DIFFERENT POTENCIES OF DIHYDROPYRIDINE DERIVATIVES IN BLOCKING T-TYPEBUT NOT L-TYPE CA2-GLIOMA HYBRID-CELLS( CHANNELS IN NEUROBLASTOMA)

Evidence has accumulated that classic L-type Ca2+ channel blockers wit h a dihydropyridine structure also inhibit T-type Ca2+ channels in cer tain types of central and peripheral neurons and in smooth muscle cell s, albeit with a lower potency. Thus beneficial therapeutic effects of dihydropyridines in cardiovascular and neurological diseases may not only be associated with L-type but also with T-type Ca2+ channel block ade. Little is known about the exact order of potency of dihydropyridi ne derivatives at T-type Ca2+ channels. Here we investigate the effica cy and potency of four therapeutically used compounds, i.e. nifedipine . nimodipine, nicardipine, niguldipine, in the neuroblastoma-glioma ce ll line NG108-15. For comparative purposes the Ca2+ channel agonist Ba y K 8634 was included. Ca2+ channel currents were measured with the wh ole-cell voltage clamp technique. Subtype Ca2+ channel currents were s eparated by clamp protocol and selective blockers. T-type Ca2+ channel currents were inhibited with decreasing potency in the order niguldip ine > nicardipine > nimodipine > nifedipine (IC50-values 244 nM, 2.5 m u M. 9.8 mu M, 39 mu M), whereas L-type Ca2+ channel currents were blo cked with similar potency (IC50 for nicardipine 75 nM). Bay K 8644 inc reased T-type Ca2+ channel current at nanomolar concentrations (i.e. 9 5 +/- 16% increase by 300 nM). T-type Ca2+ channel block was completel y reversible with exception of the block by niguldipine. Our results i ndicate a variability of two orders of magnitude in potency of T-type Ca2+ channel block by the dihydropyridine derivatives investigated. It is speculated that the relation between the L-and T-type Ca2+ channel block may determine the therapeutic profile of a dihydropyridine deri vative. (C) 1998 Elsevier Science B.V.