EFFECT OF PYRIDOSTIGMINE PRETREATMENT, HI-6 AND TOXOGONIN(R) 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 ]methoxy ]methyl]-2[(hydroxyimino)methyl]pyridinium dichloride) or Toxogonin(R) s[4-[(hydroxyimino)methyl]-pyridinium]dichloride). In vivo pretreatme nt with pyridostigmine was achieved by subcutaneous (s. c.) implantati on 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 e x vivo cholinergic tracheal smooth muscle response increased during th e first 60 min after soman exposure in animals pretreated with pyridos tigmine. The amplitude of the contraction response in pyridostigmine p retreated 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) activ ity in plasma, but not in trachea and lung. Intraperitoneal (i. p.) in jection of HI-6 or Toxogonin(R) (50 mg/kg), immediately after 10 min i nhalation exposure to soman, also significantly improved the ex vivo c holinergic contraction response of the trachea (decapitation 15 min af ter oxime administration). The recovery of the physiological response with Toxogonin(R) was, however, not stable. HI-6 was superior to Toxog onin(R) with respect to the initial airway contraction response, and t he response increased up to a stable level not significantly different from control. There was no significant reactivation of the ChE activi ty after treatment with the oximes. Combination of pyridostigmine pret reatment and oxime treatment enhanced the recovery of the tracheal con traction response and the ChE activity in the trachea compared to trea tment with oximes alone. Experiments with in vitro exposure to soman f ollowed by washout and addition of oximes were also performed. The res ults show that both oximes effectively re-establish the tracheal respo nse when administered 10 min, but not 30 min, after soman. The effect of Toxogonin(R) was, however, contrary to the effect of HI-6, not stab le. 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 Tox ogonin(R) after 10 min inhalation exposure to soman.