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Persistence of inspiratory muscle activity during the early phase of expiratory airflow slows the rate of lung deflation, whereas heightened expiratory muscle activity produces the opposite effect. To examine the influence of increased chemoreceptor drive and the role of vagal afferent activity on these processes, the effects of progressive hypercapnia were evaluated in 12 anesthetized tracheotomized dogs before and after vagotomy. Postinspiratory activity of inspiratory muscles (PIIA) and the activity of expiratory muscles were studied. During resting breathing, the duration of PIIA correlated with the duration of inspiration but not with expiration. Parasternal intercostal PIIA was directly related to that of the diaphragm. Based on their PIIA, dogs could be divided into two groups: one with prolonged PIIA (mean 0.57 s) and the other with brief PIIA (mean 0.16 s). Hypercapnia caused progressive shortening of the PIIA in the dogs with prolonged PIIA during resting breathing. The electrical activity of the external oblique and internal intercostal muscles increased gradually during CO2 rebreathing in all dogs both pre- and postvagotomy. After vagotomy, abdominal activity continued to increase with hypercapnia but was less at all levels of PCO2. The internal intercostal response to hypercapnia was not affected by vagotomy. The combination of shorter PIIA and augmented expiratory activity with hypercapnia might, in addition to changes in lung recoil pressure and airway resistance, hasten exhalation.

To assess the effects of endogenous opiates on respiratory muscle responses to CO2, naloxone was administered intravenously to paralyzed, vagotomized and artificially ventilated cats anesthetized with alpha-chloralose. Neural activity was recorded from the phrenic, hypoglossal (HG), glossopharyngeal (GP) and recurrent laryngeal (RL) nerves. Before naloxone, phasic activity began first in the phrenic at a PETCO2 of 30.0 +/- 1.8 Torr, followed by the RL at a PETCO2 of 33.5 +/- 1.7 Torr, the HG at a PETCO2 of 39.9 +/- 2.1 Torr and the GP at a PETCO2 of 42.5 +/- 2.2 Torr during CO2 rebreathing. Naloxone had no significant effect on the apneic threshold of any of the nerves studied. Naloxone did, however, increase respiratory frequency (P less than 0.01) mainly by causing a significant (P less than 0.01) shortening of TE as it had no significant effect on TI. Naloxone also significantly increased the rate at which peak nerve activity increased with CO2 in the HG (P less than 0.01) and the GP (P less than 0.01) nerves, but not in the phrenic and RL nerves. Instead, the maximum activity produced by hypercapnia and the PETCO2 level at which maximum activity occurred in the phrenic, but not the RL, increased after naloxone. The result of these effects was that naloxone extended the range over which the HG and GP behaved proportionally with the phrenic, but it did not change the curvilinear nature of these relationships.

We examined the effects of chemical and reflex drives on the postinspiratory inspiratory activity (PIIA) of phrenic motoneurons using a single-fiber technique. Action potentials from "single" fibers were recorded from the C5 phrenic root together with contralateral mass phrenic activity (also from C5) in anesthetized, paralyzed, and artificially ventilated cats with intact vagus and carotid sinus nerves. Nerve fibers were classified as "early" or "late" based on their onset of discharge in relation to mass phrenic activity during hyperoxic ventilation. Only the early fibers displayed PIIA but not the late fibers, even when their activity began earlier in inspiration with increased chemical drives. Isocapnic hypoxia increased, whereas hyperoxic hypercapnia shortened the duration of PIIA. Pulmonary stretch and "irritant" receptors inhibited PIIA. Hypercapnia and stimulation of peripheral chemoreceptors by lobeline excited both early and late units to the same extent, but hypoxic ventilation had a less marked excitatory effect on late fiber activity. Irritant receptor activation increased the activity of early more than late fibers. Hyperoxic hyperventilation eliminated late phrenic fiber activity, whereas early fibers became tonically active. Bilateral vagotomy abolished this sustained discharge in eight of nine early units, suggesting the importance of vagal afferents in producing tonic firing during hyperventilation. These results suggest that early and late phrenic fibers have different responses to chemical stimuli and to vagally mediated reflexes; late units do not discharge in postinspiratory period, whereas early fibers do; the PIIA is not affected in the same way by various chemical and vagal inputs; and early units that exhibit PIIA display tonic activity with hyperoxic hypocapnia.

The purpose of the present study was to assess the effects of bronchoconstriction on respiratory changes in length of the costal diaphragm and the parasternal intercostal muscles. Ten dogs were anesthetized with pentobarbital sodium and tracheostomized. Respiratory changes in muscle length were measured using sonomicrometry, and electromyograms were recorded with bipolar fine-wire electrodes. Administration of histamine aerosols increased pulmonary resistance from 6.4 to 14.5 cmH2O X l-1 X s, caused reductions in inspiratory and expiratory times, and decreased tidal volume. The peak and rate of rise of respiratory muscle electromyogram (EMG) activity increased significantly after histamine administration. Despite these increases, bronchoconstriction reduced diaphragm inspiratory shortening in 9 of 10 dogs and reduced intercostal muscle inspiratory shortening in 7 of 10 animals. The decreases in respiratory muscle tidal shortening were less than the reductions in tidal volume. The mean velocity of diaphragm and intercostal muscle inspiratory shortening increased after histamine administration but to a smaller extent than the rate of rise of EMG activity. This resulted in significant reductions in the ratio of respiratory muscle velocity of shortening to the rate of rise of EMG activity after bronchoconstriction for both the costal diaphragm and the parasternal intercostal muscles. Bronchoconstriction changed muscle end-expiratory length in most animals, but for the group of animals this was statistically significant only for the diaphragm. These results suggest that impairments of diaphragm and parasternal intercostal inspiratory shortening occur after bronchoconstriction; the mechanisms involved include an increased load, a shortening of inspiratory time, and for the diaphragm possibly a reduction in resting length.

Previous studies suggest that structures within 1 mm of the ventral surface of the medulla (VMS) are involved in the regulation of airway resistance. Furthermore, neurons containing tachykinin peptides have been observed near the surface of the VMS. In the present work, we examined the effects of mammalian tachykinins, substance P (SP) and neurokinin A (NKA), applied locally to the intermediate area of the VMS of cats on tracheal tone and phrenic nerve activity. Since neutral endopeptidase (enkephalinase) has been shown to degrade tachykinin peptides in other tissues, we also investigated the effect of the neutral endopeptidase (NEP) inhibitors (thiorphan and phosphoramidon) on airway tone and phrenic nerve responses to tachykinins when the animals were ventilated with 100% O2 and during hyperoxic hypercapnia and isocapnic hypoxia. Experiments were performed in chloralose-anesthetized cats hyperventilated to phrenic neural apnea or so that the end tidal CO2 was just above the apneic threshold. Trachealis smooth muscle tension was assessed by measuring changes in pressure in a balloon placed in a bypassed segment of trachea (Ptseg). Application to the VMS of SP (10(-5)-10(-3) M) significantly increased tracheal muscle tension. Similar effects were found with applications of NKA. In addition, thiorphan and phosphoramidon potentiated the effects of tachykinins and the responses to hypercapnia and hypoxia of tracheal tone and phrenic nerve activity. Pretreatment with atropine (1 mg/kg) blocked tracheal but not phrenic responses to tachykinins. These suggest that (1) tachykinins acting on structures located on the VMS can increase cholinergic outflow to the airways and augment respiratory motor output, and (2) NEP may be one important modulator of tachykinin-induced effects.

Attacks of acute airway obstruction often complicate the course of chronic obstructive pulmonary disease (COPD). In asthmatic subjects, bronchospasm triggers an increase in respiratory drive, which results in hyperventilation and hypocapnia. In the present study, we assessed the effects of acute bronchoconstriction induced by aerosolized methacholine on breathing and lung mechanics in 12 patients with stable COPD. Even low doses of methacholine markedly increased airway resistance and caused hyperinflation and decreased inspiratory muscle performance in the patients. Increasing airway obstruction produced a progressive rise in PCO2 despite an increase in minute ventilation. Breathing frequency and average inspiratory flow were greater, but tidal volume decreased because of shortening of the inspiratory duration. The magnitude of CO2 retention during acute bronchoconstriction was inversely related to the changes in tidal volume and inspiratory time (p less than 0.01 for each). In subjects with COPD, the occlusion pressure response to progressive hypercapnia failed to increase during bronchoconstriction. These results show that patients with COPD retain CO2 during acutely increasing airway obstruction induced by bronchoconstriction partly because of a rapid shallow breathing pattern that reduces alveolar ventilation.

Electrical stimulation of the central end of the sciatic nerve was used to assess the effect of increased somatic sensory input on respiratory muscle electrical activity in anesthetized, spontaneously breathing dogs. Graded electrical stimulation of the sciatic nerve was associated with progressively greater activity of the upper airway dilating muscles (alae nasi, genioglossus, and posterior cricoarytenoid) as well as the diaphragm. Breathing frequency also increased because of a reduction in inspiratory and expiratory time. After cessation of stimulation of the sciatic nerve, increased activity of all the muscles studied persisted and only gradually returned to control levels. The responses to sciatic nerve stimulation were independent of the CO2 concentration of the inspired gas mixture. At any level of chemical drive electrical stimulation caused greater increases in the electrical activity of upper airway dilating muscles than that of diaphragm. Based on these results, it is concluded that stimulation of sciatic nerve activates upper airway muscles as well as the diaphragm, and the upper airway muscle activity is augmented to a greater degree than diaphragm activity. It seems possible that somatosensory afferent input produces unequal effects on different respiratory motoneurons.

The regions adjacent to the ventrolateral medullary surface (VMS) play critical roles in the regulation of respiratory and cardiovascular function. Furthermore, these areas seem to be important sites for the integration of afferent inputs from certain sensory organs and the source of excitatory inputs to preganglionic sympathetic and parasympathetic neurons. To determine whether the VMS contributes to the generation of nonrespiratory-related periodic oscillations of arterial blood pressure (Mayer waves), excitatory substances, such as N-methyl-D-aspartate (NMDA), cholinergic agonists, and neuropeptides (substance P, neurokinin A, neurotensin), were applied topically to the intermediate area of VMS in anesthetized cats. In addition, the effects of application of lidocaine and inhibitory substances (benzodiazepines) on Mayer waves were studied. After application of excitatory substances to the VMS, we observed oscillations of arterial blood pressure, recurring with a period of 17.8 +/- 10 (SE) s, which had similar characteristics as the Mayer waves recorded during hypercapnia or hypoxia. In addition, cyclic changes in phrenic nerve activity and tracheal tone occurred with the same periodicity as arterial blood pressure oscillation. Application of lidocaine or benzodiazepines on the intermediate area of the VMS abolished Mayer waves observed during hypercapnia, hypoxia, or application of excitatory substances. These findings show for the first time that the VMS can be considered as one of several synaptic relays involved in the generation of arterial blood pressure oscillation, as well as the cyclic changes in phrenic nerve activity and tracheal smooth muscle tone that occur simultaneously.

The electromyographic (EMG) activities of the costal and crural diaphragm were recorded from bipolar fine-wire electrodes placed in the costal fibers adjacent to the central tendon and in the anterior portions of the crural fibers in 12 anesthetized cats. The EMG activities of costal and crural recordings were compared during posture changes from supine to head up and during progressive hyperoxic hypercapnia in both positions. The activity of both portions of the diaphragm was greater in the head up compared with supine posture at all levels of CO2; and increases in crural activity were greater than those in costal activity both as a result of changes in posture and with increasing CO2 stimuli. These results are consistent with the concept that diaphragm activation is modulated in response to changes in resting muscle length, and further, that neural control mechanisms allow separate regulation of costal and crural diaphragm activation.

The ventilatory and occlusion pressure (P100) responses to hypercapnia, maximal inspiratory airway and transdiaphragmatic pressures, and the separate volume contributions of the rib cage and abdomen to tidal breathing were evaluated in 16 patients with chronic stable interstitial lung disease. Compared with those in the normal subjects, ventilation and P100 at a PCO2 = 55 mmHg were significantly higher (p less than 0.05 and p less than 0.01, respectively) in the patients with interstitial lung disease. However, the ventilatory and occlusion pressure responses to hypercapnia (delta VE/delta PCO2 and delta P 100/delta PCO2, respectively) were not significantly different between the groups. Maximal inspiratory airway pressure was significantly reduced in the patient group (p less than 0.05); maximal transdiaphragmatic pressure was also reduced but not significantly. At any given level of ventilation, tidal volume was decreased and breathing frequency increased in the patients with interstitial lung disease (p less than 0.05). The greater respiratory frequency was caused by reductions in both expiratory and inspiratory time. Because of smaller tidal volumes, rib cage expansion was reduced in the group of patients when compared with that in normal subjects during both spontaneous breathing and when compared at the same level of hypercapnia; abdomen volume was reduced to a lesser extent. We conclude that in patients with interstitial lung disease, non-chemical, presumably neural, mechanisms, increase respiratory drive and alter the breathing pattern. We speculate that both vagal mechanisms and mechanoreceptors in the chest wall sensitive to rib cage expansion contribute to these responses.

These studies investigated the role of the intermediate area of the ventral surface of the medulla (VMS) in the tracheal constriction produced by hypercapnia. Experiments were performed in chloralose-anesthetized, paralyzed, and artificially ventilated cats. Airway responses were assessed from pressure changes in a bypassed segment of the rostral cervical trachea. Hyperoxic hypercapnia increased tracheal pressure and phrenic nerve activity. Intravenous atropine pretreatment or vagotomy abolished the changes in tracheal pressure without affecting phrenic nerve discharge. Rapid cooling of the intermediate area reversed the tracheal constriction produced by hypercapnia. Graded cooling produced a progressive reduction in the changes in maximal tracheal pressure and phrenic nerve discharge responses caused by hypercapnia. Cooling the intermediate area to 20 degrees C significantly elevated the CO2 thresholds of both responses. These findings demonstrate that structures near the intermediate area of the VMS play a role in the neural cholinergic responses of the tracheal segment to CO2. It is possible that neurons or fibers in intermediate area influence the motor nuclei innervating the trachea. Alternatively, airway tone may be linked to respiratory motor activity so that medullary interventions that influence respiratory motor activity also alter bronchomotor tone.

It has been shown that gas exchange between the alveolar space and pulmonary capillary blood is affected by the pattern of airflow at the mouth in the non-homogeneous lung. The present theoretical study shows that even in the homogeneous lung, the pattern of airflow can affect gas exchange. When tidal volume, inspiratory and expiratory times remain constant, variations in the pattern of airflow result in significantly different values of steady state arterial PO2 and PCO2. This difference in steady state blood gases is exaggerated by low levels of minute ventilation and by long inspiratory times, but is unaffected by changes in the diffusion coefficient of the alveolar-capillary membrane.

1. In cats under pentobarbitone anaesthesia the effects of focal temperature changes of the ;chemoceptive' areas on the ventral surface of medulla, described by Loeschcke and his associates, were studied with respect to tidal volume, V(T), tidal variation in efferent phrenic activity, Phr(T), and respiratory rate. The cats were either paralysed and ventilated at various constant P(A,CO2) and P(a,O2) levels, or breathing spontaneously.2. It was confirmed that focal bilateral cooling of the intermediate, ;I((S))', areas caused rapid depression of respiration even at constant artificial ventilation. In normocapnic and normoxic conditions apnoea usually ensued at brain surface temperatures of 20-22 degrees C.3. The effects were graded along continuous temperature-response curves with enhancements of ventilation above and depression below normal body temperature.4. The strongest effects on V(T) and Phr(T) were obtained from the I((S)) areas with no or only small effects on inspiratory or expiratory timing in the vagotomized animal. The Hering-Breuer inflation reflex and its effects on timing and amplitudes were not affected by cooling this area.5. Focal cooling of the caudal or the rostral ;chemoceptive' areas, ;C((L))' and ;R((M))' areas, caused smaller effects on V(T) and Phr(T) but produced significant effects on respiratory rate even after vagotomy.6. The effects of focal cooling of these areas could be mimicked by topical application of procaine solution which has been shown not to penetrate deeper than 100 mum from the surface.7. Moderate focal cooling of area I((S)) to temperatures above 28-30 degrees C caused a parallel shift in the CO(2)-response (V(T), Phr(T)) curves to the right with little change in slope. The P(CO2) thresholds for apnoea were correspondingly raised. These focal temperature effects could be compensated by changes in P(CO2) with, on the average, 2.7 torr/ degrees C. Focal temperatures below 28 degrees C usually caused some decrease in slope of the CO(2)-response curves in addition to further shifts.8. Added hypoxic stimulus or electrical stimulation of the carotid sinus nerves caused an almost parallel increase of Phr(T) at all P(CO2) levels and all focal temperatures suggesting an additive type of interaction between the input from the peripheral chemoreceptors and that from the central (CO(2), H(+)) sensing structures whether the latter was altered by changing P(CO2) or by focal temperature changes on the I((S)) areas.9. In contrast to these effects of hypoxia and stimulation of the carotid sinus nerves the reflex increase of inspiratory activity caused by lung deflation or by electrical stimulation of the glossopharyngeal nerve distal to the carotid sinus nerves was CO(2) dependent. These reflex effects decreased with focal cooling of the I((S)) areas as with hypocapnia, suggesting a mainly multiplicative or ;gain-changing' type of interaction with the central chemoceptive drive.10. The close similarities in effect of focal cooling and of hypocapnia on the different respiratory parameters even during constant artificial ventilation indicate that focal temperature changes of the I((S)) areas intervene effectively with the normal ventilatory response to CO(2) without changing the chemical or physical environment of those neural structures in the brain stem which set respiratory pattern.

THE VENTILATORY RESPONSE TO HYPOXIA WAS STUDIED IN TWO GROUPS OF SUBJECTS WITH ABNORMAL SYMPATHETIC NERVOUS CONTROL: (a) human subjects with familial dysautonomia (Riley-Day syndrome), and (b) unanesthetized goats treated with an alpha-adrenergic blocking agent (phenoxybenzamine). The ventilatory response to hypoxia was evaluated in two ways: (a) from the slope of the relationship between ventilation and alveolar P(Co2) ([unk]V(E)-P(ACo2) slope) during the rebreathing of hypoxic and hyperoxic gases, and (b) from the change in ventilation produced when hypoxia was abruptly relieved. The ventilatory and circulatory responses of the unanesthetized, phenoxybenzamine-treated goats were qualitatively similar to those of dysautonomic patients. In contrast to the sustained stimulation of ventilation produced by hypoxia in normal subjects, hypoxia either did not change, or decreased, the [unk]V(E)-P(ACo2) slope of dysautonomic patients and phenoxybenzamine-treated goats; CO(2)-free hypoxia produced a fleeting hyperventilation, which was followed by apnea when hypoxia was abruptly relieved. Unlike normal subjects, the dysautonomic patients and phenoxybenzamine-treated goats became hypotensive while hypoxic. The results indicate that peripheral chemoreceptor reflex responses to hypoxia are preserved in subjects in whom sympathetic nervous responses are impaired. However, the central nervous depression of ventilation by hypoxia is enhanced simultaneously. The inordinate central depression is attributed to the inability of the dysautonomic subjects and goats to maintain systemic blood pressure and, consequently, cerebral blood flow during hypoxia, thereby aggrevating central nervous hypoxia.

Although the pulmonary blood vessels receive an ample supply of nerves, it has been difficult to prove that these nerves operate in the regulation of the pulmonary circulation. In the present study, using the isolated lobe of the lung perfused in situ, waves in pulmonary arterial pressure were induced and were shown, as in the case of Traube-Hering waves in the systemic circulation, to be nervous in origin.