Interaction of bupivacaine and tetracaine with the sarcoplasmic reticulum Ca2+ release channel of skeletal and cardiac muscles

Background Although various local anesthetics can cause histologic damage t o skeletal muscle when injected intramuscularly, bupivacaine appears to hav e an exceptionally high rate of myotoxicity, Research has suggested that an effect of bupivacaine on sarcoplasmic reticulum Ca2+ release is involved i n its myotoxicity, but direct evidence is lacking. Furthermore, it is not k nown whether the toxicity depends on the unique chemical characteristics of bupivacaine and whether the toxicity is found only in skeletal muscle. Methods: The authors studied the effects of bupivacaine and the similarly l ipid-soluble local anesthetic, tetracaine, on the Ca2+ release channel-ryan odine receptor of sarcoplasmic reticulum in swine skeletal and cardiac musc le. [H-3]Ryanodine binding was used to measure the activity of the Ca2+ rel ease channel-ryanodine receptors in microsomes of both muscles. Results: Bupivacaine enhanced (by two times at 5 mM) and Inhibited (66% inh ibition at 10 mM) [H-3]ryanodine binding to skeletal muscle microsomes. In contrast, only inhibitory effects were observed with cardiac microsomes (ab out 3 mM for half-maximal inhibition). Tetracaine, which inhibits [H-3]ryan odine binding to skeletal muscle microsomes, also inhibited [H-3]ryanodine binding to cardiac muscle microsomes (half-maximal inhibition at 99 mu M). Conclusions: Bupivacaine's ability to enhance Ca2+ release channel-ryanodin e receptor activity of skeletal muscle sarcoplasmic reticulum most Likely c ontributes to the myotoxicity of this local anesthetic, Thus, the pronounce d myotoxicity of bupivacaine may be the result of this specific effect on C a2+ release channel-ryanodine receptor superimposed on a nonspecific action on Lipid bilayers to increase the Ca2+ permeability of sarcoplasmic reticu lum membranes, an effect shared by all local anesthetics. The specific acti on of tetracaine to Inhibit Ca2+ release channel-ryanodine receptor activit y may in part counterbalance the nonspecific action, resulting in moderate myotoxicity.