Different potencies of dihydropyridine derivatives in blocking T-type but not L-type Ca2+ channels in neuroblastoma-glioma hybrid cells.
Evidence has accumulated that classic L-type Ca2+ channel blockers with a dihydropyridine structure also inhibit T-type Ca2+ channels in certain types of central and peripheral neurons and in smooth muscle cells, 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 blockade. Little is known about the exact order of potency of dihydropyridine derivatives at T-type Ca2+ channels. Here we investigate the efficacy and potency of four therapeutically used compounds, i.e. nifedipine, nimodipine, nicardipine, niguldipine, in the neuroblastoma-glioma cell line NG108-15. For comparative purposes the Ca2+ channel agonist Bay K 8644 was included. Ca2+ channel currents were measured with the whole-cell voltage clamp technique. Subtype Ca2+ channel currents were separated by clamp protocol and selective blockers. T-type Ca2+ channel currents were inhibited with decreasing potency in the order niguldipine > nicardipine > nimodipine > nifedipine (IC50-values 244 nM, 2.5 microM, 9.8 microM, 39 microM), whereas L-type Ca2+ channel currents were blocked with similar potency (IC50 for nicardipine 75 nM). Bay K 8644 increased T-type Ca2+ channel current at nanomolar concentrations (i.e. 95 +/- 16% increase by 300 nM). T-type Ca2+ channel block was completely reversible with exception of the block by niguldipine. Our results indicate 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 derivative.
Stengel
W
W
Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, University of Technology, Dresden, Germany.
Jainz
M
M
Andreas
K
K
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism*; D006822:Hybrid Cells; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured
D002121:Calcium Channel Blockers; D004095:Dihydropyridines