title: Blockade by NNC 55-0396, mibefradil, and nickel of calcium and exocytotic signals in chromaffin cells: implications for the regulation of hypoxia-induced secretion at early life.
abstract: Adrenal chromaffin cells (CCs) express high-voltage activated calcium channels (high-VACCs) of the L, N and PQ subtypes; in addition, T-type low-VACCs are also expressed during embryo and neonatal life. Effects of the more frequently used T channel blockers NNC 55-0396 (NNC), mibefradil, and Ni2+ on the whole-cell Ba2+ current (IBa), the K+-elicited [Ca2+]c transients and catecholamine secretion have been studied in adult bovine CCs (BCCs) and rat embryo CCs (RECCs). NNC, mibefradil, and Ni2+ blocked BCC IBa with IC50 of 1.8, 4.9 and 70 μM, while IC50 to block IBa in RECCs were 2.1, 4.4 and 41 μM. Pronounced blockade of K+-elicited [Ca2+]c transients and secretion was also elicited by the three agents. However, the hypoxia-induced secretion (HIS) of catecholamine in RECCs was blocked substantially (75%) with thresholds concentrations of NCC (IC20 to block IBa); this was not the case for mibefradil and Ni2+ that required higher concentrations to block the HIS response. Thus, out of the three compounds, NNC seemed to be an adequate pharmacological tool to discern the contribution of T channels to the HIS response, without a contamination with high-VACC blockade.
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Morales
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Fernando Padín
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vestring
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Diego C
authors.initials: DC
authors.lastname: Musial
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Antonio-Miguel G
authors.initials: AM
authors.lastname: de Diego
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain. Electronic address: agg@uam.es.
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001464:Barium / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D020748:Mibefradil / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002395:Catecholamines; D003521:Cyclopropanes; D009281:Naphthalenes; C484287:NNC 55-0396; D001464:Barium; D020748:Mibefradil; D009532:Nickel; D011188:Potassium; D002118:Calcium
keywords: Bovine chromaffin cells; Calcium; Hypoxia; NNC 55-0396; NNC 55-0396 (CID: 11957578); Rat embryo chromaffin cells; Voltage activated calcium channels