PubMed · 12987542
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
1952. EXPLOSION hazards.. https://doi.org/10.1093/bja%2F24.4.300
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.
The objective of the present investigation was to characterize the pharmacodynamic interaction between the synthetic neuroactive steroid alphaxalone and the benzodiazepine midazolam. The time course of the electroencephalographic (EEG) effect (11.5-30 Hz) was determined in rats in conjunction with plasma concentrations. Alphaxalone was administered as a continuous intravenous infusion of 0, 1.2, 2.2, or 5.2 mg over 360 min. Midazolam was administered as a 5-min intravenous bolus infusion of 4 mg.kg-1. The pharmacokinetic profiles of both drugs were described by a two-compartment model. No pharmacokinetic interaction was observed. The EEG effect versus time profiles of midazolam and alphaxalone, when administered separately and in combination, were modeled on the basis of the recently proposed mechanism-based pharmacokinetic/pharmacodynamic model for GABAA receptor modulators, which contains separate expressions to describe the drug-receptor interaction and the stimulus-response relationship. The pharmacodynamic interaction between alphaxalone and midazolam was best characterized using an independent drug-drug interaction model without an expression for allosteric modulation of the effect of midazolam by alphaxalone. The final model contained an exponential expression to account for acute functional adaptation to the EEG effect upon continuous infusion of alphaxalone. The mechanism-based analysis showed that this functional adaptation is best explained by a change in the system-specific stimulus-response relationship, rather than the drug-receptor activation process. It is concluded that the pharmacodynamic interaction between alphaxalone and midazolam in vivo is best described using an independent interaction model without allosteric modulation.
Although inhaled nitric oxide (NO(i)) is considered to act selectively on pulmonary vessels, EEG abnormalities and even occasional neurotoxic effects of NO(i) have been proposed. Here, we investigated cerebrovascular effects of increasing concentrations of 5, 10 and 50 ppm NO(i) in seven anesthetized pigs. Cerebral hemodynamics were assessed non-invasively by use of near-infared spectroscopy and indicator dilution techniques. NO(i) increased cerebral blood volume significantly and reversibly. This effect was not attributable to changes of macrohemodynamic parameters or arterial blood gases. Simultaneously, cerebral transit time increased while cerebral blood flow remained unchanged. These data demonstrate a vasodilatory action of NO(i) in the cerebral vasculature, which may occur preferentially in the venous compartment.