title: 'Wide-spectrum Ca2+ channel antagonists': lipophilicity, inhibition, and recovery of secretion in chromaffin cells.
abstract: 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 microM 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 microM) (+)-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-thiaz olamine) 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' (omega-conotoxin GVIA) and 'wide-spectrum' (omega-conotoxin MVIIC) peptide toxins.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Lara
authors.forename: L
authors.initials: L
authors.lastname: Gandía
authors.forename: A
authors.initials: A
authors.lastname: Torres
authors.forename: R
authors.initials: R
authors.lastname: Olivares
authors.forename: R
authors.initials: R
authors.lastname: Martínez-Sierra
authors.forename: A G
authors.initials: AG
authors.lastname: García
authors.forename: M G
authors.initials: MG
authors.lastname: López
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism*; D005444:Flunarizine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D012636:Secretory Rate / Q000187:drug effects
chemical_list: D001559:Benzhydryl Compounds; D002121:Calcium Channel Blockers; D002395:Catecholamines; D010879:Piperazines; C083946:dotarizine; D005444:Flunarizine; D011188:Potassium