To the Editor:--The report by Johansson et al. provides further insight into the molecular site at which general anesthetics act. The investigators found that halothane quenches the tryptophan fluorescence of bovine serum albumin in a concentration-dependent manner with a dissociation constant of 1.8 mM. They also reported that diethyl ether competes with halothane with a 50% inhibition concentration of 39 mM.
These concentrations surpass those required for anesthesia. At 1.8 mM, halothane equals a partial pressure at 37 degrees Celsius of 0.06 atm (1.8 mM =(1.8 x 10 sup -6 mol/ml)(2.5436 x 104ml/mol)/0.75, where 0.75 is the partition coefficient for halothane in Krebs' solution at 37 degrees Celsius. This exceeds the anesthetizing partial pressure of halothane in humans by a factor of 8. Similarly, the partial pressure of ether at 39 mM equals 0.76 atm, assuming a partition coefficient of 13. This exceeds the anesthetizing partial pressure of ether in humans by a factor of 40. .
Although Johansson et al. performed their studies at 25 degrees Celsius, the above ratios (8 for halothane and 40 for ether) for 37 degrees Celsius will approximate ratios at 25 degrees Celsius because of the counterbalancing changes in solubility and potency of anesthetics with decreasing temperature. Furthermore, the dissociation constant of 1.8 mM for halothane quenching found by Johansson et al. is also an order of magnitude greater than the anesthetic potency of halothane measured in animals at lower temperatures: The righting reflex EC50of halothane in tadpoles is approximately 0.1 mM at 20 degrees Celsius. The calculations of partial pressure also assume that the solution used in the experiment was equivalent to an isotonic salt solution. If the albumin added appreciably to the solubility of halothane, this would lower the partial pressure calculated for halothane but not that for ether, whose solubility in blood scarcely differs from that in water. .
Even allowing for these factors, it appears that the partial pressures applied exceed those that produce anesthesia. If so, can the results provide us with insights into mechanisms of anesthetic action? Does the five-fold difference in the ratios for ether and halothane (8 vs. 40) mean that the finding for halothane does not apply equally to all anesthetics, and thus that the tryptophan site is not representative of a relevant anesthetic site of action? Finally, do results obtained at 25 degrees Celsius apply at the higher temperatures sustained by homeotherms?
Edmond I. Eger II, M.D., Professor and Vice Chairman for Research.
Donald D. Koblin, Ph.D., M.D., Professor, Department of Anesthesia, University of California, San Francisco, Box 0464, Science 455, 513 Parnassus Avenue, San Francisco, California 94143–0464.