Edward A. Brunner

General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons.

The effects of halothane, isoflurane, and enflurane on ionic currents induced by bath application of γ‐aminobutyric acid (GABA) were studied with the rat dorsal root ganglion neurons maintained in primary culture. The whole‐cell patch clamp technique was used to record the current. In normal neurons before exposure to anesthetics, GABA at low concentrations (1‐3 times 10−6 M) induced a small sustained inward current. At higher concentrations (3 times 10−5 M‐1 times 10−3 M), GABA induced a large inward current, which decayed to a steady‐state level (desensitization). Halothane (0.86 mM), isoflurane (0.96 mM), and enflurane (1.89 mM), each equivalent to the respective 2 minimum alveolar concentration (MAC) units, augmented the sustained current evoked by 3 times 10−6 M GABA to 330‐350% of control and the peak current evoked by 3 times 10−5 M of GABA to 136‐145% of control. The decay phase of the current was accelerated by the anesthetics, the time for the current to decline to 70% of the peak being reduced to 23‐39% of control. In contrast, the desensitized steady‐state current evoked by high concentrations of GABA was decreased by anesthetics. In conclusion, general anesthetics exert a dual effect on the GABA receptor channel complex: to potentiate the nondesensitized (both peak and sustained) current and to suppress the desensitized steady‐state current. The potentiation of the GABA receptor channel response may be a primary action of anesthetics leading to surgical anesthesia.—Nakahiro, M.; Yeh, J. Z.; Brunner, E.; Narahashi, T. General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons. FASEB J. 3: 1850‐1854; 1989.

The effect of volatile anaesthetics on levels of metabolites and on metabolic rate in brain.

Anaesthesia with ether, halothane, methoxyflurane (Penthrane) and Ohio 347 (Ethrane) increased the energy stores in mouse brain as much as 1·7‐fold above the control values. The greatest increases were observed in glucose and glycogen. Glucose‐6‐P was increased in some cases and UDP glucose was consistently lower in the anaesthetized animals. Hypothermia in conjunction with anaesthesia modified some of the observed changes. Hypothermia alone was associated with an increase in P‐creatine and glucose and a decrease in UDPglucose in the brain.

Effects of hyperosmotic mannitol infusion on hemodynamics of dog kidney.

This study evaluated the effect of systemic infusion of hypertonic mannitol on renal hemodynamics (aortic pressure [P]-renal blood flow [RBF] relationship, glomerular filtration rate [GFR], and effective renal plasma flow [ERPF]) during 50% reduction of left kidney blood flow. Conditioned mongrel dogs anesthetized with halothane were hydrated by continuous infusion of lactated Ringers solution containing creatinine to measure GFR and p-aminohippurate (PAH), to measure ERPF. The left kidney was exposed and two hydraulic occluders were placed, one around the aorta just above the renal arteries and the other around the left renal artery. Experimental design consisted of measuring P near the left renal artery, RBF by electromagnetic flowmeter, and ERPF and GFR by clearance methods in both kidneys in response to stepwise reduction in the aortic pressure by aortic occlusion before and after 50% reduction in the left kidney blood flow. The P-RBF relationship, GFR, and ERPF thus obtained were compared with those obtained during systemic intravenous infusion of 20% mannitol for a period of 1 h. We found that 1) a transient increase occurred in RBF with step reduction of P from 80 to 60 mm Hg under control conditions; 2) reducing the RBF by 50% changed the shape of the P-RBF relationship from a convex to the P axis to a linear form with a marked shift toward the P axis; 3) infusion of mannitol, during reduced RBF, caused a significant shift of the P-RBF curve toward the RBF axis and returned the linear P-RBF relationship toward normal, but had no effect on altered yield pressure; and 4) infusion of hypertonic mannitol had slightly increased GFR and ERPF in the right (unconstricted) kidney. However, hypertonic mannitol significantly increased GFR and ERPF values in the left (constricted) kidney suggesting a beneficial effect of mannitol on ischemic kidney. The results are consistent with the hypothesis that infusion of hypertonic mannitol to ischemic kidney increases RBF, presumably by decreasing the intrarenal vascular resistance. We speculate that this compensatory response may be mediated either 1) by stimulating the release of a vasodilator substance (e.g., prostaglandins), or 2) by washing out interstitial sodium, thereby reducing the sensitivity of the renal vasculature to ischemia-induced stimulation of renin-angiotensin system. (Anesth Analg 1996;82:902-8)

Effects of Anesthetic Agents on Synaptosomal GABA Disposal

In brain slices, halothane was shown to inhibit the metabolic breakdown of GABA (μ-aminobutyric acid), an inhibitory neurotransmitter. This inhibition leads to increased brain GABA content, presumably in the synaptic areas, and to the postulation that halothane anesthesia may arise from an enhanced synaptic inhibition due to this elevated GABA. The ability of many neurotropic agents to inhibit GABA breakdown was studied by assessing synaptosomal “GABA disposal”. GABA disposal by intact synaptosomes, which simulate miniature synapses, measures the conversion of [1-14C]GABA to 14CO2 and includes the processes of uptake, release, and catabolism of GABA. The most potent inhibitor is chloroform, followed by halothane, enflurane, ether, and thiopental. Pentobarbital, ethanol, paraldehyde, and ketamine are weak inhibitors. Phenobarbital, morphine, and phenytoin are not inhibitory at pharmacologic concentrations. As a whole, anesthetic agents show particular inhibitory action on this metabolic process in this model system where the ID10 values (i.e., concentration of a drug necessary to produce 10 per cent inhibition of GABA disposal) correlate well with known pharmacologic potencies, ED50 values, or MACs. These observations support the possibility that anesthesia may be related to an inhibition of GABA disposal.

The effects of altered endocrine states and of ether anaesthesia on mouse brain.

The effects of ether anaesthesia on metabolites of mouse brain in altered endocrine states has been examined. Alloxan diabetic mice, with elevated levels of blood and brain glucose, exhibited changes in brain metabolites after ether anaesthesia that were comparable to those seen in normal animals. Sympathectomized and/or adrenalectomized mice had decreased levels of brain glucose. The percentage elevation of glucose in the brains of these animals under ether anaesthesia approximated to normal values, although the absolute cerebral levels were lower. Increases in glycogen in the brains of these animals were somewhat diminished. In none of the altered endocrine states were the changes in brain metabolites following ether anaesthesia eliminated.

Inhibition of GABA Metabolism in Rat Brain Slices by Halothane

Based on studies with rat cerebral cortex slices, it was previously hypothesized that halothane anesthesia may result from increased GABA (γ-aminobutyric acid) content in the synapses. Since GABA is an inhibitory neurotransmitter, such increases may cause a reduction in synaptic activity. The increase in GABA content could arise from several possible causes which are examined in this study using rat cerebral cortex slices as a model. The effects of halothane on uptake, release, and catabolism of GABA were determined. Uptake was studied by the amounts of radioactive GABA accumulated by the slices, and release studied by that discharged into the medium from slices preloaded with radioactive GABA. Catabolism was assessed by preloading the slices with radioactive GABA and then followed by measuring the amount of radioactivity found in unmetabolized GABA or in pooled GABA metabolites. Since CO2 was established as a major metabolite, it was subsequently used alone to measure the inhibition of GABA catabolism in the presence of varying amounts of halothane. Halothane (3 per cent) did not affect the high-affinity uptake or the release of GABA but did inhibit the catabolism of GABA. Using 14CO2 production as an index of catabolism, the inhibition of GABA catabolism by halothane was dose-related (8.79 per cent inhibition/per cent halothane). Such results support the hypothesis that halothane anesthesia may result at least in part from an inhibition of GABA catabolism which, in turn, causes increased GABA level in the synapse with resultant synaptic inhibition.

ALTERATION OF TRICARBOXYLIC ACID CYCLE METABOLISM IN RAT BRAIN SLICES BY HALOTHANE

Abstract— 1 Metabolism of [2‐14C]pyruvate, [1‐14C]acetate and [5‐14C]citrate in the rat cerebral cortex slices was studied in the presence of halothane. Metabolites assayed include acetylcholine (ACh), citrate, glutamate, glutamine, γ‐aminobutyrate (GABA) and aspartate. The trichloroacetic acid soluble extract, the trichloroacetic acid insoluble precipitate and its lipid extract were also studied. 2 In control experiments, pyruvate preferentially labelled ACh, citrate, glutamate, GABA and aspartate. Acetate labeled ACh, but to a lesser extent than pyruvate. Acetate also labeled lipids and glutamine. Citrate labeled lipids but not ACh and served as a preferential precursor for glutamine. These data support a three‐compartment model for cerebral tricarboxylic acid cycle metabolism. 3 Halothane caused increases in GABA and aspartate contents and a decrease in ACh content. It has no effect on the contents of citrate, glutamate and glutamine. 4 Halothane preferentially inhibited the metabolic transfer of radioactivity from pyruvate into almost all metabolites, an effect probably not related to pyruvate permeability. This is interpreted as halothane depression of the‘large metabolic compartment’ which includes the nerve endings. 5 Halothane increased the metabolic transfer of radioactivity from acetate into lipids but did not alter such a transfer into the trichloracetic acid extract. 6 Halothane increased the metabolic transfer of radioactivity from citrate into the trichloroacetic acid precipitate, lipids and especially glutamine. Transfer of citrate radioactivity into GABA was somewhat decreased. 7 The differential effects of halothane on acetate and citrate utilization suggest that the ‘small metabolic compartment’ should be subdivided. Therefore, at least three metabolic compartments are demonstrated. 8 Halothane did not interfere with the dicarboxylic acid portion of the tricarboxylic acid cycle.

The Changing Pattern of Neuromuscular Blockade Caused by Succinylcholine in Man

The parameters involved in the change of neuromuscular block caused by succinylcholine were studied in man. In 28 patients during operation, stimulation of the ulnar nerve and recording from the adductor pollicis was accomplished, with muscle contractions recorded via a force displacement transducer. Phase II block developed in 20 patients. Time and dose relationships were studied. Post-rest facilitation and change in mode of onset of the block were newly described symptoms indicative of phase II. Edrophonium reversed phase II blockade. Time of reversal of the block to the first twitch remained unchanged from phase I to phase II, but time to full recovery of twitch and tetanus was prolonged in phase II. Tachyphylaxis occurred independently of phase of the block. Correlation with clinical muscle paralysis was poor during the administration of succinylcholine but good at the time of reversal of the block.

Relationship between past academic performance and results of specialty in-training examinations.

In this study, the authors review the records of 63 graduates of Northwestern University Medical School who were residents in its graduate medical education programs of anesthesia and orthopedic surgery. They examine the relationship among college grades, medical school performance, and the results of assessment by annual, nationwide, medical specialty in-training examinations. For the anesthesia group, the best predictors of in-training examination performance were the Medical College Admission Test (MCAT) Verbal Ability score, the college grade-point average for nonscience subjects, and the MCAT Science, General Information, and Quantitative Ability scores. For the orthopedic group, the best predictors were the MCAT Verbal Ability score, the college grade-point average in nonscience subjects, the MCAT Science score, and the National Board of Medical Examiners Part I and Part II examination scores. The previous academic records for the 63 residents contained little to presage results in the in-training examination. The correlation obtained between nonscience college subjects and the in-training examination results was negative.

Clinical use of etomidate for anesthesia induction: a preliminary report.

Etomidate (0.3 mg/kg) and thiopental (4 mg/kg) were administered IV for induction of general anesthesia, comparing heart rate, blood pressure, respiration, and side effects. No significant difference between the drugs was found in the circulatory parameters, but respiration was more depressed by thiopental. A high incidence of the side effects of myoclonia and pain on injection was seen with etomidate. The incidence of side effects was not affected by speed of injection or type of premedication. Mechanisms to reduce the incidence of side effects are needed for etomidate to become a useful induction agent.