Interaction of the local anesthetics dibucaine and tetracaine with sarcoplasmic reticulum membranes. Differential scanning calorimetry and fluorescence studies

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Abstract
The local anesthetics dibucaine and tetracaine inhibit the (Ca2+ + Mg2+)-ATPase from skeletal muscle sarcoplasmic reticulum [DeBoland, A. R., Jilka, R. L., and Martonosi, A. N. (1975) J. Biol. Chem. 250,7501-7510; Suko, J., Winkler, F., Scharinger, B., and Hellmann, G. (1976) Biochim. Biophys. Acta 443, 571-586]. We have carried out differential scanning calorimetry and fluorescence measurements to study the interaction of these drugs with sarcoplasmic reticulum membranes and with purified (Ca2+ + Mg2+)-ATPase. The temperature range of denaturation of the (Ca2+ + Mg2+)-ATPase in the sarcoplasmic reticulum membrane, determined from our scanning calorimetry experiments, is ca. 45-55.degree. C and for the purified enzyme ca. 40-50.degree. C. Millimolar concentrations of dibucaine and tetracaine, and ethanol at concentrations higher than 1% v/v, lower a few degrees (.degree.C) the denaturation temperature of the (Ca2+ + Mg2+)-ATPase. Other local anesthetics reported to have no effect on the ATPase activity, such as lidocaine and procaine, did not significantly alter the differential scanning calorimetry pattern of these membranes up to a concentration of 10 mM. The order parameter of the sarcoplasmic reticulum membranes, calculated from measurements of the polarization of the fluorescence of diphenylhexatriene, is not significantly altered at the local anesthetic concentrations that shift the denaturation temperature of the (Ca2+ + Mg2+)-ATPase. It has been found, however, that the intrinsic fluorescence of these membranes is largely quenched by these local anesthetic concentrations and that this quenching of the intrinsic fluorescence can be adequately fitted to the theoretical energy-transfer prediction using the membrane/water partition coefficients determined in this study. It is suggested that the shift of the denaturation temperature of the (Ca2+ + Mg2+)-ATPase by these anesthetics, and likely the inhibition of this activity, is related to the progressive disruption of the lipid annules by these drugs.

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