In the present study, the effect of the blockade of membrane calcium channels activated by intracellular Ca2+ store depletion on basal and depolarization-induced [H-3]norepinephrine ([H-3]NE) release from SH-SY5Y human neuroblastoma cells was examined. The second-generation H-1 receptor blockers astemizole, terfenadine, and loratadine, as well as the first-generation compound hydroxyzine, inhibited [H-3]NE release induced by high extracellular K+ concentration ([K+](e)) depolarization in a concentration-dependent manner (the IC(50)s were 2.3, 1.7, 4.8, and 9.4 muM, respectively). In contrast, the more hydrophilic second-generation H-1 receptor blocker cetirizine was completely ineffective (0.1-30 muM). The inhibition of high [K+](e)-induced [H-3]NE release by H-1 receptor blockers seems to be related to their ability to inhibit Ca2+ channels activated by Ca-i(2+) store depletion (SOCs). In fact, astemizole, terfenadine, loratadine, and hydroxyzine, but not cetirizine, displayed a dose-dependent inhibitory action on the increase in intracellular Ca2+ concentrations ([Ca2+](i)) obtained with extracellular Ca2+ reintroduction after Ca-i(2+) store depletion with thapsigargin (1 muM), an inhibitor of the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA) pump. The rank order of potency for SOC inhibition by these compounds closely correlated with their inhibitory properties on depolarization-induced [H-3]NE release from SH-SY5Y human neuroblastoma cells. Nimodipine (1 muM) plus omega -conotoxin (100 nM) did not interfere with the present model for SOC activation. In addition, the inhibition of depolarization-induced [H-3]NE release does not seem to be attributable to the blockade of the K+ currents carried by the K+ channels encoded by the human Ether-a-Gogo Related Gene (I-HERG) by these antihistamines. In fact, whole-cell voltage-clamp experiments revealed that the IC50 for astemizole-induced hERG blockade is about 300-fold lower than that for the inhibition of high K+-induced [H-3]NE release. Furthermore, current-clamp experiments in SH-SY5Y cells showed that concentrations of astemizole (3 muM) which were effective in preventing depolarization-induced [H-3]NE release were unable to interfere with the cell membrane potential under depolarizing conditions (100 mM [K+](e)), suggesting that hERG K+ channels do not contribute to membrane potential control during exposure to elevated [K+](e). Collectively, the results of the present study suggest that, in SH-SY5Y human neuroblastoma cells, the inhibition of SOCs by some second-generation antihistamines can prevent depolarization-induced neurotransmitter release. (C) 2001 Elsevier Science Inc. All rights reserved.
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