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 microM nimodipine reversibly inhibited < or = 80% of L-type calcium channels when applied in the external bath solution. At concentrations of 0.1-1 microM, 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 (< or = 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 microM lacidipine; this concentration inhibited < or = 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.
Gambale
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F
Istituto di Cibernetica e Biofisica, CNR, Genova, Italy.
Dellacasagrande
F
F
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C060285:lacidipine; D002118:Calcium