Respiratory survival mechanisms in acetylcholinesterase knockout mouse

Abstract

Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (AChE) by organophosphates produces respiratory failure but AChE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation. AChE-/- mice presented no AChE activity but unaffected butyrylcholinesterase (BChE) activity. In vivo, bambuterol (50-500 microg/kg s.c.) decreased BChE activity peripherally but not in brain tissue and induced apnea and death in adult and neonate AChE-/- mice without affecting littermate AChE+/+ and +/- animals. In vitro, bath-applied bambuterol (1-100 microm) and tetraisopropylpyrophosphoramide (10-100 microm) decreased BChE activity in the brainstem but did not perturb central respiratory activity recorded from spinal nerve rootlets. In vitro, the cholinergic agonists muscarine (50-100 microm) and nicotine (0.5-10 microm) induced tonic activity in respiratory motoneurons and increased the frequency of inspiratory bursts in AChE+/+ and +/- animals. These effects were greatly attenuated in AChE-/- animals. The results suggest that, in mice lacking AChE, (i) BChE becomes essential for survival peripherally but plays no critical role in central rhythm-generating structures and (ii) a major adaptive mechanism for respiratory survival is the down-regulated response of central respiratory-related neurons and motoneurons to muscarinic and nicotinic agonists.

Reduced acetylcholine receptor density, morphological remodeling, and butyrylcholinesterase activity can sustain muscle function in acetylcholinesterase knockout mice

“…2E). A similar role for BChE was Twitch potentiation is considered to arise from suggested by Chatonnet et al, 7 based on their results multiple muscle action potentials following a single with the selective BChE inhibitor, bambuterol. stimulus, which may be triggered by repetitive nerve A second possible mechanism for maintenance impulses (backfiring) or from a single prolonged of tetanic tension in AChE-/-mice is downregulation endplate potential.…”

“…In AChE-inhibmice. 3 4 Downregulation of both nAChRs and ited muscle, reductions in tension during repetitive mAChRs was reported by Chatonnet et al, 7 who stimulation reflect an underlying desensitization of found reduced sensitivity to nicotine and muscarine nAChRs following accumulation of ACh.12" 7 Desenin isolated brainstem preparations of AChE--mice. sitization is suggested by the decrease in the ampliInhibition of AChE activity results in repeated tude of successive responses at 20 Hz and by tetanic binding of ACh to nAChRs, a key factor responsible fade at 200 Hz and 400 Hz (Fig.…”

“…The endplate of AChE-/" synapses apmuscle weakness, tremors, and a high susceptibility peared to be located on the surface of the muscle to seizures. 7 , 1 4 Despite these abnormalities, the abil- (Fig. 5B), rather than in synaptic troughs below the ity of these mice to survive in the absence of the muscle surface, as seen in wild-type specimens (Fig. critical enzyme AChE is remarkable and suggests 5A).…”

The Butyrylcholinesterase Knockout Mouse as a Model for Human Butyrylcholinesterase Deficiency

“…It has been reported that a 30-mg dose of bambuterol in adult humans inhibits 90% of the plasma BChE and that the bambuterol-induced BChE deficiency causes succinylcholine apnea (Bang et al, 1990). AChE Ϫ/Ϫ mice die when they are treated with bambuterol, suggesting that inhibition of BChE is responsible for their death (Xie et al, 2000;Chatonnet et al, 2003). Because no drug is completely specific in vivo, it was possible that other enzymes were also involved in this response.…”

Mechanism and Clinical Importance of Respiratory Failure Induced by Anticholinesterases

“…These and other findings suggest the involvement of both muscarinic and nicotinic receptors in the anticholinesterase-induced central respiratory failure (31).…”