Biomedical subjects

R O Davies

Publications and source records attributed to R O Davies.

At least 19 recordsLinked to original sources

PubMed1994

Changes in serotonin level in the hypoglossal nucleus region during carbachol-induced atonia.

The excitability of hypoglossal (XII) motoneurons innervating genioglossal muscles is markedly suppressed during the rapid-eye-movement (REM) stage of sleep. This may contribute to airway obstructions in sleep apnea patients. Based on our earlier studies in decerebrate cats using injections of carbachol into the pons to induce a REM sleep-like atonia and microinjections of serotonin (5HT) into the XII motor nucleus, we hypothesized that a sleep-related withdrawal of the serotonergic excitatory input to XII motoneurons may play a major role in these processes. To test one aspect of this hypothesis, we inserted microdialysis probes into the XII nucleus region of decerebrate, paralyzed, vagotomized and artificially ventilated cats. The probes were perfused without or with the addition of a 5HT reuptake blocker, clomipramine. The levels of 5HT and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined using HPLC and electrochemical detection in dialysate samples collected over successive 20 min periods under four successive experimental conditions: control (at least 2 h after probe insertion); during the postural atonia and respiratory depression produced by pontine microinjection of carbachol; recovery from the effects of carbachol produced by pontine microinjection of atropine; and, to verify that the presence of 5HT in the dialysate was related to the activity of serotonergic cells of the brainstem, following administration of 8-OH-DPAT, a 5HT 1A receptor agonist known to suppress activity in the serotonergic cells of the raphe system. After correcting for recovery rates of individual probes, the mean control 5HT level in the extracellular space of the XII nucleus region was 7.9 +/- 4.4 nM (S.D.) in eight experiments without reuptake blockers. During the carbachol-induced depression, it was reduced to 70 +/- 20% of the pre-carbachol level. It increased to the original control level 98 +/- 27% after pontine injection of atropine. 8-OH-DPAT reduced the 5HT level to 43 +/- 14% of the post-atropine level. Changes in the 5HIAA level were not as consistent as for 5HT and did not reach statistical significance under any of the experimental conditions. Thus, a functionally significant amount of 5HT is present in the extracellular space within the XII nucleus region, and its decrement during carbachol-induced, REM sleep-like atonia is likely to reflect that occurring during natural REM sleep; this may contribute to the decreased tone of upper airway muscles and airway patency.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Behavior of VRG neurons during the atonia of REM sleep induced by pontine carbachol in decerebrate cats.

The microinjection of carbachol into the pons of acute decerebrate cats elicits a REM sleep-like atonia and a profound suppression of respiratory motoneuronal activity (J. Appl. Physiol., 69 (1990) 2280-2289). To assess whether this suppression is mediated by medullary neurons that provide respiratory drive to motoneurons of the respiratory pump muscles (diaphragm and intercostals), we studied the effect of pontine carbachol on the activity of neurons of the ventral respiratory group (VRG) in decerebrate, vagotomized, paralyzed and artificially ventilated cats. VRG neurons were recorded extracellularly along with the activity of phrenic and intercostal (external and internal) nerves. Both inspiratory (I) and expiratory (E) VRG neurons had incrementing, ramp-like bursts of activity during their firing periods and were not vagal motoneurons. Carbachol produced a depression of the peak firing rate in most (42/57) neurons studied. However, five cells showed no change and ten had an increase in activity in spite of consistent depression at the motoneuronal level. For the total population of cells (34 I and 23 E), the peak firing was reduced to 88.5% +/- 16.3 (S.D.) of control. The simultaneously recorded phrenic activity was reduced to 77.9% +/- 11.5, while inspiratory intercostal activity fell to 63.4% +/- 21.6 and expiratory to 23.2% +/- 21.2 of control. The carbachol-induced changes in peak firing of both I and E cells were quantitatively similar, and positively correlated to changes in peak phrenic activity. Analysis of this correlation suggested that phrenic and intercostal activities will be depressed to some degree by carbachol even when the average VRG cell activity remains unchanged. In addition, our data show that VRG cells may receive a combination of inhibitory and excitatory inputs during the carbachol-induced depression of respiratory motoneurons. Thus, although some disfacilitation from VRG cells may occur, there must be additional inhibitory or disfacilitatory pathways that mediate the decrease in activity of both phrenic and intercostal motoneurons that accompanies the REM sleep-like atonia.

Animals↗

PubMed1992

Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat.

In decerebrate, paralyzed, vagotomized and artificially ventilated cats, serotonin (5-HT) and its analogues, microinjected into the hypoglossal (XII) motor nucleus, altered the activity of the genioglossal branch of XII nerve. 5-HT, carboxamidotryptamine maleate (5-CT) and DOI (1-5 mM) increased the activity by over 200%. Methysergide reversed this increase. Methysergide, mianserin, or ketanserin (100-250 nl, 1 mM) reduced the spontaneous hypoglossal activity by 20-50%. Buspirone, 8-OH-DPAT and (-)-propranolol were without effect. Thus, 5-HT provides a substantial tonic excitatory drive to XII motoneurons. The 5-HT receptors involved are likely to be type 1C or 2, but uncertainty regarding the affinity profiles of the drugs used in in vivo conditions in the cat precludes a definite identification.

Animals↗

PubMed1992

Spontaneous ventilation and respiratory motor output during carbachol-induced atonia of REM sleep in the decerebrate cat.

Microinjections of carbachol into the pons induce a state that resembles rapid eye movement (REM) sleep in intact cats and, in decerebrate, artificially ventilated cats, produce postural atonia accompanied by a powerful depression of the respiratory motor output. In this study, pontine carbachol was used in decerebrate, spontaneously breathing cats to assess the effects of mechanical and chemical respiratory reflexes on the magnitude and pattern of the carbachol-induced depression of breathing, and to determine whether the depression is altered in those animals in which rapid eye movements are present. Phrenic nerve activity and tidal volume were only transiently depressed at the onset of the carbachol-induced postural atonia, whereas the decrease in respiratory rate and the depressions of hypoglossal and intercostal activities persisted until the response was reversed by a pontine microinjection of atropine 15-101 minutes after the onset of carbachol response. Ventilation was reduced to 70% of control during the steady-state conditions. The irregularity of breathing, characterized by the inter-quartile ranges of the distributions of the peak phrenic nerve activity and respiratory timing, did not increase following pontine carbachol. Neither vagotomy nor vigorous eye movements were associated with increased breathing irregularity. This contrasts with the irregular breathing (with minor average changes in ventilation) typical of natural REM sleep. We propose that the carbachol-injected decerebrate cat provides a useful model of the depressant effects that neural events associated with REM sleep may have on breathing.

Animals↗

PubMed1991

The medullary projections of afferent bronchopulmonary C fibres in the cat as shown by antidromic mapping.

1. The activity of eighty-seven bronchopulmonary vagal afferent neurones with unmyelinated axons (C fibres) was recorded extracellularly in the nodose ganglia of decerebrate, paralysed and artificially ventilated cats. On the basis of their response latencies following the right atrial injection of capsaicin or phenyldiguanide, the cells were classified as having their receptor endings within the reach of pulmonary (latency less than 3.5 s) or bronchial (latency above 3.5 s) circulation. 2. Pulmonary and bronchial receptor cells differed only slightly in their response characteristics (firing rate, burst duration) and the conduction velocity of their peripheral axons. Bronchial C fibres represented about 70% of the population studied. 3. The medullary distributions of the central branches of six pulmonary and six bronchial C fibres were determined by means of the antidromic mapping technique. The two receptor subtypes did not differ in their central projection patterns. 4. Rostral to the obex, the central branches of the bronchopulmonary C fibres were localized within the medial portions of the nucleus tractus solitarii (NTS) and area postrema, and were most densely distributed along the borders of the parvicellular subnucleus of the NTS. Caudal to the obex, the most dense branching was found in the dorsal portion of the commissural subnucleus. Projections to the contralateral NTS were found, but these were of a much lower density. 5. The central distribution of bronchopulmonary C fibres is compared to the projection patterns of vagal and glossopharyngeal afferents of other modalities that are involved in respiratory and cardiovascular control. This is discussed in relation to the concept of a modality-specific organization of the NTS.

Animals↗

PubMed1990

Startle-evoked changes in diaphragmatic activity during wakefulness and sleep.

Tonic inhibition of some respiratory muscles occurs as part of the generalized muscle atonia of rapid-eye-movement sleep (REMS). A second type of inhibition of the diaphragm during REMS, fractionations, consists of brief pauses in the diaphragmatic electromyogram (DIA EMG) in association with phasic events. Because motor inhibition can occur as part of the startle response, and the brain is highly activated during REMS, we hypothesized that the neural basis of the fractionations might be activation of a startle network. To test this hypothesis, tone bursts (100 dB, 20-ms duration at 15-s intervals) were applied to cats at a fixed inspiratory level in the DIA moving average during REMS, non-rapid-eye-movement sleep (NREMS), and wakefulness. Parallel sham studies (no tone applied) were obtained for each state. The response of the DIA EMG was averaged over 100 ms by using the tone pulse as a trigger, and the following parameters of the DIA EMG were measured: latency to peak and/or nadir, increment or decrement in activity, and duration of peak and/or nadir. After a tone, all five animals studied displayed a profound suppression of DIA activity during REMS (latency to nadir 42.4 +/- 10.0 ms, duration of suppression 35.9 +/- 17.6 ms). Similarly, DIA activity was suppressed in all cats during NREMS (latency to nadir 40.9 +/- 13.3 ms, duration 23.9 +/- 13.4 ms). An excitatory response was observed in only two cats during NREMS and wakefulness. The similarity of startle-induced DIA EMG pauses to spontaneous fractionations of DIA activity during REMS suggests that the latter result from activation of a central startle system.

Acoustic Stimulation↗

PubMed1990

Effect of dorsolateral pontine lesions on diaphragmatic activity during REMS.

Muscle atonia is a feature of normal rapid-eye-movement sleep (REMS). The suppression of accessory respiratory muscle activity has been investigated and a role for sleep-disordered breathing hypothesized, but the suppression of diaphragmatic activity has rarely been considered. We hypothesized that the activity of the diaphragm was suppressed by an area of the dorsolateral pons during REMS. Lesions in this region have previously been shown to abolish the atonia of REMS. The diaphragmatic electromyogram (EMG) activity was analyzed in five naturally sleeping cats before and after pontine lesions leading to REMS without atonia. Although respiratory timing parameters were not altered by the lesion, the inspiratory rate of rise was significantly increased in all cats, and the brief pauses (40-100 ms) in the diaphragmatic EMG normally seen in REMS were virtually abolished. We conclude that the dorsolateral pons has a role in suppressing diaphragmatic activation during REMS. This suppression affects the average rate of rise of diaphragmatic activity and also leads to brief intermittent complete cessation of ongoing muscle activity. These decrements in diaphragm activity could jeopardize ventilation during REMS.

Animals↗

PubMed1990

Cholinergic stimulation of the pons depresses respiration in decerebrate cats.

The injection of carbachol into the pontine tegmentum of decerebrate cats evokes a postural motor atonia that has many of the characteristics of the atonia of natural rapid-eye-movement (REM) sleep (Morales et al. J. Neurophysiol. 57: 1118-1129, 1987). We have used the carbachol-injected decerebrate cat to study the changes in respiratory neuronal activity that accompany the atonia. The activities of representative respiratory motor nerves--phrenic, intercostal, and hypoglossal--and that of a motor branch of C4 were recorded in decerebrate, vagotomized, paralyzed, and artificially ventilated cats. After the microinjection of carbachol, there was a profound suppression of activity in all the nerves and a decrease in respiratory rate. This was a consistent stereotyped response in which the magnitude of the suppression of respiratory-related activity was phrenic (to approximately 65% of control) less than inspiratory intercostal (approximately 50%) less than hypoglossal (approximately 10%) less than expiratory intercostal (approximately 5%). The decrease in respiratory rate (to approximately 70% of control) was caused by a prolongation of both inspiratory and expiratory durations. Complete reversal of the carbachol effect was elicited by the microinjection of atropine into the same site as the carbachol injection. This allowed us to produce a second episode of atonia by the injection of carbachol into the contralateral pons. Thus we have demonstrated the existence of neural pathways originating in the cholinoceptive cells of the pons that have the potential to powerfully and differentially depress various respiratory motoneuronal pools and to reduce the respiratory rate. These pathways are likely to be activated along with the atonia of REM sleep.

Animals↗

PubMed1988

Sites of termination and relay of pulmonary rapidly adapting receptors as studied by spike-triggered averaging.

The sites of termination and relay of pulmonary rapidly-adapting receptors (RARs) were determined by averaging the extracellular field potentials produced in the nucleus tractus solitarii of the cat by individual RAR neurons. Action potentials of individual RARs were recorded extracellularly in the nodose ganglion during mechanical stimulation of the receptive field in the lung and used as triggers for the averaging. The averaged records (2000-4000 sweeps) revealed the presence of terminal and focal synaptic potentials. These potentials, indicating the presence of pre- and postsynaptic elements at the recording site, were found ipsilaterally in the caudal medial and commissural subnuclei and contralaterally in the commissural subnucleus.

Action Potentials↗

PubMed1987

Biotransformation of sulindac in end-stage renal disease.

In normal humans sulindac, a prodrug, undergoes two major biotransformations: irreversible oxidation to the inactive sulfone metabolite and reversible reduction to the pharmacologically active sulfide metabolite. To assess any effect of end-stage renal failure on sulindac biotransformation, six patients were given 200 mg sulindac orally. Plasma was sampled over 24 hours. Protein binding of sulindac and metabolites was determined by equilibrium dialysis. Results were compared with historic controls. AUC(0-12) for sulindac and the sulfone were similar to controls. AUC(0-12) for the sulfide was significantly reduced to 4.85 micrograms X hr/ml from 13.1 micrograms X hr/ml (P less than 0.02). Protein binding of all three compounds was significantly reduced by renal failure. When corrected for protein binding, the AUC(0-12) for sulindac and the sulfone was twice that of controls whereas that of the sulfide was 42 ng X hr/ml compared with 83 ng X hr/ml in normal individuals (P less than 0.001). This suggests that end-stage renal failure impairs the reduction of sulindac to the active sulfide whereas oxidation to the sulfone is intact.

Administration, Oral↗

PubMed1987

Pulmonary stretch receptor relay neurones of the cat: location and contralateral medullary projections.

1. The activity of pump (p.) cells, second-order neurones in the pulmonary stretch receptor pathway, was recorded extracellularly in the nucleus of the tractus solitarius (n.t.s.) of the decerebrate cat. Their firing was proportional to changes in lung volume but unrelated to the centrally determined respiratory rhythm. A systematic search of the n.t.s. for the location of p. cells was made and an assessment of their efferent projection to the contralateral n.t.s. was determined electrophysiologically by the antidromic mapping technique. 2. P. cells were located around, and in close proximity to, the solitary tract. The two sites of greatest density were ventromedial and dorsolateral to the tract, with lower concentrations found laterally and ventrolaterally. 3. For twelve of the thirty p. cells tested, evidence of a projection to the contralateral n.t.s. was obtained; in seven of these cells, axonal arborizations within the projection area were identified. Almost all the cells that sent axons to the contralateral n.t.s. were located dorsolateral to the tract; there was no evidence that cells in the ventromedial region had contralateral projections. 4. No evidence that R beta neurones project to the contralateral commissural and ventrolateral subnuclei was found. 5. No p. cells projected to the contralateral ventrolateral n.t.s. The site of projection and branching was consistently localized just caudal to the obex and medial to the solitary tract, in the caudal medial, and commissural subnuclei of the n.t.s. This same region has been shown to receive a dense, direct projection from pulmonary rapidly adapting receptors.

Animals↗

PubMed1987

Role of medullary inspiratory neurones in the control of the diaphragm during oesophageal stimulation in cats.

1. The effect of oesophageal distension and swallowing on the activity of medullary respiratory neurones was recorded in decerebrate, spontaneously breathing cats. The distension, produced by inflating a balloon in the thoracic portion of the oesophagus, was of sufficient magnitude to induce inhibition of the peri-oesophageal part of the crural diaphragm, with little effect on the respiratory function of the diaphragm as measured by the activity in the C5 branch of the phrenic nerve. 2. 424 neurones were tested. They were located bilaterally, in the region of the nucleus tractus solitarius (dorsal respiratory group) or the ambiguous complex (ventral respiratory group). No cell exhibited a change in activity during periods of strong inhibition of crural electrical activity induced by distension or swallowing. The activity of all cells paralleled that of the C5 phrenic neurogram, which was unaffected by the tests. 3. We conclude that the reflex inhibition of the crural diaphragm during oesophageal distension does not result from an inhibition of medullary premotor inspiratory neurones of the dorsal and ventral groups. Additional central pathways must exist that inhibit motoneurones to the crural diaphragm during gastrointestinal reflexes.

Action Potentials↗

PubMed1987

Bilateral convergence of pulmonary stretch receptor inputs on I beta-neurons in the cat.

Extracellular recordings were made from inspiratory beta- (I beta) neurons in the nucleus of the tractus solitarius in decerebrate cats. A reversible direct current block of myelinated fibers in the ipsilateral vagus nerve was used to evaluate the input from pulmonary stretch receptor afferents (PSR) of the contralateral vagus to individual I beta-neurons. This block served to remove all ipsilateral (which includes all monosynaptic) inputs from PSR to I beta-cells. The effect of withholding inflation on the firing rate and the time of onset of firing of I beta-neurons was determined before, during and after application of the direct current block. There was considerable variation in the strengths of the inputs from the ipsilateral and contralateral nerves; some cells received PSR inputs from only the ipsilateral vagus, but the majority were excited with varying magnitude from both vagi. Several neurons had powerful excitatory inputs from PSR of the contralateral vagus, with the ipsilateral (monosynaptic) contribution being of minor importance.

Afferent Pathways↗

PubMed1987

Monitoring, anesthesia equipment, and space requirements.

General anesthesia is provided in the dental office primarily to reduce fear, block pain, produce amnesia, and provide a more comfortable surgical environment. Because the perception of pain is a major obstacle to the obtainment of dental health in the United States, general anesthesia has become an essential part of the practice of dentistry. It benefits both the patient and the surgeon to make dentistry a pleasant, painless experience.

Anesthesia Recovery Period↗

PubMed1986

Effects of lung inflation on the excitability of dorsal respiratory group neurons.

The effect of lung inflation on the excitability of inspiratory neurons of the dorsal respiratory group was studied in decerebrate, paralyzed, artificially ventilated cats. Variations in the antidromic latency (AL) were used as a measure of the changes in excitability. The antidromic responses of single cells were recorded extracellularly during electrical stimulation (20 Hz) of their spinal axons. Single-breath test inflations were delivered at the onset of inspiration (I) or expiration (E), and then maintained for the duration of that respiratory phase. In the absence of inflation during E, most of the inspiratory cells underwent progressive lengthening of the AL, indicating inhibition or disfacilitation. This effect was stronger in I beta than in I alpha cells but there was considerable overlap. In every cell (21 I alpha, 17 I beta), inflation during E caused a prompt AL shortening (excitation or disinhibition) that was evident in single tests. On average, I beta neurons were more strongly excited by the test inflation during E, but again there was considerable overlap. The excitation was maintained for the duration of the inflation, indicating that pulmonary stretch receptor afferents (PSR) were involved. The response to slow inflations (that preferentially excite PSR) was a progressive shortening of the AL that mirrored the increase in lung volume. The results emphasize the qualitative similarity in the responses of I alpha and I beta neurons to lung inflation and in their excitability changes during normal respiratory cycles.

Adaptation, Physiological↗

PubMed1986

Enalapril in congestive heart failure: acute and chronic invasive hemodynamic evaluation.

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.

Adult↗

PubMed1986

Projection of pulmonary rapidly adapting receptors to the medulla of the cat: an antidromic mapping study.

The activity of pulmonary rapidly adapting receptor (r.a.r.) neurones was recorded extracellularly in the nodose ganglion of the decerebrate cat. The receptors were identified by their rapid adaptation to 'ramp and hold' hyperinflations of the lung. The antidromic mapping technique was used to determine the sites of projection and branching patterns within the nucleus of the tractus solitarius (n.t.s.) of eleven r.a.r.s. The medulla was explored with a stimulating electrode to activate the r.a.r.s. antidromically. In each penetration, depth-threshold measurements were made for each antidromic response characterized by a distinct latency. Using the anatomical sites of the minimum threshold points, the locations of central branches of individual r.a.r.s. were determined. The main axons of all of them coursed within the tractus solitarius (t.s.) at levels from 2 mm rostral to 0.5 mm caudal to the obex. The axonal conduction velocities within the t.s. were 6.2-9.7 m/s, where the peripheral conduction velocities were 11.2-20.4 m/s (28 degrees C). Different latencies of response evoked in a single penetration were considered to indicate branching. The densest branching was found in the ipsilateral commissural subnucleus of the n.t.s. at levels 0.3-1.3 mm caudal to the obex and, to a lesser degree, in the contralateral commissural subnucleus. All r.a.r.s. sent a few branches to the medial n.t.s. rostral to the obex. Four r.a.r.s. ramified in the ventrolateral n.t.s. where inspiratory cells are located. Depth-threshold graphs were interpolated by best fitting parabolic equations: Ith = Ad2 + Bd + C; where Ith is the threshold current, d the corresponding depth of stimulation, and A, B and C are coefficients. Coefficient A is a measure of steepness of the parabola. The A coefficients were inversely related to the conduction velocity (v) of the stimulated branch. An analysis of the data from the present study (v = 5.0-9.7 m/s) combined with data from the literature (v = 2.2-85 m/s) led to a simple relationship between the A coefficient and the conduction velocity of the stimulated fibre: A = 6500/v, where A is expressed in microA/mm2 and v is expressed in m/s. Within the range 3-35 m/s, the formula is useful in predicting the effective current spread when the conduction velocity is known, or to estimate the conduction velocity from the shape of a depth-threshold curve. Two slowly adapting pulmonary stretch receptors (p.s.r.s) were studied.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1986

Responses of pulmonary stretch receptors during ramp inflations of the lung.

Studies were conducted in anesthetized paralyzed dogs to determine how the dynamic and proportional sensitivity of pulmonary stretch receptors change during lung inflation. The firing of each receptor was examined at multiple levels of static transpulmonary pressure and during multiple identical inflations at each of several rates. The averaged response of the receptor was computed and receptor activity related to transpulmonary pressure. On the basis of a quantitative criterion, employed to distinguish type I from type II receptors, the receptors could not be divided into distinct subpopulations. Thus all receptors were treated as coming from a single population. For all receptors we observed that their proportional sensitivity (increases in firing produced by increases in lung expansion at a constant rate of inflation) declined as the lung was inflated. In contrast, the dynamic sensitivity (increases in firing produced by increased rates of inflation at constant transpulmonary pressure) increased or remained relatively constant with increasing lung expansion. Thus, as inflation volume increases, the pulmonary stretch receptor acts increasingly as a rate receptor. The rate of inflation may have a more important role in control of the inspiratory duration than previously realized.

Adaptation, Physiological↗