Cardiac Steroids Research Articles

On the mechanisms by which hypoxia eliminates digitalis-induced tachyarrhythmias.

The mechanism by which hypoxia abolishes the tachyarrhythmias induced by cardiac steroids was studied in cardiac Purkinje and ventricular muscle fibres. In muscle fibres, hypoxia reduces excitability markedly, reduces the size and increases the time to peak of the oscillatory potentials (Vos) and of the aftercontractions induced by cardiac steroids, thereby abolishing the tachyarrhythmias. In Purkinje fibres, hypoxia also decreases Vos and excitability but abolishes the tachyarrhythmias only if repeated or prolonged. In Purkinje-muscle preparations, hypoxia blocks impulse conduction from the fast discharging Purkinje fibres to the myocardial fibres when the latter are still little intoxicated. It is concluded that hypoxia affects promptly ventricular muscle fibres and (depending on the experimental conditions) Purkinje fibres also, and readily blocks impulse transmission to muscle fibres. Hypoxia abolishes arrhythmias by decreasing Vos size (probably through an impaired calcium uptake into the sarcoplasmic reticulum), by causing a conduction block at the Purkinje-muscle junction (probably through an increase in cytoplasmic calcium) and by reducing excitability.

Structure-activity relationship of cardiac steroids having a doubly linked sugar and related compounds for the inhibition of Na+,K+-adenosine triphosphatase.

Forty-three different cardiac steroids having a doubly linked sugar and related compounds were tested for inhibition of Na+,K+-adenosine triphosphatase from guinea pig heart, and the structure-activity relationship has been discussed. The doubly linked glycosides showed higher activities than the respective genins. The inhibitory activities of these compounds were also dependent upon the presence of ring C substituents. The bufadienolide rhamnosides exhibited greater than three times the inhibitory activity of the parent genin, while the glucosyl residue exerted no significant activity.

<b>Novel polyhydroxylated cardiac steroids in the nuchal glands of the snake, <i>Rhabdophis </i></b><b>tigrinus </b>

New polyhydroxylated cardiac steroids (I, II, III, IV, V and VI) were found in nuchal gland secretions of the snake, Rhabdophis tigrinus. The steroids contained an α-pyron ring at position 17 as those in bufodienolides but were not conjugated with suberoyl arginine. Hydroxylation occurred at position 3, 5, 11, 14; 3, 7, 11, 14, or 3, 5, 14, 16, respectively. This is the first report that the snake (Rhabdophis tigrinus) contains cardiac steroids in the nuchal glands.

Structure-activity relationship of bufotoxins and related compounds for the inhibition of Na+, K+ -adenosine triphosphatase.

Forty kinds of bufotoxins and related compounds were tested for inhibition of Na+, K+ -adenosine triphosphatase from guinea pig heart, and the structure-activity relationship has been discussed. The inhibitory activities of bufotoxins were dependent upon the dicarboxylic acid and amino acid components. The compounds having both the arginine and suberic acid moieties showed the higher inhibitory activities. The sulfates and glucuronides of cardiac steroids exhibited much less potency than the parent genins. The mode of inhibition was determined by means of the Dixon and Lineweaver-Burk plots.

A structural and biological analysis of cardiac steroids and their glycosides

A structural and biological analysis of cardiac steroids and their glycosides

115 Effects of cardiac steroids on the growth rate and morphology of L1210 cells

115 Effects of cardiac steroids on the growth rate and morphology of L1210 cells

Influence of 16β formylation on Na, K-ATPase inhibition by cardiac glycosides

The inhibitory effect of formylated cardiac steroids (gitaloxin and its derivatives) on guinea-pig heart Na, K-ATPase was compared to that of other cardiac steroids with various hydroxy substituents. The decreasing order of potency of aglycones at equilibrium was as follows: gitaloxigenin greater than digitoxigenin greater than ouabagenin greater than digoxigenin greater than gitoxigenin greater than diginatigenin. This sequence was different to the sequence of drugs hydrophobic character. The compounds with hydroxy groups in the vicinity of the lactone ring (gitoxigenin, diginatigenin) were less potent than the hydrophilic compound ouabagenin. We propose that intramolecular bounding between 16 beta-OH and the lactone ring contributes to the relatively low potency of gitoxigenin and diginatigenin. The formylation of 16 beta-OH increased the potency of gitoxigenin by a factor of 41. The formylated compound (gitaloxigenin) was 5-fold more potent than digitoxigenin. The 3 beta-glycosylation of digoxigenin lead to pseudo-irreversible inhibitors of Na, K-ATPase. The half-time to achieve the equilibrium (for 5 mumol/l) was equal to 54 s, 90 s and 108 s respectively for digoxigenin monodigitoxoside, digoxin and desacetyllanatoside C. However, at equilibrium the three glycosides were equipotent, suggesting the existence of steric effects at the sugar site of the receptor. The sequence of potency observed for monodigitoxosides, monodigitalosides and tridigitoxosides after 60 min incubation was similar to that observed for the corresponding aglycones. These results suggest that the strongly negative inductive group 16 beta-OCHO is tightly bound to Na, K-ATPase, possibly to the same receptor site than that which is thought forming hydrogen and ionic bonds with the lactone ring. They show that the high toxicity of gitaloxin in guinea-pig heart is likely due to its high potency as Na, K-ATPase inhibitor.

Isolation and characterization of cardiac steroids from seeds of Elaeopendron glaucum Pers. Structures of elaeodendrosides A, D, E, H, I, J and elaeodendrogenin.

Six cardiac glycosides having a methylenedioxy group in the sugar moiety, elaeodendroside A, D, E, H, I and J, were isolated from seeds of Elaeodendron glaucum PERS. Their structures were elucidated on the basis of chemical correlation with elaeodendroside A, which was characterized by X-ray analysis. A new cradiac steroid named elaeodendrogenin was also isolated from the same plant materials and its structure was established by direct comparison with a synthetic sample obtained from digitoxigenin. The cardiac activities of these compounds were tested with Straub's preparation.

Separation of digitalis cardenolides by HPLC

AbstractThe separation of Digitalis cardenolides has been carried out by HPLC on an adsorbent column. By choice of suitable mobile phase, isocratic elution permitted resolution of mixtures of (a) aglycones, (b) secondary glycosides, and (c) primary glycosides, while gradient elution provided a means of resolving more complex mixtures of these cardiac steroids. HPLC could therefore be used in the quality control of cardiotonic drugs replacing the TLC tests for related compounds currently used, and by suitable calibration could replace the colorimetric assay procedure normally used for such drugs.

Thin-layer chromatography of cardenolides in the presence of boric acid

The thin-layer chromatography behaviour of cardenolides and their derivatives was investigated in the presence of boric acid, which forms cyclic derivatives with cis-1,2- and -1,3-diols. Boric acid reduces the mobility of cardenolide glycosides containing diol units in their carbohydrate moiety whereas with cardenolides or cardenolide glycosides possessing 1,3-diol units in the genin part it increases the mobility. The formation of boric acid derivatives resulted in an improved separation of certain cardiac steroids and afforded the possibility of detecting cardenolides containing reactive diol units. A method of impregnation in the vapour phase was developed which ensured mild treatment of the layers and yielded an extremely uniform impregnation.

Separation and determination of cardiac steroids by high-pressure liquid chromatography.

A method for the simultaneous analysis of cardiac steroids by high-pressure liquid chromatography has been developed. Reversed phase chromatography on a μ-Bondapak C18 column was particularly effective for the separation of sixteen bufadienolides and nine cardenolides. Determination of the principal bufogenins in the fresh venom of the Japanese toad was carried out by the internal standard method. The relationship between chemical structures and retention values is also discussed.

201) - Action of cardiac steroids on the intestinal smooth muscle in relation to changes in electrical properties of membrane and the role of calcium ion

201) - Action of cardiac steroids on the intestinal smooth muscle in relation to changes in electrical properties of membrane and the role of calcium ion

Inhibitory action of cardiac steroids on the contraction of the taenia coli of the guinea-pig — with special respect to the membrane properties of the smooth muscle

Inhibitory action of cardiac steroids on the contraction of the taenia coli of the guinea-pig — with special respect to the membrane properties of the smooth muscle

(Na +-K +)-ATPase from the frog bladder and its relationship to sodium transport

1. 1. (Na +-K +)-ATPase activity in the bladder and kidney of frog ( Rana catesbiana) and toad ( Bufo bufo japonicus) was measured, and the effects of cardiac steroids and temperature on the enzyme activity observed. 2. 2. Active Na + transport in the urinary bladder was measured by the short-circuit current (s.c.c.) method in the presence or absence of cardiac steroids and at various temperatures. 3. 3. The systems for measuring the (Na +-K +)-ATPase activity from R. catesbiana and the s.c.c. shared the following characteristics: 3.1. a. Both systems required Na + and K + together. 3.2. b. Both systems were completely inhibited by ouabain and digitoxigenin at a concentration of 1 · 10 −5 M. The s.c.c. was inhibited when these substances were added to the serosal surface of the membrane. 3.3. c. Inhibition by digitoxigenin was reversible in both systems. 3.4. d. Concentrations for half-maximal inhibition by digitoxigenin in the presence of Na + plus K + were 3 · 10 −7 M for the enzyme and 4 · 10 −7 M for the s.c.c. at 22°. 3.5. e. Both systems showed the same characteristic temperature dependency. Q 10 values were 2.1 (over 13°) and 3.7 (under 13°) for the enzyme, and 2.0 (over 13°) and 3.5 (under 13°) for the s.c.c. respectively. 3.6. f. The electrothermodynamic work needed for the s.c.c. did not exceed the amount of free energy released from hydrolysis of ATP by the (Na +-K +)-ATPase system. 4. 4. In conclusion, the greater part of the active Na + transport through the urinary bladder of R. catesbiana was closely related to (Na +-K +)-ATPase activity.

Inhibitory effects of cardiac glycosides and adrenal steroids on amino acid transport

The cardiac glycosides, ouabain, scillaren, and scilliroside, inhibit the transport of α-aminoisobutyric acid (AIB) into isolated intact rat diaphragm when present in the medium at a concentration of 10–3 m. Lower concentrations of the glycosides do not inhibit AIB uptake, but cause marked shifts in the distribution of sodium and potassium in the diaphragm. Decreasing or increasing the concentration of potassium in the medium does not markedly alter the ability of ouabain to inhibit amino acid transport, although high extracellular potassium alone causes inhibition of AIB uptake. Ouabain does not alter the ATP content of the diaphragm. For these and other reasons which are discussed, the inhibitory effects of cardiac glycosides on AIB transport appear to be independent of their effects on ion transport, and not related to a possible action on limiting the ATP supply of the cell. It is suggested that their action on amino acid transport may be related to their structural similarity to steroid hormones, which also inhibit amino acid transport. Corticosterone, deoxycorticosterone, and aldosterone inhibit AIB transport when present in vitro at concentrations in the micromolar range. The possible physiological significance of this in vitro effect of adrenal steroid hormones is discussed.

Contracture of slow muscle fibre induced by cardiac active steroids.

The mechanism of the contracture induced by cardiac active steroids in frog skeletal muscles containing slow fibres was investigated. The fact that the contracture is of nervous origin was confirmed. Some additional findings related to the release of ACh were reported and discussed.

PROTECTIVE ACTION OF CARDIAC GLYCOSIDES AND ADRENAL CORTICAL HORMONE AGAINST THYROXIN1

THE POSSIBILITY of a relationship between the physiologic activity of the cardiacsteroid-glycosides and those derived from the adrenal cortex was suggested by Zwemer, Lowenstein, and Pines (1). They demonstrated the ability of certain of these glycosides to protect animals against insulin shock and also confirmed a corticaHike effect of strophanthin upon plasma potassium and blood sugar levels previously reported by Ginsburg (2). On the basis of clinical and experimental findings, a definite degree of antagonism would seem to exist between the thyroid and adrenal cortical hormones (3–15). Clinically, the hyperthyroid patient presents many of the accepted criteria for the administration of drugs of the digitalis series: tachycardia, and varying degrees of failure, with or without fibrillation. We therefore felt that an investigation of possible corticaHike effects of cardiac steroids, in relation to experimentally induced hyperthyroidism, would be in order.