PubMed · 13110680
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1953-10-30. [CORNECAIN].. https://pubmed.ncbi.nlm.nih.gov/13110680/
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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.
The neocortex is thought to be organized into functional columns of neurons, each of which processes an element of a larger representation. In the barrel cortex, the thalamic input to the column preferentially terminates in a barrel. To study the extent and nature of functional connections between columns, we measured the degree to which whisker responses are relayed between columns in the barrel cortex. Inactivating a single barrel by iontophoresis of the GABA(A) agonist muscimol abolished the representation of that barrel's whisker in neighboring barrels. Reactivating a single barrel by iontophoresis of the GABA(A) antagonist bicuculline while the rest of the cortex was blocked by muscimol led to single whisker receptive fields. Under the same conditions, septal cells tended to exhibit multiwhisker receptive fields. These studies demonstrate that the surround receptive fields of barrel cells are generated by intracortical transmission and that many septal cells derive a component of their surround receptive field from the thalamus.