Effects of strophanthidin upon contraction and ionic exchange in rabbit ventricular myocardium: relation to control of active state.
01 Mar 1970-Journal of Molecular and Cellular Cardiology (J Mol Cell Cardiol)-Vol. 1, Iss: 1, pp 65-90
TL;DR: It is proposed that the ionic mechanisms associated with the inotropic response which follows increased frequency of contraction (Bowditch Staircase) and glycoside administration are essentially the same.
About: This article is published in Journal of Molecular and Cellular Cardiology.The article was published on 1970-03-01. It has received 170 citations till now. The article focuses on the topics: Cardiac glycoside & Heart septum.
Citations
More filters
TL;DR: In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial.
Abstract: The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.
1,715 citations
TL;DR: Data indicate that heart cell is a target organ for PTH and may have receptors for the hormone, and PTH increases beating rate of heart cells and causes early death of cells, and suggests that myocardial damage may occur in uremia due to prolonged exposure to very high blood levels of PTH.
Abstract: Myocardiopathy is common in uremia, but its cause in unknown. Excessive entry of calcium in heart cells by catecholamines has been shown to cause necrosis of myocardium. The high blood levels of parathyroid hormone (PTH) in uremia may also enhance entry of calcium into heart cells and exert deleterious effects on the heart. We examined the effect of PTH on rat heart cells grown in culture. Both amino-terminal (1-34) PTH and intact (1-84) PTH, but not the carboxy-terminal (53-84) PTH produced immediate and sustained significant rise in beats per minute and the cells died earlier than control. The effect was reversed if PTH was removed from medium, and was abolished by inactivation of the hormone. There was a dose-response relationship between both moieties of PTH and the rise in heart beats, but the effect of 1-84 PTH was significantly greater than that of 1-34 moiety. PTH stimulated cyclic AMP production within 1 min, and cyclic AMP remained significantly elevated thereafter. The effect of PTH required calcium, was mimicked by calcium ionophore, was prevented by verapamil and was not abolished by alpha- or beta-adrenergic blockers. PTH action was additive to phenylephrine and synergistic with isoproterenol. Sera from uremic parathyroidectomized rats did not effect heart beats, but sera from uremic rats with intact parathyroid glands or from uremic-parathyroidectomized rats treated with PTH had effects similar to PTH. Data indicate that (a) heart cell is a target organ for PTH and may have receptors for the hormone; (b) PTH increases beating rate of heart cells and causes early death of cells; (c) PTH effect appears to be due to calcium entry into heart cells; (d) the locus of action through which PTH induces calcium entry is different from that for catecholamines; and (e) uremic serum has no effect unless it contains PTH. Data suggest that myocardial damage may occur in uremia due to prolonged exposure to very high blood levels of PTH, and assign new dimensions to PTH toxicity in uremia.
330 citations
TL;DR: The intracellular Na activity of sheep heart Purkinje fibres has been measured using recessed‐tip Na+‐sensitive glass micro‐electrodes with results comparable to that of animals treated with Na 2.1.
Abstract: 1. The intracellular Na activity of sheep heart Purkinje fibres has been measured using recessed-tip Na(+)-sensitive glass micro-electrodes.2. The internal Na activity was 7.2 +/- 2.0 mM (mean +/- S.D., n = 32) at the normal external Na concentration, [Na](o), in these experiments of 140 mM (equivalent to an external Na activity of 105 mM). The equilibrium potential for Na across the fibre membrane was therefore approximately + 70 mV.3. When the [K](o) was altered the internal Na activity changed, reaching a new level within about 20 min. Increasing the [K](o) from 4 to 25 mM decreased the internal Na by approximately 30%, while decreasing the [K](o) from 4 to 1 mM increased internal Na by 20%.4. The removal of external K produced an easily reversible increase in the internal Na with an initial rate equivalent to a concentration change of 0.24 +/- 0.07 m-mole/min (mean +/- S.D., n = 8).5. Ouabain produced increases in the internal Na activity that were only very slowly reversible. The threshold concentration for producing an increase was approximately 10(-7)M.6. When [Na](o) was reduced the internal Na activity fell rapidly with a single exponential time course (time constant 3.3 +/- 0.8 min, mean +/- S.D., n = 16) to a new, relatively stable level. The recovery of internal Na on return to the normal [Na](o) did not have a simple time course. It was normally complete within 10-30 min.7. The relationship of the stabilized level of the internal Na activity to the [Na](o) was approximately linear over the range 140-14 mM-[Na](o). When [Na](o) was reduced from 140 to 14 mM the internal Na activity fell by 72 +/- 5% (mean +/- S.D., n = 21).8. When the [Na](o) was reduced, the decrease in the internal Na activity was partially inhibited by Mn or by removal external Ca.9. When the [Ca](o) was altered over the range 0.2-16 mM the internal Na activity was reduced by approximately 50% for a tenfold increase in the [Ca](o).10. The relationship between internal Na and contractility is discussed.
294 citations
TL;DR: It was concluded that a regenerative release of Ca2+ could be demonstrated in heart muscle under these conditions and localized cyclic contractions were not observed in disrupted fibers of frog heart, in which spontaneously beating cells could be separated with enzymes.
Abstract: Single cells of adult rat ventricle were separated with 0.1% trypsin and 0.05-0.1% collagenase. Ten percent of these cells were tubular and striated, contracted spontaneously in the presence of 0.05 mM CaCl2 or after addition of 0.1-0.5 mM CaCl2, and developed contracture in 1 mM CaCl2. A resting potential of -30 to -50 mv and an action potential more than 100 msec in duration were recorded in some of the cells. These relatively intact cells were contrasted with myocardial fibers (10-100µ) obtained by homogenization. In the presence of 0.025 mM ethyleneglycol bis(β-aminoethylether)-N, N'-tetraacetic acid (EGTA), localized cyclic contractions with intracellular asynchrony were observed under the phase microscope in obviously disrupted areas of these mechanically separated fibers. These contractions were insensitive to the ratio of Na+ to K+, and neither resting potentials nor action potentials were observed. Thus, these disrupted fibers were considered skinned fibers of cardiac muscle; this assumption was ...
225 citations
TL;DR: The ability of glycolysis, oxidative phosphorylation, the creatine kinase system, and exogenous ATP to suppress ATP-sensitive K+ channels and prevent cell shortening were compared in patch-clamped single guinea pig ventricular myocytes as mentioned in this paper.
Abstract: The ability of glycolysis, oxidative phosphorylation, the creatine kinase system, and exogenous ATP to suppress ATP-sensitive K+ channels and prevent cell shortening were compared in patch-clamped single guinea pig ventricular myocytes. In cell-attached patches on myocytes permeabilized at one end with saponin, ATP-sensitive K+ channels were activated by removing ATP from the bath, and could be closed equally well by exogenous ATP or substrates for endogenous ATP production by glycolysis (with the mitochondrial inhibitor FCCP present), mitochondrial oxidative phosphorylation, or the creatine kinase system. In the presence of an exogenous ATP-consuming system, however, glycolytic substrates (with FCCP present) were superior to substrates for either oxidative phosphorylation or the creatine kinase system at suppressing ATP-sensitive K+ channels. All three groups of substrates were equally effective at preventing cell shortening. In 6 of 38 excised inside-out membrane patches, ATP-sensitive K+ channels activated by removing ATP from the bath were suppressed by a complete set of substrates for the ATP-producing steps of glycolysis but not by individual glycolytic substrates, which is consistent with the presence of key glycolytic enzymes located near the channels in these patches. Under whole-cell voltage-clamp conditions, inclusion of 15 mM ATP in the patch electrode solution dialyzing the interior of the cell did not prevent activation of the ATP-sensitive K+ current under control conditions or during exposure to complete metabolic inhibition. In isolated arterially perfused rabbit interventricular septa, selective inhibition of glycolysis caused an immediate increase in 42K+ efflux rate, which was prevented by 100 microM glyburide, a known blocker of ATP-sensitive K+ channels. These observations suggest that key glycolytic enzymes are associated with cardiac. ATP-sensitive K+ channels and under conditions in which intracellular competition for ATP is high (e.g., in beating heart) that act as a preferential source of ATP for these channels.
219 citations
Cites methods from "Effects of strophanthidin upon cont..."
...By measuring the time constant of 42K+ washout during the control washout period, and using the assumption that the 42K+ uptake and washout rate are identical during control perfusion (Langer and Serena, 1970), the specific activity of the tissue at the start of 4~K+ washout was calculated....
[...]
References
More filters
TL;DR: This work has shown that the sodium efflux from the axons of Loligo forbesi increases when external sodium is replaced by lithium.
Abstract: 1. Previous work has shown that the sodium efflux from the axons of Loligo forbesi increases when external sodium is replaced by lithium.
2. The increase in efflux in lithium was unaffected by ouabain but was abolished by removal of external calcium; in these respects it differed from the potassium-dependent sodium efflux which was abolished by ouabain but not reduced by removal of external calcium.
3. Strontium but not magnesium could replace calcium in activating the ouabain-insensitive sodium efflux; lanthanum had an inhibitory effect.
4. Replacing all the external NaCl by choline chloride or dextrose gave a rise in Na efflux which was abolished by ouabain but not by removal of external calcium.
5. The rise in Na efflux resulting from partial replacement of NaCl by dextrose or choline chloride consisted of two components one of which was ouabain-insensitive and calcium-dependent and the other was inhibited by ouabain but calcium-insensitive.
6. The ouabain-insensitive component of the Na efflux was activated by low concentrations of Na, Li or K but inhibited by high concentrations of Na and to a lesser extent Li. The inhibiting effect of high Na was of the kind expected if these ions displace calcium from an external site.
7. The ouabain-insensitive component of the Na efflux was abolished by cyanide, had a Q10 of 2·7; and was roughly proportional to [Na]i2. It was much more variable in magnitude than the ouabain-sensitive, potassium-dependent component of the sodium efflux.
8. The calcium influx increased five to fortyfold when external NaCl was replaced by LiCl or dextrose, the increase for Li being larger than the increase for dextrose.
9. The calcium influx from Na, Li or dextrose sea water was increased three to tenfold by increasing the internal Na about fourfold.
10. The experiments provide evidence for a coupling between an inward movement of calcium and an outward movement of sodium.
887 citations
Journal Article•
TL;DR: It is difficult to summarise when so much that has been said is tentative but it is probably fair to state that it is doubtful whether therapeutic doses of cardiac glycosides cause appreciable lowering of the internal potassium concentration.
Abstract: It is difficult to summarise when so much that has been said is tentative but it is probably fair to state that:
1) The cardiotonic effect is not primarily on the action potential mechanism or on the contractile mechanism but is on "excitation-contraction coupling."
2) The sensitivity to cardiac glycosides of the sodium and potassium transport mnechanism in the muscle membrane is sufficient for sodium and potassium transport to be affected by cardiac glycoskies in therapeutic concentrations.
Nevertheless
3) it is doubtful whether therapeutic doses of cardiac glycosides cause appreciable lowering of the internal potassium concentration. A gain in sodiumn may occur.
4) A positive inotropic action is probably associated with increased uptake of calcium.
5) It is possible that the cardiotonic action of the cardiac glycosides is caused by interference with the removal or inactivation of the calcium that enters the muscle at each contraction. Such interference might be a primary effect of the cardiac glycoside or it might be secondary to a rise in the intracellular sodium concentration.
441 citations
303 citations
TL;DR: An important advance in understanding the mechanism of muscular activation is Wilbrandt & Koller's (1948) finding that the strength of the heart beat remains approximately constant if the ratio [Ca]/[Na]2 is kept constant.
Abstract: An important advance in understanding the mechanism of muscular activation is Wilbrandt & Koller's (1948) finding that the strength of the heart beat, which has long been known to alter with changing Ca and Na concentrations in the external fluid (Ringer, 1883; Daly & Clark, 1921) remains approximately constant if the ratio [Ca]/[Na]2 is kept constant. This result has been explained as being due to a competition of Ca and Na ions for a hypothetical site or molecule, R (assumed for simplicity to be divalent), a process which may be represented as a reversible bimolecular reaction (Luttgau & Niedergerke, 1958):
243 citations
TL;DR: The course of active state in heart muscle has been analyzed using a modified quick release method and norepinephrine (10-5 M) shortened the latency from electrical stimulus to mechanical response, accelerated the onset of maximum active state, increased its intensity, decreased its duration, and accelerated its rate of decline.
Abstract: The course of active state in heart muscle has been analyzed using a modified quick release method. The onset of maximum active state was found to be delayed, requiring 110–500 msec from time of stimulation, while the time to peak isometric tension required 250–650 msec. Further, the time from stimulation to peak tension was linearly related to the time required to establish maximum intensity of active state as well as to the duration of maximum active state. The duration of maximum active state was prolonged (90–220 msec), occupying most of the latter half of the rising phase of the isometric contraction. Norepinephrine (10-5 M) shortened the latency from electrical stimulus to mechanical response, accelerated the onset of maximum active state, increased its intensity, decreased its duration, and accelerated its rate of decline. These changes were accompanied by an increase in the rate of tension development and the tension developed while the time from stimulation to peak isometric tension was abbreviated. Similar findings were shown for strophanthidin (1 µg/ml) although lesser decrements in the duration of maximum active state and time to peak tension were found than with norepinephrine for similar increments in the maximum intensity of active state.
114 citations