Effects of different cardiac steroids on intracellular sodium, inotropy and toxicity in sheep purkinje fibers

The purpose of the present study was to examine the differences between cardiac steroids that might underlie the variations in toxic/therapeutic ratios that have been reported to occur in vitro as well as in vivo. We used Na⁺-sensitive microelectrodes to measure changes in intracellular Na⁺ activity (a(i)Na) associated with positive inotropic and toxic effects of acetylstrophanthidin (AS) and a semisynthetic agent, actodigin. Measurements of a(i)Na, twitch tension and transmembrane potential were made in sheep Purkinje fibers stimulated at 0.03, 1 and 2 Hz. Ca⁺⁺(i) overload toxicity was indicated by the presence of transient depolarizations (TD). The following results were obtained: 1) at a stimulation frequency of 1 Hz, a(i)(Na) was significantly higher at peak tension with AS (13.6 ± 1.1 mM) than with actodigin (11.0 ± 0.4 mM, P < .01), yet TD occurred at the same a(i)(Na) (10.9 ± 0.7 vs. 11.9 ± 0.7 mM, respectively, N.S.); 2) at frequencies of 1 to 2 Hz, a(i)(Na) was lower when TD occurred (10.4 ± 0.9 mM at 2 Hz) than at peak tension (12.1 ± 0.8 mM, P < .05) during exposure to AS, whereas a(i)(Na) was the same at peak tension (10.6 ± 1.1 mM) when TD occurred (10.5 ± 1.1 mM, N.S.) during exposure to actodigin; 3) the degree of positive inotropy at a high stimulation frequency (2 Hz) was significantly greater with actodigin (about 12-fold increase in force compared to control) than with AS (about 6-fold increase in force). We conclude that observed improvement of the toxic/therapeutic ratio with actodigin results from an additional direct cardiac action, possibly involving increased Ca⁺⁺ release from the sarcoplasmic reticulum.