Structure-activity relationships of several cardiotonic steroids with respect to inhibition of ion transport in frog muscle.

Cesium uptake by sodium-loaded frog sartorius muscles was inhibited 100% by 10(-6)M ouabain and 10(-6)M cymarin. The doses for 50% inhibition of cesium uptake by five cardiotonic aglycones were 1.5 x 10(-6)M for strophanthidin, 2 x 10(-7)M for telocinobufagin, 1.6 x 10(-6) for digitoxigenin, 2.4 x 10(-6)M for periplogenin, and 6.3 x 10(-6)M for uzarigenin. Because of the limited solubility of sarmentogenin the maximum concentration studied was 2 x 10(-6)M which inhibited cesium uptake about 36%. Inhibition of cesium uptake by cymarin was not reversed during a 3.5 hr incubation in fresh solution while the muscles treated with ouabain and strophanthidin recovered partly during this time. Cymarin was a more potent inhibitor of sodium efflux than strophanthidin and periplogenin was less potent. Increased cesium ion concentration in the external solution decreased the strophanthidin inhibition of cesium uptake but 25 mM cesium did not overcome the inhibition by 10(-8)-10(-6)M strophanthidin. Increased potassium ion concentration in the external solution decreased but did not completely overcome inhibition of sodium efflux by strophanthidin. It is concluded that potassium or cesium ions do not compete with these drugs for a particular site on the ion transport complex. The same structural features of the drugs are necessary for inhibition of ion transport in frog muscle as are required for inhibition of ion transport in other tissues, inhibition of sodium-potassium-stimulated ATPases, and toxicity to animals.