Na+/Ca2+ exchangers (NCXs) and members of the canonical transient receptor potential (TRPC) channels play an important role in Ca2+ homeostasis in heart and brain. With respect to their overlapping expression and their role as physiological Ca2+ influx pathways a functional discrimination of both mechanisms seems to be necessary. Here, the effect of the reverse-mode NCX inhibitor KB-R7943 was investigated on different TRPC channels heterologously expressed in HEK293 cells. In patch-clamp recordings KB-R7943 potently blocked currents through TRPC3 (IC50 = 0.46 mu M), TRPC6 (IC50 = 0.71 mu M), and TRPC5 (IC50 = 1.38 mu M). 1-Oleoyl-2-acetyl-sn-glycerol-induced Ca2+ entry was nearly completely suppressed by 10 mu M KB-R7943 in TRPC6-transfected cells. Thus, KB-R7943 is able to block receptor-ope rated TRP channels at concentrations which are equal or below those required to inhibit reverse-mode NCX activity. These data further suggest that the protective effects of KB-R7943 in ischemic tissue may, at least partly, be due to inhibition of TRPC channels. (C) 2007 Elsevier Inc. All rights reserved.