Über die ursache der speciesunterschiede in der digitalisempfindlichkeit

Repke, K.; M, Est; Portius, H. J.

doi:10.1016/0006-2952(65)90269-8

Cited by 185 publications

(41 citation statements)

References 26 publications

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“…Later, Repke et al (1965) showed that the toad is about 400 times and the rat about 30 times less sensitive to cardioactive steroids than is, for instance, the cat (short review by Detweiler, 1967). The question arises whether the ouabain-sensitive and the ouabain-resistant Na,K-ATPase forms are produced by two different genes or whether they can be converted after translation.…”

Section: The Ouabain-resistance Genementioning

confidence: 99%

The receptor function of the Na+, K+-activated adenosine triphosphatase system

Anner¹

1985

Biochemical Journal

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Section: The Ouabain-resistance Genementioning

confidence: 99%

The receptor function of the Na+, K+-activated adenosine triphosphatase system

Anner¹

1985

Biochemical Journal

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“…It is well known that the adult rat heart is remarkably resistent to the action of the digitalis glycosides (7,8). Doses of glycosides which are markedly toxic to most mammalian hearts produce little or no effect in the rat.…”

Section: Day Digitalis Glycosidesmentioning

confidence: 99%

“…In the area of mammalian myocardial physiology the rat has provided just such an anomalous condition. The rat heart demonstrates anomalies with respect to its action potential (1, 2), forcefrequency response (1-3), ionic exchange parameters (2,(4)(5)(6) and response to digitalis glycosides (2,7,8). Investigation of these characteristics has provided further insight into fundamental properties of myocardial function not only in the rat but in other mammalian species.…”

mentioning

confidence: 99%

Interspecies variation in myocardial physiology: the anomalous rat

Langer¹

1978

Environ Health Perspect

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The heart of the adult rat has long been recognized to be anomalous in at least two respects: an absent or negative inotropic response to an increase in rate of electrical stimulation (negative staircase); resistance to digitalis glycosides. The heart of the neonatal rat (less than 2 weeks old), on the other hand, demonstrates a markedly positive staircase and a large increase in force upon application of glycoside. It is significant that the action potential of the neonate ventricle demonstrates a prolonged plateau component which progressively decreases with age. The shortening of the plateau correlates with the disappearance of the positive staircase and glycoside responses. Previous studies indicated that a major factor contributing to the prolonged plateau of the neonate was a high level of sodium (Na) conductance. Thus transmembranous Na movement associated with excitation is considerably greater in the neonatal heart as compared to the heart of the adult rat. The higher level of intracellular Na would produce increased activity of a proposed sodium-calcium (Na-Ca) carrier. This is believed to mediate the augmented influx of Ca which is responsible for positive staircase and glycoside responses.Ventricular muscle from the hearts of most mammalian species demonstrates a prolonged plateau with maintenance of a "slow" channel for Na. It appears that in the rat this channel closes with age. It follows that there would be a reduced tendency for the adult rat heart to accumulate intracellular Na, [Na]i, when excitation frequency is increased or the Na pump is inhibited by digitalis. Since elevation of [Na]i is the stimulus for the proposed Na-Ca carrier, this system would not be activated, Ca influx would not increase and contractility would not be augmented.In many biological investigations it is the mutant organism or the anomalous species which frequently provides additional insights into basic mechanisms of function. Definition of the basis for an anomaly may further define the normal condition. In the area of mammalian myocardial physiology the rat has provided just such an anomalous condition. The rat heart demonstrates anomalies with respect to its action potential (1, 2), forcefrequency response (1-3), ionic exchange parameters (2, 4-6) and response to digitalis glycosides (2,7,8). Investigation of these characteristics has provided further insight into fundamental properties of myocardial function not only in the rat but in other mammalian species.I will first review the anomalies and then attempt to correlate them in such a manner as to indicate how the information has provided further definition of a model for control of myocardial force development.

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“…Until just over a decade ago, the hypothesis suggesting that myocardial Na'-K+-ATPase is the 'receptor' for the positive inotropic activity of the cardiotonic steroids still claimed widest support as an explanation for their mode of action (Repke & Portius, 1963;Glynn, 1964;Repke et al, 1965;Schwartz et al, 1974). However, with the use of more sophisticated and specific biochemical methods for receptor studies, profound scepticism has developed towards this hypothesis (Dutta & Marks, 1969;Okita et al, 1973;Park & Vincenzi 1975;Fricke, 1978;Isenberg;.…”

Section: Introductionmentioning

confidence: 99%

Lipophilicity and pharmacodynamics of cardiotonic steroids in guinea‐pig isolated heart muscle preparations

Dzimiri

Fricke

1988

British J Pharmacology

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1The inhibitory potency of cardiotonic steroids on myocardial Na'-K+-ATPase increases with increasing lipophilicity. Employing the inotropic action on guinea-pig isolated left atria, the relationship between lipophilicity, chemical structure and the pharmacodynamic properties of cardiac glycosides was further examined. Nineteen digitoxigenin-and digoxigenin-derivatives, whose lipophilic nature and inhibitory effects on the myocardial Na+-K+-ATPase have been previously investigated, were tested. 2 All steroids exhibited positive inotropic effects which varied with the lipophilicity of these drugs. The dependence of the relationship between these two parameters on structural transformations of the steroids showed qualitatively very close parallelism to that between lipophilicity and their inhibitory effects on myocardial Na+-K+-ATPase. 3 The positive inotropic effects and the inhibitory effects on myocardial Na+-K+-ATPase also correlated very well, exhibiting similar patterns in their respective correlations with the individual lipophilicity parameters. 4 It is inferred that (a) the positive inotropic effects of the cardiac glycosides vary with their lipophilicity, exhibiting trends similar to those shown for their inhibitory effects on myocardial Na+-K+-ATPase, (b) this interdependence is secondary to the influence of structural changes, particularly on the steroid nucleus, and (c) both the lipophilic nature and pharmacodynamic behaviour of the cardiac glycosides almost exclusively depend on the steroid nucleus itself.

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Über die ursache der speciesunterschiede in der digitalisempfindlichkeit

Cited by 185 publications

References 26 publications

The receptor function of the Na+, K+-activated adenosine triphosphatase system

The receptor function of the Na+, K+-activated adenosine triphosphatase system

Interspecies variation in myocardial physiology: the anomalous rat

Lipophilicity and pharmacodynamics of cardiotonic steroids in guinea‐pig isolated heart muscle preparations

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