Presynaptic Ca2+-dependent mechanisms have already been implicated in depression of evoked synaptic transmission by high pressure (HP). Therefore, pressure effects on terminal Ca2+ currents were studied in Rana pipiens peripheral motor nerves. The terminal currents, evoked by nerve or direct stimulation, were recorded under the nerve perineurial sheath with a loose macropatch clamp technique. The combined use of Na+ and K+ channel blockers, [Ca2+]o changes, voltage-dependent Ca2+ channel (VDCC) blocker treatments and HP perturbations revealed two components of presynaptic Ca2+ currents: an early fast Ca2+ current (ICaF), possibly carried by N-type (CaV2.2) Ca2+ channels, and a late slow Ca2+ current (ICaS), possibly mediated by L-type (CaV1) Ca2+ channels. HP reduced the amplitude and decreased the maximum (saturation level) of the Ca2+ currents, ICaF being more sensitive to pressure, and may have slightly shifted the voltage dependence. HP also moderately diminished the Na+ action current, which contributed to the depression of VDCC currents. Computer-based modeling was used to verify the interpretation of the currents and investigate the influence of HP on the presynaptic currents. The direct HP reduction of the VDCC currents and the indirect effect of the action potential decrease are probably the major cause of pressure depression of synaptic release.