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At least 343 records · Page 19Linked to original sources
PubMed1992

Fluorescence study on cardiac glycoside binding to the Na,K-pump. Ouabain binding is associated with movement of electrical charge.

Recently we have presented evidence that the fluorescence probe RH 421 can be used to detect binding and release of ions at the extracellular face of the pump since these processes are associated with translocation of electrical charge. Applying this method to experiments with cardiac glycosides we found that: (1) ouabain induced fluorescence changes of the electrochromic dye, RH 421, were caused by the change of charges bound to the enzyme; (2) independent of the sodium concentration, the final fluorescence amplitude indicated that approximately 2 Na+ ions were bound to the pump; (3) the sodium release to the extracellular side involved two distinct electrogenic steps; (4) the kinetics of inhibition depended on the Na(+)-concentration. Experiments with hydrophobic ions indicated that the kinetics of ouabain binding to the Na-ATPase is voltage dependent; and (5) the applied technique is a convenient tool to characterize binding of cardiac glycosides to the Na,K-pump.

Animals↗
PubMed1984

Effects of thyroid hormone on sodium pump sites, sodium content, and contractile responses to cardiac glycosides in cultured chick ventricular cells.

Sensitivity of cardiac muscle to digitalis glycosides depends on the thyroid state. The mechanism of this interaction was investigated at the cellular level using spontaneously beating monolayers of cultured chick embryo ventricular cells. Cells were grown for 48 h in serum-free medium containing concentrations of triiodothyronine (T3) from zero to 10(-7) M, and the total number of sodium pump sites, sodium content, and contractile amplitude in the presence and absence of various concentrations of ouabain were determined. T3 caused a concentration-dependent increase in the number of specific ouabain binding sites; the maximal increase to 160% of control was observed in response to 10(-8) M T3. T3 lowered steady-state cellular sodium content in a concentration-dependent manner, also. Ouabain (1 microM) exposure elevated cellular sodium content in all cells, but the increase was greatest in cells grown in T3-free medium and least in cells grown in 10(-8) M T3. The positive inotropic and toxic effects of ouabain in cells grown in 10(-8) M T3 were diminished at any given ouabain concentration, and thus, the dose-response curve was shifted to the right. These results indicate that T3 causes induction of additional sodium pump sites that are functional. The increased tolerance of hyperthyroid cells and reduced tolerance of hypothyroid cells to cardiac glycosides can be explained by these changes in the number of sodium pump sites and cellular sodium content, and consequently, calcium influx via sodium-calcium exchange.

Animals↗
PubMed1989

Multiple effects of cocaine upon evoked secretion in bovine adrenal medullary chromaffin cells. Additional insight into the mechanism of action of cardiac glycosides.

Experiments to determine the effects of the catecholamine neuronal uptake blockers cocaine and desipramine, and of the cardiac glycoside, ouabain, upon 3H-(noradrenaline) efflux have been performed with bovine adrenal medullary chromaffin cells in tissue culture. Both cocaine and desipramine reduced 3H-noradrenaline uptake into chromaffin cells. Inhibitable uptake was 80% of total accumulation over 60 min; this degree of inhibition was produced by cocaine (30 mumol/l) or desipramine (1 mumol/l). Cocaine (30 mumol/l) had no effect upon spontaneous 3H-efflux measured over 60 min, but reduced that evoked over the same period by carbachol (EC50), veratridine (EC50) and by ouabain (100 mumol/l). Cocaine did not reduce that efflux evoked by raised levels of K+ (28 mmol/l; EC50). Desipramine (1 mumol/l), like cocaine, had no effect upon spontaneous efflux of 3H, but reduced that efflux evoked by carbachol, veratridine and ouabain. Tetrodotoxin (TTX) inhibited veratridine-evoked 3H efflux (IC50 0.2 mumol/l). The degree of inhibition caused by TTX (0.2 mumol/l) was not increased by cocaine (30 mumol/l). TTX also inhibited ouabain-evoked 3H efflux: this was reduced by 55% by a concentration of TTX (1 mumol/l) sufficient to virtually abolish veratridine-evoked efflux. Cocaine (30 mumol/l) in the presence of TTX (1 mumol/l) did not further inhibit ouabain-evoked efflux. Cocaine (30 mumol/l) did not alter 86Rb+ uptake into chromaffin cells, nor did it alter that inhibition of 86Rb+ uptake produced by ouabain (100 mumol/l) indicating that cocaine has no effect upon Na,K-ATPase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1972

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle.

1. The uptake of (3)H-digitoxin, (3)H-ouabain and (3)H-dihydro-ouabain by isolated guinea-pig atria has been studied and compared with the inhibition of the sodium pump and with the inotropic effect.2. Analysis of the curve relating the uptake of digitoxin and ouabain at equilibrium to the bath concentration enabled a non-saturable and a saturable binding site to be distinguished.3. The uptake of inactive doses of dihydro-ouabain was only by a non-saturable mechanism.4. The uptake of labelled digitoxin and ouabain was reduced in the presence of another glycoside. The amount of bound glycoside was nearly equivalent to the estimated non-saturable uptake.5. The uptake was reduced at 4 degrees C to the clearance of the non-saturable site.6. ED50 of digitoxin and of ouabain for inhibition of the sodium pump were measured and compared to the ED50 for inotropic effect and to the concentrations producing a half-saturation of the saturable binding site.7. It is concluded that binding to the saturable site may be responsible for the cardiac actions of the glycosides.

Animals↗
PubMed1976

Pharmacological studies of a new 4-aminosugar cardiac glycoside (ASI-222).

ASI-222,3beta-O-(4-amino-4,6-dideoxy-beta-d-galactopyranosyl) digitoxigenin, is a semi-synthetic cardiac glycoside patterned after a natural glycoside obtained from Cambodia. Effects of ASI-222 on contractile force in the isolated rabbit atria, cardiac contractile force, cardiac rate, ventricular excitability and functional refractory period in dogs, and acute toxicity in mice have been compared to those effects of ouabain. Both electrically driven and spontaneously beating atria demonstrated more rapid onset and greater maximum increases in contractile force with ASI-222 than with ouabain in equal bath concentrations. In the dog, ASI-222 increased cardiac contractile force more rapidly and at a lower cumulative dose than ouabain. Moreover, the maximum increase in contractile force obtained with ASI-222 was greater than that obtained with ouabain. The occurrence of ventricular ectopic beats was observed at a higher cumulative dose of ASI-222 than for ouabain. Also, ASI-222 produced a decrease in ventricular excitability and an increase in functional refractory period ot the ventricle. Ouabain, in the same molar dose, produced either no change or a slight increase in these parameters. Our data indicate that ASI-222 has a greater therapeutic index than ouabain. This difference may be partially explained by effects of ASI-222 on electrical properties of the heart.

Aminoglycosides↗
PubMed1991

Lipophilic character of cardiac glycosides: correlation between RM values and acute toxicity data in different animal species.

The RM for a new series of cardiac glycosides were calculated by means of some of the delta RM values previously derived from another series of compounds. The experimental or calculated RM values of both series of derivatives were correlated with the acute toxicity data (log 1/C). The slopes of the linear equations for cats, dogs, guinea-pigs and frogs are very close, showing that the dependence of toxicity on the lipophilic character is the same in these animal species.

Animals↗
PubMed1991

[The past and the present of cardiac glycosides. III. Pharmacokinetics].

The molecular structure is one of the keypoints that govern both the extent of extracardiac action of cardiac glycosides and their different kinetics. The apolar, fat soluble digitoxin is very well absorbed from the intestine, its onset of action is slow, binds to a high degree to albumin and undergoes enterohepatic recirculation which accounts for a long elimination half time and stability of plasmatic levels. Digitoxin is largely excreted via gastrointestinal tract. The absorption of digoxin is less reliable, onset of action occurs earlier and the binding to albumin is considerably less than that of digitoxin. The drawback, however small, of digoxin lies in a lower stability of plasma levels and prevailing renal excretion. The molecule of strophatin is highly polar, its absorption from the intestine negligible and can be administered only intravenously. The onset of action is prompt, elimination half time short and about half the injected amount is excreted extrarenally.

Cardiac Glycosides↗
PubMed1984

Effect of cardiac glycosides on the coronaries: physiologic and morphologic studies in the dog heart.

The effect of K- strophanthoside on coronary blood flow (CBF) was studied in open chest dogs anaesthetized with pentobarbital sodium. K- strophanthoside (3.5 and 7.0 X 10(-8) mol X kg-1 i.v.) elicited a dose-dependent decrease of CBF and an increase of late diastolic coronary resistance. Intracoronary injections of the drug (1.2 X 10(-8) mol) produced selective coronary constriction. The haemodynamic pattern indicated a direct vasoconstrictor effect, independent of the extracoronary (cardiotonic) action of the drug. In the polarization microscope Romh anyi 's aldehyde bisulphite-toluidine blue (ABT) reaction as adapted for the detection of cardiac glycosides showed profuse binding of strophanthoside to the coronary vessel wall. K- strophanthoside significantly reduced the CBF increase elicited by adenosine infusion (2 X 10(-7) mol X kg-1) into the left heart. Verapamil (4 X 10(-7) mol X kg-1, i.v.), on the other hand, counteracted the strophanthoside action on CBF. The results suggest that restricted intracellular availability of Ca2+, a prerequisite of physiologic CBF increase, is opposed by cardiac glycosides.

Adenosine↗
PubMed1985

Comparative studies of some semisynthetic K-strophanthins with natural cardiac glycosides.

In this study the pharmacological effects of seven semisynthetic cardenolides have been investigated and compared with those of 11 natural cardiac glycosides. These compounds are of different potency on electrically driven isolated guinea-pig atria. Their concentration response curves showed different slopes, which could be an indication of varying therapeutic range. The pharmacodynamics of these compounds on isolated guinea-pig atria are in good correlation with the data obtained from binding studies on guinea-pig ventricular homogenate as well as that obtained from comparative experiments on Na+,K+-ATPase activity inhibition.

Animals↗