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

Eur J Pharmacol. 1996 Apr 22;301(1-3):59-66. doi: 10.1016/0014-2999(96)00027-1.


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.

MeSH terms

  • Acetylcholine / metabolism*
  • Acetylcholinesterase / metabolism
  • Animals
  • Bronchi / drug effects
  • Bronchi / metabolism*
  • Butyrylcholinesterase / metabolism
  • Calcium Channel Blockers / pharmacology
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Reactivators / pharmacology*
  • Enzyme Activation / drug effects
  • Male
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / innervation
  • Muscle, Smooth / metabolism*
  • Obidoxime Chloride / pharmacology*
  • Oximes
  • Parasympathetic Nervous System / drug effects
  • Parasympathetic Nervous System / metabolism*
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / metabolism
  • Protein Kinase Inhibitors
  • Protein Kinases / metabolism
  • Pyridines / pharmacology*
  • Pyridinium Compounds / pharmacology*
  • Rats
  • Rats, Wistar
  • Soman / pharmacology


  • Calcium Channel Blockers
  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Oximes
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyridinium Compounds
  • HLo 7
  • Obidoxime Chloride
  • Soman
  • Protein Kinases
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • asoxime chloride
  • Acetylcholine