogyna Jacq. and to find out the best ecological conditions to cultivate hawthorn in Northern Italy.

Terminalia arjuna prevents Interleukin-18-induced atherosclerosis via modulation of NF-κB/PPAR-γ-mediated pathway in Apo E-/- mice.

PubMed

Bhat, Owais Mohammad; Kumar, P Uday; Rao, K Rajender; Ahmad, Ashfaq; Dhawan, Veena

2018-04-01

Terminalia arjuna is a medicinal plant well known as a cardiotonic in Ayurvedic system of medicine. We hypothesized that aqueous stem bark extract of T. arjuna (TAE) may inhibit IL-18-induced atherosclerosis via NF-κB/PPAR-γ-mediated pathway in Apo E-/- mice. 12-week-old, male Apo E-/- mice divided into four groups (n = 6/group) fed with normal chow-diet were employed: GP I: phosphate buffer saline (PBS) (2 month); GP II: rIL-18 (1 month) followed by PBS (1 month); GP III: rIL-18 (1 month) followed by TAE (1 month); GP IV: rIL-18 (1 month) followed by atorvastatin (1 month). IL-18 treatment induced a significant increase (p < 0.001) in pro-inflammatory marker (IL-18) (170 ± 9.16 vs. 1178.66 ± 8.08, pg/ml), and downregulated cholesterol efflux gene (PPAR-γ) by ~0.6-fold vs. 1.00 in IL-18-treated mice as compared to the control animals, respectively. TAE treatment to both groups caused a significant reduction in IL-18 to 281.66 ± 9.60 vs. 1178.66 ± 8.08 (pg/ml), upregulated cholesterol efflux gene by ~1.5- vs. 0.6-fold in TAE-treated group, decreased atherogenic lipids, and percentage atherosclerotic lesion area, demonstrating comparable effects with atorvastatin. Our data demonstrate that TAE protects against IL-18-induced atherosclerosis via NF-κB/PPAR-γ-mediated pathway.

Pandanus odoratissimus (Kewda): A Review on Ethnopharmacology, Phytochemistry, and Nutritional Aspects

PubMed Central

Adkar, Prafulla P.; Bhaskar, V. H.

2014-01-01

Pandanus odoratissimus Linn. (family: Pandanaceae) is traditionally recommended by the Indian Ayurvedic medicines for treatment of headache, rheumatism, spasm, cold/flu, epilepsy, wounds, boils, scabies, leucoderma, ulcers, colic, hepatitis, smallpox, leprosy, syphilis, and cancer and as a cardiotonic, antioxidant, dysuric, and aphrodisiac. It contains phytochemicals, namely, lignans and isoflavones, coumestrol, alkaloids, steroids, carbohydrates, phenolic compounds, glycosides, proteins, amino acids as well as vitamins and nutrients, and so forth. It is having immense importance in nutrition. A 100 g edible Pandanus pericarp is mainly comprised of water and carbohydrates (80 and 17 g, resp.) and protein (1.3 mg), fat (0.7 mg), and fiber (3.5 g). Pandanus fruits paste provides 321 kilocalories, protein (2.2 g), calcium (134 mg), phosphorus (108 mg), iron (5.7 mg), thiamin (0.04 mg), vitamin C (5 mg), and beta-carotene (19 to 19,000 μg) (a carotenoid that is a precursor to vitamin A). Pandanus fruit is an important source of vitamins C, B1, B2, B3, and so forth, usually prepared as a Pandanus floured drink. Traditional claims were scientifically evaluated by the various authors and the phytochemical profile of plant parts was well established. The methods for analytical estimations were developed. However, there is paucity of systematic compilation of scientifically important information about this plant. In the present review we have systematically reviewed and compiled information of pharmacognostic, ethnopharmacology, phytochemistry, pharmacology, nutritional aspects, and analytical methods. This review will enrich knowledge leading the way into the discovery of new therapeutic agents with improved and intriguing pharmacological properties. PMID:25949238

The Na+/K+-ATPase and the amyloid-beta peptide aβ1-40 control the cellular distribution, abundance and activity of TRPC6 channels.

PubMed

Chauvet, Sylvain; Boonen, Marielle; Chevallet, Mireille; Jarvis, Louis; Abebe, Addis; Benharouga, Mohamed; Faller, Peter; Jadot, Michel; Bouron, Alexandre

2015-11-01

The Na(+)/K(+)-ATPase interacts with the non-selective cation channels TRPC6 but the functional consequences of this association are unknown. Experiments performed with HEK cells over-expressing TRPC6 channels showed that inhibiting the activity of the Na(+)/K(+)-ATPase with ouabain reduced the amount of TRPC6 proteins and depressed Ca(2+) entry through TRPC6. This effect, not mimicked by membrane depolarization with KCl, was abolished by sucrose and bafilomycin-A, and was partially sensitive to the intracellular Ca(2+) chelator BAPTA/AM. Biotinylation and subcellular fractionation experiments showed that ouabain caused a multifaceted redistribution of TRPC6 to the plasma membrane and to an endo/lysosomal compartment where they were degraded. The amyloid beta peptide Aβ(1-40), another inhibitor of the Na(+)/K(+)-ATPase, but not the shorter peptide Aβ1-16, reduced TRPC6 protein levels and depressed TRPC6-mediated responses. In cortical neurons from embryonic mice, ouabain, veratridine (an opener of voltage-gated Na(+) channel), and Aβ(1-40) reduced TRPC6-mediated Ca(2+) responses whereas Aβ(1-16) was ineffective. Furthermore, when Aβ(1-40) was co-added together with zinc acetate it could no longer control TRPC6 activity. Altogether, this work shows the existence of a functional coupling between the Na(+)/K(+)-ATPase and TRPC6. It also suggests that the abundance, distribution and activity of TRPC6 can be regulated by cardiotonic steroids like ouabain and the naturally occurring peptide Aβ(1-40) which underlines the pathophysiological significance of these processes. Copyright © 2015 Elsevier B.V. All rights reserved.

Influence of acidosis on cardiotonic effects of colforsin and epinephrine: a dose-response study.

PubMed

Hagiya, Keiichi; Takahashi, Hiroshi; Isaka, Yumi; Inomata, Shinichi; Tanaka, Makoto

2013-10-01

Acidosis produces a negative inotropic effect on cardiac muscle against which catecholamines and phosphodiesterase III inhibitors have limited therapeutic effects. This study evaluated the effects of colforsin, which directly activates adenylate cyclase without β-adrenergic receptor activation, in isolated Langendorff rat hearts in a pH- and concentration-dependent manner. Experimental animal study. A university laboratory. Sprague-Dawley rats. Hearts were isolated and perfused with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid/Tyrode solution (pH 7.4) in the Langendorff preparation. The hearts were assigned randomly to the control (pH 7.4), mild acidosis (pH 7.0), or severe acidosis (pH 6.6) group (n = 8 per group) and were perfused continuously with colforsin 10(-7), 10(-6), and 10(-5) mol/L. Maximum dP/dt was determined, and the concentration-response relation was evaluated at each pH. Colforsin at 10(-6) mol/L increased the maximum dP/dt from 2,592 ± 557 to 5,189 ± 721 mmHg/s (p < 0.001) and from 1,942 ± 325 to 3,399 ± 608 mmHg/s (p < 0.001) in the control and mild acidosis groups, respectively; whereas colforsin, 10(-5) mol/L, significantly increased the maximum dP/dt even in the severe acidosis group. No significant difference was seen in maximum dP/dt among the 3 groups after infusion with colforsin 10(-5) mol/L. In contrast to catecholamines and other inodilators, colforsin at a high concentration restores decreased cardiac contractility against severe acidosis to an extent similar to physiologic pH. Copyright © 2013 Elsevier Inc. All rights reserved.

In vitro antimicrobial and antimycobacterial activity and HPLC-DAD screening of phenolics from Chenopodium ambrosioides L.

PubMed

Jesus, Roberta S; Piana, Mariana; Freitas, Robson B; Brum, Thiele F; Alves, Camilla F S; Belke, Bianca V; Mossmann, Natália Jank; Cruz, Ritiel C; Santos, Roberto C V; Dalmolin, Tanise V; Bianchini, Bianca V; Campos, Marli M A; Bauermann, Liliane de Freitas

The main objective of this study was to demonstrate the antimicrobial potential of the crude extract and fractions of Chenopodium ambrosioides L., popularly known as Santa-Maria herb, against microorganisms of clinical interest by the microdilution technique, and also to show the chromatographic profile of the phenolic compounds in the species. The Phytochemical screening revealed the presence of cardiotonic, anthraquinone, alkaloids, tannins and flavonoids. The analysis by HPLC-DAD revealed the presence of rutin in the crude extract (12.5±0.20mg/g), ethyl acetate (16.5±0.37mg/g) and n-butanol (8.85±0.11mg/g), whereas quercetin and chrysin were quantified in chloroform fraction (1.95±0.04 and 1.04±0.01mg/g), respectively. The most promising results were obtained with the ethyl acetate fraction, which inhibited a greater number of microorganisms and presented the lowest values of MIC against Staphylococcus aureus and Enterococcus faecalis (MIC=0.42mg/mL), Pseudomonas aeruginosa (MIC=34.37mg/mL), Paenibacillus apiarus (MIC=4.29mg/mL) and Paenibacillus thiaminolyticus (MIC=4.29mg/mL). Considering mycobacterial inhibition, the best results were obtained by chloroform fraction against M. tuberculosis, M. smegmatis, and M. avium (MIC ranging from 156.25 to 625μg/mL). This study proves, in part, that the popular use of C. ambrosioides L. can be an effective and sustainable alternative for the prevention and treatment of diseases caused by various infectious agents. Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Nephroprotective potential of Bacopa monniera on hypercholesterolemia induced nephropathy via the NO signaling pathway.

PubMed

Kamesh, Venkatakrishnan; Sumathi, Thangarajan

2014-10-01

Bacopa monniera L. (Scrophulariaceae) is used as a traditional medicine in India for various ailments such as epilepsy, mental disorders, and also as a cardio-tonic. However, its nephroprotective role is still unknown. The present study assesses the modulatory impact of the alcoholic (ethanol) extract of Bacopa monniera (AEBM) on renal oxido-lipidemic stress in hypercholesterolemic rats. B. monniera (1 kg) was extracted with 90% ethanol, filtered, and dried (52 g). Group-I rats as control, Group-II rats fed with a hypercholesterolemic diet (HCD) for 45 d [4% cholesterol and 1% cholic acid], Group-III rats fed with HCD for 45 d + AEBM (40 mg/kg, body weight) for last 30 d, and Group-IV AEBM alone rats. Blood and kidney were removed to analyze lipid, antioxidant status, and histological analysis. The levels of total cholesterol (TC), triacylglycerol (TG), phospholipids (PLs), renal functional parameters (urea, creatinine, and uric acid), and lipid peroxidation (LPO) products were significantly attenuated (p < 0.01) in AEBM-treated hypercholesterolemic rats. Activities of both enzymic (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR)) and non-enzymic antioxidant (GSH, Vit-C, and Vit-E) were significantly increased (p < 0.01), on supplementation with AEBM. Administration with AEBM the mRNA levels of eNOS and iNOS genes was significantly up-regulated and down-regulated (p < 0.01). Histomorphological observations also evidenced that AEBM effectively protects the kidney from hypercholesterolemia-mediated oxido-lipidemic damage. From this study, we hypothesized that AEBM can act as renoprotective agent by attenuating the renal oxido-lipidemic stress via regulating NOS level and thereby protects the nephron in hypercholesterolemic rats.

Ouabain interactions with the α4 isoform of the sodium pump trigger non-classical steroid hormone signaling and integrin expression in spermatogenic cells.

PubMed

Upmanyu, Neha; Dietze, Raimund; Kirch, Ulrike; Scheiner-Bobis, Georgios

2016-11-01

In addition to the ubiquitous α1 isoform of the sodium pump, sperm cells also express a male-specific α4 isoform whose function has been associated with sperm motility, fertility, and capacitation. Here we investigate in the murine spermatogenic cell line GC-2 interactions of the α4 isoform with the cardiotonic steroid ouabain in signaling cascades involved in the non-classical action of steroid hormones. Exposure of GC-2 cells to low concentrations of ouabain stimulates the phosphorylation of Erk1/2 and of the transcription factors CREB and ATF-1. As a consequence of this signaling cascade, ouabain stimulates on the mRNA level the expression of integrins αv, β3 and α5, whose expression is also modulated by the cAMP response element. Increased expression of integrins αv and β3 is also seen in cultures of seminiferous tubules exposed to 10nM ouabain. At the protein level we observed a significant stimulation of β3 integrin expression by ouabain. Abrogation of α4 isoform expression by siRNA leads to the complete suppression of all ouabain-induced signaling mentioned above, including its stimulatory effect on the expression of β3 integrin. The results presented here demonstrate for the first time the induction of signaling cascades through the interaction of ouabain with the α4 isoform in a germ-cell derived cell line. The novel finding that these interactions lead to increased expression of integrins in GC-2 cells and the confirmation of these results in the ex vivo experiments indicate that hormone/receptor-like interactions of ouabain with the α4 isoform might be of significance for male physiology. Copyright © 2016 Elsevier B.V. All rights reserved.

The sodium pump α1 sub-unit: a disease progression–related target for metastatic melanoma treatment

PubMed Central

Mathieu, Véronique; Pirker, Christine; Martin de Lassalle, Elisabeth; Vernier, Mathieu; Mijatovic, Tatjana; DeNeve, Nancy; Gaussin, Jean-François; Dehoux, Mischael; Lefranc, Florence; Berger, Walter; Kiss, Robert

2009-01-01

Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump α sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump α1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis-resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump α sub-units in melanoma clinical samples and cell lines and also to characterize the role of α1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump α sub-units. In vitro cytotoxicity of various cardenolides and of an anti-α1 siRNA was evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Our data show that all investigated human melanoma cell lines expressed high levels of the α1 sub-unit, and 33% of human melanomas displayed significant α1 sub-unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumour effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti-tumour activity in the aggressive human metastatic brain melanoma model in vivo. The α1 sodium pump sub-unit could represent a potential novel target for combating melanoma. PMID:19243476

Mangiferin: A review of sources and interventions for biological activities.

PubMed

Jyotshna; Khare, Puja; Shanker, Karuna

2016-09-10

Xanthones are naturally synthesized in various biological systems such as plants, lichens, and fungi and are stored as by-products. In addition to taxonomic significance they are also important in the treatment/management of a number of human disorders. Mangiferin and its derived lead molecule have never qualified for use in a clinical trial despite a number of pharmacological studies that have proven its effectiveness as an antioxidant, analgesic, antidiabetic, antiproliferative, chemopreventive, radioprotective, cardiotonic, immunomodulatory, and diuretic. For centuries in the traditional practice of medicine in India and China the use of plants containing mangiferin has been a major component for disease management and health benefits. While it resembles biflavones, the C-glucosyl xanthone (mangiferin) has great nutritional and medicinal significance due to its unique structural characteristics. The C-glycoside link of mangiferin, mimicked to nucleophilic phloroglucinol substitution, facilitates its bioavailability and also is responsible for its antioxidant properties. Researchers have also utilized its xanthonic framework for both pharmacophoric backbone and for its use as a substitution group for synthesis and prospects. To date more than 500 derivatives using about 80 reactions have been generated. These reactions include: lipid peroxidation, phosphorylation, glycosylation, methylation, fermentation, deglycosylation, hydrolysis, polymerization, sulfation, acylation, etherification, peroxidation among others. Multiple studies on efficacy and safety have increased the global demand of mangiferin-based food supplements. This review highlights the distribution of mangiferin in plants, its isolation, and assay methods applicable to different sample matrices. In addition we include updates on various strategies and derived products intended for designated pharmacological actions. © 2016 BioFactors, 42(5):504-514, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

The pump, the exchanger, and the holy spirit: origins and 40-year evolution of ideas about the ouabain-Na+ pump endocrine system.

PubMed

Blaustein, Mordecai P

2018-01-01

Two prescient 1953 publications set the stage for the elucidation of a novel endocrine system: Schatzmann's report that cardiotonic steroids (CTSs) are all Na + pump inhibitors, and Szent-Gyorgi's suggestion that there is an endogenous "missing screw" in heart failure that CTSs like digoxin may replace. In 1977 I postulated that an endogenous Na + pump inhibitor acts as a natriuretic hormone and simultaneously elevates blood pressure (BP) in salt-dependent hypertension. This hypothesis was based on the idea that excess renal salt retention promoted the secretion of a CTS-like hormone that inhibits renal Na + pumps and salt reabsorption. The hormone also inhibits arterial Na + pumps, elevates myocyte Na + and promotes Na/Ca exchanger-mediated Ca 2+ gain. This enhances vasoconstriction and arterial tone-the hallmark of hypertension. Here I describe how those ideas led to the discovery that the CTS-like hormone is endogenous ouabain (EO), a key factor in the pathogenesis of hypertension and heart failure. Seminal observations that underlie the still-emerging picture of the EO-Na + pump endocrine system in the physiology and pathophysiology of multiple organ systems are summarized. Milestones include: 1) cloning the Na + pump isoforms and physiological studies of mutated pumps in mice; 2) discovery that Na + pumps are also EO-triggered signaling molecules; 3) demonstration that ouabain, but not digoxin, is hypertensinogenic; 4) elucidation of EO's roles in kidney development and cardiovascular and renal physiology and pathophysiology; 5) discovery of "brain ouabain", a component of a novel hypothalamic neuromodulatory pathway; and 6) finding that EO and its brain receptors modulate behavior and learning.

Effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 on the left ventricular pressure-volume relationship in the halothane-anesthetized dogs.

PubMed

Honda, Atsushi; Nakamura, Yuji; Ohara, Hiroshi; Cao, Xin; Nomura, Hiroaki; Katagi, Jun; Wada, Takeshi; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Sugiyama, Atsushi

2016-03-15

Cardiac effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 were assessed in the halothane-anesthetized dogs under the monitoring of left ventricular pressure-volume relationship, which were compared with those of clinically recommended doses of dopamine, dobutamine and milrinone (n=4-5 for each treatment). ONO-AE1-329 was intravenously administered in doses of 0.3, 1 and 3 ng/kg/min for 10 min with a pause of 20 min. Dopamine in a dose of 3 µg/kg/min for 10 min, dobutamine in a dose of 1 µg/kg/min for 10 min and milrinone in a dose of 5 µg/kg/min for 10 min followed by 0.5 µg/kg/min for 10 min were intravenously administered. Low dose of ONO-AE1-329 increased the stroke volume. Middle dose of ONO-AE1-329 increased the cardiac output, left ventricular end-diastolic volume, ejection fraction, maximum upstroke/downstroke velocities of the left ventricular pressure and external work, but decreased the end-systolic pressure and internal work besides the change by the low dose. High dose of ONO-AE1-329 increased the heart rate and maximum elastance, but decreased the end-systolic volume besides the changes by the middle dose. Dopamine, dobutamine and milrinone exerted essentially similar cardiac effects to ONO-AE1-329, but they did not significantly change the end-diastolic volume, end-systolic volume, stroke volume, ejection fraction, end-systolic pressure, maximum elastance, external work or internal work. Thus, EP4-receptor stimulation by ONO-AE1-329 may have potential to better promote the passive ventricular filling than the conventional cardiotonic drugs, which could become a candidate of novel therapeutic strategy for the treatment of heart failure with preserved ejection fraction. Copyright © 2016 Elsevier B.V. All rights reserved.

Na/K-ATPase/src complex mediates regulation of CD40 in renal parenchyma.

PubMed

Xie, Jeffrey X; Zhang, Shungang; Cui, Xiaoyu; Zhang, Jue; Yu, Hui; Khalaf, Fatimah K; Malhotra, Deepak; Kennedy, David J; Shapiro, Joseph I; Tian, Jiang; Haller, Steven T

2017-12-22

Recent studies have highlighted a critical role for CD40 in the pathogenesis of renal injury and fibrosis. However, little is currently understood about the regulation of CD40 in this setting. We use novel Na/K-ATPase cell lines and inhibitors in order to demonstrate the regulatory function of Na/K-ATPase with regards to CD40 expression and function. We utilize 5/6 partial nephrectomy as well as direct infusion of a Na/K-ATPase ligand to demonstrate this mechanism exists in vivo. We demonstrate that knockdown of the α1 isoform of Na/K-ATPase causes a reduction in CD40 while rescue of the α1 but not the α2 isoform restores CD40 expression in renal epithelial cells. Second, because the major functional difference between α1 and α2 is the ability of α1 to form a functional signaling complex with Src, we examined whether the Na/K-ATPase/Src complex is important for CD40 expression. We show that a gain-of-Src binding α2 mutant restores CD40 expression while loss-of-Src binding α1 reduces CD40 expression. Furthermore, loss of a functional Na/K-ATPase/Src complex also disrupts CD40 signaling. Importantly, we show that use of a specific Na/K-ATPase/Src complex antagonist, pNaKtide, can attenuate cardiotonic steroid (CTS)-induced induction of CD40 expression in vitro. Because the Na/K-ATPase/Src complex is also a key player in the pathogenesis of renal injury and fibrosis, our new findings suggest that Na/K-ATPase and CD40 may comprise a pro-fibrotic feed-forward loop in the kidney and that pharmacological inhibition of this loop may be useful in the treatment of renal fibrosis. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Red maca (Lepidium meyenii) reduced prostate size in rats

PubMed Central

Gonzales, Gustavo F; Miranda, Sara; Nieto, Jessica; Fernández, Gilma; Yucra, Sandra; Rubio, Julio; Yi, Pedro; Gasco, Manuel

2005-01-01

Background Epidemiological studies have found that consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer. This effect seems to be due to aromatic glucosinolate content. Glucosinolates are known for have both antiproliferative and proapoptotic actions. Maca is a cruciferous cultivated in the highlands of Peru. The absolute content of glucosinolates in Maca hypocotyls is relatively higher than that reported in other cruciferous crops. Therefore, Maca may have proapoptotic and anti-proliferative effects in the prostate. Methods Male rats treated with or without aqueous extracts of three ecotypes of Maca (Yellow, Black and Red) were analyzed to determine the effect on ventral prostate weight, epithelial height and duct luminal area. Effects on serum testosterone (T) and estradiol (E2) levels were also assessed. Besides, the effect of Red Maca on prostate was analyzed in rats treated with testosterone enanthate (TE). Results Red Maca but neither Yellow nor Black Maca reduced significantly ventral prostate size in rats. Serum T or E2 levels were not affected by any of the ecotypes of Maca assessed. Red Maca also prevented the prostate weight increase induced by TE treatment. Red Maca administered for 42 days reduced ventral prostatic epithelial height. TE increased ventral prostatic epithelial height and duct luminal area. These increases by TE were reduced after treatment with Red Maca for 42 days. Histology pictures in rats treated with Red Maca plus TE were similar to controls. Phytochemical screening showed that aqueous extract of Red Maca has alkaloids, steroids, tannins, saponins, and cardiotonic glycosides. The IR spectra of the three ecotypes of Maca in 3800-650 cm (-1) region had 7 peaks representing 7 functional chemical groups. Highest peak values were observed for Red Maca, intermediate values for Yellow Maca and low values for Black Maca. These functional groups correspond among others to benzyl glucosinolate. Conclusions Red Maca, a cruciferous plant from the highland of Peru, reduced ventral prostate size in normal and TE treated rats. PMID:15661081

A review on phytochemistry and pharmacological activities of the processed lateral root of Aconitum carmichaelii Debeaux.

PubMed

Zhou, Guohong; Tang, Liying; Zhou, Xidan; Wang, Ting; Kou, Zhenzhen; Wang, Zhuju

2015-02-03

The processed lateral root of Aconitum carmichaelii Debeaux (Ranunculaceae), an extensively used traditional Chinese medicine, is known as Fuzi in China (Chinese: ), "bushi" in Japan, "Kyeong-Po Buja" in Korea, Chinese aconite, monkshood or Chinese wolfsbane. It has been used to treat shock resulting from acute myocardial infarction, low blood pressure, coronary heart disease, chronic heart failure, etc. The present paper aims to provide an up-to-date review at the advancements of the investigations on the ethnopharmacology, phytochemistry, pharmacological effect and toxicity of Fuzi. Besides, the possible tendency and perspective for future research of this plant are discussed, as well. All available information on Fuzi was collected via electronic search (using Elsevier, PubMed, ACS, CNKI, Google Scholar, Baidu Scholar, and Web of Science), books and classic works about Chinese herb. 122 chemical constituents, among which C19-diterpenoid alkaloids and C20-diterpenoid alkaloids are the predominant groups, have been isolated and identified from Fuzi. Fuzi with its active compounds is possessed of wide-reaching biological activities, including effects on cardiovascular system, anti-inflammation and analgesic action, anti-tumor activity, effect on the immune system, hypoglycemic and hypolipidemic effects, anti-aging effect, effect of protecting kidney and effect on energy metabolism. Nearly all of compounds were found from the roots of the plant, so further phytochemical studies should focus more on the other parts of the plant, such as the leaves, flowers or stems. Besides, a majority of the pharmacological studies were carried out using crude and poorly characterized extracts. Thus, more bioactive components particularly cardiotonic and analgesic compounds should be identified through bioactivity-guided isolation strategies. Moreover, investigations on how to develop Fuzi׳s new clinical usage on the basis of its pharmacological effects are in requirement. Copyright © 2014. Published by Elsevier Ireland Ltd.

Botany, traditional uses, phytochemistry and pharmacology of Apocynum venetum L. (Luobuma): A review.

PubMed

Xie, Wenyan; Zhang, Xiaoying; Wang, Tian; Hu, Jianjun

2012-05-07

Apocynum venetum L. (Apocynaceae, Luobuma ) has a long history as a Chinese traditional medicine with uses to calm the liver, soothe the nerves, dissipate heat, and promote diuresis. Recently, Luobuma tea has been commercialized as a sedative and anti-aging supplement that has become increasingly popular in North American and East Asian health food markets. The aim of this review is to provide an up-to-date and comprehensive overview of the botany, chemical constituents, traditional uses, pharmacological activities and safety aspects of Apocynum venetum in order to assess its ethnopharmacological use and to explore its therapeutic potentials and future opportunities for research. The accessible literature on Apocynum venetum written in English, Chinese and Japanese were collected and analyzed. The literatures included ancient Chinese herbal classics, pharmacopoeias and articles that included in Pubmed, Web of Science, Google Scholar and Wanfang. Modern pharmacological studies demonstrated that Apocynum venetum possess wide pharmacological activities that include antihypertensive, cardiotonic, hepatoprotective, antioxidant, lipid-lowering, antidepressant and anxiolytic effects, which can be explained by the presence of various flavonoid compounds in this plant. The traditional (Lop Nor region) use of Apocynum venetum with tobacco as an agent to detoxify nicotine may receive interest as a possible therapeutic option to detoxify the body from smoking. Based on animal studies and clinical trials, Apocynum venetum causes no severe side effects, even in a stable daily dosage (50mg/person/day) for more than three years. Apocynum venetum potentially has therapeutic potential in the prevention and treatment for the cardiovascular and neurological diseases, especially for high blood pressure, high cholesterol, neurasthenia, depression and anxiety. Further investigations are needed to explore individual bioactive compounds responsible for these in vitro and in vivo pharmacological effects and the mode of actions. Further safety assessments and clinical trials should be performed before it can be integrated into medicinal practices. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Saussurea lappa extract suppresses TPA-induced cell invasion via inhibition of NF-κB-dependent MMP-9 expression in MCF-7 breast cancer cells

PubMed Central

2014-01-01

Background Saussurea lappa (SL) has been used as a traditional herbal medicine to treat abdominal pain and tenesmus, and has been suggested to possess various biological activities, including anti-tumor, anti-ulcer, anti-inflammatory, anti-viral, and cardiotonic activities. The effect of SL on breast cancer metastasis, however, is unknown. Cell migration and invasion are crucial in neoplastic metastasis. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix, is a major component in cancer cell invasion. Methods Cell viability was examined by MTT assay, whereas cell motility was measured by invasion assay. Western blot, Real-time PCR, and Zymography assays were used to investigate the inhibitory effects of ESL on matrix metalloproteinase-9 (MMP-9) expression level in MCF-7 cells. EMSA confirmed the inhibitory effects of ESL on DNA binding of NF- κB in MCF-7 cells. Results Cells threated with various concentrations of Saussurea lappa (ESL) for 24 h. Concentrations of 2 or 4 μM did not lead to a significant change in cell viability or morphology. Therefore, subsequent experiments utilized the optimal non-toxic concentration (2 or 4 μM) of ESL. In this study, we investigated the inhibitory effect of ethanol extract of ESL on MMP-9 expression and cell invasion in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MCF-7 cells. ESL inhibited the TPA-induced transcriptional activation of nuclear factor-kappa B (NF-κB). However, this result obtained that ESL did not block the TPA-induced phosphorylation of the kinases: p38, ERK, and JNK. Therefore, ELS-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of NF-kB pathway in MCF-7 cells. Conclusions These results indicate that ELS-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of NF-kB pathway in MCF-7 cells. Thus, ESL has potential for controlling breast cancer invasiveness in vitro. PMID:24885456

Revealing of endogenous Marinobufagin by an ultra-specific and sensitive UHPLC-MS/MS assay in pregnant women.

PubMed

Lenaerts, Charline; Bond, Liz; Tuytten, Robin; Blankert, Bertrand

2018-09-01

Marinobufagenin (MBG) is a bufadienolide cardiac inotrope implicated in volume expansion-mediated hypertensive states including essential hypertension and preeclampsia (PE). Endogenous MBG is an inhibitor of the α1-isoform of Na + ,K + -ATPase with vasoconstrictive and cardiotonic properties, causing hypertension and natriuresis. Elevated endogenous MBG-like material levels have been described by immunoassays in salt-sensitive pregnant and preeclamptic rats as well as in preeclamptic human patients. The rise of endogenous MBG-like material appears prior the development of the main symptoms of PE, leading us to consider MBG as one of the potential biomarkers for PE. The weak specificity and the high variability of the published immunoassays gives no certification about endogenous MBG existence. This led us to set-up a highly specific and sensitive analytical method to detect MBG in plasma at low levels relying on liquid chromatography combined to mass spectrometry (UHPLC-MS/MS) with recording of 7 highly specific MRM transitions for MBG. Pure MBG standard used in the method development was obtained by purification from the Bufo marinus toad venom. d 3 -25-hydroxyvitamin D3 was used as internal standard. An increasing organic gradient with mobile phase A and B composed of 97:3 (v/v) H 2 O: MeOH and 50:45:5 (v/v/v) MeOH:IPA:H 2 O at pH 4.5 respectively was used on a Pursuit 3 PFP column (100 mm × 3 mm; 3 µm) to allow elution and separation of the plasmatic compounds. Chromatographic analyses of plasma samples were preceded by a precipitation of proteins pretreatment. The developed UHPLC-MS/MS assay has been applied to early-pregnant women plasma samples allowing us to investigate MBG plasma levels. Thanks to the high specificity of the assay we were able to authenticate and certify the presence of endogenous MBG in early-pregnant women plasma with the use of the 7 selected specific mass transitions. These pioneering preliminary results are giving a promising perspective for early preeclampsia risk assessment in pregnant women. Copyright © 2018 Elsevier B.V. All rights reserved.

Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland

PubMed Central

Sanderson, Julie; Dartt, Darlene A.; Trinkaus-Randall, Vickery; Pintor, Jesus; Civan, Mortimer M.; Delamere, Nicholas A.; Fletcher, Erica L.; Salt, Thomas E.; Grosche, Antje; Mitchell, Claire H.

2014-01-01

This review highlights recent findings that describe how purines modulate the physiological and pathophysiological responses of ocular tissues. For example, in lacrimal glands the cross-talk between P2X7 receptors and both M3 muscarinic receptors and α1D-adrenergic receptors can influence tear secretion. In the cornea, purines lead to post-translational modification of EGFR and structural proteins that participate in wound repair in the epithelium and influence the expression of matrix proteins in the stroma. Purines act at receptors on both the trabecular meshwork and ciliary epithelium to modulate intraocular pressure (IOP); ATP-release pathways of inflow and outflow cells differ, possibly permitting differential modulation of adenosine delivery. Modulators of trabecular meshwork cell ATP release include cell volume, stretch, extracellular Ca2+ concentration, oxidation state, actin remodeling and possibly endogenous cardiotonic steroids. In the lens, osmotic stress leads to ATP release following TRPV4 activation upstream of hemichannel opening. In the anterior eye, diadenosine polyphosphates such as Ap4A act at P2 receptors to modulate the rate and composition of tear secretion, impact corneal wound healing and lower IOP. The Gq11-coupled P2Y1-receptor contributes to volume control in Müller cells and thus the retina. P2X receptors are expressed in neurons in the inner and outer retina and contribute to visual processing as well as the demise of retinal ganglion cells. In RPE cells, the balance between extracellular ATP and adenosine may modulate lysosomal pH and the rate of lipofuscin formation. In optic nerve head astrocytes, mechanosensitive ATP release via pannexin hemichannels, coupled with stretch-dependent upregulation of pannexins, provides a mechanism for ATP signaling in chronic glaucoma. With so many receptors linked to divergent functions throughout the eye, ensuring the transmitters remain local and stimulation is restricted to the intended target may be a key issue in understanding how physiological signaling becomes pathological in ocular disease. PMID:25151301

Cysteine residues 244 and 458-459 within the catalytic subunit of Na,K-ATPase control the enzyme's hydrolytic and signaling function under hypoxic conditions.

PubMed

Petrushanko, Irina Yu; Mitkevich, Vladimir A; Lakunina, Valentina A; Anashkina, Anastasia A; Spirin, Pavel V; Rubtsov, Peter M; Prassolov, Vladimir S; Bogdanov, Nikolay B; Hänggi, Pascal; Fuller, William; Makarov, Alexander A; Bogdanova, Anna

2017-10-01

Our previous findings suggested that reversible thiol modifications of cysteine residues within the actuator (AD) and nucleotide binding domain (NBD) of the Na,K-ATPase may represent a powerful regulatory mechanism conveying redox- and oxygen-sensitivity of this multifunctional enzyme. S-glutathionylation of Cys244 in the AD and Cys 454-458-459 in the NBD inhibited the enzyme and protected cysteines' thiol groups from irreversible oxidation under hypoxic conditions. In this study mutagenesis approach was used to assess the role these cysteines play in regulation of the Na,K-ATPase hydrolytic and signaling functions. Several constructs of mouse α1 subunit of the Na,K-ATPase were produced in which Cys244, Cys 454-458-459 or Cys 244-454-458-459 were replaced by alanine. These constructs were expressed in human HEK293 cells. Non-transfected cells and those expressing murine α1 subunit were exposed to hypoxia or treated with oxidized glutathione (GSSG). Both conditions induced inhibition of the wild type Na,K-ATPase. Enzymes containing mutated mouse α1 lacking Cys244 or all four cysteines (Cys 244-454-458-459) were insensitive to hypoxia. Inhibitory effect of GSSG was observed for wild type murine Na,K-ATPase, but was less pronounced in Cys454-458-459Ala mutant and completely absent in the Cys244Ala and Cys 244-454-458-459Ala mutants. In cells, expressing wild type enzyme, ouabain induced activation of Src and Erk kinases under normoxic conditions, whereas under hypoxic conditions this effect was inversed. Cys454-458-459Ala substitution abolished Src kinase activation in response to ouabain treatment, uncoupled Src from Erk signaling, and interfered with O 2 -sensitivity of Na,K-ATPase signaling function. Moreover, modeling predicted that S-glutathionylation of Cys 458 and 459 should prevent inhibitory binding of Src to NBD. Our data indicate for the first time that cysteine residues within the AD and NBD influence hydrolytic as well as receptor function of the Na,K-ATPase and alter responses of the enzyme to hypoxia or upon treatment with cardiotonic steroids. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

[TRANSPORT OF OXYGEN DURING GEOMETRICAL RECONSTRUCTION OF THE LEFT VENTRICLE IN CONJUNCTION WITH CORONARY ARTERY BYPASS GRAFTING AND USING OF HIGH THORACIC EPIDURAL ANESTHESIA AS A MAJOR COMPONENT OF GENERAL ANAESTHESIA].

PubMed

Zatevahina, M V; Farzutdinov, A F; Rahimov, A A; Makrushin, I M; Kvachantiradze, G Y

2015-01-01

The purpose of the study is to examine the perioperative dynamics of strategic blood oxygen transport indicators: delivery (DO2), consumption (VO2), the coefficient of oxygen uptake (CUO2) and their composition, as well as the dynamics of blood lactate indicators in patients with ischaemic heart disease (IHD) who underwent surgery under cardiopulmonary bypass with high thoracic epidural anaesthesia (HTEA) as the main component of anesthesia. Research was conducted in 30 patients with a critical degree of operational risk, during the correction of post-infarction heart aneurysmn using the V. Dor method in combination with coronary artery bypass grafting. The strategic blood oxygen transport indicators (delivery, consumption and the oxygen uptake coefficient) showed a statistically significant decrease compared to the physiological norm and to the initial data at two points of the research: the intubation of the trachea and during cardiopulmonary bypass. The system components of oxygen were influenced at problematic stages by the dynamics of SvO2 (increase), AVD (decrease), hemodilution withe fall of the HIb- in the process of JR in the persence of superficial hypothermia. The maintenance of optimal CA in the context of HTEA, combined with a balanced volemic load and a minimized cardiotonic support ensured the stabilisation of strategic blood oxygen transport indicators aithe postperfusion stage and during the immediate postoperative period The article is dedicated to the study of strategic blood oxygen transport indicators and their components during the operation of geometric reconstruc-tion of the left ventricle combined with coronary artery-bypass using cardiopulmonary bypass and with high thoracic epidural anesthesia as the main component of general anaesthesia. The analysis has covered the stagewise delivery dynamics, consumption and the oxygen uptake coefficient at II stages of the operation and of the immediate postoperative period. The study has ident (fled the causes qf reduced oxygen transport during the preperfu- sion and postperfusion periods, under IR and during the immediate postoperative period. Values of CA, SvO2, AVD, Hb, hemnodilution, T qf the body in oxygen transport indicator dynamics have been proven. A way of maintaining oxygen transport indicators close to the physiological norm in the immediate postoperative period has been justified.

Antihypertensive effect of the methanolic extract from Eruca sativa Mill., (Brassicaceae) in rats: muscarinic receptor-linked vasorelaxant and cardiotonic effects.

PubMed

Salma, Umme; Khan, Taous; Shah, Abdul Jabbar

2018-06-15

Eruca sativa Mill., (Brassicaceae) is a popular remedy for the treatment of hypertension in Pakistan. However, direct effect of the extract and its fractions on blood pressure and vascular tone are unknown. This investigation was aimed to explore the pharmacological base for the traditional use of E. sativa in hypertension. In-vivo blood pressure study was carried out using normotensive and high salt-induced hypertensive rats under anaesthesia. The cardiovascular mechanisms were explored using rat aorta and atria in-vitro. Preliminary phytochemical analysis, spectrophotometric detection of total phenols, flavonoids and HPLC analysis of crude extract were performed using quercetin and erucin as marker compounds. Intravenous injection of crude extract induced a fall in mean arterial pressure (MAP) in both normotensive (max fall: 41.79±1.55% mmHg) and hypertensive (max fall: 58.25±0.91% mmHg) rats. Atropine (1mg/kg) pretreatment attenuated this effect significantly (p < 0.001), suggesting the involvement of muscarinic receptor in its antihypertensive effect. Fractions also induced atropine-sensitive antihypertensive effect. Similarly, oral administration of crude and aqueous extracts resulted a fall in MAP in the hypertensive rats. In isolated rat aortic rings from normotensive rats, crude extract and fractions induced an endothelium-dependent relaxation. This relaxation was partially inhibited with L- NAME and atropine pretreatment and with denudation of aortic rings, indicating involvement of muscarinic receptor-linked nitric oxide (NO). In aorta from the hypertensive rats, crude extract and fractions induced endothelium-independent relaxation. This relaxation was not affected by pretreatment with L- NAME or atropine. Crude extract and fractions also suppressed phenylephrine contractions in Ca +2 free/EGTA medium. In isolated rat atrial preparations, crude extract and fractions induced negative inotropic and chronotropic effects with a positive inotropic effect by the n-hexane fraction, which were not affected with atropine pretreatment. Phytochemical screening and spectrophotometric analysis indicated the presence of phenols and flavonoids, whereas HPLC analysis of crude extract revealed the presence of quercetin (flavonoid) and erucin (isothiocyanate). The results suggest that E. sativa is an antihypertensive remedy which is mainly due to its vasodilatory and partly cardiac effects. Muscarinic receptors-linked NO release and dual inhibitory effect on Ca +2 influx and release underlie the vasodilation. This finding provides pharmacological base to the traditional use of E. sativa in hypertension. The presence of quercetin and erucin further support this finding. Copyright © 2018. Published by Elsevier B.V.

Potential pitfalls in the nuclear medicine imaging: Experimental models to evaluate the effect of natural products on the radiolabeling of blood constituents, bioavailability of radiopharmaceutical and on the survival of Escherichia coli strains submitted to the treatment with stannous ion

NASA Astrophysics Data System (ADS)

Soares, Scheila F.; Brito, Lavínia C.; Souza, Deise E.; Bernardo, Luciana C.; Oliveira, Joelma F.; Bernardo-Filho, Mario

2006-12-01

Single photon emission computed tomography (SPECT) allows studies of physiological or pathological processes. Red blood cells labeled with technetium-99m ( 99mTc-RBC) are used as a radiopharmaceutical in several evaluations. The radiolabeling efficiency and bioavailability of radiopharmaceuticals can be altered by natural/synthetic drugs and may induce pitfalls in the analysis of the nuclear medicine imaging. The labeling with 99mTc requires a reducing agent and stannous chloride (SnCl 2) is widely utilized. However, SnCl 2 presents a citotoxic and/or genotoxic potential in Escherichia coli ( E. coli) strains. The aim of this work was to evaluate the influence of aqueous extracts of Baccharis genistelloides (BG), Terminalia chebula (TC), Maytenus ilicifolia (MI), Cassia angustifolia (CA) and Equisetum arvense (EA) on (i) radiolabeling of blood constituents, (ii) bioavailability of sodium pertechnetate(Na 99mTcO 4) radiopharmaceutical, (iii) survival of E. coli. In vitro labeling of RBC was performed with blood ( Wistar rats) incubated with each extract, SnCl 2 and Na 99mTcO 4. Plasma (P) and blood cells (BC) were isolated, another aliquots precipitated and soluble (SF) and insoluble (IF) fractions isolated and counted. In the bioavailability of Na 99mTcO 4, Wistar rats were treated (7 days) with aqueous extract or with 0.9%NaCl, the radiopharmaceutical was administered, the animals sacrificed, the organs isolated, weighted and radioactivity counted. To evaluate the effect on the bacterial survival, E. coli was treated with: (a) SnCl 2; (b) 0.9% NaCl; (c) vegetal extract; or (d) SnCl 2 and vegetal extract. Radiolabeling efficiency showed a significantly decrease (ANOVA/Tukey post-test, p<0.05) after treatment with BG, TC, MI and CA extracts. The bioavailability results showed that the uptake of Na 99mTcO 4 was altered significantly (unpaired t-student test, p<0.05) in blood, lungs (CA/TC extracts), bone, heart, ovary (EA /TC), spleen, kidney (TC) , pancreas, thyroid (CA) and liver (all the extracts). The alterations promoted by TC extract could be related to cardiotonic, antidiabetes and renal toxicity. The alteration in liver in EA and CA extracts could be related to its hepatoprotective activities. The extracts (EA, MI, BG) were not capable to interfere in the survival of E. coli. Moreover, these extracts have protected the E. coli against the SnCl 2 action and this fact can be related to the free radical scavenging properties of the chemical compounds of the extracts. In conclusion these findings could be worthwhile to try to understand and to avoid some pitfalls in the nuclear medicine.

Inhibition of gastric acid secretion by a standardized aqueous extract of Cecropia glaziovii Sneth and underlying mechanism.

PubMed

Souccar, C; Cysneiros, R M; Tanae, M M; Torres, L M B; Lima-Landman, M T R; Lapa, A J

2008-06-01

Cecropia glazioui Sneth (Cecropiaceae) is used in folk medicine in tropical and subtropical Latin America as cardiotonic, diuretic, hypotensive, anti-inflammatory and anti-asthmatic. The hypotensive/antihypertensive activity of the plant aqueous extract (AE) and isolated butanolic fraction (BuF) has been confirmed and putatively related to calcium channels blockade in vascular smooth musculature [Lapa, A.J., Lima-Landman, M.T.R., Cysneiros, R.M, Borges, A.C.R., Souccar, C., Barreta, I.P., Lima, T.C.M., 1999. The Brazilian folk medicine program to validate medicinal plants - a topic in new antihypertensive drug research. In: Hostettman, K., Gupta, M.P., Marston, A. (Eds.), Proceedings Volume, IOCD/CYTED Symposium, Panamá City, Panamá, 23-26 February 1997. Chemistry, Biological and Pharmacological Properties of Medicinal Plants from the Americas. Harwood Academic Publishers, Amsterdam, pp. 185-196; Lima-Landman, M.T., Borges, A.C., Cysneiros, R.M., De Lima, T.C., Souccar, C., Lapa, A.J., 2007. Antihypertensive effect of a standardized aqueous extract of Cecropia glaziovii Sneth in rats: an in vivo approach to the hypotensive mechanism. Phytomedicine 14, 314-320]. Bronchodilation and antidepressant-like activities of both AE and BuF have been also shown [Delarcina, S., Lima-Landman, M.T., Souccar, C., Cysneiros, R.M., Tanae, M.M., Lapa, A.J., 2007. Inhibition of histamine-induced bronchospasm in guinea pigs treated with Cecropia glaziovi Sneth and correlation with the in vitro activity in tracheal muscles. Phytomedicine 14, 328-332; Rocha, F.F., Lima-Landman, M.T., Souccar, C., Tanae, M.M., De Lima, T.C., Lapa, A.J., 2007. Antidepressant-like effect of Cecropia glazioui Sneth and its constituents -in vivo and in vitro characterization of the underlying mechanism. Phytomedicine 14, 396-402]. This study reports the antiulcer and antisecretory gastric acid activities of the plant AE, its BuF and isolated compounds with the possible mechanism involved. Both AE and BuF were assayed on gastric acid secretion of pylorus-ligated mice, on acute models of gastric mucosal lesions, and on rabbit gastric H(+), K(+)-ATPase preparations. Intraduodenal injection of AE or BuF (0.5-2.0g/kg, i.d) produced a dose-related decrease of the basal gastric acid secretion in 4-h pylorus-ligated mice. At 1.0g/kg, BuF decreased the volume (28%) and total acidity (33%) of the basal acid secretion, and reversed the histamine (2.5mg/kg, s.c.)- or bethanecol (1.0mg/kg, s.c.)-induced acid secretion to basal values, indicating inhibition of the gastric proton pump. Pretreatment of mice with the BuF (0.05-0.5g/kg, p.o.) protected against gastric mucosal lesions induced by 75% ethanol, indomethacin (30mg/kg, s.c.) or restraint at 4 degrees C. BuF also decreased the gastric H(+), K(+)-ATPase activity in vitro proportionately to the concentration (IC(50)=58.8microg/ml). The compounds isolated from BuF, consisting mainly of cathechins, procyanidins and flavonoids [Tanae, M.M., Lima-Landman, M.T.R., De Lima, T.C.M., Souccar, C., Lapa, A.J., 2007. Chemical standardization of the aqueous extract of Cecropia glaziovii Sneth endowed with antihypertensive, bronchodilator, antacid secretion and antidepressant-like activities. Phytomedicine 14, 309-313], inhibited the in vitro gastric H(+), K(+)-ATPase activity at equieffective concentrations to that of BuF. The results indicate that C. glazioui constituents inhibit the gastric proton pump; this effect may account for the effective antisecretory and antiulcer activities of the standardized plant extract.