Mechanism of long-lasting block of ganglion nicotinic receptors by mono-ammonium compounds with long aliphatic chain

• Published in: Journal of the autonomic nervous system Vol. 48; no. 3; pp. 231 - 240
• Main Authors: Kurenny, Dmitry E., Selyanko, Alexander A., Derkach, Victor A., Gmiro, Valery E., Skok, Vladimir I.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.08.1994; Elsevier Science
• Subjects: Acetylcholine; Acetylcholine - pharmacology; Animals; Biological and medical sciences; Channel blocking agents; Cholinergic system; Electrophysiology; Ganglia, Spinal - cytology; Ganglia, Spinal - drug effects; Ganglionic Blockers - pharmacology; In Vitro Techniques; Iontophoresis; Kinetics; Medical sciences; Membrane Potentials - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotinic Antagonists; Patch clamp; Pharmacology. Drug treatments; Piperidines - pharmacology; Propylamines - pharmacology; Quaternary Ammonium Compounds - pharmacology; Rat sympathetic neurone; Rats; Patch clamp; Acetylcholine; Rat sympathetic neurone; Channel blocking agents; Rat; Rodentia; Superior cervical ganglion; Cholinergic receptor; Vertebrata; Mammalia; Autonomic nervous system; Ammonium compound; Animal; Neurotransmitter; Mechanism of action; Nicotinic receptor; Sympathic nervous system
• ISSN: 0165-1838; 1872-7476
• DOI: 10.1016/0165-1838(94)90052-3

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 μM) 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 ≥ 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 μM) or trimethaphan (30 μM), a competitive antagonist of ACh in ganglia. Neither the short-chain MAC (IEM-1405, 100 μM) nor ACh (100 μM) 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 μM). 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 alipathic chain and (ii) a slow reversible block of the nAChR channel with the MAC's ammonium head.