title: Comparison of the effects of aminosugar cardiac glycosides with ouabain and digoxin on Na+, K+ -adenosine triphosphatase and cardiac contractile force.
abstract: Two aminosugar cardiac glycosides, 3-beta-O-(4-amino-4,6-dideoxy-beta-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) 7). 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.
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000617:Aminoglycosides / Q000494:pharmacology; D000818:Animals; D004071:Digitalis Glycosides / Q000494:pharmacology*; D004077:Digoxin / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D004071:Digitalis Glycosides; D010042:Ouabain; D004077:Digoxin; D012964:Sodium; D000251:Adenosine Triphosphatases; D011188:Potassium