The eupnoic breathing rhythm in mammals is generated and regulated in a respiratory network localised in the ponto-medullary brainstem. The generated breathing pattern is dependent on the coordinated activity of cranial and spinal motor outputs to both ventilate the lungs and to adjust respiratory airflow by regulating upper-airway resistance. Disturbances in the eupnoeic breathing-pattern are life threatening and can cause death by suffocation. Intoxication with organophosphorus compounds (OP) such as pesticides or nerve agents can cause such serious poisonings due to the inhibition of the enzyme acetyl cholinesterase (AChE) and a resulting accumulation of acetylcholine (ACh) along with a peripheral and central induced respiratory arrest. The aim of this study was to test if this central apnoe is probably intensified by the peripher induced hypoxia using the in situ arterially perfused brainstem preparation of rat. This preparation allows investigation of complex network function and assesses the effects of the central cholinergic modulation of breathing before and after systemically administered Carbachol (ACh-agonist) or Crotylsarin (OP). To monitor respiratory output phrenic and vagal nerve activity (PNA, VNA) was recorded. To simulate peripher collapse and breathing arrest the perfusion pressure was stopped for 1 minute and increased afterwards gradually. After systemic application of Carbachol the eupnoeic-like breathing pattern was disturbed and transferred from ramping inspiratory to a decrementing inspiratory activity. The changes in the discharge pattern were accompanied by a prolongation of Ti (time of inspiration) and a reduction of the frequency. Also a rather tonic-like VNA was observed. During hypoxia a central apnoe of several minutes occurred. But afterward a fairly normal breathing pattern recovered gradually and spontaneously. The application of Crotylsarin led to an apnoe of several seconds accompanied by a tonic firing vagus nerve. Thereafter a decrementing PNA including un-coordinated VNA was observed for several minutes. After spontaneous recovering of PNA, a central apnoe of several minutes was induced by hypoxia. But again only transient, one hour later a nearly normal breathing pattern was recorded. Analysis of the AChE-activity after the experiments showed a complete inhibition of the enzyme, suggesting that the recovery of respiration was not caused by spontaneous reactivation of AChE-activity. The experiments demonstrate the central effects of OP intoxication to the central breathing activity within the functional respiratory network in situ and the impact of accompanied periphery hypoxia to these effects. It can be speculated whether an intrinsic central protective mechanism compensated for the disturbed activity of the cholinergic system.

Supported by a Contract-Research-Project for the Bundeswehr Medical Service.