Multiple effects of reserpine on chromaffin-granule membranes

The tranquilizer reserpine has several effects on adrenal medullary chromaffin-granule membrane vesicles (ghosts). At low concentrations (0.20 +/0 0.12 nmol/mg of membrane protein), reserpine inhibits proton-linked epinephrine uptake but does not affect transmembrane pH and electrical potential gradients. Reserpine apparently binds to and blocks the catecholamine translocator. At intermediate concentrations (14.3 +/- 4.8 nmol/mg of membrane protein), reserpine abolishes the ATP-dependent enhancement of 8-anilinonaphthalene-1-sulfonate fluorescence without affecting the ATP-dependent membrane potential. At high concentrations (550 +/- 390 nmol/mg of membrane protein), reserpine stimulates the efflux of epinephrine from preloaded chromaffin-granule ghosts. Because it is highly hydrophobic, reserpine partitions into the membrane and probably exerts a nonspecific detergent-like action. At high concentrations (74 +/- 25 nmol/mg of lipid), reserpine also increases the permeability of phospholipid vesicles to epinephrine. The effectiveness of reserpine in inhibiting epinephrine transport correlates with the reserpine/membrane ratio but not with the molar concentration. This may account for the larger variation in reports of effective reserpine concentrations.