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

Haustein, Knut-Olaf

doi:10.1159/000136677

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…Corresponding results were obtained in isolated cardiac fibers (19), isolated heart preparations (1,6). in the heart in situ (2), and in healthy volunteers. The results with 16a-gitoxin encour aged us to draw conclusions from in vitro experiments to the situation in vivo.…”

Section: Ratio O F Inotropically To Toxically Effective Concentrationmentioning

confidence: 99%

“…Stock solutions (1 10 mmol/1) were diluted with Tyrode's solution immediately be fore use. Some glycosides were dissolved immediately before use (2,3,(15)(16)(17)(18). The tested glycosides are des ignated by current numbers in brackets [ ) (table 1).…”

Section: Glycosidesmentioning

confidence: 99%

“…In the isolated guinea pig auricle, 3"', 4"'-acetonide [4| and 4'"-isopropyl sulfonate [5] were more effective than 16a-gitoxin, while the cor responding 16a-acetate acetonide [8] was less effective than the 16a-acetate [7:8 = 1.0:0.34], The 3'-nitrate of 16a-gitoxin [2] had a stronger effect than the corresponding 3"-nitrate [3] although the activity could not be exactly determined because of the limited solubility of both nitrates. The 3'-nitrate of 16a-gitoxin 16a-nitrate (i.e.…”

Section: Variation In the Sugar Moiety ( Tables / Ii)mentioning

confidence: 99%

“…In preceding papers we reported on the cardioactivity of 16a-gitoxin which, in compar ison with the naturally occurring glycoside, ouabain, possesses a stronger effect on contrac tility than on rhythmicity (2,6,8,19). Since 16a-gitoxin is effective at relatively high con centrations, more potent glycosides were re searched.…”

Section: Introductionmentioning

confidence: 99%

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Studies on Cardioactive Steroids

Ko¹,

Glusa²

1980

Pharmacology

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The potency of 17 derivatives of 16α-gitoxin was tested in the isolated atrium and heart of the guinea pig and the contractility-increasing activity of the 16α-gitoxin 16α-acetate was compared with that of 16α-gitoxin in the anesthetized dog. The potency of 16α-gitoxin was increased by the substitution of 16α-OH for 16α-methyl ether, 16α-acetate and 16α-nitrate. Substitution of the 16α-acetyl group for substituents with a higher molar volume diminished this enhanced potency. Variation in the digitoxose moiety caused an increase or decrease in potency depending on the position and number of the substituted OH groups. In spite of changes in 16α-OH, the low influence on rhythmicity persisted, as was found in experiments in the dog.

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Section: Ratio O F Inotropically To Toxically Effective Concentrationmentioning

confidence: 99%

Section: Glycosidesmentioning

confidence: 99%

Section: Variation In the Sugar Moiety ( Tables / Ii)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Studies on Cardioactive Steroids

Ko¹,

Glusa²

1980

Pharmacology

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Differentiation between isoforms of Na+/K+-transporting ATPase from human and guinea-pig cardiac muscle through use of digitalis derivatives as analytical probes

Weiland

Megges

et al. 1995

Naunyn-Schmiedeberg's Arch Pharmacol

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The aims of the study included: to explore the protein structure basis for the differences in digitalis sensitivity between isoforms of Na/K-ATPase from human and guinea-pig cardiac muscle; to determine the relative significance of the constituents of tripartite digitalis compounds in their inhibitory action on these Na/K-ATPase isoforms; to evaluate the potential significance of the receptor kinetics for pharmacological characteristics. The analytical method has been the recording of the inhibitory interaction of various digitalis derivatives with the Na/K-ATPase isoforms. The protein structure basis for the isoform differences in digitalis susceptibility has been explored by analysing in free-energy plots the kinetics of their inhibitory interaction with 53 digitalis derivatives of grossly different structure. The slope of the regression line and the parameters of the regression equation proved to be similar for the two isoforms in spite of the great difference in their digitalis susceptibilities. This surprising uniformity indicates that a uniform "macroscopic" mechanism underlies the inhibitory effect of the various derivatives on the two isoforms. On the other hand, the differences in the positions of delta G*on and delta G*off values for particular inhibitors relative to the regression line reveal differences in the "microscopic" interaction energy surfaces of the two isoforms. In conclusion, the origin of the isoform distinctions in their susceptibility towards inhibition by various digitalis derivatives is essentially confined to differences in the chemotopology of the digitalis recognition matrix and binding cleft. Specific observations allowed to disentangle the impact of various steroid derivatizations at carbon atoms 3, 17, and diverse other positions on the kinetics of their interaction with the enzyme isoforms. The steroid nucleus of the cardiac glycosides, 5 beta, 14 beta-androstane, proves to be the basal structural element for discrimination of Na/K-ATPase isoforms. This discrimination becomes much enlarged by steroid glycosidation at C3 beta-OH and/or by steroid substitution of C17 beta-H by a lactone ring. The higher inhibitory sensitivity of the human isoform is based either on an increased association rate or a decreased dissociation rate, depending on the nature of derivatization.(ABSTRACT TRUNCATED AT 400 WORDS)

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Pharmacokinetic investigations in man of two acetyl derivatives of 16?-gitoxin

Haustein

1977

Eur J Clin Pharmacol

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3H-16-acetyl-16alpha-gitoxin or 3H-penta-acetyl-16alpha-gitoxin were injected iv or administered po to 15 volunteers and 3 patients. The elimination half-life and excretion in urine within 4 days were estimated as a percentage of the administered radioactivity, and metabolic studies on the fate of the administered glycosides were performed. In volunteers the following results were obtained: 3H-16-acetyl-16alpha-gitoxin 1 mg iv.: 50 +/- 11 h, 28.3 +/- 4.1%; 3H-16-acetyl-16alpha-gitoxin 1mg po: 48 +/- 8 h, 25.4 +/- 2.8%; 3H-penta-acetyl-16alpha-gitoxin 2 mg po: 51 +/- 12 h, 20.7 +/- 3.2%, respectively. In 3 patients with a cannulated bile duct 9.9% (mean) of the administered 3H-16-acetyl-16alpha-gitoxin was excreted. By comparison of the radioactivity excreted in urine following the 2 routes of 16-acetate administration, the percentage absorption was calculated to be 88.5%. In serum and urine 16-acetyl-16alpha-gitoxin and 16alpha-gitoxin were found as possible metabolites of both glycosides, in the ratio of 75-85:15-25, and both metabolites were also found in bile. Within 16 h after penta-acetate administration, two additional metabolites (bis-acetyl-derivatives of 16alpha-gitoxin) were detected in serum and urine within 16 h after administration of penta-acetate.

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

Cited by 6 publications

References 11 publications

Studies on Cardioactive Steroids

Studies on Cardioactive Steroids

Differentiation between isoforms of Na+/K+-transporting ATPase from human and guinea-pig cardiac muscle through use of digitalis derivatives as analytical probes

Pharmacokinetic investigations in man of two acetyl derivatives of 16?-gitoxin

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