Julien F. Biebuyck

Up-and-down Regulation of Skeletal Muscle Acetylcholine Receptors Effects on Neuromuscular Blockers

Multiple factors alter the interaction of muscle relaxants with the NMJ. This review has focused on the aberrant responses caused principally by alterations in AChRs (table 1). Many pathologic states increase (up-regulate) AChR number. These include upper and lower motor neuron lesions, muscle trauma, burns, and immobilization. Pre- or postjunctional inhibition of neurotransmission by drugs or toxins also up-regulate AChRs. These include alpha- and beta-BT, NDMR, anticonvulsants, and clostridial toxins. We speculate that other bacterial toxins also up-regulate AChR. With proliferation of AChRs, agonist drug dose-response curves are shifted to the left. The exaggerated release of potassium when depolarization occurs with the use of agonists such as SCh and decamethonium can be attributed to the increased number of AChR. Thus, SCh should be avoided in patients who are in the susceptible phase (see section V). In the presence of increased AChR, the requirement for NDMR is markedly increased. Thus, the response to NDMR may be used as an indirect estimator of increased sensitivity to SCh (table 1). The most extensively studied pathologic state in which there is a decrease in AChRs is myasthenia gravis; there is immunologically mediated destruction and/or functional blockade of AChRs. The pathophysiologic and pharmacologic changes in LEMS are quite distinct from those of myasthenia gravis. Decreased AChRs in myasthenia gravis result in resistance to agonists and increased sensitivity to competitive antagonists. In conditioning exercise, the perturbed muscles show sensitivity to NDMR that may be due to decreased AChRs. Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs. In this condition, SCh should be avoided because its metabolic breakdown would be impaired; the requirement for NDMR may be decreased. All of the varied responses to SCh and NDMR, which are associated with concomitant changes in AChRs, are analogous to drug-receptor interactions observed in other biologic systems.

Regional Blood‐Brain Barrier Permeability to Amino Acids After Portacaval Anastomosis

Abstract: The influx of phenylalanine, tryptophan, leucine, and lysine across the blood‐brain barrier of individual brain structures was studied in rats 7–8 weeks after a portacaval shunt or sham operation. The method involved a brief infusion of labeled amino acid in tracer quantity and quantitative autoradiography. The clearance rates of phenylalanine, tryptophan, and leucine were increased in proportion to each other in every region examined, but not by the same factor. Tryptophan clearance increased the most (about 200%) and leucine the least (about 30%), compared with phenylalanine (about 80%). This was unexpected, as all three amino acids are believed to be transported by the same mechanism. The changes were most marked in several limbic structures and the reticular formation, whereas the hypothalamus was least affected. Plasma clearance of lysine was decreased in all areas by about 70%. Since the circulating lysine concentration was decreased by 13%, the actual rate of lysine influx was even more reduced. The results demonstrate specific alterations in two different amino acid transport systems. The resulting excess brain neutral amino acids, some of which are neurotransmitter precursors, as well as reduced basic amino acid availability, may be of etiological significance in hepatic encephalopathy.

CORRELATION OF PLASMA AND BRAIN AMINO ACID AND PUTATIVE NEUROTRANSMITTER ALTERATIONS DURING ACUTE HEPATIC COMA IN THE RAT

During acute hepatic coma following two‐stage hepatic devascularization in the rat, profound changes occurred in plasma and whole‐brain amino acids and putative neurotransmitters. Brain ammonia, glutamine and GABA were increased, aspartate was decreased, while glutamate was unchanged. An increase in brain tryptophan was accompanied by a similar increase in plasma unbound tryptophan but decreased plasma total tryptophan. These changes occurred in the presence of high plasma levels of the other neutral amino acids, including the branched chain amino acids. Plasma insulin was unchanged while glucagon levels rose, resulting in a decreased insulin to glucagon ratio. These results suggest that while plasma unbound tryptophan may influence brain tryptophan levels, altered plasma concentrations of neutral amino acids which compete with tryptophan for transport into the brain do not contribute to the increase in brain tryptophan observed during acute hepatic coma.

Anaesthesia and insulin secretion: The effects of diethyl ether, halothane, pentobarbitone sodium and ketamine hydrochloride on intravenous glucose tolerance and insulin secretion in the rat

SummaryFasting hyperglycaemia occurred in 48 h starved rats after 30 min of anaesthesia with ether or halothane. Plasma insulin increased only with ether. Halothane caused basal hyperglycaemia in fed rats, but decreased plasma insulin by 50%. Intravenous pentobarbitone (30 mg/kg) did not affect blood glucose in starved rats, but decreased plasma insulin with a small rise in blood glucose in fed rats. Following intravenous glucose (0.5 g/kg), hyperglycaemia and impaired glucose tolerance with normal insulin/glucose ratios occurred in starved animals anaesthetised with ether and pentobarbitone. The latter had no effect on glucose tolerance in fed rats. In contrast, halothane caused hyperglycaemia without glucose intolerance in starved animals, but decreased the insulin response by 40% in fed animals. Ketamine (30 mg/ kg) caused only a 15% increase in glucose area in starved rats and was otherwise without effect. Halothane had no significant effect on glucose stimulated insulin secretion in the isolated perfused rat pancreas. — Possible mechanisms for these effects are discussed.

Mechanisms of Differential Axial Blockade in Epidural and Subarachnoid Anesthesia

The mechanisms of persistent differential blocks that accompany subarachnoid and epidural anesthesia are clarified here with the aid of two principles derived from in vitro study of individual myelinated axons: 1) conduction can leap two consecutive blocked nodes but not three, and 2) a fiber length with more than three consecutive nodes bathed by weak anesthetic may block by decremental conduction, the requisite concentration varying inversely with the number of nodes bathed by anesthetic. Principle 1 applies in epidural blockade, where anesthetic bathes only a few millimeters of segmental nerve extradurally in the intervertebral foramen. Here, three-node block will be rare in large, long-internode fibers but likely in small, short internode fibers, thus explaining the differential retention of motor power in the presence of block of pain, which is achieved in epidural anesthesia when relatively weak solutions are used, as in obstetrics. Principle 2 may intervene in subarachnoid blockade where, cephalad to the site of puncture, increasingly concentrated anesthetic bathes increasing lengths of fibers in the craniocaudal succession of spinal nerve roots. This will produce decremental conduction block in increasingly long internode fibers in successive roots, reflected in a corresponding craniocaudal segmental sequence of blocked physiological functions: vasoconstriction, cutaneous temperature discrimination, pinprick pain sensibility, and skeletal motor activity. The segmental spatial differential sequence migrates with time but resembles the temporal differential sequence of loss seen at the onset of peripheral nerve blocks. Several other previously disparate clinical observations follow logically from the new interpretation.

TRYPTOPHAN TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER DURING ACUTE HEPATIC FAILURE

Abstract— Tryptophan transport across the blood‐brain barrier was studied using a single injection dual isotope label technique, in the following three conditions: normal rats, rats with portacaval shunts, and rats with portacaval shunts followed 65 h later by hepatic artery ligation. In both normal rats and those with acute hepatic failure the tryptophan transport system was found to be comprised of two kinetically distinct components. One component was saturable and obeyed Michaelis‐Menten kinetics (normal: Vmax= 19.5 nmol.min−1.g−1. Km= 113 μM; hepatic failure: Vmax, = 33.8 nmol.min−1.g−1, Km= 108 μM), and the second was a high capacity system which transported tryptophan in direct proportion to concentration over the range tested (normal: K= 0.026 ml.min−1.g−1; hepatic failure: K= 0.067 ml.min−1.g−1). Since the saturable low capacity component transports several neutral amino acids, and their collective plasma concentration is high in relation to the individual Kms, tryptophan transport by this component is reduced by competitive inhibition under physiological conditions. Thus it was calculated that in normal rats approx 40% of tryptophan influx occurs via the high capacity system. During acute hepatic failure transport via both components was increased substantially, approximately doubling the rate of tryptophan penetration of the blood‐brain barrier at all concentrations tested. The contribution by the high capacity component became even more significant than in normal rats, accounting for about 75% of all tryptophan passage from plasma to brain. Brain tryptophan content was 29.9 nmol/g in normal rats and rose to 45.2 nmol/g in rats with portacaval shunts and 50.5 nmol/g in those with acute hepatic failure, correlating with the increased rate of tryptophan transport. In a previous study we found that plasma competing amino acids were greatly increased during acute hepatic failure. Calculations predict that these increased concentrations would cause a reduction in tryptophan transport by the low capacity system. However, because of the increase in the rate of transport by the high capacity component, net tryptophan entry across the blood‐brain barrier was actually increased. This increased rate of transport clearly contributes to the increased content of brain tryptophan found during hepatic failure.

Portacaval Anastomosis: Brain and Plasma Metabolite Abnormalities and the Effect of Nutritional Therapy

Abstract: Rats with portacaval shunts were used as a model of hepatic encephalopathy and compared to sham‐operated controls. First, the changes in intermediary metabolites and amino acids in blood and whole brain were characterized and found to be similar at 4 and 7 weeks after shunting. Second, the effects of nutritional therapy on selected metabolites and tryptophan transport into brain were assessed in rats 5 weeks after surgery. Ordinary food was removed and the rats were treated with glucose given either by mouth or intravenously, or intravenous glucose plus branched chain amino acids. Several abnormalities in plasma amino acid concentrations were reversed by treatment. The abnormally high brain uptake index of tryptophan, a consequence of portacaval shunting, was not lowered by any of the treatment regimens; it was even higher in the groups given glucose by mouth and glucose plus amino acids. Calculated competition for entry of tryptophan, phenylalanine, and tyrosine into brain was unchanged (glucose plus amino aicds), or reduced (glucose alone). Brain glutamine content was brought to near normal by all treatments. Infusion of glucose plus branched chain amino acids normalized brain content of tryptophan, phenylalanine, and tyrosine, even though the brain uptake index of tryptophan was higher in this group. Thus, partial or complete reversal of several abnormalities found after portacaval shunting was achieved by removal of oral food and administration of glucose. The addition of branched chain amino acids to the glucose infusion restored brain content of three aromatic amino acids to near normal, by a mechanism which appeared to be unrelated to transport across the blood‐brain barrier.

Hyperpyrexia During Anaesthesia

Work in pigs has shown that malignant hyperpyrexia during anaesthesia may occur without suxamethonium having been given. A virtually constant feature in reported cases and in our own observations is that all subjects developing hyperpyrexia had received nitrous oxide and halothane.

ACUTE HEPATIC COMA TREATED BY CROSS-CIRCULATION WITH A BABOON AND BY REPEATED EXCHANGE TRANSFUSIONS

Abstract A patient in terminal hepatic coma with high-brain-stem dysfunction was treated by multiple exchange blood-transfusions and by cross-circulation with a baboon ( Papio ursinus ursinus ) after the animals blood had been replaced with human blood compatible with that of the patient. Spontaneous respiration was restored by the cross-circulation which was free from complications and the patient subsequently became fully conscious and lost all her abnormal neurological signs.

The influence of ketamine on regional brain glucose use

The purpose of this study was to determine the effect of different doses of ketamine on cerebral function at the level of individual brain structures as reflected by glucose use. Rats received either 5 or 30 mg/kg ketamine intravenously as a loading dose, followed by an infusion to maintain a steady-state level of the drug. An additional group received 30 mg/kg as a single injection only, and was studied 20 min later, by which time they were recovering consciousness (withdrawal group). Regional brain energy metabolism was evaluated with (6-14C) glucose and quantitative autoradiography during a 5-min experimental period. A subhypnotic, steady-state dose (5 mg/kg) of ketamine caused a stimulation of glucose use in most brain areas, with an average increase of 20%. At the larger steady-state dose (30 mg/kg, which is sufficient to cause anesthesia), there was no significant effect on most brain regions; some sensory nuclei were depressed (inferior colliculus, –29%; cerebellar dentate nucleus, –18%; vestibular nucleus, –16%), but glucose use in the ventral posterior hippocampus was increased by 33%. In contrast, during withdrawal from a 30-mg/kg bolus, there was a stimulation of glucose use throughout the brain (21–78%), at a time when plasma ketamine levels were similar to the levels in the 5 mg/kg group. At each steady-state dose, as well as during withdrawal, ketamine caused a notable stimulation of glucose use by the hippocampus.