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Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells
Author(s) -
Gandía Luis,
Villarroya Mercedes,
Lara Baldomero,
Olmos Virginia,
Gilabert JuanAntonio,
LÓPEZ Manuela G.,
MartínezSierra Rafael,
Borges Ricardo,
García Antonio G.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15213.x
Subject(s) - nicotinic agonist , chemistry , endocrinology , chromaffin cell , medicine , channel blocker , acetylcholine , agonist , receptor , pharmacology , catecholamine , adrenal medulla , biology , biochemistry , calcium
1 Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide‐spectrum Ca 2+ channel blocker in bovine adrenal chromaffin cells. 2 45 Ca 2+ uptake into chromaffin cells stimulated with high K + (70 mM, 1 min) was blocked by otilonium with an IC 50 of 7.6 μ m . The drug inhibited the 45 Ca 2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC 50 = 0.096 μ m ). 3 Whole‐cell Ba 2+ currents (I Ba ) through Ca 2+ channels of voltage‐clamped chromaffin cells were blocked by otilonium with an IC 50 of 6.4 μ m , very close to that of K + ‐evoked 45 Ca 2+ uptake. Blockade developed in 10–20 s, almost as a single step and was rapidly and almost fully reversible. 4 Whole‐cell nicotinic AChR‐mediated currents (250 ms pulses of 100 μ m DMPP) applied at 30 s intervals were blocked by otilonium in a concentration‐dependent manner, showing an IC 50 of 0.36 μ m . Blockade was induced in a step‐wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5 In experiments with recordings in the same cells of whole‐cell I DMPP , Na + currents ( I Na) and Ca 2+ currents ( I Ca ), 1 μ m otilonium blocked 87% I DMPP , 7% I Na and 13% I Ca . 6 Otilonium inhibited the K + ‐evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC 50 of 10 μ m , very close to the IC 50 for blockade of K + ‐induced 45 Ca 2+ uptake and I Ba . 7 Otilonium inhibited the secretory responses induced by 10 s pulses of 50 μ m DMPP with an IC 50 of 7.4 nM. Hexamethonium blocked the DMPP‐evoked responses with an IC 50 of 29.8 μ m , 4,000 fold higher than that of otilonium. 8 In conclusion, otilonium is a potent blocker of nicotinic AChR‐mediated responses. The drugs also blocked various subtypes of neuronal voltage‐dependent Ca 2+ channels at a considerably lower potency. Na + channels were unaffected by otilonium. This extraordinary potency of otilonium in blocking nicotinic AChR, unrecognised until now, might account in part for its well known spasmolytic effects.