Exposure to hardly soluble indium compounds in ITO production and recycling plants is a new risk for interstitial lung damage.

OBJECTIVES: To identify the effects of indium on the lung and to assess exposure-effect and exposure-response relations between indium exposure and effects on the lungs. METHODS: Ninety three male indium exposed and 93 male non-exposed workers from four ITO manufacturing or ITO recycling plants were analysed in a cross-sectional study. Indium in serum (In-S) was determined as a biological exposure index. Geometric means (GSD) of In-S were 8.25 ng/ml (4.55) in the exposed workers and 0.25 (2.64) in the non-exposed workers. The maximum concentration of In-S was 116.9 ng/ml. A questionnaire for respiratory symptoms and job histories, spirometry, high-resolution computerised tomography (HRCT) of the chest, serum KL-6, serum SP-A, serum SP-D and serum CRP were measured as the effect indices. RESULTS: Spirometry, subjective symptoms and the prevalence of interstitial or emphysematous changes on lung HRCT showed no differences between exposed and non-exposed workers. Geometric means (GSD) of KL-6, SP-D and SP-A in the exposed workers were 495.4 U/ml (2.26), 85.2 ng/ml (2.02) and 39.6 ng/ml (1.57), and were significantly higher than those in the non-exposed workers. The prevalence (%) of the exposed and non-exposed workers exceeding the reference values were also significantly higher in KL-6 (41.9 vs 2.2), SP-D (39.8 vs 7.5), and SP-A (43.0 vs 24.7). Very sharp exposure-effect and exposure-response relations were discovered between In-S and KL-6 and between In-S and SP-D when the exposed workers were classified into seven groups by In-S. CONCLUSIONS: The study outcomes with regard to the basis of serum immunochemistry biomarkers and HRCT indicate that exposure to hardly soluble indium compound dust may represent a risk for interstitial lung damage.

Interstitial pulmonary disorders in indium-processing workers.

The production of indium-tin oxide has increased, owing to the increased manufacture of liquid-crystal panels. It has been reported that interstitial pneumonia occurred in two indium-processing workers; therefore, the present study aimed to evaluate whether interstitial pulmonary disorders were prevalent among indium workers. The study was carried out in 108 male workers in the indium plant where the two interstitial pneumonia patients mentioned above were employed, and included high-resolution computed tomography (HRCT) of the lungs, pulmonary function tests and analysis of serum sialylated carbohydrate antigen KL-6 and the serum indium concentration. Significant interstitial changes were observed in 23 indium workers on HRCT and serum KL-6 was abnormally high (>500 U x mL(-1)) in 40 workers. Workers with serum indium concentrations in the highest quartile had significantly longer exposure periods, greater HRCT changes, lower diffusing capacity of the lung for carbon monoxide and higher KL-6 levels compared with those in the lowest quartile. The serum indium concentration was positively correlated with the KL-6 level and with the degree of HRCT changes. In conclusion, the results of the present study indicated that serum KL-6 and high-resolution computed tomography abnormalities were prevalent among indium workers and that these abnormalities increased with the indium burden, suggesting that inhaled indium could be a potential cause of occupational lung disease.

[Determination of azoxystrobin in tea by HPLC].

A determination method has been developed for azoxystrobin in tea by HPLC. Azoxystrobin was extracted from a sample with acetone, and the extract was passed through an alumina column to remove tannin. The eluate was concentrated to ca. 25 mL and passed through a Sep-Pak Vac tC18 to remove pigments. The eluate was cleaned-up by using liquid-liquid partition, and Florisil and silica-gel columns. The HPLC analysis for azoxystrobin was carried out on a C18 column with acetonitrile-water (9:11) as the mobile phase, with ultraviolet detection at 260 nm. The recovery of azoxystrobin fortified at the level of 0.4 microgram/g was 90.2% and the limit of determination was 0.2 microgram/g.

Influence of sustained hypoxia on the sensation of dyspnea.

We assessed the effect of sustained isocapnic hypoxia (PCO2 = 40 Torr, SaO2 = 80%) on the sensation of dyspnea in 16 normal healthy males. Subjects rated the sensation of dyspnea (c) on 15 cm visual analog scales during 20 min of sustained hypoxia. Following this hypoxic period, 8 subjects undertook mild exercise (10-50 W on a bicycle ergometer for 3 min) under the continuation of hypoxia. During sustained hypoxia, psi increased initially with ventilation from 0.6 +/- 0.2 (n = 16, mean +/- SE) to 2.9 +/- 0.6 at peak ventilation, but it decreased with ventilatory depression to 1.6 +/- 0.4. Dyspnea intensity during hypoxic exercise was significantly smaller than that at peak ventilation in the resting hypoxic period (2.3 +/- 0.7 vs. 3.9 +/- 1.0), although the ventilation was greater during exercise (24.0 +/- 3.0 vs. 19.7 +/- 1.4 l/min). These results indicate that sustained hypoxia has a biphasic, i.e., initial stimulatory and delayed depressant, effect on dyspnea and on ventilation. It is suggested that the dyspnea sensing mechanism is suppressed during mild exercise under sustained hypoxia.

Effect of intramedullary procaine injection on tracheal tone and phrenic neurogram.

To map the superficial locations which are involved in the control of respiration and tracheal smooth muscle tone in ventrolateral medulla, we examined the effects of local anesthesia on phrenic activity and tracheal tone in twelve anesthetized, paralyzed, and artificially ventilated dogs. 0.5 microliter of 5% procaine was injected 0.3 to 0.5 mm below the surface unilaterally to the ventral superficial layer (from the rostral part of the trapezoid body to the caudal hypoglossal rootlets and lateral from the pyramids to 5.5 mm from the midline), which included rostral, intermediate and caudal areas, and the area lateral to the hypoglossal rootlets. The peak amplitude of the integrated phrenic neurogram was decreased by procaine injection to the intermediate area and the area lateral to the hypoglossal rootlets. Tracheal tone decreased only by procaine injection to the intermediate area. In the intermediate area, some injections decreased either phrenic output alone or tracheal tone alone. These results suggest that the two ventral medullary areas, i.e. the intermediate and caudolateral parts, contain neural structures which are involved in the shaping of phrenic output, but only the intermediate area is involved in the regulation of tracheal tone. It is also suggested that, in the intermediate area, the structures responsible for the maintenance of respiration and tracheal tone are, at least in part, separable.

Upper airway muscle activity during sustained hypoxia in awake humans.

To examine the effects of sustained hypoxia on upper airway and chest wall muscle activity in humans, we measured genioglossus muscle (GG) activity, inspiratory intercostal muscle (IIM) activity, and ventilation during sustained hypoxia in 17 normal subjects and 17 patients with obstructive sleep apnea (OSA). The trial of sustained hypoxia was performed as follows: after an equilibration period of 3 min, isocapnic hypoxia (arterial O2 saturation = 80 +/- 2%) was maintained for 20 min. GG EMG was measured with a fine-wire electrode inserted percutaneously, and IIM EMG was measured with surface electrodes. Ventilatory response to sustained hypoxia was initially increased and subsequently decreased. Stable phasic GG activity during spontaneous tidal breathing was observed in 6 normal subjects and 10 patients with OSA. Responses of GG and IIM activities to sustained hypoxia showed a biphasic response qualitatively similar to the ventilatory response in these 16 subjects. The absolute value of the subsequent decline in GG activity was similar to that of the initial increase, whereas the subsequent decline in IIM activity was smaller than that of the initial increase. Percent GG activity was significantly lower than both percent IIM activity and percent minute ventilation during the decline and plateau phases. There were no significant differences in ventilatory and EMG responses between the normal subjects and the patients with OSA. We conclude that, during wakefulness, upper airway muscle activity declined to a greater extent than inspiratory pump muscle activity during sustained hypoxia.

Effects of posture on carbon dioxide responsiveness in patients with obstructive sleep apnoea.

BACKGROUND: It is well known that upper airway resistance increases with postural change from a sitting to supine position in patients with obstructive sleep apnoea (OSA). It is not known, however, how the postural change affects the ventilatory and occlusion pressure response to hypercapnia in patients with OSA when awake. METHODS: The responses of minute ventilation (VE) and mouth pressure 0.1 seconds after the onset of occluded inspiration (P0.1) to progressive hypercapnia (delta VE/delta PCO2, delta P0.1/delta PCO2) both in sitting and supine positions were measured in 20 patients with OSA. The ratio of the two (delta VE/delta P0.1) was obtained as an index of breathing efficiency. The postural changes in response to carbon dioxide (CO2) after uvulopalatopharyngoplasty (UPPP) were also compared in seven patients with OSA. RESULTS: There were no significant changes in the resting values of end tidal PCO2, P0.1, or VE between the two positions. During CO2 rebreathing, delta VE/delta PCO2 did not differ between the two positions, but delta P0.1/delta PCO2 was significantly higher in the supine than in the sitting position (supine, mean 0.67 (SE 0.09) cm H2O/mm Hg; sitting, mean 0.57 (SE 0.08) cm H2O/mm Hg), and delta VE/delta P0.1 decreased significantly from the sitting to the supine position (sitting, 4.6 (0.4) l/min/cm H2O; supine, 3.9 (0.4) l/min/cm H2O). In seven patients with OSA who underwent UPPP, delta VE/delta P0.1 improved significantly in the supine position and postural change in delta VE/delta P0.1 was eliminated. CONCLUSIONS: These results suggest that in patients with OSA the inspiratory drive in the supine position increases to maintain the same level of ventilation as in the sitting position, and that the postural change from sitting to supine reduces breathing efficiency. Load compensation mechanisms of patients with OSA appear to be intact while awake in response to the rise in upper airway resistance.

Role of chemical drive in recruiting upper airway and inspiratory intercostal muscles in patients with obstructive sleep apnea.

Upper airway dilating muscle activity increases during apneic episodes in patients with obstructive sleep apnea (OSA). To elucidate the relative contribution of chemical and nonchemical stimuli to augmentation of the upper airway dilating muscle, we measured the response of genioglossus muscle (GG) and inspiratory intercostal muscle (IIM) activities to obstructive apnea during non-REM sleep and compared them with the response to progressive hypoxia and hypercapnia during awake periods in seven male patients with OSA. GG EMG was measured with a wire electrode inserted percutaneously, and IIM EMG was measured with surface electrodes placed in the second intercostal space parasternally. Responses to hypoxia and to hypercapnia were assessed by rebreathing methods in the supine position while awake. Following these measurements, a sleep study was conducted with the EMG electrodes placed in the same locations. The relationship between GG and IIM activities during the cycle of apnea and postapneic ventilation in non-REM sleep was quasi-linear, and the slope of the regression line was significantly greater than those during progressive hypoxia and progressive hypercapnia. The amplitude of GG activity at 70% of maximum IIM activities in the hypoxic test was 140 +/- 20% (mean +/- SEM) during non-REM sleep, which was also significantly greater than that during hypoxia (51 +/- 10%) and that during hypercapnia (59 +/- 15%). These results suggest that nonchemical factors contribute considerably to augmentation of GG activity during obstructive apneic episodes. The nonchemical stimuli may arise from mechanoreceptors activated by upper airway obstruction and behavioral factors associated with change in sleep states.

Effects of posture on flow-volume curves during normocapnia and hypercapnia in patients with obstructive sleep apnoea.

BACKGROUND: A high ratio of forced expiratory to forced inspiratory maximal flow at 50% of vital capacity (FEF50/FIF50) may identify upper airway dysfunction. Since hypercapnia increases the motor activity of airway dilating muscles its effects on the maximum expiratory and inspiratory flow-volume curves (MEIFV) in patients with obstructive sleep apnoea and in normal subjects in different postures was studied. METHODS: The effects of posture on the maximum expiratory and inspiratory flow-volume curves during the breathing of air and 7% carbon dioxide in 11 patients with obstructive sleep apnoea were compared with those in nine normal subjects. Measurements were made in the sitting, supine, and right lateral recumbent positions. Forced expiratory flow at 50% vital capacity (FEF50), forced inspiratory flow at 50% vital capacity (FIF50) and FEF50/FIF50 were determined. RESULTS: In the normal subjects FEF50, FIF50, and FEF50/FIF50 were not affected by change in posture or by breathing carbon dioxide. In the patients there was a fall in FIF50 and an increase in FEF50/FIF50 when breathing air in the supine position compared with values in the seated and lateral position. While they were breathing carbon dioxide there was a slight increase in FEF50 when patients were seated or in the lateral position compared with values during air breathing. Hypercapnia abolished the effects of posture on FEF50/FIF50. Values for FEF50/FIF50 in the supine position while they were breathing air correlated with the apnoeic index but not with other polysomnographic data. CONCLUSION: In patients with obstructive sleep apnoea the upper airway is prone to collapse during inspiration when the patient is supine, even when awake; this tendency can be reversed by breathing carbon dioxide.

Prostaglandin E2 inhalation increases the sensation of dyspnea during exercise.

To clarify the role of vagal afferents from the lung in the sensation of dyspnea, we examined the effects of prostaglandin E2 (PGE2) inhalation on the sensation of dyspnea during exercise in eight normal male subjects. This intervention was chosen because inhaled PGE2 is known to stimulate vagal afferent receptors in the lung, in particular C-fiber endings, without a significant increase in airway resistance. After either physiologic saline or PGE2 aerosol (100 micrograms/ml) inhalation through a Bird nebulizer for 2 min, exercise tests were performed on a bicycle ergometer. The tests consisted of 3 min at rest followed by graded work loads (zero to 150 watts, 50-watt increments). Minute ventilation (VE) and respiratory rate were monitored from an expiratory line through a face mask. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were calculated from samples of mixed expired gas. The sensation of difficulty in breathing (dyspnea) was measured on a modified Borg scale at rest and at the end of each work load. We found that although airway resistance and lung volume did not change significantly between saline and PGE2 inhalations, inhaled PGE2 significantly increased the magnitude of the dyspneic sensation when compared with inhaled saline at the same levels of work load, ventilation, and oxygen consumption. These results suggest that in addition to probable roles of motor command and chemical drive, afferent vagal activity from the lung also contributes to the sensation of dyspnea during exercise.

Effects of pharyngeal lubrication on the opening of obstructed upper airway.

We examined the effect of electrical stimulation of the hypoglossal nerve and pharyngeal lubrication with artificial surfactant (Surfactant T-A) on the opening of obstructed upper airway in nine anesthetized supine dogs. The upper airway was isolated from the lower airway by transecting the cervical trachea. Upper airway obstruction was induced by applying constant negative pressures (5, 10, 20, and 30 cmH2O) on the rostral cut end of the trachea. Peripheral cut ends of the hypoglossal nerves were electrically stimulated by square-wave pulses at various frequencies from 10 to 30 Hz (0.2-ms duration, 5-7 V), and the critical stimulating frequency necessary for opening the obstructed upper airway was measured at each driving pressure before and after pharyngeal lubrication with artificial surfactant. The critical stimulation frequency for upper airway opening significantly increased as upper airway pressure became more negative and significantly decreased with lubrication of the upper airway. These findings suggest that greater muscle tone of the genioglossus is needed to open the occluded upper airway with larger negative intraluminal pressure and that lubrication of the pharyngeal mucosa with artificial surfactant facilitates reopening of the upper airway.

[Dyspnea and behavioral control].

Respiration is automatically regulated via chemo- and mechanoreceptors existing in and outside the lungs, but it is also controlled voluntarily by behavioral factors. Voluntary increase in ventilation accentuates dyspnea and the sensory intensity at a given ventilation does not differ from that of exercise-induced hyperventilation, but it is significantly smaller than that during hypercapnia or hypoxia. Voluntary constraint of ventilation augments dyspnea in proportion to the degree of constraint even under isocapnic hyperoxia, and the respiratory sensation during constrained breathing is qualitatively more discomfortable than that during hyperventilation. Changes in the level and pattern of breathing under constant levels of chemical stimuli increase respiratory sensations and the intensity of dyspnea is minimal near the spontaneous levels, which supports the hypothesis that breathing is behaviorally regulated in part to minimize dyspnea. The system of behavioral control of breathing appears to be involved in the maintenance of body homeostasis by modifying the respiratory output through respiratory sensations.

Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea.

To determine whether the intensity of dyspnea at a given level of respiratory motor output differs between bronchoconstriction and the presence of an external resistance, we compared the sensation of difficulty in breathing during isocapnic voluntary hyperventilation in six normal subjects. An external resistance of 1.9 cmH2O.1-1.s was applied during both inspiration and expiration. To induce bronchoconstriction, histamine aerosol (5 mg/ml) was inhaled until airway resistance (Raw) increased to a level approximately equal to the subject's control Raw plus the added external resistance. To clarify the role of vagal afferents on the genesis of dyspnea during both forms of obstruction to airflow, the effect of airway anesthesia by lidocaine aerosol inhalation was also examined after histamine and during external resistive loading. The sensation of difficulty in breathing was rated at 30-s intervals on a visual analog scale during isocapnic voluntary hyperpnea, in which the subjects were asked to copy an oscilloscope volume trace obtained previously during progressive hypercapnia. Histamine inhalation significantly increased the intensity of the dyspneic sensation over the equivalent external resistive load at the same levels of ventilation and occlusion pressure during voluntary hyperpnea. Inhaled lidocaine decreased the sensation of dyspnea during bronchoconstriction with no change in Raw, but it did not significantly change the sensation during external resistive loading. These results suggest that afferent vagal activity plays a role in the genesis of dyspnea during bronchoconstriction.

Inhomogeneous response of expiratory muscle activity to cold block of the ventral medullary surface.

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.

Decrease in functional residual capacity during inspiratory loading and the sensation of dyspnea.

The purposes of the present study were to determine the changes in functional residual capacity (FRC) during inspiratory loading and to examine their mechanisms. We studied seven normal subjects seated in a body plethysmograph. In both graded inspiratory elastic (35, 48, and 68 cmH2O/l) and resistive (21, 86, and 192 cmH2O.l-1.s) loading, FRC invariably decreased from control FRC and phasic expiratory activity increased. The reduction in FRC was greater with greater loads. A single inspiratory effort against an inspiratory occlusion at three different target mouth pressures (-25, -50, and -75 cmH2O) and durations (1, 2, and 5 s) also resulted in a decrease in FRC with an increase in expiratory electromyogram activity in the following expiration. The decrease in FRC was greater with greater target pressure and duration. This decrease in FRC is qualitatively similar to that during inspiratory loaded breathing, and we suspect that the same mechanisms are at work. Because neither vagal nor chemoreceptor reflex can account for these responses, we suspect conscious awareness of breathing or behavioral control to be responsible. In an additional study, the sensation of discomfort of breathing during elastic loading decreased with a decrease in FRC. These results suggest that the reduced FRC may be due to behavioral control of breathing to reduce the sensation of dyspnea during inspiratory loading.

Responses of upper airway muscles to gastrocnemius muscle contraction in dogs.

We studied electromyographic (EMG) responses of the alae nasi (AN) and the posterior cricoarytenoid (PCA) muscles, which act as upper airway dilators, during contraction of gastrocnemius muscle in six chest-intact anesthetized dogs with spontaneous breathing and in four thoracotomized, phrenicotomized and mechanically ventilated dogs with right thoracic and left cervical vagotomy. Muscle contraction was phasically induced by electrical stimulation of the intact gastrocnemius nerve or the distal cut end of this nerve for 20-30 sec. Stimulation intensity was determined as twice the motor threshold in each dog. In chest-intact animals, phasic contraction induced by intact nerve stimulation produced initial rapid increases in upper airway muscle activity, but stimulation of the distal cut end of the nerve did not show the rapid increase in upper airway muscle activity. Furthermore, stimulation of the proximal cut end did not produce any transient response with the stimulation intensity used in this study. In chest-open and vagotomized animals with artificial ventilation, responses of the upper airway muscles to contraction during the intact nerve stimulation were observed. These results suggest that the contraction of the gastrocnemius muscle activates upper airway dilating muscles via reflex mechanisms.

Effects of elastic loading and exercise on pulmonary gas exchange in dogs.

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.

Role of hypoxic drive in regulation of postapneic ventilation during sleep in patients with obstructive sleep apnea.

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)

Sensation and control of breathing: a dynamic model.

A dynamic model of the CO2 respiratory control system is proposed, which can provide a qualitative basis for predicting breathing sensations. The discomfort index, which represents breathing sensations, is assumed to be composed of two sources: the arterial CO2 level and the respiratory motor command. The respiratory controller receives inhibitory neuromechanical and excitatory CO2 signals from the plant. The CO2 signal is enhanced by exercise stimuli. This dynamic multiplicative-type controller is used in simulations of key experiments: exercise and CO2 rebreathing with and without resistive loading. The dynamics of the discomfort index, the respiratory motor command, ventilation, and arterial CO2 concentration conform to the experimental data. The perceptual sensitivity to CO2 relative to respiratory effort is significantly correlated with the slope of hypercapnic ventilatory response. This result shows a clear linkage between ventilatory response and breathing sensations. Although it is shown that the automatic controller effectively minimizes the discomfort index for perturbations about an operating point under certain conditions, the discomfort index itself does not seem to be an underlying control principle of the proposed automatic controller model. Rather, breathing sensations may influence ventilatory responses by modifying the output of the automatic controller.

Effects of focal cooling of the ventral medullary surface on breathing pattern and blood pressure in dogs.

We assessed the effect of focal graded cooling of the ventral medullary surface (VMS) on breathing pattern and blood pressure in 15 anesthetized, vagotomized and artificially ventilated dogs. Diaphragmatic electromyogram or phrenic neurogram, referred to as Ec, and blood pressure (BP) were obtained during localized (2 x 2 mm2) cooling of the VMS. Greatest depression of both Ec and BP was obtained by cooling in the areas located 4-9 mm caudal to the foramen cecum (Fc) and lateral to the pyramids. Mild cooling in these intermediate areas decreased both inspiratory duration (Ti) and the rate of rise of Ec (Ec/Ti), but respiratory rate was unchanged. Cooling of the rostral areas (0-3 mm from Fc) induced mild depression of Ec amplitude due to reduction in Ec/Ti without changing Ti, and prolonged expiratory duration (Te) significantly. Cooling of the caudal areas (12-18 mm from Fc) reduced Ec amplitude mildly due to reduction in Ti without affecting Ec/Ti, and shortened Te greatly. Cooling of the rostral areas produced mild fall in BP, but cooling of the caudal areas did not affect BP significantly. It is suggested that rostral and intermediate parts of the VMS participate in the shaping of inspiratory drive, whereas wide areas of the VMS including caudal part are involved in the determination of respiratory timing. It is also suggested that the rostral and intermediate parts, and not the caudal part, of the VMS are important in the regulation of vasomotor tone.