Effects of different cardiac steroids on intracellular sodium, inotropy and toxicity in sheep Purkinje fibers
Wasserstrom, J.A.; Farkas, D.E.; Norell, M.A.; Vereault, D.V.
Journal of Pharmacology and Experimental Therapeutics 258(3): 918-925
1991
ISSN/ISBN: 0022-3565 PMID: 1890626 Document Number: 379888
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 (aNai) associated with positive inotropic and toxic effects of acetylstrophanthidin (AS) and a semisynthetic agent, actodigin. Measurements of aNai, 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, aNai 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 aNai (10.9 .+-. 0.7 vs. 11.9 .+-. 0.7 mM, respectively, N.S.); 2) at frequencies of 1 to 2 Hz, aNai was lower when TD occurred (10.4 .+-. 0.9 mM at 2 Hz) than a peak tension (12.1 .+-. 0.8 mM, P < .05) during exposure to AS, whereas aNaa 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.