Different Toxic Effects of Ouabain and 16-Epi-Gitoxin on Purkinje Fibres and Ventricular Muscle Fibres

Nowak, G; Haustein, Knut-Olaf

doi:10.1159/000136603

Cited by 15 publications

(8 citation statements)

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“…Our finding of pronounced (76%) inhibition of monovalent cation transport in Purkinje fibers at onset of cardiac glycoside-induced arrhythmias is consistent with the role ascribed to the Purkinje network in the genesis of digitalis-induced arrhythmias by a number of authors (1)(2)(3)(4)(5)38). It seems reasonable to speculate that the relatively greater sensitivity of Purkinje fibers compared to myocardium to digitalis-induced transport inhibition may underlie, at least in part, the relatively low therapeutic ratio long known to be associated with the use of this class of drugs.…”

Section: Resultssupporting

confidence: 89%

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

Somberg¹,

Barry²,

Smith³

1981

J. Clin. Invest.

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A B S T R A C T The extent of inhibition of monovalent cation active transport in Purkinje fibers and myocardium in response to toxic and inotropic doses of digitalis were studied in the dog to elucidate the factors underlying the different relative sensitivities of these tissues to the toxic arrhythmogenic effects of digitalis. Monovalent cation transport inhibition was assessed by measuring uptake of the K+ analog Rb+ in samples of myocardium and Purkinje fibers after in vitro ouabain exposure and after acute or chronic administration of digoxin in vivo. The active uptake of Rb+ was determined as the difference between total uptake and uptake in the presence of 1.0 mM ouabain. Mean active uptake of Rb+ by Purkinje fibers from control hearts was 1.62±0.11 (SEM) nmol/mg wet wt per 15 min, significantly greater than the value of 0.49±0.05 for myocardium (P < 0.001). Concentration-effect curves for inhibition of monovalent cation active transport by in vitro exposure to graded concentrations of ouabain showed that the concentration for half-maximal inhibition of monovalent cation transport, IC50, for Purkinje fiber transport was 0.4 ,M, significantly less than the value of 1.4 uM for myocardial samples. Dogs were given toxic doses of digoxin (0.3 mg/kg i.v.). At onset of sustained ventricular tachycardia, they were killed and monovalent cation transport measured in myocardial and Purkinje fiber samples. Active Rb+ uptake was inhibited by 44% in myocardial samples, whereas a significantly greater inhibition of 76% was noted in Purkinje fibers (P < 0.01). Similar data were obtained for both transmural myocardial biopsy samples and subendocardial trabecular samples obtained from regions adjacent to Purkinje fibers. Another group of dogs received a nontoxic dose of 0.02 mg/kg i.v. daily for 6 d. 'Myocardium showed a 17% reduction in Rb+

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Section: Resultssupporting

confidence: 89%

“…Samples were placed in physiologic medium containing (mM) 4.0 KCl, 120 NaCl, 24 NaHCO3, 2.0 MgCl2, 2.5 CaCl2, 5.6 glucose, and 1.1 NaH2PO4. The pH was adjusted to 7.4 with HCI, the medium oxygenated with 95% 02 and 5% CO2, and the temperature maintained at 30°C.…”

Section: Monovalent Cation Transport Measurementsmentioning

confidence: 99%

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

Somberg¹,

Barry²,

Smith³

1981

J. Clin. Invest.

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“…The results are in agreement with those obtained in isolated cardiac prepara tions (Haustein, 1967;Haustein and Hauptmann 1974;Haustein et ai, 1970) and in isolated Purkinje and ventricular muscle fibres (Nowak and Haustein, 1976). The results of the infusion experiments in cats show that lethal effects Table III.…”

Section: Discussionsupporting

confidence: 89%

Extraordinary Cardiac Effects of 16-Epi-Gitoxin in Comparison to Ouábain in Cats and Dogs

Haustein¹

1977

Pharmacology

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The contractility and arrhythmogenic effects of 16-epi-gitoxin and ouabain were studied in dogs. ECG alteration-producing and lethal doses of both glycosides were determined in cats. 16-Epi-gitoxin was found to be a glycoside with rapid onset and short duration of action. In case of equal contractile increment ouabain caused a higher percentage of rhythm disturbances in dogs than 16-epi-gitoxin. This finding corresponds to that in cats, in which ECG changes (QRS complex prolongation) occurred after ouabain at a lower percentage of the lethal dose than after 16-epi-gitoxin. Apart from its slight arrhythmogenic effects, 16-epi-gitoxin may be compared with acetylstrophanthidin.

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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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Different Toxic Effects of Ouabain and 16-Epi-Gitoxin on Purkinje Fibres and Ventricular Muscle Fibres

Cited by 15 publications

References 7 publications

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

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

Extraordinary Cardiac Effects of 16-Epi-Gitoxin in Comparison to Ouábain in Cats and Dogs

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

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Different Toxic Effects of Ouabain and 16-Epi-Gitoxin on Purkinje Fibres and Ventricular Muscle Fibres

Cited by 15 publications

References 7 publications

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

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

Extraordinary Cardiac Effects of 16-Epi-Gitoxin in Comparison to Ou&aacute;bain in Cats and Dogs

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

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Extraordinary Cardiac Effects of 16-Epi-Gitoxin in Comparison to Ouábain in Cats and Dogs