Effects of dotarizine and flunarizine on chromaffin cell viability and cytosolic Ca2+

Dotarizine (a novel piperazine derivative with antimigraine properties) and flunarizine (a Ca2+ channel antagonist) were compared concerning: first, t heir ability to cause chromaffin cell damage in vitro; second, the possible correlation of their octanol/water partition coefficients and those of ano ther 28 compounds (i.e., Ca2+ channel antagonists, blockers of histamine H- 1 receptors, antimycotics, beta-adrenoceptor antagonists, neuroleptics), wi th their ability to cause cell damage; third, their capacity to protect the cells against the damaging effects of veratridine; and fourth, their capab ilities to enhance the basal cytosolic Ca2+ concentration in fura-2-loaded single chromaffin cells, or to modify the pattern of [Ca2+](i) oscillations elicited by veratridine. After 3-4-h exposure to 1-30 mu M dotarizine, the viability of bovine adrenal chromaffin cells (measured under phase contras t or as lactate dehydrogenase, released into the medium) was similar to tha t of control, untreated cells; at 100 mu M, 80% lactate dehydrogenase relea se was produced. At 1-3 mu M flunarizine caused no cell damage; however 10 mu M caused 20% lactate dehydrogenase release and 30 and 100 mu M over 90% lactate dehydrogenase release. The time course of cell damage was considera bly faster for flunarizine, in comparison to dotarizine. Out of 30 molecule s tested (at 10 mu M), having different octanol/water partition coefficient s (log P), dotarizine was among the molecules causing no cell damage; fluna rizine caused 20% cell loss, lidoflazine and verapamil over 50% cell loss, and penfluridol, draflazine, astemizole or nifedipine over 80% cell loss. N o correlation was found between log P and cytotoxicity. Both dotarizine (10 -30 mu M) and flunarizine (3-10 mu M) provided protection against veratridi ne-induced cell death; however, at 30 mu M dotarizine afforded a pronounced protection while flunarizine enhanced the cytotoxic effects of veratridine . Dotarizine (30 mu M) (but not flunarizine) caused a prompt transient elev ation of the basal [Ca2+](i). Both compounds abolished the K+-induced incre ases of [Ca2+](i) as well as the oscillations of [Ca2+](i) induced by verat ridine. The blocking effects of dotarizine were readily reversed after wash out, while those of flunarizine were long-lasting. These differences might be relevant to the clinical use of dotarizine as an antimigraine drug. (C) 1999 Elsevier Science B.V. All rights reserved.