The effects of inhibitors of sarcoplasmic reticulum function on the systolic Ca2+ transient in rat ventricular myocytes.

1. The effects of thapsigargin, ryanodine and caffeine were examined on systolic Ca2+ transients in indo-1-loaded rat ventricular myocytes. 2. Thapsigargin (1-10 microM) decreased the magnitude of the Ca2+ transient. This was accompanied by a decrease of the rate constant of decay of the transient. 3. Ryanodine (1-10 microM) decreased the magnitude of the Ca2+ transient. Initially there was no change in the rate of decay but further reduction of the magnitude was accompanied by a slowing. 4. Caffeine (0.5-10 mM) decreased the magnitude of the Ca2+ transient and its rate of decay. These effects were graded with caffeine concentration. 5. For a given submaximal reduction of the magnitude of the Ca2+ transient, the effect on the rate of decay was greatest for thapsigargin, least for ryanodine and intermediate for caffeine. 6. The above data are reproduced by a model in which all three agents decrease the magnitude of the Ca2+ transient by decreasing the calcium content of the sarcoplasmic reticulum (SR) (thapsigargin by inhibiting the Ca2+ pump and ryanodine and caffeine by increasing the leak of Ca2+ from the SR). The decreased contribution of the SR will thereby slow relaxation. The fact that thapsigargin inhibits the SR Ca2+ pump accounts for the observation that, for a given decrease of amplitude, it has more effect than the other agents on the rate of decay. The difference between caffeine and ryanodine is suggested to arise because caffeine potentiates Ca2+ release from the SR and thereby attenuates the effect of the decreased SR calcium content on the magnitude of the Ca2+ transient.