Comparison of the effects of aminosugar cardiac glycosides wth ouabain and digoxin on Na+, K+ adenosine triphosphatase and cardiac contractile force

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Abstract

Two aminosugar cardiac glycosides, 3-β-O-(4-amino-4,6-dideoxy-β-D-galactopyranosyl) digitoxigenin (ASI-222) and its 4-aminoglucose analog (ASI-254) have been shown in our laboratory to have a greater therapeutic index than ouabain (O) or digoxin (D). We have now compared the ability of ASI-222, its nonamino galactose analog (ASI-253), ASI-254, ouabain and digoxin to inhibit swine brain Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and to increase contractile force of isolated, driven rabbit atria. As inhibitors of Na+,K+-ATPase, both ASI-222 and ASI-254 were found to be about 10 times more potent than ASI-253, O or D (I50: ASI-222, 1.3 x 10-7 M; ASI-254, 1.4 x 10-7 M; ASI-253, 1.15 x 10-6 M; D, 1.6 x 10-6 M; O, 1.75 x 10-6 M). Moreover, the potency of these glycosides in inhibiting Na+,K+-ATPase correlates closely with the ability of these same glycosides to increase contractile force. The concentration needed to obtain 50% of the maximum increase in contractile force was 9.7 x 10-8 M for ASI-254, 1.5 x 10-7 M for ASI-222, 8.8 x 10-7 M for ASI-253, 8.4 x 10-7 M for O and 1.2 x 10-6 M for D. Since ASI-253, a nonaminogalactose analog of ASI-222, exhibits a potency in both of our test systems which is similar to the other neutral sugar cardenolides our data also indicate that the presence of an aminosugar group at position 4 of a sugar in a cardiac glycoside confers greater potency.

Original languageEnglish (US)
Pages (from-to)141-148
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume204
Issue number1
StatePublished - Jan 1 1978

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Cardiac Glycosides
Digoxin
Ouabain
Adenosine Triphosphatases
Glycosides
Digitoxigenin
Cardenolides
Galactose
ASI-222
Swine
ASI 254
Rabbits
Brain

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Comparison of the effects of aminosugar cardiac glycosides wth ouabain and digoxin on Na+, K+ adenosine triphosphatase and cardiac contractile force",
abstract = "Two aminosugar cardiac glycosides, 3-β-O-(4-amino-4,6-dideoxy-β-D-galactopyranosyl) digitoxigenin (ASI-222) and its 4-aminoglucose analog (ASI-254) have been shown in our laboratory to have a greater therapeutic index than ouabain (O) or digoxin (D). We have now compared the ability of ASI-222, its nonamino galactose analog (ASI-253), ASI-254, ouabain and digoxin to inhibit swine brain Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and to increase contractile force of isolated, driven rabbit atria. As inhibitors of Na+,K+-ATPase, both ASI-222 and ASI-254 were found to be about 10 times more potent than ASI-253, O or D (I50: ASI-222, 1.3 x 10-7 M; ASI-254, 1.4 x 10-7 M; ASI-253, 1.15 x 10-6 M; D, 1.6 x 10-6 M; O, 1.75 x 10-6 M). Moreover, the potency of these glycosides in inhibiting Na+,K+-ATPase correlates closely with the ability of these same glycosides to increase contractile force. The concentration needed to obtain 50{\%} of the maximum increase in contractile force was 9.7 x 10-8 M for ASI-254, 1.5 x 10-7 M for ASI-222, 8.8 x 10-7 M for ASI-253, 8.4 x 10-7 M for O and 1.2 x 10-6 M for D. Since ASI-253, a nonaminogalactose analog of ASI-222, exhibits a potency in both of our test systems which is similar to the other neutral sugar cardenolides our data also indicate that the presence of an aminosugar group at position 4 of a sugar in a cardiac glycoside confers greater potency.",
author = "Caldwell, {Robert William} and Nash, {C. B.}",
year = "1978",
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T1 - Comparison of the effects of aminosugar cardiac glycosides wth ouabain and digoxin on Na+, K+ adenosine triphosphatase and cardiac contractile force

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N2 - Two aminosugar cardiac glycosides, 3-β-O-(4-amino-4,6-dideoxy-β-D-galactopyranosyl) digitoxigenin (ASI-222) and its 4-aminoglucose analog (ASI-254) have been shown in our laboratory to have a greater therapeutic index than ouabain (O) or digoxin (D). We have now compared the ability of ASI-222, its nonamino galactose analog (ASI-253), ASI-254, ouabain and digoxin to inhibit swine brain Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and to increase contractile force of isolated, driven rabbit atria. As inhibitors of Na+,K+-ATPase, both ASI-222 and ASI-254 were found to be about 10 times more potent than ASI-253, O or D (I50: ASI-222, 1.3 x 10-7 M; ASI-254, 1.4 x 10-7 M; ASI-253, 1.15 x 10-6 M; D, 1.6 x 10-6 M; O, 1.75 x 10-6 M). Moreover, the potency of these glycosides in inhibiting Na+,K+-ATPase correlates closely with the ability of these same glycosides to increase contractile force. The concentration needed to obtain 50% of the maximum increase in contractile force was 9.7 x 10-8 M for ASI-254, 1.5 x 10-7 M for ASI-222, 8.8 x 10-7 M for ASI-253, 8.4 x 10-7 M for O and 1.2 x 10-6 M for D. Since ASI-253, a nonaminogalactose analog of ASI-222, exhibits a potency in both of our test systems which is similar to the other neutral sugar cardenolides our data also indicate that the presence of an aminosugar group at position 4 of a sugar in a cardiac glycoside confers greater potency.

AB - Two aminosugar cardiac glycosides, 3-β-O-(4-amino-4,6-dideoxy-β-D-galactopyranosyl) digitoxigenin (ASI-222) and its 4-aminoglucose analog (ASI-254) have been shown in our laboratory to have a greater therapeutic index than ouabain (O) or digoxin (D). We have now compared the ability of ASI-222, its nonamino galactose analog (ASI-253), ASI-254, ouabain and digoxin to inhibit swine brain Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and to increase contractile force of isolated, driven rabbit atria. As inhibitors of Na+,K+-ATPase, both ASI-222 and ASI-254 were found to be about 10 times more potent than ASI-253, O or D (I50: ASI-222, 1.3 x 10-7 M; ASI-254, 1.4 x 10-7 M; ASI-253, 1.15 x 10-6 M; D, 1.6 x 10-6 M; O, 1.75 x 10-6 M). Moreover, the potency of these glycosides in inhibiting Na+,K+-ATPase correlates closely with the ability of these same glycosides to increase contractile force. The concentration needed to obtain 50% of the maximum increase in contractile force was 9.7 x 10-8 M for ASI-254, 1.5 x 10-7 M for ASI-222, 8.8 x 10-7 M for ASI-253, 8.4 x 10-7 M for O and 1.2 x 10-6 M for D. Since ASI-253, a nonaminogalactose analog of ASI-222, exhibits a potency in both of our test systems which is similar to the other neutral sugar cardenolides our data also indicate that the presence of an aminosugar group at position 4 of a sugar in a cardiac glycoside confers greater potency.

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