title: Natural compounds endowed with cholinergic or anticholinergic activity. Enhancement of acetylcholine release by a quaternary derivative of L-hyoscyamine.
abstract: New compounds that target nicotinic receptors (nAChRs) have been sought to correct disorders affecting cholinergic transmission in central and peripheral synapses. A quaternary derivate of l-hyoscyamine, phenthonium (Phen), was shown by our group to enhance the spontaneous acetylcholine (ACh) release without altering the nerve-induced transmitter release at the neuromuscular junction. The effect was unrelated to membrane depolarization, and was not induced by an increase of calcium influx into the nerve terminal. Phen also presented a competitive antimuscarinic activity and blocked noncompetitively the neuromuscular transmission. In this work we re-examined the mechanisms underlying the facilitatory actions of Phen on [(3)H]-ACh release in isolated ganglia of the guinea pig ileal myenteric plexus. Exposure of the preparations to Phen (10-50 microM) increased the release of [(3)H]-ACh by 81 to 68% over the basal. The effect was not affected by the ganglionic nAChR antagonist hexamethonium (1 nM) at a concentration that inhibited the increase of [(3)H]-ACh release induced by the nicotinic agonist dimethylphenylpiperazinium (DMPP, 30 microM). Association of Phen (10 microM) with DMPP potentiated the facilitatory effect of Phen. [(3)H]-ACh release was not altered by the muscarinic antagonists atropine (1 nM) or pirenzepine (1 microM). However, both antagonists inhibited the release of [(3)H]-ACh induced by either the muscarinic M1 agonist McN-343 (10 microM) or Phen (20 microM). The facilitatory effect of Phen was not altered by CdCl(2) (50 mM), but it was potentiated in the presence of tetraethylammonium (40 mM). The results indicate that the facilitatory action of Phen appears to be mediated by an increase of the inwardly rectifying potassium channels conductance probably related to the compound antimuscarinic activity.
authors.affiliation: Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Caden
authors.initials: C
authors.lastname: Souccar
authors.forename: Ana Lucia V
authors.initials: AL
authors.lastname: Salamanca
authors.forename: Mirtes M
authors.initials: MM
authors.lastname: Tanae
authors.forename: Maria Teresa R
authors.initials: MT
authors.lastname: Lima-Landman
authors.forename: Antonio José
authors.initials: AJ
authors.lastname: Lapa
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000737:chemistry / Q000494:pharmacology*; D001286:Atropine Derivatives / Q000737:chemistry / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005726:Ganglia, Parasympathetic / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D009197:Myenteric Plexus / Q000187:drug effects* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: C420384:1-(3',4'-dimethoxyphenyl)propene; D000475:Alkenes; D001286:Atropine Derivatives; D018680:Cholinergic Antagonists; D018727:Muscarinic Antagonists; D018722:Nicotinic Agonists; D026902:Potassium Channel Blockers; C100112:fentonium; D019789:Tetraethylammonium; D001285:Atropine; D000109:Acetylcholine
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