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

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.