Effects of vesicular monoamine transporter inhibitors on catecholamine rele
ase from bovine chromaffin cells have been examined at the level of individ
ual exocytotic events. As expected for a depletion of vesicular stores, rel
ease evoked by depolarizing agents was decreased following 15-min incubatio
ns with reserpine and tetrabenazine, as evidenced by a decrease in exocytot
ic frequency and amount released per event. In contrast, two reserpine deri
vatives, methyl reserpate and reserpic acid, were much less effective. Surp
risingly, the incubations also decreased the accompanying rise in intracell
ular Ca2+ evoked by depolarizing agents. Subcellular studies revealed that
reserpine and tetrabenazine at concentrations near their Ri values not only
could increase cytoplasmic catecholamines but also could displace Ca2+ fro
m vesicles. Furthermore, transient exposure to tetrabenazine and reserpine,
but not methyl reserpate and reserpic acid, induced exocytotic release of
catecholamines, Reserpine induced a rise in intracellular Ca2+, as detected
by whole-cell measurements with Fura-2, It could induce exocytosis, albeit
at a lower frequency, in Ca2+-free solutions, supporting an internal Ca2source. Depletion of endoplasmic reticulum and mitochondrial Ca2+ pools did
not eliminate the reserpine-activated release. These results indicate that
vesicular Ca2+ can play an important role in exocytosis and under some con
ditions may be involved in initiating this process.