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Hemodynamic effects of K-strophanthin (0.005 mg/kg i.v.) were evaluated in 7 normal and in 13 non-failing coronary artery disease patients (CAD). Volumetric parameters were obtained by single plane left ventricular angiography. The indexes of "pump" function, the end-systolic pressure-volume relationship and the ratio of peak pressure to systolic volume were also evaluated. Heart rate was maintained constant by atrial pacing. In normal subjects K-strophanthin exerted small effects without peripheral vasoconstriction. CAD patients showed different response to K-strophanthin in vascular tone: an increase (Group 1) or a decrease (Group 2) in total systemic resistance (TSR). No significant differences were found in basal values between the two CAD groups. In Group 2 the indexes of "pump" function increased after K-strophanthin and the end-systolic pressure-volume points shifted upward and to the left, while in Group 1 no improvement in cardiac function was observed and the end-systolic pressure-volume points shifted upward and to the right. Furthermore, we found a direct significant correlation between the percent changes of TSR and end-systolic volume index, and a negative significant correlation between the percent changes of TSR and stroke volume index. Our results show that K-strophanthin in CAD non-failing patients can have either a positive effect or a lack of improvement in ventricular performance. These effects correlate with changes in total systemic resistance.
Steady-state kinetics of thioproperazine, triftazine, aminazine, and o-dianisidine oxidation with hydrogen peroxide catalyzed by horseradish peroxidase were studied in the presence of strophanthin G. Values of the inhibition and activation constants (Ki, Ka) were determined in the pH range 5.0-7.5. At acidic pH, strophanthin G activated peroxidase during the oxidation of thioproperazine by the uncompetitive mechanism, and when triftazine was oxidized, the inhibition was noncompetitive. At pH > 6.0, the patterns of activation and inhibition changed to mixed-type during the peroxidase oxidation of thioproperazine and triftazine and to competitive inhibition of peroxidase with strophanthin G during the oxidation of aminazine. These effects are suggested to be due to an ionizable enzyme group of pK approximately 6.0. Strophanthin G inhibited free-radical oxidation of o-dianisidine via binding to the enzyme-substrate complex, preventing the generation of a stable semi-oxidized product of o-dianisidine, and thus inhibiting the enzyme by the anticompetitive mechanism. Mechanisms of oxidation of slowly and rapidly oxidizable substrates of peroxidase in the presence of strophanthin G are suggested.
In vitro on skinned myocardial fibers (SMF) with extracted or functionally inactivated enzymes and membranes of mitochondria, longitudinal sarcoplasmic reticulum, triads and sarcolemma, new evidence of beta-acetyldigoxin and strophanthin K direct stimulating effects on contractile protein system of myocardium has been obtained. It has been revealed in energy release stimulation and force generation, in quantitative (beta-acetyldigoxin) or quantitative and qualitative (strophanthin K) stimulation of energy transduction, in the increase of contractile process cooperativity and Ca-sensitivity of SMF as well as in the SMF relaxation time extension (in the case of strophanthin K). It is suggested that different effects of beta-acetyldigoxin and strophanthin K are due to the differences in the conformations of actomyosin ensembles formed by strong bound (AMESB), which are induced by the influence of these cardiac glycosides. It has been demonstrated that ouabain (strophanthin K) has no direct effect on functioning of AMESB.
Using solid phase enzyme-linked immunoassay (ELISA), rate constants for the formation and dissociation as well as equilibrium dissociation constants for strophanthin complexes interaction with specific antibodies (both soluble and immobilized on activated polystyrene beads and polyamide membranes) have been determined. A satisfactory correlation was found between dissociation constants for immune complexes determined by ELISA (both soluble and immobilized ones) and associations constants for these complexes determined by the Scatchard method. The experimental values of kinetic and equilibrium constants for strophanthin K and its peroxidase complexes interaction reflect the difference in the nature of interacting particles and their environment. Strophanthin complexes with antibodies appeared to be more stable when formed on adsorbents (in comparison with those formed in solution). Strophanthin interaction with immobilized antibodies occurred at a slower rate than that with soluble antibodies. Strophanthin reacts with antibodies more readily than its complexes both in solution and on solid matrices of various polymeric nature.
For the purpose of estimating g-strophanthin radio-immunologically the following steps are described: the preparation of g-strophanthin antigen, the production of antibodies in the rabbit, the presentation of calibration curves, and the possibility of a quantitative determination of heterogenous glycosides. According to Malaprades reaction, g-strophanthin adheres to human albumin. With this antigen thus obtained antibodies are produced in rabbits. For the presentation of calibration curves, the addition of antiserum and g-strophanthin have to be matched in quantity; the calibration curves correspond to mathematical data. An increased sensitivity of the method is possible to attain by reducing the amount of labelled antigen and antiserum. The slight cross-reactivity of antibodies can be used to determine other glycosides when these are incubated labelled with tritium instead of 3H-g-strophanthin.
K-strophanthin or digoxin were added to diuretics (all cases) and vasodilators (most cases) for treating advanced congestive heart failure in 22 patients with dilated cardiomyopathy and sinus rhythm. K-strophanthin (0.125 mg intravenously) or digoxin (0.25 mg orally) were administered daily in two 3-month periods, during which vasodilators and diuretics were kept constant and patients received one of the two digitalis preparations in a double-blind fashion, crossing over to the alternative preparation in the next period. Blindness was assured throughout the trial with a daily intravenous injection of 10 ml normal saline solution either containing K-strophanthin or not, and with daily oral administration of either placebo or active digoxin. At the end of the run-in period, 15 days after starting active preparations, and thereafter every month for the next 6 months, we evaluated left ventricular pump function at rest and patients' functional performance by a cardiopulmonary exercise test. At Day 15, cardiac index and ejection fraction at rest, compared with run-in, were significantly raised with both glycosides; during exercise while on K-strophanthin, peak oxygen consumption was augmented by 1.4 ml/min/kg (p < 0.01) and oxygen consumption at anaerobic threshold by 2.2 ml/min/kg (p < 0.01); corresponding variations on digoxin (-0.1 and +0.3, respectively) were not significant versus run-in. These patterns were duplicated at repeated tests during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Time course and extent of strophanthin-K induced disturbances of flash electroretinogram (F-ERG) has been observed in 12 albino rabbits treated by a single dose of 1, 3 and 9 ug/0.1 ml of intravitreal injection. A phenomenon of the dependence of a- and b-wave amplitude changes on dosage was demonstrated. A 9 ug/0.1 ml dose caused a flat a- and b-wave showing the F-ERG wave could be completely suppressed by larger dose of strophanthin-K. Two parameters of "attenuation kinetics" are proposed to identify the pharmacodynamics and toxic kinetics on retina as time profile is concerned: 1) B (the slope of attenuation curve); 2) Et1/2 (half attenuative time). B and Et1/2 are helpful in making a tentative identification of the target cells on retina and in demonstrating a synergism or antagonism between drugs if any. The a-wave of F-ERG, having a steeper slope, is more sensitive than b-wave in terms of strophanthin-K toxicity bringing forth a quantitative criterion in visual pharmacology. The attenuation of amplitude in a-wave may therefore be considered as an early response to this drug. The direct pupillary response test were also done pre- and post-strophanthin-K, and the results of this test support that of F-ERG.
The conditions of potassium transport were investigated in isolated rabbit hear mitochondria. In the presence of 5 to 40 mM potassium chloride there is a rapid initial phase of potassium influx of less than 2 min duration in which 65-75% of the total K+ uptake occurs. This is followed by a slow phase of K+ uptake of about 45 min during which 25 to 35% of the total potassium was taken up. While the rapid phase is due to passive diffusion, the slow phase is an active process which requires either ATP or respiratory substrates as an energy source. It can be totally abolished by 0.5 mM antimycin A. An increase of the calcium concentration in the incubation medium to more than 5 X 10(-5)M resulted in an inhibition of the energy-dependent uptake of potassium which was directly proportional to the calcium level. k-Strophanthin induced a distinct inhibition only at very high concentration (greater than 10(-4)M). The inhibition of potassium uptake by 1. 3 or 5 mM calcium chloride was gradually cancelled by increasing k-strophanthin concentrations above 10(-8)M. Maximal cancellation was found with 10(-5)M of k-strophanthin. This concentration almost completely prevented the inhibition by calcium ions. On the other hand, 10(-5)M k-strophanthin had no inhibitory effect on the energy-dependent uptake of 0.5 mumoles of calcium chloride or on the oxidative phosphorylation of 0.5 mumoles of ADP added to the incubation medium.
Experiments conducted with mice, rats and cats demonstrated ether-oxygen anesthesia to reduce the tolerance of the animals to strophanthin in the LD50 and MDL tests. The premedication agents (atropine, promedol, diprazine) increased, according to observations on mice and rats, the resistance of the animals to strophanthin. In tests on dogs involving determination of the cardiac ejection by thermodilution strophanthin in a dose of 44 gamma/kg and under ether-oxygen anesthesia with premedication produced a statistically significant increase of the systolic cardiac index and well-marked bradycardia. Exclusion of thepremedicationagents drastically lowered the effect of strophanthin.
In experiments on 183 rats it was shown that cordarone, anapriline, dimedrol and riboxine increasing in experimental cardiac insufficiency tolerance to the cardiotoxic effect of strophanthin differ significantly by their influence on the hemodynamic effects of this cardiac glycoside. Cordarone increased intensity of the hemodynamic effects of strophanthin and accelerated their development. Under the action of anapriline and dimedrol the stimulating effect of strophanthin on hemodynamics decreased to a much lesser degree than its cardiotoxicity. Riboxine virtually abolished the hemodynamic effects of strophanthin.