Bernard Hoop

Brainstem amino acid neurotransmitters and hypoxic ventilatory response

The ventilatory response to acute hypoxia in mammalian species is biphasic, an initial hyperventilatory response is followed by a reduction in ventilation within 2-3 min below the peak level (roll-off). Brain amino acid neurotransmitters also change during hypoxia. This study explores the role of neurotransmitters in anesthetized adult Sprague Dawley rats mechanically ventilated during 20 min of 10% O2 breathing. Phrenic nerve activity was recorded, and microdialysate concentrations of selected amino acids were determined at 3- to 5-min intervals in respiratory chemosensitive areas of the ventrolateral medulla (VMS) 1.25-2.00 mm below the surface. Phrenic nerve output was biphasic during hypoxia, concurrent with a rapid glutamate and gradual GABA increase. Taurine first decreased, then increased. In both intact and chemodenervated animals, time-dependent change in phrenic nerve activity during hypoxia was associated with corresponding changes in glutamate, GABA, and taurine concentrations, suggesting that cumulative effects of changes in the concentration of these three amino acids could account for response of the phrenic nerve to hypoxia.

Rescaled range analysis of resting respiration

Fluctuations in resting depth of breathing (tidal volume) at constant breathing rate in the anesthetized adult rat exhibit fractal properties when analyzed by a rescaled range method characterized by a mean (+/-SD) exponent H=0.83+/-0.02 and 0.92+/-0.03 with and without sighs, respectively, for up to 400 breaths. Values of H determined from shuffled tidal volumes and simulated tidal volumes taken randomly from a Gaussian distribution of mean and variance approximating that of the actual data are consistent with the expected value of H=0.5 for an independent random process with finite variances. An empirical description is proposed to predict the change in H with length of time record.

Correlation in stimulated respiratory neural noise

Noise in spontaneous respiratory neural activity of the neonatal rat isolated brainstem-spinal cord preparation stimulated with acetylcholine (ACh) exhibits positive correlation. Neural activity from the C4 (phrenic) ventral spinal rootlet, integrated and corrected for slowly changing trend, is interpreted as a fractal record in time by rescaled range, relative dispersional, and power spectral analyses. The Hurst exponent H measured from time series of 64 consecutive signal levels recorded at 2 s intervals during perfusion of the preparation with artificial cerebrospinal fluid containing ACh at concentrations 62.5 to 1000 &mgr;M increases to a maximum of 0.875+/-0.087 (SD) at 250 &mgr;M ACh and decreases with higher ACh concentration. Corrections for bias in measurement of H were made using two different kinds of simulated fractional Gaussian noise. Within limits of experimental procedure and short data series, we conclude that in the presence of added ACh of concentration 250 to 500 &mgr;M, noise which occurs in spontaneous respiratory-related neural activity in the isolated brainstem-spinal cord preparation observed at uniform time intervals exhibits positive correlation. (c) 1995 American Institute of Physics.

Brain uptake and organ distribution of 11C from 11C-labeled glucose

The time course of the distribution of carbon-11 (11C, t1/2 = 20.4 min) in brain after the i.v. administration of 11C-labeled glucose [( 11C]glucose) was studied in an effort to understand and explore its behavior in relation to the known factors concerning the catabolic fate of glucose carbon in the brain. The biodistribution of 11C from [11C]glucose was studied in rats using organ dissection. Human radiation doses were estimated from rat biodistribution data. All the rat organs except the brain cleared with a half time of 30-60 min. The brain showed delayed uptake that plateaued from 20 to 60 min. The 11C distribution in normal, non-ischemic, brain 30 min after intravenously administered [11C]glucose is due to labeled carbon incorporation into amino acids associated with tricarboxylic acid cycle intermediates. External imaging with the Massachusetts General Hospital positron camera, PC I, was performed in dogs and humans and the time course of 11C incorporation was similar to the rat brain results. Regional uptake paralleled known metabolic differences between grey and white matter in normal human volunteers. A patient with progressive dementia had less uptake in an area of decreased perfusion as demonstrated angiographically, suggesting that the image obtained 20 min after tracer administration could be used to detect abnormalities in cerebral metabolism due to pathology.

Fractal Noise in Breathing

Our understanding of respiration derives from applications of a variety of physical and life science disciplines, methods, and models to a critical physiological process: exchange and balance of oxygen and carbon dioxide. We know that breathing at rest arises from a diversity of interrelated and interactive physical and chemical mechanisms involving molecular and cellular processes in the brainstem which include-among other phenomena common to the central nervous system-metabolism, synaptic transmission of neurochemicals, neurochemical-mediated alteration of neural cell membrane potential, transmembrane ion conductance, neural electrical signal propagation, and neuromodulation by afferent chemoreceptive and mechanoreceptive inputs.

A system for oxygen-15 labeled blood for medical applications.

Abstract Oxygen-15 labeled compounds in blood have been used successfully for cerebral circulation and cerebral oxygen metabolism measurements. The present paper describes a system for the rapid sequential production of 15OHgB, C15OHgb and H215O in blood under sterile and pyrogen-free conditions. A tonometer has been adopted for labeling blood without hemolysis and foam production.

Temporal Correlation in Phrenic Neural Activity

Neural activity which gives rise to eupnea fluctuates in a complex manner. Apparently “noisy” variations in activity of the phrenic nerve may display a fractal scaling relationship. Fractal scaling in eupnea is the consequence of physical and chemical processes acting over short time scales at the cellular level, and which are correlated with similar processes acting simultaneously over longer time scales. Specifically, variations in phrenic neural bursts may not be independent random fluctuations or entirely due to short-range influences4, but may exhibit temporal correlation indicative of fractal scaling. West and Deering20 have demonstrated that fractal processes are essentially unresponsive to error and very tolerant of variability in the physiological environment. In this view, eupnea with its concomitant stability to error from a broad spectrum of inputs must have the error-tolerant properties of fractals.

Phrenic Nerve Response to Glutamate Antagonist Microinjection in the Ventral Medulla

Effects of amino acid neurotransmitters on central respiratory drive roughly parallel their excitation or inhibition of neurons1. The major amino acid neurotransmitter glutamic acid is of particular interest because it stimulates ventilatory drive centrally at sites and via mechanisms within the surface of the ventral medulla (VM). Glutamate metabolism in the brain is directly related to CO2 metabolism and fixation in the brain. Decarboxylation of glutamate via the enzyme glutamic acid decarboxylase (GAD) localized substantially in nerve endings, results in formation of the inhibitory amino acid and central respiratory depressant, γ-aminobutyric acid (GABA)4. Recent studies5,6 have shown that the classic biphasic ventilatory response to acute hypoxia has a glutamatergic component, namely, the initial hyperventilatory response is mediated in part by central glutamate. Topical application of glutamatergic receptor antagonists during normoxia to the surface of the VM diminishes central ventilatory drive via reduction in phrenic nerve output11. The present study was therefore undertaken with multiple microinjections of the selective noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to localize in the VM the effects of blocking glutamate receptor on phrenic nerve output and to quantitate the effects via a model of chemoreceptor-antagonist interaction.

Afferent Input from Peripheral Chemoreceptors in Response to Hypoxia and Amino Acid Neurotransmitter Generation in the Medulla

The ventilatory response to acute hypoxia is biphasic with an initial hyperventilatory response followed by a fall in ventilation within a few minutes (roll-off) to levels above the pre-hypoxic values, but below the peak. The physiological sequence of events underlying the biphasic ventilatory response to hypoxia has not been completely elucidated. Different experimental approaches suggest that both local (i.e., neurochemical activity) and global (i.e., metabolic) mechanisms may very well be crucial during this transient phase of ventilatory hypoxic response. Numerous investigations (Bianchi et al, 1995; Weil, 1994), as well as work in our own laboratory (Kazemi et al, 1989; Hoop et al, 1990; Kazemi & Hoop, 1990), have directed attention to a possible central locus of the phenomenon in the ventrolateral medullary surface (VMS). The excitatory amino acid glutamate and the inhibitory amino acids γ-aminobutyric acid (GABA) and glycine appear to have special roles to play in the response. Namely, afferent stimuli from peripheral chemoreceptors lead to release of excitatory glutamate in the intermediate area of the VMS which cause the increase in central ventilatory output (Soto-Arape et al, 1995). Brain hypoxia also causes a rise in inhibitory GABA and glycine which then diminishes respiratory neuronal output.

Evaluating diagnostic strategies for pulmonary embolism.

To the Editor, Diagnosis of venous thrombosis and pulmonary embolism remains a complex and controversial issue, in spite of new technologies brought to bear upon the problem [1]. In a recent editorial, Adelstein and McNeil [2] make an appeal for objective assessment of the value of new diagnostic technologies. They refer specifically to a promising new noninvasive but not widely available test for diagnosis of pulmonary embolism, proposed by Nichols et al. [3]. This test is one of a number of tests in recent years that have successfully employed imaging technology to measure the spatial distributions in a patient of pulmonary ventilation and perfusion, as well as of related physiological parameters [4,5]. Information on these distributions has proved useful in diagnosing and treating pulmonary embolism [6]. The appeal made by Adelstein and McNeil provides an opportunity to consider some of the issues involved in a decision-analytic method by which new technologies for diagnosing pulmonary embolism may be systematically and objectively evaluated. Adelstein and McNeil propose a strategy in which indeterminate results of a perfusion-ventilation scintigraphic test be further tested with pulmonary angiography. A model of this strategy is diagrammed in Figure 1. The strategy consists of a pulmonary ventilation-perfusion study (Circle 1) for which all patients incur an overhead cost Ci, followed by a pulmonary angiographic study (Circle 2) only for patients for whom the results of the first study are indeterminate; these patients incur an additional overhead