`Wide-spectrum Ca²⁺ channel antagonists': lipophilicity, inhibition, and recovery of secretion in chromaffin cells

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• 作者：Lara ; Baldomero ; Gandí ; a ; Luis ; Torres ; André ; s ; Olivares ; Romá ; n ; Martí ; nez-Sierra ; Rafael ; et. al.
• 关键词：Dotarizine ; Flunarizine ; Lubeluzole ; Catecholamine release ; Chromaffin cell ; Ca²⁺ channel antagonist ; `wide-spectrum'
• 刊名：European Journal of Pharmacology
• 出版年：1997
• 出版时间：April 23, 1997
• 年：1997
• 卷：325
• 期：1
• 页码：109-119
• 全文大小：944 K

文摘

Repetitive application of short depolarizing K⁺ pulses (70 mM K⁺, 2 mM Ca²⁺ Krebs-HEPES solution, for 10 s every 5 min) produced reproducible catecholamine secretory responses from superfused bovine chromaffin cells. At 10 μM for 15 min, the piperazine derivatives dotarizine, flunarizine and lidoflazine inhibited secretion by around 90 % ; cinnarizine halved the secretory response. Recovery of secretion after 30-min washout with Krebs-HEPES solution amounted to 75 % in the case of dotarizine, 8 % for flunarizine, 46 % for lidoflazine and 21 % for cinnarizine. The benzothiazol derivatives (10 μM) (+)-S-lubeluzole and R91154 (the (−)-R-enantiomer of lubeluzole) blocked the response by 75 % ; sabeluzole inhibited secretion by only 34 % and R56865 (N-[1-(4-(4-fluorophenoxy)butyl]-4-piperidinyl-N-methyl-2-benzo-thiazolamine) by 61 % . Recoveries were around 70 % in the case of these four benzothiazol derivatives. The diphenylbutyl-piperazine derivatives fluspirilene and penfluridol inhibited secretion by over 80 % ; no recovery was produced after 30-min washout. The inhibition of secretion was time dependent, as the recovery of the response was. Blockade of secretion by dotarizine and flunarizine occurred even in the absence of intermittent K⁺ stimulations of the cells. No obvious correlation was seen between the octanol/water partition coefficients of the ten compounds tested (that ranged between 6 and 4.61), the rate and extent of blockade of secretion, and the recovery of the secretory response upon washout. Rather than non-specific actions on ion channels (and secretion) due to their high lipophilicity, we believe that blockade of various Ca²⁺ channels relates to their binding properties to specific channel micro and macrodomains, as the case might be for ‘narrow' (ω-conotoxin GVIA) and ‘wide-spectrum' (ω-conotoxin MVIIC) peptide toxins. © 1997 Elsevier Science B.V.