The anesthetic steroid (+)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile blocks N-, Q-, and R-type, but not L- and P-type, high voltage-activated Ca2+ current in hippocampal and dorsal root ganglion neurons of the rat.
High voltage-activated (HVA) Ca2+ current (ICa) was recorded from neonatal rat hippocampal and adult rat dorsal root ganglion neurons. In both cell types, (+)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile [(+)-ACN], a neuroactive steroid, had no effect on nifedipine- (L-type) or omega-agatoxin IVA- (P-type) sensitive ICa. Selective blockade of N-type current with omega-conotoxin GVIA and of Q-type current with omega-conotoxin MVIIC indicated that (+)-ACN inhibits both N- and Q-type current components in both cell types. Current persisting after blockade of all other current components (R-type) was also sensitive to (+)-ACN. Half-blockade of (+)-ACN-sensitive HVA current occurred in the range of 3-25 microM, 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 relatively ineffective at inhibiting total HVA current. Neither guanosine-5'-O-(2-thio)diphosphate nor guanosine-5'-O-(3-thio)triphosphate altered the ability of (+)-ACN to inhibit HVA current in dorsal root ganglion 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 useful strategy in the generation of more selective, more potent, small-molecular-weight HVA channel blockers.
Nakashima
Y M
YM
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Todorovic
S M
SM
Covey
D F
DF
Lingle
C J
CJ
D000732:Androstanols / Q000494:pharmacology*; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000145:classification* / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D020866:omega-Conotoxin GVIA; D020960:omega-Conotoxins
D000732:Androstanols; D000777:Anesthetics; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009570:Nitriles; D010455:Peptides; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; C084682:3-hydroxy-5-androstane-17-carbonitrile; D020866:omega-Conotoxin GVIA; D019204:GTP-Binding Proteins; D002118:Calcium