Dichlorvos exposure to the Kölliker-fuse nuclei is sufficient but not necessary for OP induced apnea.
Patients exposed to organophosphate (OP) compounds demonstrate a central apnea. The Kölliker-fuse nuclei (KF) are cholinergic nuclei in the brainstem involved in central respiratory control. We hypothesize that exposure of the KF is both necessary and sufficient for OP induced central apnea. We performed an animal study of acute OP exposure. Anesthetized and spontaneously breathing Wistar rats (n=24) were exposed to a lethal dose of dichlorvos using three experimental models. Experiment 1 (n=8) involved systemic OP poisoning using subcutaneous (SQ) 2,2-dichlorovinyl dimethyl phosphate (dichlorvos) at 100mg/kg or 3× LD50. Experiment 2 (n=8) involved isolated poisoning of the KF using stereotactic microinjections of dichlorvos (625μg in 50μl) into the KF. Experiment 3 (n=8) involved systemic OP poisoning with isolated protection of the KF using SQ dichlorvos (100mg/kg) and stereotactic microinjections of organophosphatase A (OpdA), an enzyme that degrades dichlorvos. Respiratory and cardiovascular parameters were recorded continuously. Animals were followed post exposure for 1h or until death. There was no difference in respiratory depression between animals with SQ dichlorvos and those with dichlorvos microinjected into the KF. Despite differences in amount of dichlorvos (100mg/kg vs. 1.8mg/kg) and method of exposure (SQ vs. CNS microinjection), 10min following dichlorvos both groups (SQ vs. microinjection respectively) demonstrated a similar percent decrease in respiratory rate (51.5 vs. 72.2), minute ventilation (49.2 vs. 68.8) and volume of expired gas (17.5 vs. 0.0). Animals with OpdA exposure to the KF during systemic OP exposure demonstrated less respiratory depression, compared to SQ dichlorvos alone (p<0.04). No animals with SQ dichlorvos survived past 25min post exposure, compared to 50% of animals with OpdA exposure to the KF. In conclusion, exposure of the KF is sufficient but not necessary for OP induced apnea. Protection of the KF during systemic OP exposure mitigates OP induced apnea.
Department of Emergency Medicine, University of Massachusetts, Worcester, MA 01655, United States. Electronic address: Romolo.gaspari@umassmemorial.org.
Romolo J
RJ
Gaspari
Courtney
C
Dunn
D000704:Analysis of Variance; D000818:Animals; D001049:Apnea / Q000139:chemically induced*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004006:Dichlorvos / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D010755:Organophosphates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects; D012125:Respiratory Center / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D004006:Dichlorvos
Central apnea; Kolliker-fuse; Organophosphatase; Organophosphate; Respiratory failure