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Strophanthine (5 X 10(-7) - 1 X 10(-5) g/ml) applied to the epicardium of the right and left auricles of an isolated frog heart produced negative chronotropic and positive inotropic effects. Specific effects of strophanthine developed during complete blockade of alpha-, beta- and M-cholinoreceptors of the heart. Upon isolated blockade or stimulating of the receptors indicated, the effects of strophanthine were shown to be changed. Attempts are made to prove the existence in the auricles and ventricles of the heart of glycoside inhibitory and stimulating receptors that form the constellation system of reciprocal relationships, with the mediator receptors, with this system participating in the triggering mechanism of heart membranes.
The approximate minimal effective dose of activated charcoal, given to sheep 12 h after the administration of a lethal dose of Moreae polystachya, was found to be 2 g/kg. Serum cation levels remained within normal limits throughout the experiment.
The effects of ASI-222 HCl and digoxin on cardiac contractile force, dP/dt, heart rate and mean blood pressure in the dog were evaluated following i.v. administration. Additional studies were performed on isolated, electrically driven rabbit atria with both ASI-222 and digoxin. Our data show that ASI-222 (40 microgram/kg) in non-vagotomized dogs produced a two-fold greater increase in cardiac contractile force and dP/dt than did an equimolar dose of digoxin. ASI-222 caused a peak increase in contractile force and dP/dt 10 min after administration, whereas the peak to digoxin occurred at 30 min. ASI-222 was more effective in non-vagotomized dogs in increasing contractile force and dP/dt than in vagatonized dogs. The inotropic responses to digoxin were not reduced by vagotomy. Studies on isolated electrically driven rabbit atria indicate ASI-222 to be 7-8 times more potent than digoxin in increasing contractile force. These data demonstrate that ASI-222 produces an earlier and greater increase in contractile force and dP/dt than digoxin in equimolar doses.
In the experiments on 112 white mongrel male rats using cytophotometric investigation the authors showed that digoxin in doses 0.89 and 8.9 micrograms/g in single and repeated subcutaneous administration influences differently the level of RNA in cardio-regulating structures of the hindbrain.
By using the method of the measurement of the degree of actomyosin superprecipitation of the rabbit cardiomyocytes it was shown that isolanide (0.1 mg/kg), adoniside (0.1 ml/kg), strophanthin K (0.05 mg/kg) and corglycon (0.15 mg/kg) prevented the allergic process-induced disturbance of ATP energy utilization by myocardial contractile proteins.
An improved procedure has been developed for preparing glycosides of cardenolide genins. The method uses specially prepared Fétizon's reagent as catalyst, combined, in most cases, with mercuric cyanide and mercuric bromide. In the presence of this catalyst, genins react readily, at room temperature, with per-acetylated 1-bromo-sugars to give the acetylated glycosides in high yield with little or no side reaction. The reaction proceeds almost to completion in 30 to 60 min. The free glycoside is obtained by mild deacetylation using triethylamine/methanol/water (20:20:1) at room temperature for 72 h. Proof of structure was obtained using chemical ionization mass spectrometry, NMR spectroscopy and comparison of physical constants with published data. The compounds were tested for inotropic activity using the isolated guinea pig atrium.
The pharmacokinetic data of methylepoxyproscillaridin (3'-methyl-4'-5'-epoxyproscillaridin) (P35) after 1 mg i.v. or oral administration in two different galenic preparations (hard and soft gelatin capsules) in randomized succession were studied in 9 healthy volunteers, showing a bioavailability of 88 +/- 10.5% (soft gelatin capsule) and 81 +/- 12% (hard gelatin capsule). The half-life of P35 was calculated to be 80 +/- 13.3 h.
The hydroalcoholic extract of the powdered bark of the Indian-snuff Maquira sclerophylla Duck was purified by column chromatography in silica-gel and the major cardenolide isolated from preparative TLC was identified by 1H-NMR, 12C-NMR and IR analyses. The spectra showed that the active substance has strophanthidin as the aglycone.
In terms of evolution, the Na+,K+-ATPase is one of the oldest proteins. It is intriguing that this membrane-based enzyme has become biologically consistent with a multifunctional protein. One of the most interesting aspects of the Na+,K+-ATPase is that it contains a specific receptor domain for the oldest plant origin cardiotonic drug and that it is involved in the regulation of myocardial contractility.
Six out of 6 steers survived a lethal dose of Moraea polystachya (blue tulp) when treated with activated charcoal alone and 3 out of 4 wethers survived when treated with activated charcoal plus potassium chloride. Barbeque charcoal was not of therapeutic value. An increase in the level of serum potassium served as indicator of acute poisoning in only a third of the animals.
Tests conducted with rabbits, cats and mice showed methyluracil to lower the sensitivity to strophanthin in rabbits with myocardial infarction and in intact mice and its intravenous introduction reducing the toxicity of Adonis L. in cats. Oral administration of methyluracil for one week did not prevent in critical tests a strophanthin-induced arrhythmia in intact rabbits and in those with myocardial infarction. Intravenous administration of methyluracil caused an increase of the coronary circulation rate.
1. A comparison of the complex binding constants of different glycosides show no significant differences between these different glycosides at least not in the model containing ATP. 2. There are greater differences regarding the ATP-ase activity of the different glycoside complexes measured by means of the Rb-transport method. 3. The absorption of different proscillaridin and methylproscillaridin preparations was investigated with this method. 4. Using the rat as experimental animal the effect of different glycosides on the Na-K and Ca ATP-ase of the heart muscle was demonstrated showing a remarkable activation of the Ca-activated ATP-ase caused by proscillaridin. In order to find an explanation for the therapeutic and toxic effects these investigations have to be repeated in the pig, which shows more similarities in the ATP-ase distribution to man than the rat.
In experiments on isolated neurones from the gastropod mollusc P. corneus, strophantin and digoxin in low concentrations produce slow hyperpolarization, in higher ones--depolarization; at concentrations about 1 mM, hyperpolarization was more evident. In all cases, the decrease in membrane resistance was observed. Presumably, membrane permeability for potassium ions increases. During application of the drugs in concentrations 10-100 microM, hyperpolarization may be masked by depolarization due to block of Na,K-pump. Higher concentrations, increasing potassium permeability of the membrane, may result in substitution of depolarization by hyperpolarization.
We compared the abilities of digoxin and aminogalactose digitoxigenin (ASI-222) to bind to, or inhibit, purified dog heart Na+,K+-ATPase in the presence of 1, 10, or 80 mM potassium chloride. Changing the potassium concentration from 1 to 10 mM increased the dose producing 50% inhibition of enzyme activity (IC50) by 9- and 2.5-fold for digoxin and ASI-222 respectively. Raising the potassium concentration to 80 mM increased the IC50 for digoxin 3-fold but did not alter significantly the IC50 for ASI-222. Equilibrium binding studies showed that this enzyme exhibited a single class of specific binding sites for both digoxin and ASI-222. Raising the potassium concentration did not affect the maximum number of binding sites (Bmax) but increased the apparent dissociation constant (KD) for digoxin. Potassium differentially affected the affinity and number of binding sites for ASI-222; raising the potassium concentration from 1 to 10 mM did not affect the Bmax or the KD, but raising it to 80 mM increased both. The effect of i.v. infusion of potassium chloride upon cardiac upon cardiac arrhythmias produced by i.v. infusion of digoxin or ASI-222 in anesthetized dogs was also determined. Infusion of potassium chloride reversed the cardiac arrhymias due to digoxin to normal rhythm, but not those due to ASI-222. In conclusion, the interaction of digoxin and the polar digitalis agent, ASI-222, with dog heart Na+,K+-ATPase was differentially affected by potassium. These agents also also produced cardiac arrhythmias, which were differentially affected by potassium.
The potassium concentrations in erythrocytes, serum and urine were continously determined in 3 patients who had taken acetyldigoxin (45 to 100 tablets Novodigal à 0,2 mg) in order to commit suicide. In the first 3 to 8 hours after ingestion of digitalis the potassium concentration in serum increased while the potassium concentration of erythrocytes declined a little. The elimination of potassium with the urine remained still normal. After this period of time the potassium concentration in serum and in erythrocytes considerably fell, simultaneously large amounts of potassium were excreted with the urine. It was not until after 14 days that the potassium metabolism normalized.
A series of digitoxigenin glycosides was studied: five with beta-D-sugars varying stepwise in sugar structure from beta-D-digitoxose to beta-D-galactose, including one beta-D/alpha-D pair. I50 values for these glycosides and digitoxigenin were determined with hog kidney Na+, K+-ATPase. These data suggest a major and unexpected role for 4'-OH conformation in the sugar. All the glycosides with an equatorial 4'-OH were more active than the two with the 4'-OH axial [digitoxigenin beta-D-galactoside (6) I50 = 6.45 X 10(-8) M; digitoxigenin 2'-deoxy-alpha-D-ribo-hexopyranoside (alpha-3a) I50 = 9.33 X 10(-8) M; digitoxigenin I50 = 1.17 X 10(-7) M]. Stereochemistry of the 3'-OH had much less of an activity role than that of the 4'-OH, in contrast to existing models of "sugar-site" binding.
Ouabain added to physiological salt solutions bathing the isolated frog retina irreversibly abolishes the electrical response to light (the electroretinogram or ERG). The time course of abolition depends on the concentration of ouabain in the medium and the surface of the retina to which it is applied. When the glycoside is placed on the receptor surface, in 7 min the ERG is completely eliminated by 10(-4)M ouabain and more than 90% inhibited by 3 x 10(-5)M ouabain. The effect is slower at lower concentrations and when the solution is applied to the vitreous surface of the retina. The evidence suggests that abolition of the ERG by ouabain is due principally to inhibition of the active transport of sodium: (a) Structurally modified glycosides which are considerably less potent inhibitors of alkali cation-activated ATPase activity in preparations of frog retinal outer segments are also poorer inhibitors of electrical activity in isolated retinas. (b) Replacing much of the sodium in the medium bathing the retina by choline, Tris, or sucrose significantly protects the retina from ouabain. It is suggested that in a standard sodium environment essentially constant activity of the sodium pump is required to prevent rapid and irreversible change. The cellular sites most critically dependent on the sodium pump have not been identified.