Experiment 1. We investigated the effects of monensin and digoxin on contraction force (CF), initial contraction velocity (ICV), average contraction velocity (ACV), initial relaxation velocity (IRV) and stimulus to response time (ST) change in fatigued (defined as the level at which papillary muscle contraction had lost 30% of its original contraction force with the elapse of time) and non-fatigued guinea-pig papillary muscles. The five hours of measurement in Experiment 3 were divided into five periods (T0 was equilibration, T1, T2, T3, and T4 were respectively one, two, three, and four hours after drug administration). We found that both monensin and digoxin increased the CF and ACV at T1 and increased the IRV at T2. Digoxin lost its effect with the elapse of time while monensin did not. Digoxin also increased the ICV at T1 and decreased the ST at T2, T3 and T4. However, monensin increased the ICV at T4 and did not change the ST. We also found that although fatigued and non-fatigued guinea-pig papillary muscles behaved differently during four hours of experimentation, they did not respond to the drug treatment differently. We concluded that the initial effects of these two drugs on guinea-pig papillary muscles are similar regarding contractility but in time digoxin loses its positive inotropic effect while monensin does not. Thus, monensin should be studied further to determine if it is useful in the treatment of congestive heart failure;Experiment 2. We also examined whether monensin and digoxin affect the (Ca2+) i of cardiac myocytes and if so is this effect is due to an increase in (Na+) i. We found that both monensin (3 [mu]mol/l) and digoxin (3 [mu]mol/l) increased (Ca2+) i in normal Krebs solution. Digoxin did not increase the (Ca2+) i in Na+-free solution. However, monensin increase the (Ca2+) i in Na+-free solution but the increase was not as great as in a Na+-containing solution. We concluded that effect of digoxin to increase (Ca2+) i depends on (Na+) o. However, monensin can increase (Ca2+) i in the absence of (Na+) o.