Differential mechanism of the effects of ester-type local anesthetics on sarcoplasmic reticulum Ca-ATPase

Abstract

The effect of the local anesthetics procaine and tetracaine on sarcoplasmic reticulum membranes isolated from two masticatory muscles, masseter and medial pterygoid, was tested and compared to fast-twitch muscles. The effects of the anesthetics on Ca-ATPase activity, calcium binding, uptake, and phosphorylation of the enzyme by inorganic phosphate (Pi) were tested with radioisotopic methods. Calcium binding to the Ca-ATPase was non-competitively inhibited, and the enzymatic activity decreased in a concentration-dependent manner. The inhibition of the activity depended on pH, calcium concentration, the presence of the calcium ionophore calcimycin, and the membrane protein concentration. Unlike fast-twitch membranes, the pre-exposure of the masseter and medial pterygoid membranes to the anesthetics enhanced the enzymatic activity in the absence of calcimycin, supporting their permeabilizing effect. Procaine and tetracaine also interfered with the calcium transport capability, decreasing the maximal uptake without modification of the calcium affinity for the ATPase. Besides, the anesthetics inhibited the phosphorylation of the enzyme by Pi in a competitive manner. Tetracaine revealed a higher inhibitory potency on Ca-ATPase compared to procaine, and the inhibitory concentrations were lower than usual clinical doses. It is concluded that procaine and tetracaine not only affect key steps of the Ca-ATPase enzymatic cycle but also exert an indirect effect on membrane permeability to calcium and suggest that the consequent myoplasmic calcium increase induced by the anesthetics might account for myotoxic effects, such as sustained contraction and eventual rigidity of both fast-twitch and masticatory muscles.

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

“…The most commonly used LAs were bupivacaine (n¼20), 1,13,18e29,34e36,41e43 lidocaine (n¼8), 15,22,32e34,39,41,43 tetracaine (n¼6), 15,31,32,37,40,42 and procaine (n¼5). 15,31,32,37,40 One study examined the effect of administering a combination of LAs and certain additives, such as caffeine 1 and dantrolene. 1 Each of the liposomal LA formulations 26 and microsphere formulations 22 was used by one study.…”

“…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...…”