Mechanism of long-lasting block of ganglion nicotinic receptors by mono-ammonium compounds with long aliphatic chain.
The effect of long-chain mono-ammonium compounds (long-chain MACs), t-butyldecylammonium (IEM-1078), 2,2,6,6-tetramethyldecylpiperidine (IEM-1559), and diisopropyldecylammonium (IEM-1194), on nicotinic acetylcholine receptors (nAChRs) was studied in sympathetic ganglion neurons using the patch clamp method. Long-chain MACs (1-10 microM) strongly inhibited acetylcholine (ACh)-induced current (ACh-current); the block persisted for hours after washing the drugs out. Short-chain MACs had a much weaker and completely reversible blocking effect. Suppression of ACh-current by MACs was dose- and voltage-dependent; it was absent at low ACh doses or at potentials > or = 60 mV and increased with higher ACh doses or hyperpolarization. The second of two ACh-currents induced by paired application of ACh was inhibited by long-chain MACs more strongly than the first. This use-dependent block also persisted for hours after washing the drugs out. Additional inhibition of the second ACh-current was reduced by lengthening the time interval between ACh applications in the pair. Time constants of the recovery of the second ACh-current in the presence and after washing out of long-chain MACs were similar, ranging from 45 to 140 s at -50 mV for different long-chain MACs, and decreased with de- or hyperpolarization. The use-dependent block produced by long-chain MACs could be prevented by another long-chain MAC with a small ammonium head (IEM-1195, 75-100 microM) or trimethaphan (30 microM), a competitive antagonist of ACh in ganglia. Neither the short-chain MAC (IEM-1405, 100 microM) nor ACh (100 microM) could exert this protective effect. Long-chain MACs did not exert any use-, dose- or voltage-dependent suppression of ACh-current when applied intracellularly. Single-channel conductance was not affected by IEM-1194 (3-10 microM). We suggest that inhibition of ACh-current by long-chain MACs is accounted for by (i) a long-lasting, apparently irreversible, binding of the drug near the channel of nAChR via its long aliphatic chain and (ii) a slow reversible block of the nAChR channel with the MAC's ammonium head.
Kurenny
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Department of Autonomic Nervous System Physiology, A.A. Bogomoletz Institute of Physiology, Kiev, Ukraine.
Selyanko
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Derkach
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Gmiro
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Skok
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D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D005730:Ganglionic Blockers / Q000494:pharmacology*; D066298:In Vitro Techniques; D007478:Iontophoresis; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018733:Nicotinic Antagonists; D010880:Piperidines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats
D005730:Ganglionic Blockers; C090123:IEM 1078; D018733:Nicotinic Antagonists; D010880:Piperidines; D011437:Propylamines; D000644:Quaternary Ammonium Compounds; C060661:N-decyl-N,N-diisopropylamine; C090124:2,2,6,6-tetramethyldecylpiperidine; D000109:Acetylcholine