Inhibition of recombinant low-voltage-activated Ca2+ channels by the neuroprotective agent BW619C89 (Sipatrigine)

T-type Ca2+ currents were recorded in 2 mM Ca2+ from HEK 293 cells stably expressing recombinant low-voltage-activated Ca2+ channel subunits. Current-voltage relationships revealed that these currents were low-voltage activated in nature and could be reversibly antagonised by mibefradil, a known T-type channel blocker. At a test potential of -25 mV alpha(11)-mediated Ca2+ currents were rapidly and reversibly inhibited by 1-100 mu M BW619C89 (IC50 =14 mu M, Hill coefficient 1.3). In contrast to its actions on N-type Ca2+ channels, a near IC50 dose (10 mu M) of BW619C89 produced no alterations in either the kinetics or voltage-dependence of T-type currents. In additional single dose experiments, currents mediated by rat alpha(1G), human alpha(1H) or human alpha(11) channel subunits were also inhibited by BW619C89, Overall our data indicate that T-type Ca2+ channels are more potently blocked by BW619C89 than either type-II Na+ channels or N-type Ca2+ channels. It seems, therefore, that inhibition of low-voltage-activated Ca2+ channels is likely to contribute to the anticonvulsant and neuroprotective actions of this and related compounds. (C) 2000 Elsevier Science Ltd. All rights reserved.