The action of tetrandrine on spontaneous and phasic acetyl-choline (ACh) release was investigated at the mouse neuromuscular junction recording miniature endplate potentials (MEPPs) and endplate potentials. Superfusion of muscles with tetrandrine (10 microM) in normal Krebs-Ringer solution induced an increase of the mean regular MEPP amplitude and the overall MEPP frequency. In addition a larger than normal proportion of high-amplitude MEPPs appeared, described as "giants." This enhancement by tetrandrine of spontaneous ACh release also occurred in the presence of tetrodotoxin (1 microM). In elevated magnesium Krebs-Ringer solution the mean amplitude as well as the quantal content of endplate potentials was reduced simultaneously with the enhancement of spontaneous ACh release. Superfusion of muscles with emetine (20 microM), an alkaloid chemically of the same kind as tetrandrine, induced an enhancement of spontaneous ACh release as recorded by MEPPs qualitatively similar to that of tetrandrine. These results suggest that the isoquinolines tetrandrine and emetine similarly increased the spontaneous ACh release. This action of tetrandrine appeared to be presynaptic and was accompanied by a decrease of phasic ACh release.