Frequent stimulation of the guinea-pig myocardium raises the inotropic efficacy of tissue-bound ouabain
3H-Ouabain binding to frequently (1 Hz) stimulated papillary muscles from reserpine-pretreated guinea pigs was evaluated at ouabain concentrations of 18.5 and 200 nmol/l. Myocardial activity increased the amount of3H-ouabain bound to the tissue in comparison with quiescent preparations. Since the shape of the time course of ouabain binding changed with frequent stimulation, a greater number of ouabain-accessible binding sites of the Na pump as induced by the rise in intracellular Na with frequent stimulation cannot be the sole mechanism of the frequency dependence.
In view of their stimulatory properties on the Na pump the effects of intracellular Na and extracellular K could be equivalent. By contrast, both interventions were differently effective. The K antagonism on3H-ouabain binding was independent from stimulation frequency. Furthermore, the shape of the time course of binding was not altered by [K]o.
As evidenced by the dependence of half-times to steady-state effect on muscle diameter, the apparent rate of diffusion of ouabain was accelerated with the frequency of contractions. This acceleration could have interfered with the time course of binding at frequent stimulation.
After correlating the time courses of positive inotropic effect and ouabain binding (concentration of ouabain in the medium 200 nmol/l), frequent stimulation was found to raise the inotropic efficacy of tissue-bound ouabain. The relation of excitation-dependent Na influx to the saturable, ouabain-inhibited, Na pump explained the frequency dependence of the inotropic efficacy of ouabain; that is, the observed change of efficacy was consistent with Na-pump saturation in dependence on intracellular Na.
Key wordsStimulation frequency Ouabain Inotropic efficacy Na pump
Unable to display preview. Download preview PDF.
- Bentfeld M, Lüllmann H, Peters T, Proppe D (1977) Interdependence of ion transport and the action of ouabain in heart muscle. Br J Pharmacol 61:19–27Google Scholar
- Brown AM, Lew VL (1983) The effect of intracellular calcium on the sodium pump of human red cells. J Physiol 343:455–493Google Scholar
- Cohen ChJ, Fozzard HA, Sheu Sh-Sh (1982) Increase in intracellular sodium ion activity during stimulation in mammalian cardiac muscle. Circ Res 50:651–662Google Scholar
- Dunn MJ (1974) Red blood cell calcium and magnesium: effects upon sodium and potassium transport and cellular morphology. Biochim Biophys Act 352:97–116Google Scholar
- Ebner F, Bachmaier A, Schönsteiner G, Reiter M (1985) Diffusion-controlled receptor occupancy determines the rate of inotropic action of some cardioactive steroids. J Mol Cell Cardiol 17: 1115–1126Google Scholar
- Ebner F, Korth M, Kühlkamp V (1986) The reaction of ouabain with the sodium pump of guinea-pig myocardium in relation to its inotropic effect. J Physiol (in press)Google Scholar
- Ebner F, Reiter M (1977) The dependence on contraction frequency of the positive inotropic effect of dihydro-ouabain. Naunyn-Schmiedeberg's Arch Pharmacol 300:1–9Google Scholar
- Ebner F, Siegl H (1985) Myocardial activity enhances3H-ouabain binding and the inotropic efficacy of bound ouabain. Naunyn-Schmiedeberg's Arch Pharmacol 329:R56Google Scholar
- Ebner F, Waud DR (1978) The role of uptake of noradrenaline for its positive inotropic effect in relation to muscle geometry. Statistical evaluation. Naunyn-Schmiedeberg's Arch Pharmacol 303:1–6Google Scholar
- Glitsch HG, Pusch H, Venetz K (1976) Effects of Na and K ions on the active Na transport in guinea-pig auricles. Pflügers Arch 365:29–36Google Scholar
- Glitsch HG, Pusch H, Schumacher T (1984) Dihydroouabain-sensitive Na efflux at low intracellular Na activity in sheep Purkinje fibres. Pflügers Arch 398:R5Google Scholar
- Lee ChO, Dagostino M (1982) Effect of strophanthidin on intracellular Na ion activity and twitch tension of constantly driven canine cardiac Purkinje fibres. Biophys J 40:185–198Google Scholar
- Levitt DG (1980) The mechanism of the sodium pump. Biochim Biophys Act 604:321–345Google Scholar
- Sheu Sh-Sh, Fozzard HA (1982) Transmembrane Na+ and Ca2+ electrochemical gradients in cardiac muscle and their relationship to force development. J Gen Physiol 80:325–351Google Scholar
- Temma K, Akera T (1982) Enhancement of cardiac actions of ouabain and its binding to Na+, K+-adenosine triphosphatase by increased sodium influx in isolated guinea-pig heart. J Pharmacol Exp Ther 223:490–496Google Scholar
- Vaughan-Jones RD, Lederer WJ, Eisner DA (1983) Ca2+ ions can affect intracellular pH in mammalian cardiac muscle. Nature 301:522–524Google Scholar
- Wasserstrom JA, Schwartz DJ, Fozzard HA (1983) Relation between intracellular sodium and twitch tension in sheep cardiac Purkinje strands exposed to cardiac glycosides. Circ Res 52:697–705Google Scholar
- Wier WG, Hess P (1984) Excitation-contraction coupling in cardiac Purkinje fibres. Effects of cardiotonic steroids on the intracellular Ca2+ transient, membrane potential, and contraction. J Gen Physiol 83:395–415Google Scholar
- Yingst DR, Hoffman JF (1981) Effect of intracellular Ca on inhibiting the Na-K pump and stimulating Ca-induced K transport in resealed human red cell ghosts. Fed Proc 40:543Google Scholar