Frederic L. Eldridge

Prolonged stimulation of respiration by a new central neural mechanism

The inspiratory responses to stimulation by peripheral chemoreceptor, central chemoreceptor and calf muscle afferents were studied in anesthetized, or decerebrate, paralyzed cats whose end-tidal PCO2 was servo-controlled and kept constant. All stimuli were associated with immediate increases of inspiratory (phrenic) activity and at offset were followed by a respiratory afterdischarge lasting approximately five minutes. The level of inspiratory activity following decay of the afterdischarge was the same as the prestimulation control after central chemoreceptor and calf muscle stimulation. However, after peripheral chemoreceptor afferent stimulation the stable level of inspiratory activity following the afterdischarge had increased over the prestimulation level and remained elevated for as long as it was followed, up to 90 min. Decerebration, vagotomy, and section of the spinal cord at C--T1 did not prevent this long-lasting increase in respiration. We conclude that we have demonstrated a new ponto-medullary neural mechanism which is uniquely activated by peripheral chemoreceptor afferent input; once activated, this mechanism sustains respiration at an increased level for a long period of time.

Prolonged stimulation for respiration by endogenous central serotonin

We have recently reported a new neural brainstem mechanism which is uniquely activated by stimulation of carotid body afferent input to the brain and which facilitates respiration for hours after the immediate affects of the stimulation have dissipated (Millhorn, Eldridge and Waldrop, 1980). In the present study respiratory responses to carotid body or carotid sinus nerve stimulation were measured in vagotomized, anesthetized, and paralyzed cats whose end-tidal PCO2 and temperature were servo-controlled and kept constant. The responses of animals pretreated with various serotonin antagonists and a dopamine-norepinephrine antagonist were compared to the responses of untreated control animals. All three differently acting serotonin antagonists (methysergide, parachlorophenylalanine, and 5, 7-dihydroxytryptamine) either prevented or significantly reduced the magnitude of the long-lasting respiratory response whereas the dopamine-norepinephrine antagonist (alpha-methyltyrosine) failed to alter it. We conclude that the long-lasting increase of respiratory activity following stimulation of carotid body afferents is due to activation of an endogenous central serotoninergic mechanism which facilitates respiration.

Respiratory-associated thalamic activity is related to level of respiratory drive

We recorded phrenic nerve activity and thalamic single unit firing in unanesthetized, suprathalamically decerebrated, paralyzed and ventilated cats, in which vagi and carotid sinus nerves (CSN) had been ablated. Seventy-six (14%) of 545 neurons in regions of the thalamus related to the ascending reticular system, which had been tonically firing at low respiratory drives, developed rhythmic increases of firing associated with each respiration when drive had been increased by CSN stimulation or hypercapnia. The increases of neuronal firing occurred in late inspiration/post-inspiration but sometimes lasted into expiration; the magnitude of change was graded according to the magnitude of respiratory activity. Thalamic neurons also fired with a rhythm related to ventilator-induced chest expansion, some units showing both the respiratory-associated and the ventilator-related rhythms. Simultaneously recorded mesencephalic and thalamic neurons developed similar rhythms when drive was increased. We suggest that these neuronal activities reflect the conveyance of information about respiration to the cortex, where it may lead to the sensation of dyspnea and perhaps to arousal.

The importance of timing on the respiratory effects of intermittent carotid body chemoreceptor stimulation

1. The respiratory response, measured directly as tidal volume or indirectly by using integrated peak phrenic activity, to brief intermittent chemical stimulation or depression of the carotid body was determined in anaesthetized cats. Recordings of carotid sinus nerve impulses allowed precise timing of the stimulus.

Input‐output relationships of central neural circuits involved in respiration in cats

1. Inspiratory output responses, measured as integrated phrenic activity, to hypercapnia, to unilateral and bilateral carotid sinus nerve stimulation and to combinations of these stimuli were determined in paralysed, vagotomized and glomectomized cats whose end‐tidal PCO2 was kept constant by means of a servo‐controlled ventilator. In addition, the effect on these responses of the mechanism that causes the respiratory after‐discharge was determined.

Mechanism of respiratory effects of methylxanthines

Neural respiratory responses to theophylline, aminophylline and ethylenediamine were determined in paralyzed, vagotomized and glomectomized cats whose end-tidal PCO2 and brain temperature were kept constant. Intravenous theophylline and aminophylline similarly stimulated respiration, but ethylenediamine had no effect. The following did not cause the response: muscular and mechanical factors, carotid body and vagal reflexes, spinally mediated mechanisms arising below C7, changes of arterial PCO2 or medullary ECF pH, changes of whole body metabolic rate or release of substances from the adrenal glands. Absence of suprapontine brain did not prevent the response. Pretreatment with a serotonin antagonist did not affect the response but two different dopamine antagonists caused its attenuation. When administered into the third ventricle, theophylline did not stimulate respiration, but both aminophylline and ethylenediamine, due to the latters ability to mimic the inhibitory effects on neurons of gamma-aminobutyric acid (GABA), caused significant depression of respiration. We conclude that the neural respiratory response to systemically administered theophylline is mediated at the level of the brainstem, and somehow involves the action of the neurochemical dopamine. The failure of cerebroventricularly administered theophylline to stimulate respiration must be related to its inability to reach the appropriate neurons from the cerebrospinal fluid.

The importance of timing on the respiratory effects of intermittent carotid sinus nerve stimulation

1. The respiratory response, measured directly as tidal volume or indirectly by using integrated peak phrenic activity, to intermittent electrical stimulation of the carotid sinus nerve was determined in anaesthetized cats.

Central neural respiratory drive and afterdischarge

Different modes of stimulation of the carotid sinus nerve were used in anesthetized cats to study development of inspiratory neural activity and respiratory afterdischarge. Continuous and inspiratory-only stimulations produced rapid rises of activity; cessation led to equally rapid initial falls followed by slowly decaying afterdischarges. Expiratory-only stimulations produced more slowly rising and smaller increases of inspiratory activity and the offset led to no rapid fall of activity; nevertheless, the time course of the afterdischarge was similar to those of continuous and inspiratory runs. During alternate cycle stimulation, the developing pattern of activity of stimulated breaths resembled that of continuous or inspiratory stimulation, whereas that of unstimulated breaths was like expiratory. The findings support conclusions that the neural network causing the afterdischarge is separate from and does not require input from inspiratory neurons in the medulla. Both the activation and decay times of this neural mechanism are relatively long.

Role of endogenous adenosine in recurrent generalized seizures

We induced generalized seizures by cortical injection of penicillin in anesthetized, paralyzed cats. After they had developed recurrent ictal-interictal ECoG cycling and fictive tonic-clonic motor convulsions (status epilepticus), we studied the effect of systemically administered neuropharmacological agents on the seizure cycling. Antagonists of adenosine receptors, theophylline and 8-cyclopentyltheophylline, increased the cycle period due to marked prolongation of duration of ictal discharge, often to more than 30 min. Dipyridamole, an inhibitor of adenosine reuptake, lengthened the interictal phase of the seizure with no effect on ictal duration. Antagonists of gamma-aminobutyric acid and opioid peptides had no effect on either ictal or interictal phases nor did the nonspecific neural excitant, doxapram. These findings suggest that a major mechanism of ictal-interictal cycling during status epilepticus is the alternating accumulation during the ictal phase and clearance during the interictal phase of the inhibitory neurochemical, adenosine.

Prolonged inhibition of respiration following acute hypoxia in glomectomized cats

Respiratory responses to several minutes exposure to hypoxia (PaO2 less than 30 torr) were determined in anesthetized, paralyzed, vagotomized and glomectomized cats whose end-tidal PCO2 and body temperature were kept constant. Respiratory activity was quantified from phrenic nerve activity. Animals breathed 100% O2 during the control period. The study reaffirmed that in glomectomized animals hypoxia causes depression of respiratory activity. The new finding was that phrenic activity remained significantly depressed below the original control level for more than one hr after return to the hyperoxic state. Medullary ECF pH was measured in 3 cats. There was an acid shift of pH during hypoxia that persisted for more than one hour after return to hyperoxic state. We pretreated another group (n = 5) of animals with theophylline, a specific antagonist of the inhibitory neurotransmitter adenosine. Hypoxia still caused depression of respiratory activity, but it was less severe than in untreated animals. Upon return to the hyperoxic state, respiratory activity returned to the original control level within 10 min. We conclude that the long-lasting depression of respiration following hypoxia is mediated by adenosine. Furthermore, adenosine appears to be partially responsible for the acute depression of respiration during the hypoxic exposure.