title: In vitro effects of toxogonin, HI-6 and HLö-7 on the release of [3H]acetylcholine from peripheral cholinergic nerves in rat airway smooth muscle.
abstract: The purpose of this work was to evaluate the possible non-reactivating effects of toxogonin (1,1'[oxybis(methylene)]bis[4-[hydroxyimino) methyl]pyridinium]-dichloride), HI-6 (1-[[[(4-aminocarbonyl)pyridinio] methoxy]methyl]-2-[(hydroxyimino)methyl]pyridinium-dichloride) and HLö-7 (pyridinium, 1-[[[4-(aminocarbonyl)pyridino]methoxy] methyl]-2,4-bis-[(hydroxyimino)methyl]diiodide) on the release of acetylcholine from cholinergic nerves. The oximes have been tested in our rat bronchial smooth muscle model, with respect to the effects of oximes on the K+ (51 mM)-evoked release of [3H]acetylcholine in the presence and absence of soman (1.0 microM). Toxogonin (100 microM) had no effect on the K(+)-evoked release of [3H]acetylcholine in the presence or absence of soman (1.0 microM). Similar results were found for HI-6 (100 microM). In contrast, HLö-7 (100 microM) enhanced the K(+)-evoked release of [3H]acetylcholine in the absence of soman. In the presence of soman HLö-7 did not alter the release of [3H]acetylcholine induced by K+ stimulation. The potentiating effect of HLö-7 on the release of [3H]acetylcholine could be blocked by the L-, N- and P-Ca2+ channel blockers verapamil (0.1 and 1.0 microM), omega-conotoxin GVIA (1.0 microM) and omega-agatoxin IV-A (0.2 microM), respectively. Muscarinic receptor antagonists (atropine (10 microM), pirenzepine (M1) (1.0 microM) and methoctramine (M2) (1.0 microM) had no effects on the HLö-7 (100 microM)-enhanced release of [3H]acetylcholine. Protein kinase inhibitors (H-7 (20 microM), calphostin C (1.0 microM) and KN-62 (10 microM) inhibited the HLö-7 (100 microM)-enhanced K(+)-evoked release of [3H]acetylcholine. The results showed that only HLö-7 had a direct enhancing effect on the release of acetylcholine through activation or opening of Ca2+ channels and a subsequent protein phosphorylation in the nerve terminal.
authors.affiliation: Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Aas
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D009768:Obidoxime Chloride / Q000494:pharmacology*; D010091:Oximes; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011726:Pyridinium Compounds; C058577:HLo 7; D009768:Obidoxime Chloride; D012999:Soman; D011494:Protein Kinases; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C022870:asoxime chloride; D000109:Acetylcholine