Evidence for a dissociation between positive inotropic effect and inhibition of the Na+N+-ATPase by ouabain, cassaine and their alkylating derivatives

Peters, T.; Raben, Ralph-Holger; Wassermann, O.

doi:10.1016/0014-2999(74)90223-4

Cited by 65 publications

(20 citation statements)

References 17 publications

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“…Our results appear to be inconsistent with the alternative proposal that binding of digitalis to NaK-ATPase causes the release of calcium from enzyme-associated sarcolemmal sites (41)(42)(43)(44). A lesser rather than greater inotropic response to a given ouabain concentration was observed in cells with increased numbers of sodium pump sites, despite the fact that a greater absolute number of NaK-ATPase sites would be occupied because of the unchanged affinity of sites for ouabain (Fig.…”

Section: Discussioncontrasting

confidence: 97%

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

Kim¹,

Smith²

1984

J. Clin. Invest.

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Abstract. 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 ,uM) 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

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Section: Discussioncontrasting

confidence: 97%

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

Kim¹,

Smith²

1984

J. Clin. Invest.

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“…In sheep Purkinje fibers, 0.1 M ouabain produced depletion of cleft potassium as judged from reversal potential for the iK2 current, again suggesting pump stimulation (20 The indices of Na-K pumilp f'unctioll examined in this study are a, and a'. These indices have certain advantages over the kinetic indices from tracer flux studies (9) or l)iochemical indlices from enzyme isolatioIn studies (31). In particular, all tracer flux technii(Ites rely oIn compartmental models that often fail to r-eflect the known morphological coomplexity of cardiac tissue (32).…”

Section: Discussionmentioning

confidence: 99%

Ouabain effects on intracellular potassium activity and contractile force in cat papillary muscle.

Browning¹,

Guarnieri²,

Strauss³

1981

J. Clin. Invest.

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A B S T R A C T The relationship between the positive inotropic and toxic effects of cardiac glycosides and their effects on intracellular ionic composition is incompletely defined. We measured intracellular potassium activity (ak), extracellular potassium activity (at), resting potential, action potential duration, and contractile force at 32°C in paired papillary muscles from feline right ventricles exposed to ouabain. Muscles used for electrophysiological measurements were quiescent except for isolated stimulation to confirm impalement and record action potential duration. Muscles used for contractile force measurements were quiescent except for 4-min periods when force was measured at a cycle length of 1,400 ms. Muscle length was adjusted to achieve 50% of maximal tension at this cycle length before each experiment. In four experiments, ai and contractile force were measured in the same muscle. a' was measured with single and double-barrel K-sensitive electrodes. At 10 nM ouabain, action potential duration is prolonged. Among the concentrations tested, the threshold for a clear positive inotropic effect is 0.1 ,uM ouabain. The threshold for decrease in ak, increase in aeK, and decrease in membrane potential is 1 ,uM, at which concentration toxic signs develop, including arrhythmias, aftercontractions, and alteration in the staircase response of contractile force to repetitive stimulation. Ouabain need not change a' to effect positive inotropy in ventricular muscle, a relationship different from that reported between [K], (intracellular potassium concentration) and positive inotropy. Higher ouabain concentrations, which others have shown to clearly inhibit active Na and K transport, are shown to upset

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“…Stimulation of Na,K-ATPase from cardiac muscle cells by low concentrations of a cardiotonic steroid was first reported by Repke (1963). This kind of stimulation has been reported a number of times since for cardiac muscle preparations, not only the ATPase but also intact cells (Peters et al, 1974;Cohen et al, 1976; see Lee and Klaus, 1971, for other references). Similar observations have been made for Na,K-ATPase from rabbit brain and chicken kidney (Pahner et al, 1966) and for active transport in squid axons (Baker and Manii, 1968;Baker and Willis, 1972).…”

Section: Determination Of Ouabain Bindingmentioning

confidence: 90%

Interaction of external alkali metal ions with the Na-K pump of human erythrocytes: a comparison of their effects on activation of the pump and on the rate of ouabain binding.

Hobbs¹,

Dunham²

1978

The Journal of General Physiology

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A B ST R A C T The effects of external alkali metal ions on the rate of ouabain binding and on the rate of the Na-K pump were examined in human red blood cells. In Na-containing solutions, K, Cs, and Li decreased the rate of ouabain binding. For K and Cs, the kinetics of this effect were similar to those for their activation of the pump. In Na-free (choline-substituted) solutions the rate of ouabain binding was decreased by K whereas it was promoted by Cs and Li. External Na increased the rate of ouabain binding whether or not external K was present, and the kinetics of this effect were not the same as tfiose for inhibition of the pump by Na. These findings are interpreted to mean that not only do the cations affect ouabain binding at the external loading sites on the pump from which ions are translocated inward, but that there are additional sites on the external aspect of the pump at which cations can promote ouabain binding, and that these sites can be occupied by Li, Na, and Cs. It is postulated that these latter sites are those from which Na is discharged after outward translocation by the pump.The inhibitory action of cardioactive steroids on the Na-K pump in human erythrocytes has been a subject of study by numerous laboratories in the hopes of acquiring a better understanding of the mechanism of the pump's action (

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Evidence for a dissociation between positive inotropic effect and inhibition of the Na+N+-ATPase by ouabain, cassaine and their alkylating derivatives

Cited by 65 publications

References 17 publications

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

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

Ouabain effects on intracellular potassium activity and contractile force in cat papillary muscle.

Interaction of external alkali metal ions with the Na-K pump of human erythrocytes: a comparison of their effects on activation of the pump and on the rate of ouabain binding.

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