Thapsigargin attenuates the potentiation of positive inotropic effect of digoxin induced by pretreatment with rimalkalim in the guinea pig heart.

The influence of thapsigargin, a selective inhibitor of sarcoplasmic reticulum (SR) Ca2+ ATPase, on the positive inotropic effects of digoxin before and after pretreatment with rimalkalim [(3S,4R)-3-hydroxy-2,2-dimethyl-4-(oxopyrrolidinyl)-6-phenyl-su lfonylchroman hemihydrate (formerly HOE 234)], a known activator of ATP-sensitive K+ channels, was studied in the guinea pig heart. The isolated papillary muscles from the guinea pig heart were used to study these effects. The following parameters were measured: force of contraction (Fc), rate of rise (+dF/dt) and rate of fall (-dF/dt) of Fc, time to peak contraction (ttp) and time to 10% of the total amplitude of force (tt10). After pretreatment with rimalkalim (1 microM), digoxin caused a significant increase in the amplitude of Fc and significant shortening of ttp and tt10 (p < 0.05 compared with the values obtained with digoxin alone). Thapsigargin (1 microM), a selective inhibitor of sarcoplasmic reticulum Ca2+ ATPase, added to rimalkalim, prevented the enhancement of the amplitude of Fc induced by digoxin after pretreatment with rimalkalim but had no significant influence on the effects of digoxin itself. The results demonstrate significant influence of activation of KATP channels on digoxin-induced positive inotropic effects in the guinea pig heart. Attenuation of this effects of rimalkalim by addition of thapsigargin suggests that activation of SR Ca2+ ATPase can be included in this interaction.