We electrophysiologically investigated the effects of nafamostat mesilate (NM: 6-amidino-2-naphthy] p-guanidinobenzoate dimethanesulfonate) and its two metabolites, 6-amidino-2-naphthol (AN) and p-guanidinobenzoic acid (PGBA), on three distinct types of human acid-sensing ion channels (ASICs). Acid-evoked inward currents at a holding potential of -60 mV in ASIC1a- and ASIC2a-expressing oocytes were decreased by extracellular application of NM in a concentration-dependent manner with IC50 (inhibition constant) values of approximately 13.5 and 70.6 mu M, respectively. The NM application also produced concentration-dependent inhibition of the initial-phase transient component of biphasic ASIC3 currents with an IC50 value of approximately 2.5 mu M. Application of AN showed weak blocking effects on the ASIC1a, ASIC2a, and transient ASIC3 currents with IC50 values of approximately 1.2, 1.3, and 0.14 mM, respectively, whereas PGBA was insensitive to their currents. (C) 2007 Elsevier Inc. All rights reserved.