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The effect of sustained hypoxia on respiration is reported to be biphasic and comprised of an initial stimulatory phase mediated by peripheral chemoreceptors and a following depressive phase caused by central mechanisms (Neubauer, 1990). However, it is not clear how sustained hypoxia affects respiratory sensations. In this study we wished to ascertain whether sustained hypoxia has a biphasic effects on the sensation of dyspnea as well as on ventilation.

We previously reported that submental electrical stimulation may be an effective treatment for obstructive sleep apnea (Miki et al., 1989a, Hida et al., 1991). The mechanism of relief of apneic episodes during submental stimulation may be the contraction of genioglossus and/or geniohyoid muscles, which would open the upper airway by pulling the tongue forward (Miki et al, 1989b, Gottfried et al., 1983). However, the effects of submental stimulation during consecutive nights on apneic episodes in patients with obstructive sleep apnea (OSA) have not been studied. In the present study in order to assess whether submental stimulation is necessary for treatment every night, we examined the effects of submental stimulation for a serial four or five sleep nights on apneic episodes and changes in apneic episodes on stimulation-off nights after the stimulation nights using a portable submental stimulator which we have developed.

The ventilatory responses to external resistive and elastic loadings of the respiratory system have been extensively studied in a variety of experimental animals as well as also humans. It has been known that there are marked differences in the pattern of breathing during sustained inspiratory loadings between awake and anesthetized subjects (Margaria et al., 1973; Cherniack and Altose,1981; Milic-Emili and Zin,1986). In awake subjects sustained external elastic loading generally leads to increased breathing frequency and decreased tidal volume, whereas inspiratory resistive loading causes decreased frequency and increased tidal volume. By contrast in anesthetized subjects the changes in respiratory frequency are small or absent and independent of the type of external loading (Milic-Emili and Zin, 1986). Because the different responses between the awake and anesthetized subjects cannot be explained as a simple reflex (Cherniack and Altose,1981; Milic-Emili and Zin, 1986), it is assumed that conscious awareness of breathing or behavioral response may be responsible for the different breathing pattern observed during inspiratory resistive and elastic loadings. However, the nature of the behavioral control has not yet been evaluated. Thus, the aim of the present study was to examine the hypothesis that the breathing pattern during inspiratory loading might be optimized through cortical response so that the sensation of dyspnea would be minimized.

Phrenic nerve damage, which is frequently the result of cervical trauma or spinal nerve diseases, may cause respiratory muscle failure. Previous studies have shown that the acetylcholine receptors on the surface of skeletal muscles increased after denervation1, and the resting membrane potential changed to depolarization within two days after denervation2. Another study showed that transformation of muscle fibers occurs in experimental hyperthyroidism, i. e., soleus (slow-twitch fiber) changes to fast and plantaris muscles (fast-twitch fiber) changes to slow within 40 days3. However, it is still unclear whether diaphragm muscle, which is a combination of fast and slow twitch muscle fiber, changes to slower or faster after denervation compared to intact diaphragm. Therefore, we examined the subacute effect of denervation on the physiological changes in muscle contractility and fatigability.

We assessed the effects of cooling the ventral medullary surface (VMS) on the activity of chest wall and abdominal expiratory muscles in eight anesthetized artificially ventilated dogs after vagotomy and denervation of the carotid sinus nerves. Electromyograms (EMGs) of the triangularis sterni, internal intercostal, abdominal external oblique, abdominal internal oblique, and transversus abdominis muscles were measured with EMG of the diaphragm as an index of inspiratory activity. Bilateral localized cooling (2 x 2 mm) in the thermosensitive intermediate part of the VMS produced temperature-dependent reduction in the EMG of diaphragm and abdominal muscles. The rib cage expiratory EMGs were little affected at 25 degrees C; their amplitudes decreased at lower VMS temperatures (less than 20 degrees C) but by significantly fewer degrees than the diaphragmatic and abdominal expiratory EMGs at a constant VMS temperature. With moderate to severe cooling (less than 20 degrees C) diaphragmatic EMG disappeared, but rib cage expiratory EMGs became tonic and resumed a phasic pattern shortly before the recovery of diaphragmatic EMG during rewarming of the VMS. These results indicate that the effects of cooling the VMS differ between the activity of rib cage and abdominal expiratory muscles. This variability may be due to inhomogeneous inputs from the VMS to expiratory motoneurons or to a different responsiveness of various expiratory motoneurons to the same input either from the VMS or the inspiratory neurons.

We assessed the effects of negative intrathoracic pressure induced by inspiratory elastic loading on pulmonary, gas exchange with and without electrically induced hindlimb exercise in 8 normal, anesthetized dogs. Two elastic loads (EL) were used; one of 81 and one of 140 cmH2O/liter. These are equivalent to doubling and tripling the normal elastance of the dog's respiratory system, respectively. Elastic loading decreased ventilation and caused hypoxemia and hypercapnia, but it did not affect systemic arterial pressure or heart rate. During exercise, increase in ventilation was limited, whereas increase in cardiac output was not affected by elastic loading. Alveolar-arterial O2 tension difference (A-aDO2) was not changed significantly by exercise alone. However, elastic loading accompanied by exercise increased A-aDO2. Although comparable end-inspiratory pleural pressure was achieved with large EL (-29 +/- 2 cmH2O, mean +/- SE) and small EL with exercise (-30 +/- 2 cmH2O), the latter increased A-aDO2 whereas the former did not. Large negative intrapleural pressure combined with increased cardiac output may have caused transient interstitial edema.

To elucidate the role of chemoresponsiveness in determining postapneic ventilation in sleep-disordered periodic breathing, we measured ventilatory response associated with apnea-induced arterial oxygen desaturation during sleep and compared it with the awake hypoxic ventilatory response (HVR) in 12 male patients with obstructive sleep apnea (OSA). Awake HVR was measured at a slight hypocapnic level (end-tidal PCO2 = 37 +/- 1 mm Hg, mean +/- SEM), and separately at a PCO2 of 45 mm Hg. During non-REM sleep both the ventilatory rate (VE) and the average respiratory frequency (f) in the ventilatory phase between apneic episodes were inversely correlated with the nadir of arterial oxygen saturation (nSaO2) produced by the preceding apneic phase in all patients (VE versus nSaO2; r = -0.74 +/- 0.03, mean +/- SEM; f versus nSaO2, r = -0.56 +/- 0.04). The average tidal volume (VT) also was correlated with nSaO2 in 10 of the patients (r = -0.56 +/- 0.05). During REM sleep VE was correlated with nSaO2 in 11 patients (r = -0.75 +/- 0.03, p less than 0.02). The response of VE to nSaO2 (delta VE/delta nSaO2) varied widely among the patients (non-REM, 0.52 to 2.16; REM, 0.29 to 1.44 L/min/%) and was significantly lower during REM than non-REM sleep (p less than 0.01). The value of delta VE/delta nSaO2 during both non-REM and REM sleep was correlated with awake HVR at an end-tidal PCO2 of 45 mm Hg (non-REM, r = 0.83, p less than 0.02; REM, r = 0.76, p less than 0.05) but not with that at the hypocapnic level.(ABSTRACT TRUNCATED AT 250 WORDS)

The first purpose of the present study was to develop a new method to examine oxygen consumption of respiratory muscles (VO2resp) in human subjects. The apparatus consists of an expandable dead space and a respirometer. When the dead space was increased at a constant rate (approximately 100 ml/min), minute ventilation (VE) and VO2resp increased gradually. Because the logarithm of VO2 was found to be approximately linearly related to VE, we characterized this relationship by the slope (logVO2/VE) and the intercept at VE = 0 (VO2met) of the semilog regression line. The second purpose of this study was to examine the relationship between VO2resp and aging. Six anthropometric and spirometric factors (age, height, weight, vital capacity, forced expiratory volume in 1 s, and body surface area) were analyzed in 37 normal subjects by simple and stepwise multiple regression analyses. We found a significant increase in logVO2/VE and a significant decrease in VO2met with age. In conclusion, 1) the present method is convenient to use, and we are able to study VO2resp over a wide range of ventilation without voluntary effort, and 2) age per se is one of the factors accounting for the observed increase in VO2resp with age.

In order to elucidate the mechanism of the bronchial response of monkeys to constrictive stimuli, the effects of pretreatment with aerosolized lidocaine, atropine, and isoproterenol were studied. Treatment with aerosolized lidocaine and atropine not only extinguished the cough reflex, but also decreased bronchial susceptibility to aerosolized methacholine. Moreover, the pretreatment with lidocaine blocked the histamine challenge, but atropine did not. The aerosolized lidocaine decreased the bronchoconstriction induced with methacholine, but not with histamine. Pretreatment with over 1% of isoproterenol did not extinguish the cough reflex. However, this dose of isoproterenol did suppress an increase in Rrs due to the challenge of both methacholine and histamine. Isoproterenol also decreased the bronchoconstriction due to the previous challenge by both methacholine and histamine. The antagonistic effects of lidocaine, atropine, and isoproterenol on the broncho-constriction of monkeys are discussed in relation to the subepithelial receptor.

We examined the relationship between response to hypercapnia and ventilatory response to exercise under graded anesthesia in eight dogs. The response to hypercapnia was measured by the CO2 rebreathing method under three grades of chloralose-urethan anesthesia. The degrees of response to hypercapnia (delta VE/delta PETCO2, 1 X min-1 X Torr-1) in light (L), moderate (M), and deep (D) anesthesia were 0.40 +/- 0.05 (mean +/- SE), 0.24 +/- 0.03, and 0.10 +/- 0.02, respectively, and were significantly different from each other. Under each grade of anesthesia, exercise was performed by electrically stimulating the bilateral femoral and sciatic nerves for 4 min. The time to reach 63% of full response of the increase in ventilation (tauVE) after beginning of exercise was 28.3 +/- 1.5, 38.1 +/- 5.2, and 56.0 +/- 6.1 s in L, M, and D, respectively. During steady-state exercise, minute ventilation (VE) in L, M, and D significantly increased to 6.17 +/- 0.39, 5.14 +/- 0.30, and 3.41 +/- 0.16 1 X min-1, from resting values of 3.93 +/- 0.34, 2.97 +/- 0.17, and 1.69 +/- 0.14 1 X min-1, respectively, while end-tidal CO2 tension (PETCO2) in L decreased significantly to 34.8 +/- 0.9 from 35.7 +/- 0.9, did not change in M (38.9 +/- 1.1 from 38.9 +/- 0.8), and increased significantly in D to 47.3 +/- 1.9 from 45.1 +/- 1.7 Torr.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined airway responsiveness to allergen inhalation using a novel technique by which dynamic compliance (Cdyn) and pulmonary resistance (Rl) are simultaneously calculated by Fourier-series analysis of flow and transpulmonary pressure during tidal breathing. C0 and C0.5 (Cdyn at the frequency of zero and 0.5 Hz, respectively) were computed using the regression line of Cdyn versus frequency measured at the fundamental and first three harmonics in each breathing cycle. First, the validity of this system was tested by comparing Rl, C0 and C0.5 during five consecutive breaths with those obtained by the conventional method. A good correlation was seen in Rl, C0 and C0.5 between the two methods. Second, we studied airway response to allergen inhalation before and after oral administration of a long-acting β 2 -stimulant (procaterol, 50 μg or 100 μg) or placebo in a double-blind crossover trial in six atopic asthmatic subjects. In control allergen inhalation tests by administration of placebo, Rl increased progressively, and C0.5, expressed as percentage of control compliance at zero frequency (C0.5/C0cont), decreased progressively. After 100 μg procaterol, Rl response to allergen was almost completely inhibited. However, a decrease in C0.5/C0cont was still observed. These findings suggest that pretreatment of asthmatic patients with procaterol can release allergen-induced bronchoconstriction of the central airways, but cannot release that of the peripheral airways.

For diagnosis of sleep apnea syndrome (SAS), there are three important steps wihch we have to consider. As the first step, we have to derive the following clinical symptoms from repeated questioning of patients and their families, for example, snoring, morning headache, daytime sleepiness, general fatigue, dyspnea, abnormal behavior during sleep or nocturnal enuresis, etc. Furthermore, we have to consider background diseases and complications. As the second step, it is necessary to take a screening test for patients, who are thought to have breathing disorders of sleep. We have developed a home sleep monitoring system which is very useful for a screening test. Home sleep monitor is consisted of two thermisters for mouth and nasal flow, a microphone for tracheal sound, three electrodes for electrocardiogram, amplifiers and microcomputer. The weight of this device is 280g. This device is equipped just before patient goes to bed, and brought back to hospital on the following day. Data such as trend display of apnea episodes, histogram of apnea episodes or trend display of heart rate are analyzed by a personal computer. As the third step, patient who is suspected of SAS by a screening test needs polysomnography to get correct diagnosis for SAS after admission to hospital. By polysomnography, we can obtain the informations of sleep stage, apnea type, degree of desaturation or hemodynamics during sleep.

We studied bronchial responsiveness to methacholine in 10 normal subjects, in 60 patients with bronchial asthma and in 30 patients with bronchitis using a new device, with which we were able to obtain the dose-response curve of respiratory resistance (Rrs) continuously and graphically by the 3 Hz oscillation method during inhalation of methacholine. All normal subjects were non-responders, while all of the bronchial asthma cases, 63% of the chronic bronchitis cases and 50% of the acute bronchitis cases were responders. Among responders we found a very poor correlation between the initial respiratory conductance (Grs.cont) and the bronchial sensitivity (defined as the reverse of the cumulative dose until Rrs starts to increase); yet we found a good correlation between Grs.cont and the bronchial reactivity (defined as the slope of the decreasing rate of Grs). Metaproterenol and atropine decreased the bronchial sensitivity and reactivity in 28 asthmatic patients. We concluded that for clinical purposes the new method was very useful for assessing bronchial responsiveness to inhalation challenge because of its simplicity of operation as well as the quantitative differentiation between bronchial sensitivity and reactivity. Our results suggest that the bronchial response system to methacholine is explainable by a model of multiple dose-response curves without any parallel shift.

We studied the effective site of an inhaled aerosol of procaterol, a beta 2-selective adrenergic bronchodilator, in 8 asthmatic patients whose basal lung functions are almost within the normal range in both slow vital capacity (VC) and forced expiratory volume in one second (FEV1.0), and are free from asthmatic attack. In patients who had received procaterol 30 min after inhalation of aerosol, there was no significant change in VC, although FEV1.0, maximal expiratory flow at 50% VC (V50), maximal expiratory flow at 25% VC (V25) and maximal expiratory flow at 30% VC of partial maximal expiratory flow volume curve (V30p) improved significantly. On the other hand, in those who had received placebo, none of the parameters changed. Furthermore, R1 decreased and C0.5 increased significantly during the first 5 min after inhalation of procaterol aerosol. After an interval of 5 min, R1 did not change any further, while C0.5 continued to improve until 30 min after inhalation of procaterol. These results suggest that procaterol may first dilate the large airway and then may gradually dilate the small airway in bronchial asthma.

We developed a new method of direct-writing recording of the frequency dependence of dynamic compliance analysed from one cycle of breathing and pulmonary resistance. Both pulmonary resistance (RL) and frequency dependence of dynamic compliance (Cdyn.f) are calculated by Fourier-series analysis of flow and transpulmonary pressure in a single cycle of breathing. RL was obtained from fundamental harmonics. Cdyn.f was calculated from 1st and 2nd harmonics and estimated by the ratio of Cdyn at 0.5 Hz to Cdyn at zero frequency, C0.5/C0. We used fenoterol aerosol which contained 0.2 mg of fenoterol with one puff of aerosol. Two puffs of fenoterol aerosol were used in each subject and followed changes of RL, C0 and C0.5 as long as 30 min. After fenoterol inhalation RL decreased considerably and C0.5/C0 cont [C0.5/(control C0)] increased. With time, while RL was kept stable, C0.5/C0 cont increased further. We suggest that fenoterol has a potent effect on the small airways which is enhanced with time.

To establish a safe procedure for examining propranolol-induced bronchoconstriction, we have developed a new method for performing inhalation challenge with propranolol. Monitoring respiratory resistance during tidal breathing with continuous inhalation of propranolol in 1.5-fold increasing concentrations from 0.78 to 30 mg/ml for 1 minute at each concentration, we tested 43 subjects with stable asthma and 10 normal subjects. We also compared bronchial responsiveness with responsiveness to inhaled methacholine on separate days. In addition, to determine the role of vagal nerve activity in propranolol-induced bronchoconstriction, we studied the effect of atropine. Inhaled propranolol caused dose-related bronchoconstriction in all subjects with asthma but not in normal subjects. None of the subjects suffered severe asthmatic attack during the test, which was performed in 15 minutes or less. The minimum cumulative dose of methacholine and of propranolol, at the point where respiratory conductance began to decrease, was not significantly correlated. Increased respiratory resistance was reversed by atropine in 70% of the subjects with asthma with marked individual differences. These data suggest that, although in most subjects with asthma, vagal nerve activity contributes in varying degree to bronchoconstriction, other constricting factors may contribute in the remaining subjects. It is also suggested that the mechanism of bronchial response to propranolol differs from that of the nonspecific airway reactivity estimated by methacholine challenge.

The ventilatory response to electrically induced contraction (EIC) and passive movement (PM) of hindlimb muscles at different levels of anesthesia was studied in 11 chloralose-urethan anesthetized dogs with and without rhizotomy. The level of anesthesia was assessed by corneal reflexes and measurements of the ventilatory response to hypercapnia. Muscle contraction was induced by electrically stimulating the peripheral cut ends of the sciatic and femoral nerves for 4–5 min, and PM was induced manually at the same frequency and amplitude as during EIC. In spinal intact dogs (n = 7), initial rapid increases in minute ventilation (VE) during EIC and PM were found in both light and deep anesthesia. Further increases in VE above the initial rise were seen during EIC but not PM. The initial rapid increases in VE did not differ between the two anesthetic levels. The steady-state ventilatory response during EIC decreased as anesthesia deepened but did not do so during PM. Rhizotomy (n = 4) abolished the initial rapid increase in VE during EIC and PM and the steady-state VE response to PM at both anesthetic levels. These results suggest that the transitional ventilatory response is neurally mediated from the muscles and not affected by the level of general anesthesia. Additionally, the anesthesia-induced reduction of ventilatory response may be due to depression of responsiveness to CO2 rather than to the inspiratory motoneuron pathway.

We report a new device for examining the bronchial hyperresponsiveness by directly writing the dose-response curve of respiratory resistance (Rrs) during the continuous inhalation of the methacholine in stepwise incremental concentrations. Respiratory resistance was measured by the forced oscillation method. We found that the Rrs began to increase at a certain threshold concentration of methacholine (bronchial sensitivity) and that it has a curvilinear slope (bronchial reactivity). Subsequent inhalation of the bronchodilator drug returned the Rrs to the control level. Thus, we were able to examine bronchohyperresponsiveness in the patterns of the cumulative dose-response curves of methacholine. All normal subjects were nonresponders; while all of the asthmatic subjects, 63 percent (10) of the 16 patients with chronic bronchitis and 50 percent (7) of the 14 patients with acute bronchitis were responders. The dose-response curves were reproducible. Our device may be clinically applicable for examinations of bronchial hyperresponsiveness and for screening tests.

Ventilatory response to graded external dead space (0.5, 1.0, 2.0, and 2.5 liters) with hyperoxia and CO2 steady-state inhalation (3, 5, 7, and 8% CO2 in O2) was studied before and after 4% lidocaine aerosol inhalation in nine healthy males. The mean ventilatory response (delta VE/delta PETCO2, where VE is minute ventilation and PETCO2 is end-tidal PCO2) to graded dead space before airway anesthesia was 10.2 +/- 4.6 (SD) l.min-1.Torr-1, which was significantly greater than the steady-state CO2 response (1.4 +/- 0.6 l.min-1.Torr-1, P less than 0.001). Dead-space loading produced greater oscillation in airway PCO2 than did CO2 gas loading. After airway anesthesia, ventilatory response to graded dead space decreased significantly, to 2.1 +/- 0.6 l.min-1.Torr-1 (P less than 0.01) but was still greater than that to CO2. The response to CO2 did not significantly differ (1.3 +/- 0.5 l.min-1.Torr-1). Tidal volume, mean inspiratory flow, respiratory frequency, inspiratory time, and expiratory time during dead-space breathing were also depressed after airway anesthesia, particularly during large dead-space loading. On the other hand, during CO2 inhalation, these respiratory variables did not significantly differ before and after airway anesthesia. These results suggest that in conscious humans vagal airway receptors play a role in the ventilatory response to graded dead space and control of the breathing pattern during dead-space loading by detecting the oscillation in airway PCO2. These receptors do not appear to contribute to the ventilatory response to inhaled CO2.

In 8 healthy subjects (group A) and 4 subjects with respiratory symptoms (group B), the lung pressure-volume curve (P-V curve), maximum expiratory flow-volume curve (MEFVC) and respiratory resistance (Rrs) at all vital capacities were measured. To avoid laryngeal artifact on a mouth pressure, an intratracheal catheter was used for measurement of Rrs which was obtained with 3 cycles/sec oscillatory forced pressure. Group B did not show a different elastic recoil from group A. In comparison of the maximum expiratory flow (Vmax) at 80, 70, 60 and 50% of the total lung capacity (TLC). Vmax of group B showed lower values than that of group A. Rrs was almost the same in both groups from 70% TLC upwards, but Rrs of group B was higher than that of group A from 65%TLC downwards. Since the lung elastic recoil pressures (Pst (1)) in the two groups were not different and Rrs's were different significantly only at low lung volumes, the decrease in Vmax of group B was supposed to be due to the increased Rrs which might reflect small airway obstruction.

We examined the effects of percutaneous electrical stimulation of the genioglossus in six patients with obstructive sleep apnea syndrome (OSAS) during sleep and investigated the possible applicability of this procedure as a treatment of OSAS. Six patients with OSAS were polysomnographically studied in the supine position during all-night sessions with and without electrical stimulation of the genioglossus. Using an apnea demand-type stimulator that we developed, electrical pulses of 0.5 ms (repetition rate, 50 Hz) and 15 to 40 V were delivered through bipolar electrodes (10 mm in diameter) attached to the skin of the submental region when apnea lasted more than 5 s, and was stopped immediately after breathing resumed or after 10 s at the longest. With submental stimulation, the apnea index, apnea time/total sleep time, longest apnea duration, and the number of times per hour that oxygen saturation dropped below 85% decreased significantly compared with those on control nights. The lowest arterial oxygen saturation and the duration of sleep stages III and IV increased significantly. The stimulation employed did not cause arousal, and it did not affect blood pressure or heart rate significantly. These findings show that submental stimulation decreases the incidence of apnea episodes and promotes deeper sleep without accompanying serious side effects, suggesting that the apnea demand-type stimulator may be a noninvasive and effective treatment for OSAS.

A study was carried out in 6 patients with bronchial asthma to investigate the effects of clenbuterol, a beta 2-sympathomimetic bronchodilator, on peripheral airway obstruction. The basal lung functions of the patients were almost within normal range in both vital capacity (VC) and forced expiratory volume in 1 second (FEV1), but their maximal flow rates were lower in effort-independent phase of both maximal expiratory flow volume (MEFV) curve and partial expiratory flow volume (PEFV) curve. Furthermore, they demonstrated marked basal frequency dependence of dynamic compliance [CL,dyn]. Oral administration of clenbuterol (40 micrograms) produced a significant increase in the maximal flow in effort-independent phase of both MEFV and PEFV curves, and markedly decreased frequency dependence of CL,dyn in comparison with the baseline values, while it improved both VC and FEV1 to a lesser extent. These results suggest that clenbuterol preferentially reduced the peripheral airway obstruction in bronchial asthma.

We examined the role of CO2 responsiveness and breathing efficiency in limiting exercise capacity in 15 patients with chronic airway obstruction (FEV1 = 0.88 +/- 0.25 L, mean +/- SD). Responses of minute ventilation and P0.1 (mouth pressure 0.1 s after the onset of occluded inspiration) to hypercapnia (delta VE/delta PCO2, delta P0.1/delta PCO2) were measured by rebreathing, and the ratio of the two (delta VE/delta P0.1) was defined as an index of breathing efficiency during hyperventilation. Exercise capacity was measured as symptom-limited, maximal oxygen consumption (VO2max/BW) in an incremental treadmill test and also as the 12-min walking distance (TMD). All patients discontinued the treadmill test because of dyspnea, and the exercise capacity correlated with the degree of airway obstruction, although there was a wide variability among patients with comparable FEV1. There were no significant correlations between the responses to CO2 and exercise capacity. However, there was a significant correlation between delta VE/delta P0.1 and VO2max/BW (r = 0.87, p less than 0.001) or TMD (r = 0.78, p less than 0.001), and these correlations remained significant even when the relational effects of FEV1 were taken out. These results support the hypothesis that airway obstruction and breathing efficiency are important, but that CO2 responsiveness is not a major factor in determining the exercise capacity of patients with chronic airway obstruction.

We measured laryngeal narrowing with low-frequency sound in human subjects. A low-frequency sound of 800 Hz was forced into the mouth, and sound-pressure amplitude above (SPAa) and below the vocal cord (SPAb) was detected using two separate microphones at the anterior neck. If the subject voluntarily narrowed the larynx at functional residual capacity, the increased respiratory resistance (Rrs) was only caused by increased laryngeal resistance, and SPAa was increased and SPAb was decreased. The percent changes of SPAa (SPAa%) minus that SPAb (SPAb%) from the initial values (SPAa% - SPAb% = Y) was proportional to the increase of Rrs from the initial control state (X, cmH2O X 1-1 X s); Y = 22.4 X1.20 (coef of correlation, r = 0.96, P less than 0.01). We confirmed similar proportions in dogs by manually narrowing the vocal cord. When laryngeal resistance was directly measured by tracheal puncture with a needle, the proportions between Y and X were not significantly dependent on the increase of Rrs below the vocal cord induced by methacholine inhalation in human subjects and histamine injection in dogs. We concluded that the increase of laryngeal resistance from the initial state could be detected noninvasively by using low-frequency sound.

We examined the effect of digitalis on diaphragmatic contractility and fatigability in 19 anesthetized mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. In a first group of five dogs, Pdi-stimulus frequency relationships were compared before and after administration of ouabain in doses of 0.01, 0.02, and 0.04 mg/kg. In a second group, diaphragmatic fatigue was produced by bilateral phrenic nerve stimulation at 30 Hz. Ten seconds of stimulation and 15 s of mechanical ventilation were repeated for 30 min. The rates of decrease in Pdi were compared between two groups, one of 0.05 mg/kg deslanoside-treated dogs (n = 7) and one of nontreated dogs (n = 7). After ouabain administration Pdi was significantly greater at each frequency in a dose-dependent manner. On the other hand, the rate of decrease in Pdi in the deslanoside group was significantly smaller than that in the nontreated group, whereas deslanoside did not greatly change the Pdi-frequency curves in fresh diaphragm. We conclude that ouabain improves contractility of the fresh diaphragm and that deslanoside has a protective effect against fatigability.

We examined the relationship between the frequency of stimulation of the genioglossus and upper airway resistance in six anesthetized dogs in the supine position. The upper airway was isolated from the lower airway by transecting the cervical trachea, and the pressure flow relationship of the upper airway was obtained by applying constant negative pressure (5, 10, and 20 cm H2O) to the proximal cut end of the trachea. Electrical stimulation of the genioglossus was performed at a constant voltage (10 to 20 V) and at various frequencies (as high as 100 Hz). Upper airway resistance (Rua) during both inspiration and expiration increased with an increase in tracheal negative pressure, and at each tracheal negative pressure Rua was significantly reduced by stimulation of the genioglossus. The effects of genioglossal muscle stimulation were nonlinearly dependent on the stimulating frequency. Below 50 Hz, Rua decreased markedly as the stimulating frequency was increased, but above 50 Hz, Rua plateaued at a minimum value. These findings suggest that at a stimulating frequency of more than 50 Hz, upper airway patency is stably maintained in anesthetized dogs.

MIKI, H., HIDA, W., SHINDOH, C., TAGUCHI, O., INOUE, H. and TAKISHIMA, T. Effect of Electrical Stimulation of Genioglossus Muscle on Upper Airway Resistance in Anesthetized Dogs. Tohoku J. exp. Med., 1987, 153 (4), 397-398 - The isolated upper airway pressure and flow changes during electrical stimulation of the genioglossus muscle in spontaneously breathing anesthetized dogs were measured at given pressures in the inspiratory direction. Upper airway resistance was maximal during no stimulation and decreased rapidly with stimulation at frequencies up to about 40Hz.

We performed pulmonary function tests after antigen inhalation challenge in 6 patients with hypersensitive pneumonia. 2 patients showed a reduction in maximal expiratory flow at 25% vital capacity (V25) within the first 1-3 h (early reaction) followed by a decrease in vital capacity, forced expiratory volume at 1 s and increased respiratory resistance in the next 4-7 h (late reaction). In the other 4 patients, only V25 decreased within the first 1-3 h. Diffusion capacity did not change significantly. It is suggested that the small airway is the most sensitive site of reaction to an antigen inhalation challenge in hypersensitive pneumonia and that the obstructive change of the small airway could occur as the early reaction.

The possibility has been investigated that propranolol administration could alter bronchial reactivity to methacholine and histamine in monkeys (Macaca fuscata and Macaca fascicularis). The impedance of the total respiratory system was measured by the forced 3-HZ oscillation method through an endotracheal tube. Methacholine and histamine dose-dependently increased the impedance in monkeys irrespective of the route of administration (inhalation of aerosol or intravenous injection). Propranolol treatment increased the bronchial response to intravenously injected methacholine and caused no significant change in the bronchial response to aerosolized methacholine. No marked difference was observed in the bronchial response to histamine due to treatment with propranolol regardless of whether administered by intravenous injection or aerosol challenge.

We measured the pressure-volume curves (PV curves) of the lung simultaneously at three levels in the esophagus below the tracheal bifurcation using the three-short-balloon-catheter system in 11 normal seated men and compared the inflection points (IP's) of three PV curves with the closing volume (CV) on the single-breath nitrogen washout curve. The mean pressure gradient from the top of the uppermost balloon to the top of the lowermost balloon (10 cm apart) was 0.58 +/- 0.06 cmH2O/cm at 60% total lung capacity (TLC). The IP was dependent on depth within the esophagus; i.e., the lung volume at IP (VIP) of the uppermost balloon was the smallest and the transpulmonary pressure (Ptp) at IP (PIP) of that balloon was the largest of the three IP's. VIP's were significantly larger than CV's and the mean absolute difference between the VIP of the uppermost balloon and the closing capacity (CC) was 0.9 liter. These results suggest that IP may not exactly reflect airway closure.

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 airway 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.

The effect of the inspiratory flow rate during deep inspiration on the regulation of bronchomotor tone was studied in nine normal and 22 asthmatic subjects. Changes in bronchial tone were assessed by respiratory resistance measured by an oscillation method. In normal subjects with bronchoconstriction induced by methacholine a rapid deep inspiration reduced respiratory resistance more than a slow deep inspiration. Asthmatic subjects with spontaneous airway narrowing showed an increase in respiratory resistance after deep inspiration that was greater after rapid than after slow deep inspiration. On the other hand, in asthmatics with methacholine induced bronchoconstriction, bronchodilatation occurred after deep inspiration and this was also greater after rapid than after slow deep inspiration. Lignocaine inhalation attenuated both bronchoconstriction and bronchodilatation induced by both slow and rapid deep inspiration. These results suggest that the effects of deep inspiration are mediated at least in part via receptors in the airways. It is suggested that in asthmatic patients with spontaneous bronchoconstriction irritant receptor activity will be increased in proportion to the speed of inspiration. After methacholine induced bronchoconstriction stretch receptor activity is likely to behave in a similar fashion, leading to an opposite effect.

We studied the effects of hypercapnia on the ventilatory response to nicotine in thirty anesthetized mongrel dogs. Ventilatory (VE) and occlusion pressure (P0.2) changes were assessed before and after intravenous injection of nicotine at concentrations of 1, 4, 16 and 64 micrograms/kg in four different groups of five dogs each. An end-tidal CO2 (PETCO2) was set at 40 mm Hg or 60 mm Hg by inspiration of 7% CO2 in oxygen through a non-rebreathing valve. With PETCO2 maintained at 40 mm Hg, P0.2 had increased 1 min after nicotine injection from 1 to 16 micrograms/kg in a dose-dependent manner, and a subsequent decrease in P0.2 below the initial value was observed at around 4 min. Injection of 64 micrograms/kg of nicotine produced a marked increase in P0.2 and subsequent apnea. With PETCO2 at 60 mm Hg, the time course of P0.2 was qualitatively similar to that observed with PETCO2 at 40 mm Hg, except that the change in P0.2 was larger in the former case than in the latter, for a given nicotine dose. The ratio of the difference in maximal P0.2 observed with PETCO2 of 40 mm Hg and that at 60 mm Hg to the difference between PETCO2 values (delta PO2/delta PETCO2) increased with nicotine dose from 1 to 4 micrograms/kg and, with a further increase in nicotine dose, the maximal delta P0.2/delta PETCO2 plateaued, while delta P0.2/delta PETCO2 obtained from the minimal PO2 values decreased in a nicotine dose-dependent fashion. These results suggest that hypercapnia enhances both stimulative and subsequent depressive ventilatory responses to nicotine.

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 during 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.

To examine whether or not the respiratory muscle weakness is correlated with decrease in arterial oxygen tension (PaO2), respiratory muscle and pulmonary functions in 14 patients with neuromuscular diseases (NMD) were studied and compared with those of 12 patients with chronic pulmonary emphysema (CPE) and 15 patients with idiopathic pulmonary fibrosis (IPF). Respiratory muscle strength was assessed by maximal static inspiratory and expiratory mouth pressure at three lung volumes (RV, FRC and TLC). Although mean pulmonary functions in NMD showed virtually normal function, respiratory muscle strength was significantly less than the corresponding values in CPE and IPF. In NMD, maximal inspiratory mouth pressure at RV level (PImax) correlated positively with %TLC and %VC (r = 0.652 and r = 0.536, respectively). Moreover, PImax was significantly correlated with PaO2 (r = 0.561), but not with PaCO2. Maximal expiratory mouth pressure at TLC (PEmax) correlated positively with %TLC and %VC. In CPE and IPF, respiratory muscle strength had no correlation with PaO2 and PaCO2. These findings suggest that inspiratory muscle dysfunction in NMD may be one of the factors responsible for determination of the level of hypoxemia and lung volume.

The mechanisms governing increased central (Rc) and peripheral airway resistance (Rp) during hemodynamic edema formation were studied in anesthetized dogs. Rc and Rp were measured by forced oscillation at 1 Hz by use of a retrograde catheter to partition resistance and a pleural capsule to detect alveolar pressure. After elevation of left atrial pressure to 30 cmH2O by inflation of the left atrial balloon, Rc gradually increased an average of 60% above control in approximately 100 min. Vagotomy had a small influence on the change. On the other hand, Rp with vagus nerves intact increased triphasically: first, it increased transiently by 160% above the control value within 15–20 min before returning to near base line. It then increased gradually for approximately 40 min and finally rose sharply up to five times the control value after approximately 100 min. With vagi cut, the initial phase disappeared, but the second gradual and final rapid phases were not affected. Several sequential mechanisms of increased Rp can be proposed: 1) transient bronchoconstriction mediated by vagal reflex; 2) gradual formation of peribronchial edema; and 3) a sharp increase in airway fluid and formation of bronchial froth. In addition, narrowing of the airways by vascular engorgement may have contributed to the increase of Rp throughout all stages.

MUE, S., OHMI, T., SUZUKI, S., TAMURA, G., HIDA, W., SEKIZAWA, K., ISHIHARA, T., YAMAUCHI, K. and TAKISHIMA, T. The Effect of Adrenergic and Cholinergic Drugs on Methacholine- and Histamine-Induced Bronchoconstriction in Monkeys. Tohoku J. exp. Med., 1983, 140 (2), 109-119 - The effect of adrenergic and cholinergic drugs on bronchial contraction of monkeys was studied using bronchoconstriction induced by aerosol challenge with methacholine and histamine. Under the anesthesia with ketamine hydrochloride, changes in the total respiratory resistance were continuously measured in monkeys to estimate the bronchial response to both histamine and methacholine. Isoprenaline decreased bronchial susceptibility to aerosol challenge with both methacholine and histamine. Isoprenaline was also potent in antagonizing the bronchoconstriction induced by methacholine and histamine. Atropine decreased bronchial susceptibility to aerosol challenge with methacholine and also partially with histamine. Atropine also antagonized the bronchoconstriction induced by methacholine, but not by histamine. Phentolamine had neither inhibitory effects on the aerosol challenge with methacholine and histamine, nor produced an antagonistic effect on bronchoconstriction induced with methacholine and histamine.

HIDA, W., TAGUCHI, O., IWASE, N., SATO, M., CHONAN, T., KIKUCHI, Y., OGATA, M., SHIRATO, K. and TAKISHIMA, T. Change in P Wave Height during Progressive Exercise in Patients with Chronic Obstructive Pulmonary Disease. Tohoku J. Exp. Med., 1989, 157 (1) 79-80 - We examined changes in P wave height in lead II of electrocardiogram during progressive exercise in patients with chronic obstructive pulmonary disease (COPD), and obtained the slope (ΔP/ΔVO2, %/ml/min) of the regression line calculated from the relationship between percent change of P wave height and oxygen consumption (VO2). Four COPD patients, who had a decrease over 5mmHg in arterial oxygen tension (PaO2) at maximal exercise (group A), had significantly greater slope (0.45±0.14%/ml/min, mean±S.E.) than in five COPD patients (group B, 0.14±0.05), who did not have a decrease over 5mmHg in PaO2 at maximal exercise. The increase in P wave height during exercise was inhibited by oxygen inhalation at the given VO2 in group A. These findings suggest that increase in P wave height during exercise in COPD patients may be correlated with hypoxemia during exercise.

MIKI, H., HIDA, W., INOUE, H. and TAKISHIMA, T. A New Treatment for Obstructive Sleep Apnea Syndrome by Electrical Stimulation of Submental Region. Tohoku J. exp. Med., 1988, 154 (1), 91-92 - Loss of upper airway muscle tone during sleep has been thought to be responsible for obstructive apnea episodes. To examine the effect of electrical stimulation of the submental region on sleep apnea episodes, patients with obstructive sleep apnea syndrome were polysomnographically studied during all-night session with and without stimulation.

Renin-Angiotensin System (RAS), oxidative stress and inflammation is involved in the pathogenesis of hypertension and salt sensitivity of hypertension. The present study was designed to evaluate the role of RAS, oxidative stress and inflammation to the regulation of blood pressure in young subjects. 111 young students (19.2±0.8 years old) who have taken health checkup were randomly selected for the study. Urinary excretions of angiotensinogen (AGT), oxidative stress (TBARS), and inflammatory markers (MCP-1) were analyzed. Urinary excretions of these parameters were estimated by 24-hour urinary creatinine excretion, age, height and body weight. Subjects were divided to two groups based on the blood pressure: below 140/90 mmHg (Normal) and over 140/90 mmHg (High). Blood pressure was significantly increased with increased BMI. Urinary AGT, TBARS, and MCP-1 of high blood pressure group were significantly (p