THE ACTION OF CALCIUM-CHANNEL BLOCKERS ON RECOMBINANT L-TYPE CALCIUM-CHANNEL ALPHA(1)-SUBUNITS

1 CHO cells expressing the alpha(1C-a), subunit (cardiac isoform) and the alpha(1C-b) subunit (vascular isoform) of the voltage-dependent L- type Ca2+ channel were used to investigate whether tissue selectivity of Ca2+ channel blockers could be related to different affinities for ale isoforms. 2 Inward current evoked by the transfected alpha(1) subu nit was recorded by the patch-clamp technique in the whole-cell config uration. 3 Neutral dihydropyridines (nifedipine, nisoldipine, (+)-PN20 0-110) were more potent inhibitors of alpha(1C-b)-subunit than of alph a(1C-a)-subunit. This difference was more marked at a holding potentia l of -100 mV than at -50 mV. SDZ 207-180 (an ionized dihydropyridine) exhibited the same potency on the two isoforms. 4 Pinaverium (ionized non-dihydropyridine derivative) was 2 and 4 fold more potent on alpha( 1C-a) than on alpha(1C-b) subunit at Vh of -100 mV and -50 mV, respect ively. Effects of verapamil were identical on the two isoforms at both voltages. 5 [H-3]-(+)-PN 200-110 binding experiments showed that neut ral dihydropyridines had a higher affinity for the alpha(1C-b) than fo r the alpha(1C-a) subunit. SDZ 207-180 had the same affinity for the t wo isoforms and pinaverium had a higher affinity for the alpha(1C-a) s ubunit than for the alpha(1C-b) subunit. 6 These results indicate mark ed differences among Ca2+ channel blockers in their selectivity for th e alpha(1C-a) and alpha(1C-b) subunits of the Ca2+ channel.