THE ANESTHETIC STEROID HA-HYDROXY-5-ALPHA-ANDROSTANE-17-BETA-CARBONITRILE BLOCKS N-TYPE, Q-TYPE, AND R-TYPE, BUT NOT L-TYPE AND P-TYPE, HIGH VOLTAGE-ACTIVATED CA2+ CURRENT IN HIPPOCAMPAL AND DORSAL-ROOT GANGLION NEURONS OF THE RAT())

High voltage-activated (HVA) Ca2+ current (I-Ca) was recorded from neo natal rat hippocampal and adult rat dorsal root ganglion neurons. In b oth cell types, (+)-3 alpha-hydroxy-5 alpha-androstane-17 beta-carboni trile [(+)-ACN], a neuroactive steroid, had no effect on nifedipine- ( L-type) or omega-agatoxin IVA- (P-type) sensitive I-Ca. Selective bloc kade of N-type current with omega-conotoxin GVIA and of Q-type current with omega-conotoxin MVIIC indicated that (+)-ACN inhibits both N- an d Q-type current components in both cell types. Current persisting aft er blockade of all other current components (R-type) was also sensitiv e to (+)-ACN. Half-blockade of (+)-ACN-sensitive HVA current occurred in the range of 3-25 mu M, with N-type current somewhat more sensitive than Q- or R-type. The (+)-ACN enantiomer, (-)-ACN, and pregnanolone were somewhat less effective at inhibiting total HVA current than (+)- ACN, whereas several steroid analogs, including alfaxalone, were relat ively ineffective at inhibiting total HVA current. Neither guanosine-5 '-O-(2-thio)diphosphate nor guanosine-5'-O-(3-thio)triphosphate altere d the ability of (+)-ACN to inhibit HVA current in dorsal root ganglio n neurons, indicating that (+)-ACN acts directly on Ca2+ channels. The partial selectivity exhibited by (+)-ACN among different HVA current components suggests that manipulations of steroid analogues may be a u seful strategy in the generation of more selective, more potent, small -molecular-weight HVA channel blockers.