Lowered sarcoendoplasmic reticulum calcium uptake and diaphragmatic SERCA1 expression contribute to diaphragmatic contractile and relaxation dysfunction in septic rats / 南方医科大学学报

<p><b>OBJECTIVE</b>The explore the mechanism responsible for diaphragmatic contractile and relaxation dysfunction in a rat model of sepsis.</p><p><b>METHODS</b>Thirty-six adult male Sprague-Dawley rats were randomized equally into a sham-operated group and two model groups of sepsis induced by cecal ligation and puncture (CLP) for examination at 6 and 12 h following CLP (CLP-6 h and CLP-12 h groups). The parameters of diaphragm contractile and relaxation were measured, and the calcium uptake and release rates of the diaphragmatic sarcoendoplasmic reticulum (SR) and the protein expressions of SERCA1, SERCA2 and RyR in the diaphragmatic muscles were determined.</p><p><b>RESULTS</b>The half-relaxation time of the diaphragm was extended in both the CLP-6 h and CLP-12 h groups with significantly reduced maximum tension declinerate and the peek uptake rate of SERCA (P<0.01). Diaphragmatic maximum twitch force development rate, the maximal twitch, tetanus tensions and the peek release rate of SR decreased only at 12h after CLP (P<0.01). The expression levels of SERCA1 protein decreased significantly in the diaphragmatic muscles at 12h following CLP (P<0.01) while SERCA2 expression level and SERCA activity showed no significant changes.</p><p><b>CONCLUSION</b>In the acute stage of sepsis, both the contractile and relaxation functions of the diaphragm are impaired. Diaphragmatic relaxation dysfunction may result from reduced calcium uptake in the SR and a decreased level of SERCA1 in the diaphragmatic muscles.</p>

Sepsis Strengthens Antagonistic Actions of Neostigmine on Rocuronium in a Rat Model of Cecal Ligation and Puncture / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>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).</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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 AChETmRNA 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).</p><p><b>CONCLUSIONS</b>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.</p>

Dexmedetomidine May Produce Extra Protective Effects on Sepsis-induced Diaphragm Injury / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>The objective was to evaluate the protective effects of dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptor, on sepsis-induced diaphragm injury and the underlying molecular mechanisms.</p><p><b>DATA SOURCES</b>The data used in this review were mainly from PubMed articles published in English from 1990 to 2015.</p><p><b>STUDY SELECTION</b>Clinical or basic research articles were selected mainly according to their level of relevance to this topic.</p><p><b>RESULTS</b>Sepsis could induce severe diaphragm dysfunction and exacerbate respiratory weakness. The mechanism of sepsis-induced diaphragm injury includes the increased inflammatory cytokines and excessive oxidative stress and superfluous production of nitric oxide (NO). DEX can reduce inflammatory cytokines, inhibit nuclear factor-kappaB signaling pathways, suppress the activation of caspase-3, furthermore decrease oxidative stress and inhibit NO synthase. On the basis of these mechanisms, DEX may result in a shorter period of mechanical ventilation in septic patients in clinical practice.</p><p><b>CONCLUSIONS</b>Based on this current available evidence, DEX may produce extra protective effects on sepsis-induced diaphragm injury. Further direct evidence and more specific studies are still required to confirm these beneficial effects.</p>

Different sensitivities to rocuronium of the neuromuscular junctions innervated by normal/damaged facial nerves and somatic nerve in rats: the role of the presynaptic acetylcholine quantal release / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Muscles present different responses to muscle relaxants, a mechanism of importance in surgeries requiring facial nerve evoked electromyography under general anaesthesia. The non-depolarizing muscle relaxants have multiple reaction formats in the neuromuscular junction, in which pre-synaptic quantal release of acetylcholine was one of the important mechanisms. This study was to compare the pre-synaptic quantal release of acetylcholine from the neuromuscular junctions innervated by normal/damaged facial nerves and somatic nerve under the effect of rocuronium in rats in vitro.</p><p><b>METHODS</b>Acute right-sided facial nerve injury was induced by nerve crush axotomies. Both sided facial nerve connected orbicularis oris strips and tibial nerve connected gastrocnemius strips were isolated to measure endplate potentials (EPP) and miniature endplate potentials (MEPP) using an intracellular microelectrode gauge under different rocuronium concentrations. Then, the pre-synaptic quantal releases of acetylcholine were calculated by the ratios of the EPPs and the MEPPs, and compared among the damaged or normal facial nerve innervated orbicularis oris and tibial nerve innervated gastrocnemius.</p><p><b>RESULTS</b>The EPP/MEPP ratios of the three neuromuscular junctions decreased in a dose dependent manner with the increase of the rocuronium concentration. With the concentrations of rocuronium being 5 µg/ml, 7.5 µg/ml and 10 µg/ml, the decrease of the EPP/MEPP ratio in the damaged facial nerve group was greater than that in the normal facial nerve group. The decrease in the somatic nerve group was the biggest, with significant differences.</p><p><b>CONCLUSIONS</b>Rocuronium presented different levels of inhibition on the pre-synaptic quantal release of acetylcholine in the three groups of neuromuscular junctions. The levels of the inhibition showed the following sequence: somatic nerve > damaged facial nerve > normal facial nerve. The difference may be one of the reasons causing the different sensitivities to rocuronium among the muscles innervated by the normal/injured facial nerves and the somatic nerve. The results may provide some information for the proper usage of muscle relaxants in surgeries requiring electromyographic monitoring for the pre-surgically impaired facial nerves.</p>

Effects of ketamine on noradrenaline release from the locus coeruleus in rabbits / 中华麻醉学杂志

Objective To investigate the effect of ketamine on the release of norepinephrine(NE)fromlocus coeruleus in the brain of rabbits,trying to elucidate the central mechanism of cardio-vascular responseinduced by ketamine.Methods Nine healthy male New Zealand rabbits weighing 2.0-2.5 kg were used in thisstudy.A trocar(0.8 mm in diameter)was inserted into locus coeruleus using the stereotactic technique and fixed.Four days later push-pull perfusion of the brain was performed.37℃ artificial cerebrospinal fluid(aCSF)wasinfused through the trocar at 0.1 ml?min~(-1).A loading dose of ketamine 2 mg?kg~(-1) was given i.v.followed byketamine infusion at 50 ?g?kg~(-1)?min~(-1) for 20 min.The perfusate from locus coeruleus was collected before duringand after ketamine infusion every 20 min.The NE concentration of the perfusate was measured by high performanceliquid chromatography(HPLC).Results The NE concentration of perfusate from locus coeruleus increasedsignificantly after ketamine infusion from(16?3) pg～?l~(-1) to(32?4)pg??l~(-1) and returned to baseline level 20min after termination of ketamine infusion.Conclusion Ketamine increases the concentration of NE in locuscoeruleus.The increased NE release from locus coeruleus may explain the central mechanism of circulatoryexcitement induced by ketamine.