Differing Sensitivities of Purkinje Fibers and Myocardium to Inhibition of Monovalent Cation Transport by Digitalis

Somberg, John C.; Barry, William H.; Smith, Thomas W.

doi:10.1172/jci110003

Cited by 23 publications

(9 citation statements)

References 28 publications

(34 reference statements)

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“…Using a stable intact dog preparation, we found that at clinically relevant plasma concentrations of ouabain or digoxin in the 1-10 nM range, inhibition of active transport of Rb+ into myocardial biopsy samples was observed at the onset and during sustained enhanced contractility (18,19,37). As noted by Noble (28) the concentration ofK+ (2.0 mM) used in the transport assay media in our earlier studies might have shifted the threshold for inhibition of active transport of cardiac glycosides to the left, i.e., into the inhibition range, but our more recent experiments, which used a K+ concentration of 4.0 mM in transport assay media, still show significant inhibition of both myocardial and Purkinje fiber monovalent cation transport at a mean steady-state plasma digoxin concentration of 2.7 nM (2.1 ng/ml) (37). Our studies of ouabain-induced inotropic effects in cultured chick embryo heart cells (devoid of adrenergic input) show enhanced contractility only at ouabain concentrations causing significant inhibition of monovalent cation active transport, accompanied by increased intracellular contents of sodium and rapidly exchangeable calcium (38).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Monovalent Cation Active Transport by Low Concentrations of Cardiac Glycosides

Hougen¹,

Spicer²,

Smith³

1981

J. Clin. Invest.

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A B S T R A C T The stimulatory effect of low concentrations ofouabain on the Na-K pump in isolated guinea pig left atria was studied in vitro by assessing active transport of the K+ analog Rb+. Active transport of Rb+ was stimulated 20+8% (SEM, P < 0.05) above control values by 3 nM ouabain, but was inhibited by concentrations >10 nM. Preincubation with the f-adrenergic antagonist propranolol (1 ,uM) completely blocked stimulation of active transport of Rb+ by 3 nM ouabain. Norepinephrine, 10 nM, increased Rb+ active transport 29±10% (P < 0.02) above control values. The /8-adrenergic agonist 1-isoproterenol, 10 nM, increased active transport of Rb+ by 33±10% (P < 0.01) above control levels. This stimulatory effect was abolished if tissues were first exposed to propranolol. Tyramine (0.1 ,uM), a stimulator of endogenous catecholamine release, increased active transport of Rb+ 26±12% (P < 0.05) above control values. Rb+ active transport was not significantly changed when left atrial tissues were incubated with a-adrenergic agonists or antagonists. Ouabain stimulation of Rb+ active transport was prevented by in vivo depletion of myocardial endogenous catecholamines by either reserpine or 6-hydroxydopamine. These findings indicated that in myocardial tissue, Na-K pump stimulation by low concentrations of ouabain is mediated at least in part through j8-adrenergic effects of endogenous catecholamines.

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Section: Discussionmentioning

confidence: 99%

Stimulation of Monovalent Cation Active Transport by Low Concentrations of Cardiac Glycosides

Hougen¹,

Spicer²,

Smith³

1981

J. Clin. Invest.

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“…Nevertheless, it appears likely that in normal hearts, digitalis arrhythmias probably arise in Purkinje cells because this tissue is more sensitive than ventricular tissue (Vassalle, Karis & Hoffman, 1962;Somberg, Barry & Smith, 1981). On the other hand, digitalis is often used after myocardial infarctions and in other conditions in which the heart is not normal.…”

Section: Membrane-independent Mechanical Oscillation8mentioning

confidence: 99%

Voltage‐clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle

Karagueuzian

Katzung

1982

The Journal of Physiology

105

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SUMMARY1. We studied the effects of a toxic concentration of ouabain on transmembrane electrical activity and on mechanical behaviour of right ventricular papillary muscles from ferrets in a single sucrose-gap using current clamp and voltage clamp.2. Ouabain (14-1-8 /M) induced oscillatory after-potentials and after-concentrations in current-clamp experiments. Voltage clamp showed that the oscillatory after-potential was caused by a transient inward current, similar to that in Purkinje fibres.3. The transient current had a sigmoidal dependence on the preceding (activating) voltage step VI, with a threshold around -13 mV and a plateau between + 10 and 20 mV. There was a decline in current amplitude for more positive clamps. When activated by a fixed VI voltage step, and measured at different repolarization levels V2, the transient current manifested an inverse dependence on V2 between -50 and -10 mV. No outward transient current could be detected. Total replacement of Na in the bathing medium by Tris or by sucrose abolished the transient current.4. Ouabain caused an increase of phasic (twitch) tension responses to voltage steps at all potentials without shifting the curve relating these variables on the voltage axis. The drug evoked an even greater increase in the tonic tension responses.5. After prolonged exposure, oscillatory mechanical responses were frequently recorded during positive voltage steps. Unlike the after-contraction, these mechanical fluctuations were not consistently damped and were not accompanied by detectable synchronous current fluctuations. Catecholamines and dibutyryl cyclic AMP markedly reduced the amplitude of the tonic contraction and the mechanical oscillations but increased their frequency. Caffeine had no effect on the tonic contraction amplitude but abolished the fluctuations.6. These results support the proposal that Ca is transiently released from the overloaded sarcoplasmic reticulum in ouabain-intoxicated muscle and may evoke oscillatory responses in nearby contractile fibrils. When these transient increases of sarcoplasmic free Ca are large enough, they may induce the transient transmembrane current described above.

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“…Because in adult animals a3 isoform is found almost exclusively in the central nervous system, we suspected that this isoform is preferentially expressed in specialized cardiac conduction tissue. This conjecture is reasonable because (i) the cardiac effects of glycosides are especially prominent in the conduction system (although this action is also mediated indirectly via the nervous system), (ii) Purkinje fibers contain pumps that are more ouabain-sensitive than those of ventricular muscle, both by electrophysiologic and transport criteria (16)(17)(18), (iii) electrophysiologic parameters have been found to differ between Purkinje myocytes and working ventricular fibers (19)(20)(21)(22). We thus used the technique of in situ hybridization to address this issue.…”

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confidence: 99%

The cardiac conduction system in the rat expresses the alpha 2 and alpha 3 isoforms of the Na+,K(+)-ATPase.

Zahler

Brines

Kashgarian

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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The sodium pump is crucial for the function of the heart and of the cardiac conduction system, which initiates the heartbeat. The a (catalytic) subunit of this pump has three isoforms; the al isoform is ubiquitous, but the a2 and a3 isoforms are localized to excitable tissue. Because rodent a2 and a3 isoforms are relatively sensitive to ouabain, which also slows cardiac conduction, we studied heart-cell-specific expression of pump isoform genes. Multiple conduction-system structures, including sinoatrial node, bundle branches, and Purkinje strands, had prominent, specific hybridization signal for a2 and a3 isoforms compared with adjacent working myocytes. This gene-expression approach may be useful for labeling conduction tissue and also for localizing specific membrane channels and receptors in this system.The sodium pump (Na+,K+-ATPase), a ubiquitous enzyme that extrudes sodium from the cell in exchange for potassium, has many important physiologic functions in the heart, such as regulation of cell volume, generation of ion gradients for solute transport, and maintenance of voltage gradients in excitable tissue. Digitalis glycosides, an important class of cardiac drugs, are highly specific inhibitors of this enzyme. Recently, Na+,K+-ATPase activity has been found to arise from a complex pattern ofgene expression involving, at least, six loci. The functional enzyme is made up of distinct a and ,l protein chains and possibly a third y subunit; the a subunit has three isoforms, and the P subunit has, at least, two isoforms. All three a isoforms are expressed in mammalian heart in developmentally complex ways (1-4). Thus, recently discovered changes (both regional, developmental, and pathophysiologic) in Na+,K+-ATPase isoform distribution (5, 6) are likely to be important in cardiac physiology.A complex cell-type-specific distribution of isoforms is already known to occur in several tissues, including brain and transport epithelia (7-9) at both the mRNA and protein levels (10). In the heart, as in most tissues, al is the predominant a isoform; yet the pattern of developmental change and response to stimuli are complex for the other isoforms. Although not all previous workers found a3 isoform in rat heart, recent data indicate that high-affinity isoform protein is present in this tissue despite the overall low glycoside sensitivity, suggesting that the isoenzymes may differ in their contribution to cardiac physiology (11). We and others have shown regional variations in isoform gene expression in both normal and pressure-overloaded heart (12-15), but the significance of these changes is unknown.The cardiac conduction system is responsible for the initiation and propagation of the heartbeat. Because in adult animals a3 isoform is found almost exclusively in the central nervous system, we suspected that this isoform is preferentially expressed in specialized cardiac conduction tissue. This conjecture is reasonable because (i) the cardiac effects of glycosides are especially prominent in the conduction system ...

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Differing Sensitivities of Purkinje Fibers and Myocardium to Inhibition of Monovalent Cation Transport by Digitalis

Cited by 23 publications

References 28 publications

Stimulation of Monovalent Cation Active Transport by Low Concentrations of Cardiac Glycosides

Stimulation of Monovalent Cation Active Transport by Low Concentrations of Cardiac Glycosides

Voltage‐clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle

The cardiac conduction system in the rat expresses the alpha 2 and alpha 3 isoforms of the Na+,K(+)-ATPase.

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