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An attempt was made to investigate the effect of TMB-8 [3,4,5-trimethoxybenzoate-8 (N,N-diethylamino) octyl ester], which is known to be an inhibitor of intracellular Ca2+ release, on catecholamines (CA) secretion evoked by Ach, excess K+, DMPP, McN-A-343 and caffeine from the isolated perfused rat adrenal glands and to clearify its mechanism of action. The pretreatment with a low dose of TMB-8 (10mcM) for 20 min led to marked inhibition in CA secretion evoked by Ach (5.32mM), excess K+ (56mM), DMPP (100mcM), McN-A-343 (100mcM) and BAY-K 8644 (10-5M). Caffeine-induced CA secretion was similar to that of control only during the first periods (0-3 min) but thereafter marked inhibition in CA secretion evoked by caffeine was observed during the rest periods up to 30 min. The increased moderate concentration of TMB-8 (30mcM) caused the result similar to that of 10mcM TMB-8. However, in adrenal glands preloaded with a high dose of TMB-8 (100mcM), CA releases evoked by Ach, excess K+, DMPP, McN-A-343 and caffeine were almost completely blocked by the drug. These experimental data demonstrate that TMB-8 may inhibit cholinergic receptor-mediated and also depolarization-dependent CA secretion, suggesting that these TMB-8 effects seem to be mediated through inhibiting influx of extracellular calcium into the rat adrenal medullary chromaffin cells as well as reducing the release of calcium from intracellular sources.
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