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(Na)i) associated with positive inotropic and toxic effects of acetylstrophanthidin (AS) and a semisynthetic agent, actodigin. Measurements of a(Na)i, 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(Na)i 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(Na)i (10.9 +/- 0.7 vs. 11.9 +/- 0.7 mM, respectively, N.S.); 2) at frequencies of 1 to 2 Hz, a(Na)i 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(Na)i was the same at peak tension (10.6 +/- 1.1 mM) and 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.