Biomedical subjects

F L Eldridge

Publications and source records attributed to F L Eldridge.

At least 37 records · Page 2Linked to original sources

PubMed1987

Effects of hyperoxia on medullary ECF pH and respiration in chemodenervated cats.

The effects of transitions from air-breathing to hyperoxia (100% O2), and the reverse, on respiration (phrenic activity) and on medullary extracellular fluid (ECF) pH, or hydrogen ion concentration [H+], were studied in 8 anesthetized, paralyzed, vagotomized and glomectomized cats whose end-tidal PCO2 was kept constant. The transition from air to hyperoxia (7 cats) led to a small (1.23 nmol/L [H+], 0.010 pH unit) acidic shift of medullary ECF and a 24% increase of neural tidal and minute respiratory activity with no significant change of frequency. Opposite changes of approximately equal magnitude followed the transition from hyperoxia to air (8 cats). We show that the slopes of the respiratory responses to changing ECF [H+] in the present study are not different than the slopes with CO2-induced changes of ECF [H+] in 25 other cats. Our findings indicate that most, if not all, of the respiratory increase after hyperoxia is due to accumulation of CO2 and H+ in medullary ECF that act on the central chemoreceptors. We suggest that decreased medullary blood flow and the Haldane effect are the main mechanisms causing the rise of medullary PCO2 and stimulation of breathing.

Animals↗

PubMed1987

Dynamics of medullary hydrogen ion and respiratory responses to square-wave change of arterial carbon dioxide in cats.

1. The dynamics of changes of medullary extracellular fluid (ECF) hydrogen ion concentration ([H+]) and respiration, measured as integrated phrenic nerve activity, were determined in anaesthetized, paralysed, vagotomized and glomectomized cats. ECF [H+] was measured directly by means of a small (2 mm diameter) glass pH electrode placed on the ventral surface of the medulla. The variables were measured continuously after a step change of arterial PCO2 produced by abruptly starting or stopping an infusion of hypercapnic fluid into the aortic arch. 2. Alteration of pH in the descending thoracic aorta at the onset or offset of infusion was complete within 1.5 s after the change began, indicating that it was nearly square wave in form. 3. In sixteen experiments, ECF [H+] began to fall within 2 s of offset of infusion, reflecting aortic-medullary circulation time. Thereafter, ECF [H+] decreased to a stable level over the next 5 min; the curve describing the decrease consisted of two exponential functions, one with a time constant (tau) of 9.5 +/- 0.6 s and a second with a tau of 53 +/- 3 s. 4. We interpret the findings at the offset of CO2 infusion in terms of CO2 wash-out from the medullary ECF. The slow function is associated with wash-out during stable medullary blood flow that develops after 1 min. The early fast function is associated with the decreasing medullary blood flow that occurs during the first minute after change from arterial hypercapnia to normocapnia. 5. We have estimated medullary blood flow using a mathematical model incorporating the two functions. The values obtained are consistent with those in the literature where other methods have been used. Changes of blood flow following the step change of CO2 are fairly rapid, half of the response occurring in 13 s. 6. The change of respiratory activity lags the change of stimulus expressed by [H+], throughout the recovery period and respiration requires up to 8 min to reach a stable level. We attribute this slow response to slow central neural respiratory dynamics, the respiratory after-discharge.

Action Potentials↗

PubMed1987

Spinal inhibition of phrenic motoneurones by stimulation of afferents from leg muscle in the cat: blockade by strychnine.

1. Phrenic nerve responses to stimulation of calf muscle receptors or their afferents were studied in paralysed high (C1) spinal cats whose phrenic nerve activity was evoked by activation of the intercostal-to-phrenic reflex. End-tidal PCO2 was maintained at a constant level by means of a servo-controlled ventilator. 2. Physical stimulation of calf muscles or electrical stimulation of the tibial nerve uniformly caused inhibition of phrenic activity evoked by facilitatory conditioning stimuli. The degree of inhibition gradually decreased as muscle stimulation continued, and there was a post-stimulus augmentation of phrenic activity. 3. Pre-treatment with subconvulsive doses of strychnine, an antagonist of the neurotransmitter glycine, partially or completely blocked the inhibitory effects on phrenic activity of muscle-afferent stimulation. The blockade was reversible with time. 4. Pre-treatment with a subconvulsive dose of bicuculline, an antagonist of the neurotransmitter gamma-aminobutyric acid (GABA), had no effect on the inhibitory mechanism. 5. We conclude that glycine is an important transmitter of the inhibition of phrenic motoneurones induced by muscle-afferent stimulation, but that GABA is not involved in this inhibitory mechanism.

Action Potentials↗

PubMed1987

Phase resetting and dysrhythmic responses of the respiratory oscillator.

This study explores resetting of respiratory rhythm by facilitatory perturbations. The midbrain reticular formation and periaqueductal gray matter were electrically stimulated to evoke facilitation of phrenic nerve activity in nine anesthetized, vagotomized, and glomectomized adult cats. The animals were paralyzed and servo-ventilated to keep end-tidal PCO2 constant. Brief midbrain stimuli were given at various times in the respiratory cycle and the times of onset of rescheduled breaths after stimulation were measured. A plot of phase resetting as a function of stimulus strength and time of delivery defined a helicoid surface. The axis of this helicoid identified a unique stimulus which, when given at the inspiratory-expiratory transition, resulted in unpredictable resetting of respiratory rhythm. This stimulus had a strength that was intermediate to that which identified types 1 and 0 resetting. In one experiment, the singular stimulus often initiated a breath having prolonged inspiratory activity; resumption of the normal rhythm was delayed significantly (P less than 0.01). We conclude that the dysrhythmias observed in this study represent the respiratory oscillator's phase singularity.

Animals↗

PubMed1987

Diencephalic regulation of respiration and arterial pressure during actual and fictive locomotion in cat.

The purpose of this study was to examine by experimentation the hypothesis that the respiratory and circulatory responses during exercise are attributable to command signals that emanate from the suprapontine brain. We studied the relations between locomotion (exercise) and phrenic nerve activity and arterial pressure in cats that walked or ran on a treadmill and in animals during fictive locomotion, i.e., locomotor activity in motor nerves to legs. Anesthetized cats with intact brains and unanesthetized decorticated cats were used. All preparations exhibited spontaneous actual and fictive locomotion. Electrical stimulation or microinjection of picrotoxin, a GABA antagonist, of the subthalamic locomotor areas always caused locomotion to develop. Phrenic nerve activity and arterial pressure increased in proportion to the level of locomotor activity despite control or ablation of feedback signals from chemoreceptors and vagal receptors. Similar relations were measured during fictive locomotion despite the absence of muscular contraction and limb movement and the lack of change in metabolic rate. These findings provide experimental support for the central command hypothesis for the genesis of the respiratory hyperpnea and increased cardiovascular function that occur during exercise. We believe that the command signals emanate from the subthalamic locomotor area of the diencephalon.

Animals↗

PubMed1986

Resetting of mammalian respiratory rhythm: existence of a phase singularity.

The purpose of this study was to use topological methods of analysis to determine if a phase singularity exists for the neural respiratory oscillator. We studied resetting behavior of central respiratory rhythm, measured as phrenic nerve activity, by using brief stimulations of the superior laryngeal nerve in anesthetized paralyzed adult cats. The strength and timing of stimuli were varied, and the times of onset of subsequent breaths were measured. Two distinct types of phase resetting were identified: type 1 resetting for weak stimuli and type 0 resetting for strong stimuli. With stimuli of intermediate strength, we obtained a series of phase-resetting curves that defined a helicoid-resetting surface having a phase singularity near the transition between late expiration and early inspiration. In this domain resumption of breathing occurred at highly variable resetting times. The mammalian respiratory oscillator thus has qualitative characteristics of response to brief stimuli that are similar to those of other biological oscillators.

Animals↗

PubMed1986

Role of ventrolateral medulla in regulation of respiratory and cardiovascular systems.

It is now widely accepted that the ventrolateral aspect of the medulla oblongata (VLM) plays an important role in regulation of the respiratory and cardiovascular systems. The VLM has been implicated as being involved in a number of different physiological functions, including central chemoreception, integration of afferent inputs from certain sense organs to the respiratory and cardiovascular controllers, the source of excitatory input to preganglionic sympathetic neurons in the spinal cord, and location of synaptic relay between the higher brain defense areas and spinal cord sympathetic elements. In recent years there have been a number of important findings concerning both the anatomical substrate and neurophysiological characteristics of VLM neurons involved in regulation of the respiratory and cardiovascular systems. New anatomical findings show that neuronal networks located in the VLM send projections to and receive projections from brain stem nuclei that have traditionally been associated with respiratory and cardiovascular regulation. Nevertheless, there are still many important questions concerning the role of the VLM in control of these vital systems that have yet to be answered. For instance, are the same VLM neurons involved in control of both systems? Is the VLM the only site for central respiratory chemoreception? This review will endeavor to examine new findings and to reexamine some older findings concerning the VLM.

Animals↗

PubMed1986

Neuromodulators and transmitters in respiratory control.

The respiratory control system is influenced by classical neurotransmitters and by neuromodulators. The neuromodulators are neuroactive substances that can be secreted at a distance from their receptors and must diffuse to their site of action. Their function can be nonsynaptic and long lasting, and their effect can be direct or indirect via other neuroactive substances. In the central nervous system, a variable degree of mismatch exists between sites of neuromodulator secretion and reception. The assignment of a natural role for a neuromodulator in respiratory control is strengthened by evidence from a variety of experimental approaches, including localization of receptor sites in respiratory-related areas and evidence for natural binding of neuromodulators to these receptors, neurophysiological and respiratory responses to the neuromodulators and their antagonists, and, finally, modulation of specific respiratory responses by neuromodulator antagonists to document the role of the endogenous modulator in eliciting the original response. Neuromodulators that are considered seriously as natural participants in respiratory control include dopamine in peripheral chemoreception and adenosine, endorphins (including enkephalins), serotonin, and substance P in central respiratory regulation.

Adenosine↗

PubMed1985

The roles of medullary extracellular and cerebrospinal fluid pH in control of respiration.

To determine the effective stimulus to the central chemoreceptors, we measured CSF and medullary extracellular fluid (ECF) pH and phrenic activity in 11 anesthetized, paralyzed, vagotomized and glomectomized cats. Flat-tipped pH electrodes (2 mm diam.) were used to measure ECF pH on the ventral surface of the medulla and CSF pH 2 mm above the surface. Changes in alveolar/arterial PCO2 were produced by airway occlusions of 10-20 sec durations. Changes in CSF PCO2 and pH were made by infusing 100% CO2 or an acid buffer into the CSF. Airway occlusion caused an increase of alveolar/arterial PCO2. ECF pH began to fall 6-10 sec later, with a maximum decrease of 0.032 pH unit at 21.9 sec. Phrenic activity increased as ECF pH decreased, the greatest activity occurring when ECF pH was most acid. CSF pH decreased after a longer delay. Its maximum decrease at 54.1 sec was smaller (0.026 pH unit) than ECF pH and did not correlate with the increase of phrenic activity. Addition of 100% CO2 or an acid buffer into the CSF produced an acid shift in the CSF pH but no change in ECF pH or phrenic activity. Prolonged (greater than 30 min) increase of acidity of CSF did not alter phrenic activity until ECF pH developed a delayed acid shift. Even then, the change of ECF pH was much smaller than that of CSF. We conclude that medullary chemoreceptors do not respond to changes of CSF pH or PCO2 and that change of pH of CSF minimally affects ECF pH. On the other hand, respiratory responses are closely linked to changes in ECF pH.

Animals↗

PubMed1985

Excitatory and inhibitory effects of morphine on the intercostal-to-phrenic respiratory reflex.

The purpose of this study was to determine the effect of intravenously administered morphine on the intercostal-to-phrenic reflex in spinal (C1) cats. The carotid and vertebral arteries were ligated. In addition a metal clamp was placed around the neck and tightened in order to occlude all blood flow to the brain. The animals were vagotomized, paralyzed and ventilated artificially. End-tidal PCO2 and body temperature were kept constant by means of servocontrollers. The intercostal-to-phrenic reflex was activated by rhythmic tapping of the lower thorax anteriorly with a metal bar. Three different doses of morphine were used. The smallest dose (1 mg/kg) caused a marked stimulation of phrenic activity that lasted for more than 5 min. A larger dose (10 mg/kg) had only a mild excitatory effect. A much larger dose (50 mg/kg), on the other hand, caused inhibition of evoked phrenic activity. Possible mechanisms involved in mediating the dose dependent effects of morphine on the intercostal-to-phrenic reflex are discussed.

Animals↗

PubMed1985

Stimulation by central command of locomotion, respiration and circulation during exercise.

We studied the relationships between exercise (locomotion) and respiratory and circulatory responses in 19 cats that walked or ran normally on a treadmill, and in 16 paralyzed animals during fictive locomotion, i.e., locomotory activity in motor nerves to the legs. Preparations included anesthetized cats with intact brains and unanesthetized decorticate (hypothalamic) and decerebrate (mesencephalic) animals. Spontaneous actual locomotion and fictive locomotion occurred in all preparations except the mesencephalic cats. Electrical stimulation or injection of a GABA antagonist (picrotoxin) into the hypothalamic locomotor region caused locomotion to develop. In all cases when locomotion occurred, respiration and arterial pressure increased in proportion to the level of locomotor activity despite control or ablation of respiratory feedback mechanisms. Respiration and arterial pressure increased similarly during fictive locomotion despite the absence of muscular contraction or limb movement and the lack of change of metabolic rate. We conclude that the study provides experimental support for the feed-forward, or command signal, hypothesis for the genesis of proportional changes of respiration and circulation that occur during exercise. Feedback mechanisms are not required for its operation. We suggest that command signals emanating from the hypothalamus provide the primary drive for changes of respiration and circulation during exercise.

Animals↗

PubMed1985

Respiratory responses to medullary hydrogen ion changes in cats: different effects of respiratory and metabolic acidoses.

The steady-state responses of respiration, measured as integrated phrenic nerve activity, to hypercapnic acidosis of the medullary extracellular fluid (e.c.f.) and to metabolically generated acidosis were compared in paralysed, vagotomized and glomectomized cats. E.c.f. hydrogen ion concentration [( H+]) was measured directly by means of a small (2 mm diameter) pH electrode placed on the ventral medulla. The results in ten cats show that changes of medullary e.c.f. [H+] were linearly related to changes of end-tidal PCO2 both before (r = 0.999) and after (r = 0.996) development of metabolic acidosis. There was a curvilinear relation between hypercapnic e.c.f. [H+] changes and the respiratory response that reflects progressive saturation of a central neural pathway between the chemoreceptors and the respiratory controller. This relation was similar in form both before and after development of metabolic acidosis. When acidosis of metabolic origin was present, apnea occurred with only small decreases of CO2 despite a high [H+]. The respiratory responses to the same e.c.f. [H+] change were only about one-half as large when they were generated metabolically as when they were generated by raising PCO2. Both exogenously induced metabolic acidosis (HCl infusion) and endogenous acidosis yielded similar results. We conclude that the e.c.f. [H+] does not represent the unique stimulus to the central chemoreceptors. We discuss several alternate mechanisms for the action of CO2 and [H+] on central chemoreceptors but none can be considered definitive at the present time.

Animals↗

PubMed1985

Mechanisms of respiratory response to isoproterenol in glomectomized cats.

Effects of intravenous isoproterenol (2-3 micrograms) on arterial pressure, end-tidal CO2 partial pressure (PCO2), medullary extracellular fluid (ECF) pH, and phrenic activity were studied in 13 anesthetized paralyzed cats whose vagi and carotid sinus nerves were cut. The cats were servo-ventilated to keep PCO2 relatively constant. Injections of Ringer solution were without effect. Isoproterenol caused arterial pressure to fall, a transient small (1 Torr) increase of PCO2, increased venous CO2 return to the lungs, a medullary ECF acidosis, and a stimulation of respiration that continued to be elevated after arterial pressure, PCO2, and medullary ECF pH had returned to control. We show that the ECF acidosis is minimally due to the hypotension and to the small transient rise of PCO2. We also show that the respiratory response cannot be explained solely by the ECF acidosis. We conclude that, in addition to its known stimulation of peripheral chemoreceptors, isoproterenol causes medullary ECF to become acidic probably due to metabolic effects on neural tissue and has a separate direct stimulating effect on neurons in the brain.

Animals↗

PubMed1985

Respiration during hypothermia: effect of rewarming intermediate areas of ventral medulla.

We studied respiration (phrenic nerve activity) during progressive hypothermia to as low as 30.5 degrees C in five anesthetized, paralyzed, glomectomized, and vagotomized cats. PCO2 was maintained at a constant level throughout the experiments. We confirmed the results of a previous study (J. P. Kiley, F. L. Eldridge, and D. E. Millhorn, J. Appl. Physiol. 58: 295-312, 1985) in which respiratory minute output decreased progressively with cooling and respiratory frequency decreased markedly. In addition we show that focal rewarming to normal temperature (37.5 degrees C) of the structures in the intermediate areas on the ventral surface of the medulla resulted in a significant reversal of the depressed respiratory minute activity observed with hypothermia. Respiratory frequency, however, was unaffected by intermediate area rewarming. We conclude that the decreased respiratory activity during hypothermia is due to a generalized interference with neural function. A major portion of these effects is due to cooling of the intermediate areas, but the slowing of respiratory frequency appears to be an independent effect.

Animals↗

PubMed1985

Antagonism by theophylline of respiratory inhibition induced by adenosine.

The effects on respiration of an analogue of adenosine, L-2-N6-(phenylisopropyl)adenosine (PIA), and of the methylxanthine, theophylline, were determined in 19 vagotomized glomectomized cats whose end-tidal PCO2 was kept constant by means of a servo-controlled ventilator. Integrated phrenic nerve activity was used to represent respiratory output. Our results show that PIA, whether given systemically or into the third cerebral ventricle, depressed respiration. Systemically administered theophylline stimulated respiration. Theophylline given intravenously, or into the third ventricle not only reversed the depressive effects of previously administered PIA but caused further increases of respiration above the control level. Prior systemic administration of theophylline blocked both respiratory and hypotensive effects of subsequently administered PIA. Effects of either agent on medullary extracellular fluid pH did not explain the results. We conclude that the adenosine analogue PIA, acts to inhibit neurons in the brain that are involved in the control of respiration and that its effects are blocked by theophylline. We suggest that adenosine acts as a tonic modulator of respiration and that theophylline stimulates breathing by competitive antagonism of adenosine at neuronal receptor sites.

Adenosine↗

PubMed1984

Effects of centrally administered naloxone on phrenic nerve activity.

The present study examined the effect on respiration of naloxone administered centrally. Experiments were performed on anesthetized, paralyzed cats whose vagi and carotid sinus nerves had been cut. The animals' end-tidal pCO2 and body temperature were kept constant with servocontrollers. Naloxone administered into the third cerebral ventricle in doses of 40 micrograms/kg and 400 micrograms/kg resulted in significant (P less than 0.05) increases in phrenic neural activity. The response to the 400 micrograms/kg dose was significantly greater (P less than 0.05) than the response to the 40 micrograms/kg dose. A dose of 40 micrograms/kg naltrexone administered to each of two animals produced similar increases in respiratory activity. These data indicate that in the preparation studied endogenous opiates exert a tonic inhibitory effect on respiration through their action on central opiate receptors.

Animals↗

PubMed1984

Respiratory effects of a long-acting analog of adenosine.

The effect on respiration, measured as integrated phrenic nerve activity, of an analog of adenosine, N6(L-2-phenylisopropyl)adenosine (PIA), was determined in 26 paralyzed, vagotomized and glomectomized cats whose end-tidal pCO2 was kept constant by means of a servocontrolled ventilator. Whether given intravenously or into the third cerebral ventricle, PIA caused a dose-related depression of respiration, involving both tidal activity and respiratory frequency. In a group of 6 cats, the effects of intraventricular PIA or its vehicle alone on medullary extracellular fluid (ECF) pH were also determined. Vehicle alone had no effect on either ECF pH or respiratory activity. PIA was associated with the development over 10-20 min of a metabolic acidosis in the medulla, but still led to marked depression of respiration, thus ruling out an increase of medullary blood flow as cause of the decreased respiration. We conclude that the adenosine analog, PIA, acts to inhibit directly neurons in the brain that are involved in the control of respiration, and we suggest that adenosine may act as a tonic modulator of respiration.

Acid-Base Equilibrium↗

PubMed1984

The effect of hypothermia on central neural control of respiration.

The effects of whole body hypothermia on metabolism, blood and medullary acid-base, and respiratory variables were determined in 29 paralyzed, vagotomized and glomectomized cats. Respiratory output was quantified from integrated phrenic nerve activity. Metabolic rate (VCO2) decreased progressively as temperature decreased. When end-tidal PCO2 was kept constant by decreasing artificial ventilation, cooling of the brain to 30.5 degrees C resulted in a large decrease of respiratory frequency (f) with prolongations of both inspiratory (TI) and expiratory (TE) times but an increase in neural tidal activity (VTN). Neural minute activity (MVN) and rate of rise of phrenic activity (RR) decreased moderately despite an acid shift of arterial and medullary extracellular fluid (ECF) pH and a decrease in the fractional dissociation of imidazole (alpha Im). Anesthesia, decerebration and spinal cord section at C7-T1 did not alter the responses. When ventilation was kept constant during cooling so that PCO2 decreased along with metabolic rate, all respiratory variables (VTN, f, MVN and RR) decreased significantly and reached near apneic levels at 30.5 degrees C. These changes were associated with an alkaline shift in ECF pH. Fractional dissociation of imidazole (alpha Im) remained constant at all temperatures. Our findings do not support the hypothesis of 'alphastat' regulation as a general explanation of central chemical control of breathing in homeotherms. We also present arguments that it may not apply to the control of breathing in ectotherms. We conclude that hypothermia affects both respiratory drive and timing mechanisms through its effect on neural synaptic function.

Acid-Base Equilibrium↗