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 o n systolic Ca2+ transients in indo-1-loaded rat ventricular myocytes. 2. Thapsigargin (1-10 muM) decreased the magnitude of the Ca2+ transie nt. This was accompanied by a decrease of the rate constant of decay o f the transient.3. Ryanodine (1-10 muM) decreased the magnitude of the Ca2+ transient. Initially there was no change in the rate of decay bu t 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 concentrat ion. 5. For a given submaximal reduction of the magnitude of the Ca2transient, the effect on the rate of decay was greatest for thapsigarg in, least for ryanodine and intermediate for caffeine. 6. The above da ta are reproduced by a model in which all three agents decrease the ma gnitude 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 effec t than the other agents on the rate of decay. The difference between c affeine and ryanodine is suggested to arise because caffeine potentiat es Ca2+ release from the SR and thereby attenuates the effect of the d ecreased SR calcium content on the magnitude of the Ca2+ transient.