By the occlusion of arteries in the ventral surface of the medulla, the blood supply to the central chemoreceptor for respiration was examined in anesthetized, paralyzed and peripheral chemodenervated cats. Phrenic nerve activities (P.N.A.), as an index of the respiratory center output, increased with an injection (3 ml/min, 10 sec) of hypercapnic blood (PCO2=104.5 mmHg) into the vertebral artery (VA injection response). The VA injection responses during occlusion of arteries in the ventral surface of the medulla were classified into three groups: 1) The response disappeared by the bilateral occlusion of the anterior inferior cerebellar arteries (AICA) in 8 out of 29 cats. 2) The response disappeared by the occlusion of both AICA and the posterior inferior cerebellar arteries (PICA) in 9 cats. 3) The response did not disappear in spite of the additional occlusion of several branches from the basilar artery in 11 cats, although the response had diminished. These different results may be due to the complexity of the central chemosensitive structure or of the central vascular system. However, among arteries the AICA blood flow seemed to be most preferentially related to the VA injection response. Thus, at least a part of the central chemosensitive structure may be located in the area perfused by the AICA.
Respiratory neurons with a highly stable rhythm have been proposed to be involved in the central neural mechanism responsible for the respiratory rhythmogenesis. In the present study it was examined whether the stably discharging inspiratory neurons are related to the high-frequency oscillation (HFO) in the phrenic nerve activity. Experiments were performed on 27 vagotomized rabbits anesthetized with diethyl ether, immobilized with gallamine triethiodide, and ventilated artificially. Spike-triggered averaging was used to evaluate the degree of the correlation between inspiratory unit spikes and the phrenic HFO. Twenty out of the 35 inspiratory units examined were related to HFO and were located in the medullary reticular formation (n=19; n, number of units) and in the vicinity of the nucleus tractus solitarius (n=1). The correlation to HFO decreased after the intravenous injection of thiamylal. The inspiratory units with little correlation to HFO were located in the reticular formation of the pons (n=3) and medulla (n=12). The inspiratory neurons with a stable respiratory rhythm (n=4) had little correlation to HFO and located in the lateral region of the medullary reticular formation. These results suggest that the central neural mechanisms responsible for phrenic HFO are not directly related to the respiratory rhythmogenesis.
Transmembrane potentials of the respiratory laryngeal motoneurons were recorded in decerebrate, vagotomized and paralyzed cats. Twenty inspiratory and thirteen postinspiratory neurons were identified. Periodic membrane potential (MP) fluctuations as well as patterns of postsynaptic potentials (PSPs) were characterized in each type of neurons by measuring the input resistance and injecting Cl- to reverse inhibitory PSPs. On the basis of PSP patterns, two subtypes of inspiratory neurons could be distinguished. Thiopental (2-3 mg/kg, i.v.) produced depolarization together with reduction of firing in most laryngeal neurons. Excitatory and inhibitory PSPs were both depressed and MP fluctuations became smaller in each phase of the respiratory cycle. Elevation of the firing threshold and separation of IS-SD spikes often occurred after thiopental. These results suggest that thiopental depresses the laryngeal motoneuron through inhibition of synaptic transmission and of spike generation.
The stereotyped reflex changes in phrenic discharge, produced by train(s) of electrical shocks to myelinated afferents in the internal branch of the superior laryngeal nerve (SLN), were studied in vagotomized cats and rabbits, mechanically ventilated with the mixture of oxygen and nitrous oxide. Single weak shocks caused a short latency (4-5 msec) phrenic response, an excitation followed by a slight inhibition for 10 msec, which was repeatable at a rate of 200 Hz or more. Repeated weak shocks at a rate higher than 100 Hz or single stronger shocks caused a powerful inhibition with a limited duration (25-30 cosec) of both the central inspiratory activity (CIA) and short latency response. This stereotyped inhibition, which was followed by a rebound excitation, could occur every 30-50 msec with some reduction and was apparently associated with a decreased slope of integrated phrenicogram. During inhalation of halothane (0.5-1.5%), the short latency phrenic response was reduced, while the stereotyped inhibition and the reduction of phrenic augmentation were markedly enhanced when the CIA was slightly depressed by halothane inhalation. Therefore, the stereotyped inhibition would represent an important mechanism of the reflex slowing of inspiration produced by myelinated laryngeal afferents.
Neural mechanisms regulating activities of diaphragm and abdominal muscles were investigated on anesthetized, tracheostomized and spontaneously breathing dogs. EMGs of costal diaphragm and external oblique (EO)abdominal muscle were recorded by fine-wire electrodes. The electrodes for diaphragm-EMG were implanted without opening abdominal cavity using laparoscopy. During quiet breathing the mean firing frequency of diaphragm-EMG was 7.6±0.7 (S.D.) Hz. The discharge spikes of diaphragm-EMG observed in early-inspiration or in post-inspiratory phase, were low in amplitudes, consistent with previous reports that phrenic motoneurons were comprised of two populations. During quiet breathing spikes were not observed in EO-EMG in a half of the animals, and were tonically-firing in the remaining dogs. Hypercapnia increased firing frequency of diaphragm-EMG, but did not recruit spikes of high amplitude. On the other hand, hypercapnia recruited EO-spikes of higher amplitude, and increased firing frequency. When spikes fired tonically in EO-EMG, hypercapnia suppressed these spikes during inspiration. Airway occlusion gradually recruited EO units of higher amplitude. Mechanical stimulation of upper airway suppressed tonic-EO activity during inspiration. In conclusion, we demonstrated that 1) abdominal wall is not related with control mechanism of diaphragm; 2) the control mechanism of dog's EO differs from cat's internal intercostal muscles; and 3) the tonic component of EO is affected by respiratory commands from higher neuronal architecture.
We investigated changes in activities of phrenic nerve (PN) and the recurrent laryngeal nerve (RLN) during progressive hypoxia produced by administration of a mixture of 5% O2 in N2 and a mixture of 5% O2 in N2O in 8 vagotomized, paralyzed, and artificially ventilated cats anesthetized with halothane. During progressive hypoxia produced by administration of 5% O2 in N2, both PN and RLN activities initially increased and then decreased at approximately the same rate. The relationship between PN and RLN activities during the respiratory stimulation and the relationship between PN and RLN activities during the depression due to hypoxia were both linear and were represented by the same linear regression line. The responses of PN and RLN activities to progressive hypoxia produced by administration of 5% O2 in N2O were basically similar to those observed during administration of 5% O2 in N2 although a concomitant increase in depth of anesthesia with N2O enhanced the occurrence of hypoxic respiratory depression. These results suggest that the respiratory modulation of recurrent laryngeal motoneuron activity is closely related to that of phrenic motoneuron activity and that both motoneurons share similar control mechanisms. Neither severe hypoxia nor addition of N2O to a halothane-anesthetized cat seems to affect the close linear relationship between PN and RLN activities.
It has been reported that triangular-shaped positive pressure pulses applied to the airway (high-frequency inflation, HFI) stimulates pulmonary stretch receptors and prolongs expiratory duration. In the present experiment, changes in the integrated curve of expiratory activity induced by HFI were investigated. Duration until the onset of the expiratory activity (El stage) was unchanged. In the E2 stage, the initial ascending slope became steeper and higher peaks were reached during HFI stimulation. The period from the onset of the slope to the peak, previously designated the stage of active expiration (Ea stage), showed no consistent change in duration and remained unchanged on average. The period after the peak until the onset of the following inspiratory activity was consistently prolonged. This period was designated the declining stage of expiration (Ed stage).
We evaluated rapid and transient changes in phrenic (PN) and internal intercostal (IIC) activities when 0.5 ml of saline saturated with 100% CO2 was injected into the vertebral artery at the C1 level before and after cisternal administration of carbonic anhydrase inhibitor (acetazolamide) in decerebrated, spontaneously breathing cats. Before acetazolamide administration, the injections evoked an initial, transient inhibition of ongoing PN or IIC activity, followed by excitation of subsequent respiratory activities with a short onset latency of less than 3 sec. On the other hand, cisternal administration of acetazolamide abolished both the initial inhibition and the subsequent rapid excitation of respiratory activities, although there still existed a delayed, weak and prolonged excitation of respiration. These results indicated that hydration of CO2 accelerated by carbonic anhydrase within the brain would be essential for the rapid changes in respiratory activity mediated by the central chemoreceptors.
We studied ventilatory responses under hypercapnic and hypoxic conditions in 18 lightly anesthetized dogs, using a vagus nerve cooling technique. One side of the cervical vagosympathetic trunks of dogs were previously severed, and a copper cooling probe was attached to the other side. When the cervical nerve was cooled below 7°C, Hering-Breuer inflation reflex ceased. We found that when the vagus nerve was not cooled or cooled up to 7°C, the respiratory frequency increased significantly in relation to hypercapnic gas inhalation. However, the increment of respiratory frequency was reduced by bilateral cervical vagotomy. On the other hand, the respiratory frequency in response to hypoxia increased significantly, even when bilateral vagotomy was done. The increment of the tidal volume in response to hypercapnic gas inhalation was reduced by the Hering-Breuer inflation reflex. We found that the effect of the vagus nerve on respiratory regulation was different between hypercapnic and hypoxic gas inhalation.
Ventilatory response to normocapnic progressive hypoxia (A/BSA) was measured in 76 healthy males to examine how arterial blood gases and acid base status are involved in interindividual variability of hypoxic chemosensitivity. A/BSA and HCO3- were significantly higher in Group 1 (26 subjects, mean age=15.8±S.D. 0.9 years) than those in Group III (26 subjects, mean age 46±7.1 years). A/BSA and HCO3- in Group II (24 subjects, mean age=29.8±6 years) were in the middle of Groups I and III. Arterial blood gases and H+ were similar among the 3 groups. Arterial H+ correlated inversely with A/BSA (subjects with lower arterial H+ on air had higher hypoxic response) in Group I, while the correlation was positive (subjects with higher H+ on air had higher hypoxic response) in Group III. The correlation was not seen in Group II. PaCO2 and H+ correlated positively in the 3 groups. Intrasubject stability was equivalent among H+, PaCO2, and HCO3- (mean coefficients of variation=1.81, 1.83, and 1.65, respectively), but smaller than that in PaO2 (3.28%). These results indicate that interindividual variability in hypoxic ventilatory response is related to arterial H+ in adolescent and middle age groups but the relation is opposite between the 2 groups.
Fourteen subjects performed cycle exercise at work loads of 0 and 1 kp, each for 3 min, during which the pedal rate was kept constant by various external cues. Six cues were used in order: no cue (Ni), a speedometer dial (S), a flashing light (F), a verbal command (V), a metronome sound (M) and no cue, again (N2). An attempt was to study the effect of these cues on breathing pattern in a lower tidel volume (VT) range during exercise, actually VT increasing to 2 times the resting levels. In N1 and N2, exercise was performed at preferred pedal rates, which were 40±4 (mean±S.E.)rpm and 52±2 rpm, respectively. Pedaling to other four cues was kept at 50 rpm. Ventilatory responses during exercise were similar in all conditions of cue except N1. Increases in respiratory frequency (f) during exercise were similar in S but greater in F at 0-kp load and in V and M at 1-kp load, compared with N2. The greater increases in fin F, V and M were due to greater shortening in inspiratory (TI) and expiratory (TE) durations. In any conditions of cue, TI and TE decreased with increasing VT in response to exercise. The present study indicates that (1) breathing pattern during rhythmic exercise is affected by external rhythmic stimuli like F, V and M, and (2) there is no such a VT range that TI and TE remain constant in the VT-TI, and VT-TE, relations during exercise.
Ventilation and cardiac output in response to four different exercises, namely, volitional pedalling using a bicycle ergometer with a very mild (7 Watt) load, passive pedalling, electrically-induced isometric twitches of one leg, and voluntary twitches simulating the previous electrical twitches, were measured simultaneously during the transient phase from rest. Cardiac output was determined by automated impedance cardiography. A sudden increase in ventilation was observed immediately after the onset of the volitional and passive pedalling whereas cardiac output increased only gradually. Only a slight difference was observed between the cardio-ventilatory responses to volitional and passive exercises. Neither ventilation nor cardiac output changed significantly in response to volitional and electrical twitches of one leg. Conclusions were then drawn that the cardio-dynamic process could be ruled out as the origin of the initial ventilatory response, and instead, other neurogenic mechanisms mediated either centrally or peripherally, should be considered.
In order to determine whether or not resting ventilatory response to hypercapnia is changed by physical training, we studied the effect of long-term physical training on the slope of ventilatory response to CO2 at rest. The subjects were 9 untrained freshmen ranging in age from 18 to 20 years. Five out of nine subjects belonged to the badminton team after entering university in April 1980, and participated in their team's training for about 3 hr per day, 3 times a week year round for about 4 years until March 1984. Maximum oxygen uptake (_??_O2 max), maximum pulmonary ventilation (_??_E max) and maximum heart rate (HR max) were determined during maximal treadmill exercise before and after training. The slope (S) of ventilatory response to carbon dioxide at rest was measured by Read's rebreathing method. _??_O2 max increased after training in the trained subjects and mean values of _??_O2 max which were measured in 1982, 1983, and 1984, were statistically higher than that of 1980. Similar tendency was observed in _??_E max and _??_O2 max/W. Average values and standard deviations of S before training were 1.91±0.52 liter/min/torr and were decreased gradually with increasing training period ; the differences in the S value before (1980) and after training, i.e., 1982, 1983, and 1984, were all significant. Such difference could still be seen after S was recalculated as SN by using normalized ventilation for 70 kg body weight, while there were no significant differences in the S and SN between baseline and repeated studies in the untrained group. In addition, CO2 responsiveness was found to correlate negatively with maximum oxygen uptake in 4 out of the 5 trained subjects. These results suggest that in normal subjects, long-term physical training, as in the present study, decreases CO2 responsiveness at rest.
We have developed a portable home sleep monitoring system using nasal airflow (NA), tracheal sound recordings (TSR), and electrocardiogram (ECG). NA was recorded by two thermisters. TSR was recorded by a microphone attached to the skin overlying the cervical trachea. Three kinds of signals were recorded with a cassette recorder. Thirty-seven outpatients who had sleep complaints were monitored duing sleep at home using this recorder. Attachment of the pickups was performed by the patients themselves. Recordings were played back and analyzed by a personal computer to evaluate apnea episodes from TSR and R-R intervals beat by beat. This home monitoring system had labor-saving and cost-saving benefits and seemed to be a satisfactory technique for screening.
In order to examine the effect of sleep position on sleep apnea episodes, seven male patients diagnosed as having obstructive sleep apnea syndrome without any organic complication of the upper aiway were studied while lying in a supine or lateral position during an all-night polysomnographic study. Apnea index, apnea time/total sleep time (%) and the number of episodes per hour in which oxyhemoglobin saturation dropped below 85% decreased significantly from 51.0±8.6 (mean±S.D.) events/hr, 40.4±5.8% and 36.2±9.8 episodes/hr during sleep in supine position to 27.6±9.1 events/hr, 19.4±6.0% and 12.9±5.3 episodes/hr during sleep in lateral position, respectively. Lowest oxyhemoglobin saturation increased significantly from 70.7±2.6% to 78.0±2.4%. Thus, sleep in the lateral position may be a simple treatment before essential treatment for patients with obstructive sleep apnea syndrome.
Two obese patients with sleep apnea syndrome were administered chlormadinone acetate (CMA), a synthetic progesterone, known as a potent respiratory stimulant to augment load compensation response as well as CO2 chemosensitivity. Before CMA administration, both cases showed normal chemosensitivity of hypoxic and hypercapnic ventilatory responses (HVR and HCVR) at daytime, although marked oxygen desaturation with sleep apnea was observed. During CMA administration for 7 days, HVR, HCVR and occlusion pressure response to flow-resistive loading were altogether augmented. In one case obstructive sleep apnea (OSA) was altered to obstructive hypopnea, and in the other case central apnea disappeared completely, resulting in remarkable improvement of oxygen desaturation at sleep and daytime somnolence in both cases. We conclude that CMA might be useful in the treatment of sleep apnea syndrome.
We studied the usefulness of the neuromuscular inspiratory drive (P0.1) and P0.1 normalized by ventilation (sP0.1) as indicators for weaning from mechanical ventilation. The patients were classified into two groups on the basis of outcome : a successful group who could have weaning and an unsuccessful group who could not be free from mechanical ventilation. The unsuccessful group showed significantly greater P0.1 (6.35±2.95 cmH2O) than successful group (2.81±1.21 cmH2O). The patients who failed in weaning also showed an increase in sP0.1 which would mean an increase in respiratory impedance. These results suggest that P0.1 and sP0.1 might be useful to follow the time course during weaning from mechanical ventilation.
We have studied 204 healthy male subjects ranging in age from 20 to 59 years. They were divided into four 10-year age groups. Each age group was further divided into 2 subgroups with high and low Panic-Fear scores. The ventilatory activities of all the groups were compared. In the younger generation (20-39 years), the low PF group revealed a higher slope in CO2 response curve than the high PF group (p<0.05). This result was considered to be related to the difference in CO2 production between the two groups. In the older age groups, however, the high PF subjects exhibited a tendency to increase the CO2 response slope with increasing ages. This contradictory result was thought to be due to the age dependent change in biogenic amine activity.