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Mechanism of soman-induced contractions in canine tracheal smooth muscle
M Adler1, D H Moore, M G Filbert
1Neurotoxicology Branch, Pathophysiology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010.
Abstract:
The actions of the irreversible organophosphorus cholinesterase (ChE) inhibitor soman were investigated on canine tracheal smooth muscle in vitro. Concentrations of soman greater than or equal to 1 nM increased the amplitude and decay of contractions elicited by electric field stimulation. The effect on decay showed a marked dependence on stimulation frequency, undergoing a 2.4-fold increase between 3 and 60 Hz. Soman also potentiated tensions due to bath applied acetylcholine (ACh). Little or no potentiation was observed for contractions elicited by carbamylcholine, an agonist that is not hydrolyzed by ChE. Concentration of soman greater than or equal to 3 nM led to the appearance of sustained contractures. These contractures developed with a delayed onset and were well correlated with ChE activity. Alkylation of muscarinic receptors by propylbenzilylcholine mustard antagonized the actions of soman on both spontaneous and electrically-evoked muscle contractions. The results are consistent with a mechanism in which the toxic actions of soman are mediated by accumulation of neurally-released ACh secondary to inhibition of ChE activity. An important factor in this accumulation is suggested to be the buffering effect of the muscarinic receptors on the efflux of ACh from the neuroeffector junction.
Insights
The organophosphorus cholinesterase inhibitor soman causes canine tracheal smooth muscle contractions by increasing acetylcholine. This toxic action is linked to soman
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Organophosphorus compounds like soman are potent cholinesterase (ChE) inhibitors.
- Cholinesterase inhibitors disrupt neurotransmission by increasing acetylcholine (ACh) levels.
- Canine tracheal smooth muscle is a relevant model for studying neurogenic contractions.
Purpose of the Study:
- To investigate the in vitro effects of soman on canine tracheal smooth muscle.
- To elucidate the mechanism underlying soman's actions on smooth muscle contractility.
- To determine the role of cholinesterase inhibition and muscarinic receptors in soman toxicity.
Main Methods:
- In vitro study using canine tracheal smooth muscle preparations.
- Exposure to varying concentrations of soman.
- Assessment of muscle contractions induced by electric field stimulation and exogenous agonists (acetylcholine, carbamylcholine).
- Measurement of cholinesterase activity and receptor blockade using propylbenzilylcholine mustard.
Main Results:
- Soman (≥1 nM) increased contraction amplitude and decay, with decay dependent on stimulation frequency.
- Soman potentiated acetylcholine-induced contractions but not carbamylcholine-induced ones.
- Soman (≥3 nM) induced sustained contractures correlated with ChE inhibition.
- Muscarinic receptor blockade antagonized soman's effects on muscle contractions.
Conclusions:
- Soman's toxic actions on tracheal smooth muscle are mediated by cholinesterase inhibition and subsequent accumulation of neurally released ACh.
- Muscarinic receptors may buffer acetylcholine efflux at the neuroeffector junction, contributing to ACh accumulation.
- These findings highlight the complex interplay between ChE inhibition, ACh dynamics, and receptor interactions in soman toxicity.