Molecular pharmacology
-
Molecular pharmacology · Mar 1984
Inhibition of binding of [3H]batrachotoxinin A 20-alpha-benzoate to sodium channels by local anesthetics.
The effects of several local anesthetics on the binding of ligands to receptors associated with voltage-sensitive sodium channels in rat brain synaptosomes have been examined. In the presence of 0.3 microM scorpion toxin, the 13 local anesthetics tested inhibited the specific binding of [3H]batrachotoxinin A 20 alpha-benzoate [( 3H]BTX-B), a ligand which binds to a receptor site responsible for the activation of sodium channel ion flux, in a dose-dependent fashion, with KD values ranging from 1.2 microM for tetracaine to 1.58 mM for benzocaine. A plot of log KD from these binding experiments against log K0.5 for inhibition of sodium currents by local anesthetics from electrophysiological experiments yielded a regression line with a slope of 0.84 and a correlation coefficient, r, of 0.86, demonstrating that the inhibition of [3H]BTX-B binding by local anesthetics occurs within a concentration range of physiological relevance. ⋯ Analysis of the effects of local anesthetics in terms of an allosteric model of drug action showed that they bind to inactive states of sodium channels with at least a 10-fold higher affinity than active states. A 7-fold difference in KD for inhibition of [3H]BTX-B binding between the local anesthetic stereoisomers RAC 109 I and RAC 109 II was observed. Similarly, the dissociation rate constant for the [3H]BTX-B/receptor complex was increased 9.3-fold in the presence of RAC 109 II and 4.3-fold in the presence of a comparable concentration of RAC 109 I.(ABSTRACT TRUNCATED AT 250 WORDS)
-
Molecular pharmacology · Jan 1984
Membrane expansion and inhalation anesthetics. Mean excess volume hypothesis.
High-precision solution densimetry was used to determine volume parameters for the interaction of inhalation anesthetics with water, nonpolar solvent, and phospholipid vesicles. The precision of the densimeter is mainly limited by the constancy of the temperature during measurement. Therefore, temperature stability was maintained within +/- 0.0005 degrees and monitored by a microprocessor-controlled Thermistor thermometer with 0.0001 degrees resolution. ⋯ Because the mean excess volume of anesthetics dissolved in water is always negative and that incorporated into phospholipid suspension is positive, anesthetics expand the total volume of the model membrane system when translocated from water to the membrane. Anesthesia occurs when the mean excess volume of the total system exceeds a limiting value, and the bulk membrane size is irrelevant. Although the present result in no way disclaims alternative hypotheses, it demonstrates that the pressure reversal of anesthesia can be explained without assuming any specific receptors for these anesthetics.
-
Molecular pharmacology · Mar 1983
Effect of calcium on halothane-depressed beating in heart cells in culture.
Heart cells in culture need no external stimulation to contract; they beat rhythmically at a rate and intensity dependent on culture conditions. These cells respond to the general anesthetic 2-bromo-2-chloro-1,1,1-trifluorethane (halothane), with a loss of beating intensity and a lessening of beating rate. Increased calcium concentrations in growth medium reversed the halothane-depressed beating intensity of heart cells in culture; however, increased calcium concentrations had no effect on the halothane-depressed beating rate. ⋯ Data in this manuscript support the theory that general anesthetics dissolve in membranes and thus disrupt membrane function. The anesthetic halothane appears to affect myocardial beating intensity through its ability to disrupt fast calcium uptake. Halothane also depresses the cardiac beating rate, but the data collected do not relate beating rate with calcium metabolism.