Effect of pyridostigmine pretreatment HI-6 and toxogonin® treatment on rat tracheal smooth muscle response to cholinergic stimulation after organophosphorus inhalation exposure

The ex vivo contraction response of the rat tracheal smooth muscle was examined after 10 min in vivo inhalation of soman and/or pretreatment with pyridostigmine and/or post-exposure treatment with HI-6 ([[[(4-aminocarbonyl) pyridinio]methoxy]methyl]-2[(hydroxyimino) methyl]pyridinium dichloride) or Toxogonin® (1,1′-[oxybis-(methylene)]bis[4-[(hydroxyimino)methyl]-pyridinium] dichloride). In vivo pretreatment with pyridostigmine was achieved by subcutaneous (s. c.) implantation of an osmotic pump that delivered pyridostigmine continuously (0.01 mg/h) in the neck region of the rat 18 h before soman exposure. The ex vivo cholinergic tracheal smooth muscle response increased during the first 60 min after soman exposure in animals pretreated with pyridostigmine. The amplitude of the contraction response in pyridostigmine pretreated animals was about 60% of control, compared to 15% of control without pyridostigmine pretreatment. Pyridostigmine pretreatment also produced significant recovery of the total cholinesterase (ChE) activity in plasma, but not in trachea and lung. Intraperitoneal (i. p.) injection of HI-6 or Toxogonin® (50 mg/kg), immediately after 10 min inhalation exposure to soman, also significantly improved the ex vivo cholinergic contraction response of the trachea (decapitation 15 min after oxime administration). The recovery of the physiological response with Toxogonin® was, however, not stable. HI-6 was superior to Toxogonin® with respect to the initial airway contraction response, and the response increased up to a stable level not significantly different from control. There was no significant reactivation of the ChE activity after treatment with the oximes. Combination of pyridostigmine pretreatment and oxime treatment enhanced the recovery of the tracheal contraction response and the ChE activity in the trachea compared to treatment with oximes alone. Experiments with in vitro exposure to soman followed by washout and addition of oximes were also performed. The results show that both oximes effectively re-establish the tracheal response when administered 10 min, but not 30 min, after soman. The effect of Toxogonin® was, however, contrary to the effect of HI-6, not stable. These results correspond to the in vivo exposure experiments. The results from this study indicate that HI-6 produces a more potent and stable recovery of an ex vivo peripheral cholinergic response than Toxogonin® after 10 min inhalation exposure to soman.