Ventilatory effects of low-dose paraoxon result from central muscarinic effects.
Paraoxon induces respiratory toxicity. Atropine completely reversed parathion- and paraoxon-induced respiratory toxicity. The aim of this study was to assess the peripheral or central origin of ventilatory effects of low-dose paraoxon. Male Sprague-Dawley rats were given paraoxon 0.215 mg/kg subcutaneously and treated with either atropine (10 mg/kg sc) or ascending doses of methylatropine of 5.42 (equimolar to that of atropine), 54.2, and 542 mg/kg administered subcutaneously 30 min after paraoxon. Ventilation at rest was assessed using whole-body plethysmography and rat temperature using infra-red telemetry. Results are expressed as mean+/-SE. Statistical analysis used two-way ANOVA for repeated measurements. Paraoxon induced a significant decrease in temperature 30 min after injection lasting the 90 min of the study period. This effect was partially corrected by atropine, but not by methylatropine whatever the dose. Paraoxon induced a decrease in respiratory rate resulting from an increase in expiratory time associated with an increase in tidal volume. Atropine completely reversed the ventilatory effects of low-dose paraoxon while the equimolar dose of methylatropine had no significant effects. The 54.2 and 542 mg/kg doses of methylatropine had no significant effects. Atropine crosses the blood-brain barrier and reverses peripheral and central muscarinic effects. In contrast, methylatropine does not cross the blood-brain barrier. Atropine completely reversed the ventilatory effects of low-dose paraoxon, while methylatropine had no significant effects at doses up to 100-fold the equimolar dose of atropine. We conclude that the ventilatory effects of low-dose paraoxon are mediated by disrupted muscarinic signaling in the central nervous system.
Houze
Pascal
P
Toxicology Laboratory, Faculty of Pharmacy, 75006 Paris, France.
Pronzola
Laetita
L
Kayouka
Maya
M
Villa
Antoine
A
Debray
Marcel
M
Baud
Frederic J
FJ
D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000493:pharmacokinetics / Q000494:pharmacology; D001286:Atropine Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D010261:Paraoxon / Q000633:toxicity*; D010276:Parasympatholytics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010993:Plethysmography, Whole Body; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012119:Respiration / Q000187:drug effects*; D012129:Respiratory Function Tests / Q000379:methods; D015398:Signal Transduction; D013686:Telemetry / Q000379:methods; D013990:Tidal Volume / Q000187:drug effects; D013997:Time Factors
D001286:Atropine Derivatives; D007306:Insecticides; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D001285:Atropine; C006649:methylatropine; D010261:Paraoxon