Sepsis Strengthens Antagonistic Actions of Neostigmine on Rocuronium in a Rat Model of Cecal Ligation and Puncture

Abstract

Background:The antagonistic actions of anticholinesterase drugs on non-depolarizing muscle relaxants are theoretically related to the activity of acetylcholinesterase (AChE) in the neuromuscular junction (NMJ). However, till date the changes of AChE activity in the NMJ during sepsis have not been directly investigated. We aimed to investigate the effects of sepsis on the antagonistic actions of neostigmine on rocuronium (Roc) and the underlying changes of AChE activity in the NMJ in a rat model of cecal ligation and puncture (CLP).Methods:A total of 28 male adult Sprague-Dawley rats were randomized to undergo a sham surgery (the sham group, n = 12) or CLP (the septic group, n = 16). After 24 h, the time-response curves of the antagonistic actions of 0.1 or 0.5 μmol/L of neostigmine on Roc (10 μmol/L)-depressed diaphragm twitch tension were measured. Meanwhile, the activity of AChE in the NMJ was detected using a modified Karnovsky and Roots method. The mRNA levels of the primary transcript and the type T transcript of AChE (AChET) in the diaphragm were determined by real-time reverse transcription-polymerase chain reaction.Results:Four of 16 rats in the septic group died within 24 h. The time-response curves of both two concentrations of neostigmine in the septic group showed significant upward shifts from those in the sham group (P < 0.001 for 0.1 μmol/L; P = 0.009 for 0.5 μmol/L). Meanwhile, the average optical density of AChE in the NMJ in the septic group was significantly lower than that in the sham group (0.517 ± 0.045 vs. 1.047 ± 0.087, P < 0.001). The AChE and AChET mRNA expression levels in the septic group were significantly lower than those in the sham group (P = 0.002 for AChE; P = 0.001 for AChET).Conclusions:Sepsis strengthened the antagonistic actions of neostigmine on Roc-depressed twitch tension of the diaphragm by inhibiting the activity of AChE in the NMJ. The reduced content of AChE might be one of the possible causes of the decreased AChE activity in the NMJ.

Sepsis decreases the activity of acetylcholinesterase by reducing its expression at the neuromuscular junction

“…It may be hypothesized that the majority of AChE at the NMJ originates from muscle fibers (6). In the present study, it was demonstrated that alterations in the expression of AChE at the NMJ lagged behind the alterations in its overall content in the whole diaphragm, and the expression levels between the NMJ and the whole diaphragm were not positively correlated.…”

“…Notably, on day 1 post-CLP, AChE activity at the NMJ was significantly decreased, whereas its expression was only slightly reduced. One possible explanation for this finding is that the level of AChE activity at the NMJ during the acute period of sepsis may be partially inhibited by factors such as severe acidosis (6,12), hypochlorous acid (13,14) or other unknown factors.…”

“…AChE activity at the NMJ in the ventral costal region of the left hemidiaphragm was detected according to a modified Karnovsky and Roots method (11). The detailed procedure was described in our previous study (6). Brown staining indicated AChE activity, which was recorded as the sum of the individual measurements of AChE activity observed at each NMJ.…”

“…By inhibiting the activity of AChE at the NMJ, these drugs decrease the hydrolysis of acetylcholine, thus increasing its concentration to overcome the effects of muscle relaxants (5). Our previous study demonstrated that acute sepsis at 24 h was able to strengthen the antagonistic action of neostigmine on rocuronium by inhibiting the activity of AChE at the NMJ in a rat cecal ligation and puncture (CLP) model (6). These results indicate that, in clinical practice, when used to reverse residual neuromuscular block, the dosage of neostigmine can be appropriately reduced in patients with sepsis, and consequently, the incidence of its side effects will decrease.…”

Placental expression of AChE, α7nAChR and NF-κB in patients with preeclampsia

“…Some mechanisms must work to regulate the activity of AChE to ensure the normal functioning of ACh. Study has shown that serum AChE activity decreased in severe trauma, burn injury and sepsis [15,16]. Cholinergic anti-inflammatory pathway that regulates neural and immune system may play a role by downregulating AChE to generate the compensatory anti-inflammatory response, thus promoting further release of ACh by vagus nerve.…”