Search

Background Recent evidence is consistent with the view that volatile anesthetics interact directly with excitable membrane-bound channel proteins. If these agents interact directly with chiral centers in the neuronal cell membrane, then their effects should be stereoselective. Using rat brain membranes enriched in gamma-aminobutyric acid type A (GABAA) receptors, we investigated the hypothesis that the permeability response of this well-characterized central nervous system channel protein to stereoisomers of isoflurane is stereoselective. Methods Rat brain synaptic microvesicles were prepared by differential centrifugation. Agonist-stimulated 36Cl- flux through membrane-bound GABAA receptors was assayed in the presence of (+)- and (-)-isoflurane and compared with control conditions. Results Both isomers increased the potency and efficacy of GABA; however, (+)-isoflurane was significantly more potent and efficacious than the (-)-isomer. For example, the (+)-isomer (140 microM) reduced the median effective concentration of GABA from 12.7 +/- 1.0 to 5.4 +/- 0.5 microM, whereas the (-)-isomer reduced it to 9.6 +/- 1.0 microM (P < 0.001). The (+)-isomer also was 1.6 times as potent as the (-)-isomer in augmenting 5 microM GABA-gated flux (79 +/- 11 vs. 130 +/- 17 microM, respectively; P = 0.01). In addition, the (+)-isomer produced significantly greater maximal enhancement of flux (9.4 +/- 0.4 vs. 7.0 +/- 0.3 nmol.mg-1.3 s-1; P < 0.001). Conclusions Isoflurane's effects on GABA-gated chloride flux were stereoselective. This result supports direct interaction with a stereoselective site, possibly the GABAA channel protein itself, rather than a nonspecific perturbation of the surrounding membrane lipid. In addition, these findings, from a functional assay using mammalian brain, agree with recent observations in invertebrate ion channels and mammalian neuronal cell cultures.

To determine whether prematurely born infants with a history of idiopathic apneic episodes are more prone than other infants to life-threatening apnea during recovery from anesthesia, the authors prospectively studied 214 infants (173 full term, 41 premature) who received anesthesia. Fifteen premature infants had a preanesthetic history of idiopathic apnea. Six of these required mechanical ventilation because of idiopathic apneic episodes during emergence from anesthesia. Two were ventilated for other reasons, and seven recovered normally. Infants ventilated for apnea were younger (postnatal age 1.6 +/- 1.2 months, mean +/- SD; conceptual age 38.6 +/- 3.0 weeks) than those who recovered normally (postnatal age 5.6 +/- 2.7 months; conceptual age 55.1 +/- 11.3 weeks) (P less than 0.01). No other premature or full-term infant was ventilated because of postoperative apneic episodes. The authors conclude that anesthetics may unmask a defect in ventilatory control of prematurely born infants younger than 41-46 weeks conceptual age who have a preanesthetic history of idiopathic apnea.