Amide-type local anesthetics action on the sarcoplasmic reticulum Ca-ATPase from fast-twitch skeletal muscle

Abstract

Myotoxic effects related to intracellular Ca(2+) disturbances have been reported for local anesthetics. Such effects might derive from Ca-ATPase dysfunction. The aim of this work was to describe the effect of lidocaine and bupivacaine on the sarcoplasmic reticulum (SR) Ca-ATPase from fast-twitch skeletal muscle and to identify the affected steps of the enzyme's cycle. SR sealed vesicles were isolated from rabbit fast-twitch muscles by ultracentrifugation. The effect of the anesthetics on Ca-ATPase activity was assessed with a colorimetric method and Ca(2+) binding, uptake, phosphorylation of the enzyme by ATP, Ca(2+) dissociation kinetics and phosphoenzyme formation and decomposition levels were tested with radioisotopic methods. Lidocaine and bupivacaine inhibited Ca-ATPase activity with half-maximal inhibitory concentrations (Ki) of 25.3 and 31.4 mM, respectively, and the steady-state Ca(2+) transport ability with Ki values of 33.6 and 46.5 mM, decreasing the maximal transport rate without modification of the Ca(2+) or ATP affinity for the enzyme. This is consistent with an absence of competition for the transport and catalytic sites. The anesthetics did not inhibit Ca(2+) binding but inhibited the phosphorylation partial reactions. Ca(2+) dissociation kinetics was not affected, but the phosphoenzyme levels were decreased, and the decomposition rate of the phosphoenzyme became faster in the presence of the anesthetics. It is concluded that lidocaine and bupivacaine at concentrations available in pharmaceutical formulations for clinical medical and dental uses inhibit the SR Ca-ATPase through inhibition of key phosphorylation steps of the enzymatic cycle.

GaAs laser therapy reestablishes the morphology of the NMJ and nAChRs after injury due to bupivacaine

“…It is possible that the myonecrosis arising from bupivacaine promotes sarcolemmal injury, allowing excessive entry of calcium. This ion leads to hypercontraction of myofibrils [27,54,55], increasing the quantity of intracellular free radicals due to the generation of oxidative stress, culminating in mitochondrial degeneration [39]. Considering that proteins in the synaptic region are transmembranic, alterations in the plasma membrane of the fiber and its sarcoplasm directly affect the muscle synapse [21], such that alterations in the NMJs can be considered responses to the pathological process of myonecrosis [29].…”

Local anaesthetic-induced myotoxicity in regional anaesthesia: a systematic review and empirical analysis

“…15,30,33e38,41,43 These mechanisms are thought to be related to LA interference with ATP phosphorylation. 37,41,43 A surge in myoblastic apoptosis is the sequela of LA exposure. 1,19e23,25e29 Apoptosis is triggered by increased Back muscles, 37 back leg muscles, 43 breast muscle, 28 C2C12 cell line, 18e23,25,26 oesophageal muscle, 24 extensor digitorum longus muscle, 1,24,35,36 first lumbrical of foot muscle, 27 flexor digitorum brevis muscle, 24 hind leg muscles 15,32,33,42 masseter muscle, 34,37,41 medial pterygoid, 37,38,41 psoas muscle 40 quadriceps muscle, 29 skeletal muscle, 13,30,31 soleus muscle, 1,24 temporalis muscle, 39 tibialis anterior muscle 1 Humans, 13,29 mice, 1,18e26,35,36 quail, 28 rats, 27 pigs, 42 rabbits 15,30e34,37e41,43 Articaine, 38 benzocaine, 32 bupivacaine, 1,13,18e21,23e29,34,35,41e43 bupivacaine S and R enantiomers, 35,36 bupivacaine with caffeine, 1 bupivacaine with dantrolene...…”