NEW DIHYDROPYRIDINE LACIDIPINE PERSISTENTLY INHIBITS L-TYPE CALCIUM CURRENTS IN GH3 CELLS

We studied the effects of two antagonist dihydropyridines (DHPs) on calcium currents in cultured pituitary GH3 cells by the perforated patch-clamp method. At depolarizing voltages, GH3 cells present both the low-voltage-activated (LVA), fast-inactivating T-type calcium channel and the high-voltage-activated (HVA), fast-deactivating L-type calcium channel. As already demonstrated in whole-cell experiments and in perforated-patch configuration, 1 mu M nimodipine reversibly inhibited less than or equal to 80% of L-type calcium channels when applied in the external bath solution. At concentrations of 0.1-1 mu M, the new DHP lacidipine inhibited L-type calcium current, but this inhibition was very persistent and never reversed, even after prolonged washout, in a typical perforated patch-clamp experiment (less than or equal to 2h). Like that of other DHPs, the potency of lacidipine block increases at more depolarizing holding potentials (HPs). The time needed to inhibit 50% (t1/2) of L-type calcium current was decreased by increasing lacidipine concentration; t1/2 was 22 +/- 3 s with addition of 1 mu M lacidipine; this concentration inhibited less than or equal to 86 +/- 1% of the L-type current. The persistent blocking induced by lacidipine can be explained in terms of a strong interaction of the drug with the membrane phospholipids, as a consequence of the enhanced hydrophobicity and specific location of this molecule with respect to other DHPs.