Effect of naloxone on maximal exercise performance and control of ventilation in COPD

Elevated endorphin levels in patients with COPD may act to diminish the sensation of dyspnea. Exogenous opioids decrease exertional dyspnea and increase exercise capacity in COPD patients. The purpose of this study was to determine the effects of endogenous opioids on the exercise capacity and control of breathing in patients with COPD. We hypothesized that naloxone, an opioid antagonist, would block the endogenous endorphins and decrease the exercise capacity of our patients. Six patients (mean age, 58.8 +/- 3.2 years) with COPD (mean FEV1, 1.28 +/- 0.46 L) underwent identical incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following the IV administration of naloxone (0.4 mg/kg) (N) or placebo (P) in a randomized, double-blind fashion. Perceived dyspnea (modified Borg scale), breathing patterns, and expired gas levels were compared at rest and at maximal workload (WL). There was no significant difference after N compared with after P in the WL or the duration of work. At Emax there were no significant differences after N compared with after P in ventilation, the level of dyspnea, P0.1, VO2, or VCO2. The ventilatory response to CO2 production during exercise (delta VE/delta VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after N compared with after P. This study does not support the hypothesis that endogenous opioids play a significant role in dampening dyspnea and facilitating exercise in patients with COPD.     

Lack of effect of dextromethorphan on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease (COPD)

We have previously shown that the exercise performance of patients with severe chronic obstructive pulmonary disease (COPD) can be increased with the administration of oral morphine (0.8 mg.kg-1). The purpose of this study was to determine whether the administration of dextromethorphan (DXT), an antitussive structurally similar to codeine, would result in increased exercise performance and decreased dyspnoea in patients with COPD, without the side-effects of opiates. Six eucapnic patients (mean age = 66 +/- 3.8 yrs) with COPD (mean forced expiratory volume in one second (FEV1) = 1.01 +/- 0.07 l) underwent two incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following first the oral administration of placebo (P) and then dextromethorphan (60 mg) in a single-blind fashion. There was no statistically significant difference in the maximal exercise performance, perceived dyspnoea (modified Borg scale), breathing pattern or expired gases after the two different treatments. In addition, the ventilatory response to CO2 production during exercise (delta VE/VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after DXT as compared with after P. Indeed the exercise performance was poorer and the ventilatory responses were brisker after DXT. We conclude from this study that the administration of this opiate analogue does not improve the exercise capacity or decrease the ventilatory response of patients with COPD.     

The effects of weight and chemosensitivity on respiratory sleep abnormalities: a family study

The relationship between low-awake chemosensitivity, exogenous respiratory load (obesity) and respiratory/oxygenation patterns during sleep was evaluated in a family with overall low ventilatory responses to hypoxia and hypercapnia. Six family members were of normal weight, in good health and had normal pulmonary function tests. Only one of these subjects had totally normal responses to the chemical control of breathing. A seventh family member had loaded breathing because of severe obesity. His ventilatory and mouth occlusion pressure responses to hypoxia or hypercapnia were severely blunted. After weight loss (200 percent of ideal body weight to 133 percent) the ventilatory responses were improved but still abnormally low. Significant nocturnal respiratory abnormalities and oxygen desaturation were only seen in the overweight member and improved following weight loss (load reduction).     

Ventilation and breathing pattern during progressive hypercapnia and hypoxia after human heart-lung transplantation

The effects of human pulmonary denervation on the ventilatory responses to progressive hyperoxic hypercapnia and isocapnic hypoxia as well as the effect on resting breathing pattern were evaluated in nine female heart-lung transplant (H-LT) recipients. The results were compared to those obtained from 10 normal women of comparable age and stature. Testing was performed 2 to 37 months after H-LT (median, 7.5 months). Cardiac function was normal in all H-LT recipients. None of the patients had spirometric evidence of airway obstruction, while six had a restrictive pattern with forced vital capacities less than 80% of predicted values. Resting minute ventilation (VE), tidal volume (VT), and ventilatory drive (VT/TI) in the H-LT recipients were not significantly different from those of the normal subjects. Inspiratory time (TI), however, was significantly shorter in the H-LT patients (1.64 +/- 0.2 versus 2.09 +/- 0.13 s, p = 0.035), and resting breathing frequency (F) tended to be greater in the H-LT recipients (16.27 +/- 2.04 versus 12.82 +/- 0.53 breaths/min, p = 0.052). The overall ventilatory response to hypercapnia was reduced after H-LT (0.91 +/- 0.17 versus 1.5 +/- 0.27 L/min/mm Hg CO2, p less than 0.043), as was the F response (0.2 +/- 0.09 versus 0.65 +/- 0.13 breaths/min/mm Hg CO2, p less than 0.01). The VT and VT/TI responses to hypercapnia did not differ between the H-LT recipients and normal subjects. There were no significant differences between the two groups with respect to the responses to progressive hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms mediating the heart rate response to hypoxemia

We studied the effect of phasic pulmonary afferent information on heart rate (HR) during a progressive reduction in oxygen saturation (SaO2). The Hering-Breuer reflex was evaluated with the use of the ratio of apnea duration after lung inflation to the preceding expiratory time (dT). Phasic afferent activity was stopped in anesthetized, paralyzed dogs by constant-flow ventilation (CFV), a technique that removes cyclic changes in lung volume. During normocapnic (PaCO2 = 36.4 +/- 1.1 mm Hg) spontaneous breathing, there was a wide variability in HR response, with a mean delta HR/delta SaO2 (+/- SE) of 0.62 +/- 0.27 beats/min/% (values greater than 0 indicate a tachycardiac response). There was a good correlation between delta HR/delta SaO2 and dT (r = .79). Mean delta HR/delta SaO2 for the combined normocapnic and hypercapnic studies during CFV was lower (-1.32 +/- 0.19 bpm/%) than that during spontaneous breathing (0.23 +/- 0.19, p less than .0001). We suggest that the HR response to hypoxemia is strongly related to the strength of the Hering-Breuer reflex, which may explain the large interdog variability in HR responses.     

The respiratory neuromuscular response to hypoxia, hypercapnia, and obstruction to airflow in asthma.

In chronic obstructive pulmonary disease (COPD), the neuromuscular response to an acute increase in airflow produced by external flow resistive loads (FRL) is impaired. The present study compared the response to FRL of 15 subjects with airway obstruction due to asthma and that of 15 normal subjects. FRL were applied during progressive hypercapnia and isocapnic hypoxia produced by rebreathing techniques to permit the response to be assessed at the same degree of CO2 or O2 drive. The neuromuscular response to FRL was assessed from the airway occlusion pressure developed 100 msec after the onset of inspiration (P100), as well as ventilation. During control rebreathing, ventilatory responses to hypercapnia (ratio of change in minute ventilation to change in PCO2, delta VE/delta PCO2) and hypoxia (ratio of change in VE to the change in percentage of O2 saturation, delta VE/deltaSO2) were the same in asthmatic and normal subjects despite differences in the mechanics of breathing. The P100 response to hypercapnia delta P100/delta PCO2) and hypoxia (delta P100/delta SO2) as well as absolute P100 at any given degree of O2 and CO2 drive was greater during control rebreathing in asthmatics than in normal subjects (P less than 0.05). FRL values of 9 and 18 cm H2O per L per sec applied during either hypercapnia or hypoxia increased the occlusion pressure to a greater extent in asthmatics than in normal subjects. Methacholine-induced bronchoconstriction was used to test the effect of acute airway obstruction on the response to FRL. Bronchoconstriction was associated with an increase in the P100 response to hypercapnia and to FRL, despite increases in lung volume and decreases in inspiratory muscle force. We conclude that: (1) asthmatics with airway dysfunction have an increased nonchemical drive to breathe mediated at least in part by sensory receptors in the airways; (2) asthmatics with airway obstruction respond supernormally to acute changes in resistance to airflow, unlike subjects with COPD. The failure of COPD subjects with prolonged airway obstruction to respond to FRL may be due to adaptation of the sensory mechanisms that respond to changes in airway resistance.     

Vagal feedback is essential for breathing in unanesthetized ground squirrels

The roles of vagal afferent feedback in terminating inspiration and modulating breathing pattern and ventilatory responses to hypoxia and hypercapnia were assessed in the golden-mantled ground squirrel, Spermophilus lateralis, during wakefulness and urethane anesthesia. Hypoxia increased ventilation primarily through increases in breathing frequency (f(R)) while hypercapnia increased ventilation primarily through increases in tidal volume (V(T)) in both anesthetized and unanesthetized animals. Vagotomy resulted in an increase in tidal volume, a decrease in breathing frequency and ventilation, and depressed ventilatory responses to both hypoxia and hypercapnia in anesthetized animals. In unanesthetized animals vagotomy produced a transient 'gasp-like' breathing pattern that rapidly progressed to a non-obstructive central apnea. These data indicate that vagal feedback shapes ventilation on a breath-by-breath basis during anesthesia and is essential for ventilation in unanesthetized animals. The mechanisms that transform the influences of vagal input on breathing between anesthetized and unanesthetized states remain unclear. Changes in breathing pattern induced by the removal of vagal feedback compromise chemoreflexes.     

Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea

BACKGROUND: The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may be implicated in increased cardiovascular stress in patients with obstructive sleep apnea (OSA). We tested the hypothesis that chemoreflex function is altered in patients with OSA. METHODS AND RESULTS: We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 16 untreated normotensive patients with OSA and 12 normal control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with OSA than in the control subjects (43+/-4 versus 21+/-3 bursts per minute; P<0. 001). During hypoxia, patients with OSA had greater increases in minute ventilation (5.8+/-0.8 versus 3.2+/-0.7 L/min; P=0.02), heart rate (10+/-1 versus 7+/-1 bpm; P=0.03), and mean arterial pressure (7+/-2 versus 0+/-2 mm Hg; P=0.001) than control subjects. Despite higher ventilation and blood pressure (both of which inhibit sympathetic activity) in OSA patients, the MSNA increase during hypoxia was similar in OSA patients and control subjects. When the sympathetic-inhibitory influence of breathing was eliminated by apnea during hypoxia, the increase in MSNA in OSA patients (106+/-20%) was greater than in control subjects (52+/-23%; P=0.04). Prolongation of R-R interval with apnea during hypoxia was also greater in OSA patients (24+/-6%) than in control subjects (7+/-5%) (P=0.04). Autonomic, ventilatory, and blood pressure responses to hypercapnia and the cold pressor test in OSA patients were not different from those observed in control subjects. CONCLUSIONS: OSA is associated with a selective potentiation of autonomic, hemodynamic, and ventilatory responses to peripheral chemoreceptor activation by hypoxia.     

Human obesity is characterized by a selective potentiation of central chemoreflex sensitivity.

The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Obesity is associated with an increased risk of alveolar hypoventilation and carbon dioxide retention, suggesting that abnormalities in chemoreflex control mechanisms may be implicated. We tested the hypothesis that chemoreflex function is altered in obesity. We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypercapnia, hypoxia, and the cold pressor test in 14 obese subjects and 14 normal-weight subjects matched for age and gender. During hypercapnia, the increase in minute ventilation was significantly greater in obese subjects (7.0+/-0.3 L/min) than in normal-weight subjects (3.3+/-1.1 L/min; P=0.03). Despite higher minute ventilation during hypercapnia in obese subjects, the increase in muscle sympathetic nerve activity was similar in obese and normal-weight subjects. When the inhibitory influence of breathing during hypercapnia was eliminated by apnea, the increase in sympathetic nerve activity in obese subjects (99+/-16%) was greater than in normal-weight subjects (44+/-16%; P=0.02). The magnitude of the ventilatory and autonomic responses to hypoxia and the cold pressor test was similar in obese and normal-weight subjects. We conclude that chemoreflex responses to hypercapnia are potentiated in eucapnic obese subjects. In contrast, responses to hypoxia and to the excitatory cold pressor stimulus in obese subjects are similar to those in normal-weight subjects. Thus, obesity is characterized by selective potentiation of central chemoreflex sensitivity.     

Involvement of respiratory perception in the resistive load compensation

Relation of threshold for perception of added inspiratory flow resistance to ventilatory and occlusion pressure response to hypercapnia during external flow-resistive loading was examined in 8 healthy volunteers and 14 patients with chronic obstructive pulmonary disease. Occlusion pressure response to hypercapnia without the load and the threshold for perception were similar between normal subjects and patients. Occlusion pressure at end-tidal PCO2 of 60 mm Hg increased to 134 +/- (SD) 23.4% (p less than 0.01) in normal subjects, but it did not change in patients (113.7 +/- 25.3%). Occlusion pressure response to hypercapnia increased to 155.4 +/- 60% (p less than 0.05) during ventilatory loading in normal subjects but it did not change in patients (105.9 +/- 33%). Inverse correlation between threshold values and changes after loading in occlusion pressure response to hypercapnia was seen in patients as well as in normal subjects. These results indicate in both normal subjects and patients with chronic obstructive pulmonary disease that occlusion pressure response to hypercapnia during the ventilatory loading includes signals from the higher central nervous system and that the lower the threshold, the higher the respiratory drive during the loaded ventilation.     

Respiratory responses of piglets to hypercapnia during postnatal development: effects of opioids.

Resting respiratory and cardiovascular functions and the response to CO2 rebreathing were compared between 2.5 +/- 0.7 (mean +/- SE) and 34.1 +/- 1.9 day old piglets, before and after the opioid antagonist naltrexone (1 mg/kg IV). At rest, tidal volume, both absolute and per m2, inspiratory and expiratory time, absolute minute ventilation, and mean arterial pressure increased with age, and breathing frequency, minute ventilation per m2, and heart rate decreased, all of these with as well as without naltrexone. During hypercapnia, the pattern, but not the quantitative aspects of breathing changed with age. At rest, naltrexone produced hyperventilation in the young, but not in the older group. During hypercapnia, naltrexone had a sparse effect in both ages. We conclude that, in the anesthetized piglet, ventilatory functions at rest undergo change with postnatal age, but breathing responses to hypercapnia exhibit maturation in pattern only and not in magnitude. Whereas resting ventilation of young piglets is modulated by endogenous opioids, hypercapnia may activate opioids to a limited extent and in a manner unrelated to age.     

Effects of vagotomy on ventilatory responses to CO2 in alligators.

Reptiles increase ventilation during hypercapnia at a constant temperature. In this study, the contributions of vagal vs non-vagal receptors to CO2 ventilatory responses were investigated in 16 sedated Alligator mississippiensis (25 mg/kg pentobarbital; 3 days prior to data collection). Four animals served as controls to assess the effects of time and/or anesthetic drift on ventilation and blood gases; significant ventilatory drift was not detected during the observation period. The effects of bilateral vagotomy on CO2 ventilatory responses were determined during spontaneous breathing (n = 6) and unidirectional ventilation (UDV; n = 6) at two body temperatures (Tb = 30 and 20 degrees C). Resting PaCO2, minute ventilation (VI), tidal volume (VT) and breathing frequency (f) were elevated at 30 degrees C relative to 20 degrees C in spontaneously breathing alligators. Increasing inspired CO2 to 5% increased PaCO2, f, VT and VI at both levels of Tb. Ventilatory sensitivity to CO2 (S = delta VI/delta PaCO2) was higher at 30 degrees C with a temperature coefficient (Q10) of 2.3. Vagotomy increased PaCO2 and VT, decreased f and had no effect on VI at either Tb. After vagotomy, hypercapnia had no effects on ventilation. When CO2 feedback loops were opened by UDV at a high flow rate (greater than 2 L/min), Tb had no effects on ventilatory efforts at constant PCO2, but hypercapnia significantly increased f, VT and VI. S was variable with a Q10 of 2.1. After vagotomy, a significant CO2-ventilatory response remained during UDV, but S was unaffected by Tb (Q10 = 0.8). The results indicate that non-vagal chemoreceptors contribute to CO2 ventilatory responses in alligators, although their contribution following vagotomy is evident only during unidirectional ventilation. Although tentative, the data also suggest that CO2-sensitive vagal receptors may be necessary for the temperature dependency of S.     

Bronchoconstriction and delayed rapid shallow breathing induced by cigarette smoke inhalation in anesthetized rats

Bronchomotor and ventilatory responses to inhalation of cigarette smoke (50% concentration, 6 ml) were studied in anesthetized and vagotomized Sprague-Dawley rats. Low-nicotine cigarette smoke did not cause any detectable delayed response, whereas high-nicotine cigarette smoke induced rapid, shallow breathing, and a marked increase in airway resistance (RL). The increase in f reached a peak (delta f = 43 +/- 8%) at the 5th breath after the onset of smoke inhalation, preceding both the decrease in VT (delta VT = -27 +/- 4%) and the increase in RL (delta RL = 89 +/- 19%); the latter 2 reached their peaks at approximately the 10th breath, displaying a similar temporal pattern of responses between them. The bronchomotor response to high-nicotine cigarette smoke was slightly attenuated but not prevented by prior administration of isoproterenol (0.2 mg/kg, intravenously [iv]), nor was the smoke-induced rapid, shallow breathing. In contrast, prior administration of mecamylamine (0.9 mg/kg, iv) completely abolished both the bronchomotor and ventilatory responses to smoke inhalation, indicating that nicotine is the primary causative agent responsible for these changes.     

Peripheral chemosensitivity assessed by the modified transient O2 test in female twins

To evaluate genetic influence on the control of breathing in adult women, we measured, in healthy female twins, ventilatory responses to isocapnic progressive hypoxia and hyperoxic progressive hypercapnia, and the withdrawal response (the modified transient O2 test) which is considered to selectively reflect peripheral chemoreceptor activity. The withdrawal response was obtained as the magnitude of initial depression in ventilation induced by two breaths of O2 from steady-state hypercapnic hypoxia. Nine monozygotic twin pairs, aged 44 +/- SD17 years, and 7 dizygotic twin pairs, aged 39 +/- 8 years, were studied. Mean values for ventilatory responses to hypoxia and hypercapnia, and the withdrawal response were not different between MZ and DZ. The within-pair variance ratio (VDZ/VMZ) for the withdrawal response was significantly greater than one (p less than 0.05), although neither VDZ/VMZ for the hypoxic response nor that for the hypercapnic response was greater than one. These observations suggest that the peripheral chemosensitivity is influenced by genetic factors even in adult women, including aged subjects, when genetic influence is not apparent in the ventilatory responses to progressive hypoxia and hypercapnia.     

Ventilatory control after pulmonary resection

Because pulmonary resection decreases pulmonary compliance, the effects of resection on ventilation might be similar to the known effects of elastic loading. We evaluated the breathing pattern and ventilatory drive in 12 patients before and after pulmonary resection with mean tissue loss of 4 segments. During resting ventilation, the only significant change after resection was a decrease in inspiratory time (Tl). At a higher level of minute ventilation (VE), induced by CO2 rebreathing, significant changes included increased respiratory frequency, decreased tidal volume and Tl, and increased occlusion pressure (P0.1). Both ventilation and occlusion pressure responses to CO2 (delta VE/delta PACO2, delta P0.1/delta PACO2) were unchanged after resection. We conclude that increased ventilation induced by CO2 rebreathing unmasks a breathing pattern after pulmonary resection which is similar to that seen with breathing against an external elastic load.     

Inspiratory muscle activity during pulmonary edema in anesthetized dogs.

Pulmonary edema is known to induce a rapid and shallow breathing pattern. However, its effects on the level and pattern of distribution of motor activity to the respiratory muscles is unclear. In the present study we evaluated the effect of oleic acid induced pulmonary edema on the electrical activity of the inspiratory muscles (costal and crural diaphragm and parasternal and external intercostal muscles) in the dog, and related it to the transdiaphragmatic pressure and ventilatory parameters over the course of CO2 rebreathing. Pulmonary edema, reflected by a 7.1 +/- 0.6 wet to dry ratio, decreased lung compliance by 57%, increased pulmonary shunt to 35%, and was associated with a rapid and shallow breathing pattern. When compared at equal levels of PCO2 during CO2 rebreathing before and during edema, ventilation and mean inspiratory flow were increased only at lower levels of hypercapnia and their responses to increasing levels of PCO2 were significantly diminished during edema. Transdiaphragmatic pressures were elevated during edema as compared to control values. The rate of rise of the electrical activity of all inspiratory muscles increased significantly during edema at all levels of PCO2. Peak activity, however, remained unchanged, due to shortening of the inspiratory duration. The EMG responses to progressive hypercapnia were not affected by edema. Pulmonary edema did not change the pattern of breathing and neural output to the inspiratory muscles in vagotomized dogs. We conclude that stimulation of pulmonary proprioreceptors during edema increases neural output to all inspiratory muscles. The neural response to hypercapnia is not altered by edema, and is additive to the vagal input. The ventilatory response to CO2 is blunted during severe edema, due to alterations in lung mechanics.     

Phrenic nerve responses to hypoxia and CO2 in decerebrate dogs

Phrenic responses to isocapnic hypoxia and hypercapnia were studied using paralyzed vagotomized dogs (either decerebrate or chloralose-anesthetized). The hypoxia-induced increase in phrenic minute activity (PMA) was significantly greater in anesthetized dogs when compared with the response observed in decerebrate dogs. Phrenic responses to hypercapnia were also significantly different in the two groups of dogs. Increases in phrenic amplitude (AMP) and frequency (FREQ) were observed in anesthetized dogs, whereas decerebrate dogs responded to CO2 without a change in FREQ. Spontaneously breathing dogs (either decerebrate or anesthetized) were used for studying the effects of vagotomy on the integrated phrenic neurogram. Changes in phrenic pattern in response to vagotomy were qualitatively similar in anesthetized and decerebrate dogs. However, in decerebrate dogs, AMP was disproportionately increased relative to the decrease in FREQ such that PMA increased following vagal transection. Conversely, in anesthetized dogs, the increase in AMP and decrease in FREQ in response to vagotomy were proportional; PMA remained unchanged. These results suggest that mesencephalic decerebration disrupts neuronal circuits which participate in the chemical control of breathing. In addition, suprapontine structures may be involved in coupling FREQ and AMP (tidal volume) so that PMA (ventilation) is stabilized. Finally, these studies provide evidence for a vagally-independent frequency controller in dogs which is sensitive to hypoxia and hypercapnia, but appears to be highly dependent upon suprapontine structures.     

Etiology of carbon dioxide retention at rest and during exercise in chronic airflow obstruction

The purpose of this project was to better define factors that influence the resting PaCO2 and the change in the PaCO2 from rest to exercise in patients with moderate to severe chronic airflow obstruction. Pulmonary function testing, symptom-limited exercise tests using arterial catheter lines, and resting ventilatory and mouth occlusion pressure responses to hypercapnia and hypoxia were obtained in 19 patients (mean FEV1 = 1.07 +/- .50 L). The resting PaCO2 was closely related to the resting hypercapnic response. The highest correlation coefficient was between the PaCO2 and the ventilation at PCO2 = 60 obtained from the resting hypercapnic response (r = -0.74, p less than 0.001). A higher PaCO2 also tended to occur in patients with a lower FEV1 and a lower PaO2. The resting PaCO2 was not correlated significantly with the VT or the VD/VT. The change in the PaCO2 from rest to exercise was not significantly related to any measure of resting hypercapnic or hypoxic response, but rather was most dependent on the ventilatory response to exercise (delta VE/delta VCO2). Patients with a lower FEV1 or smaller decreases in the PaO2 with exercise tended to have larger increases in PaCO2 with exercise. The delta VE/delta VCO2 was higher in those with a high FEV1, a low resting PaCO2, and a low resting SaO2.     

Hypercarbic ventilatory responses of human heart-lung transplant recipients

To evaluate the effects of chronic pulmonary denervation on ventilatory control, we compared the hypercarbic ventilatory responses (HCVR) of 12 human heart-lung transplant recipients (HL) and 24 normal control subjects (C). The six male HL were subsequently compared with eight male heart transplant recipients (H), as well as the 12 male C. All subjects had normal spirometry, but lung volumes of both transplant groups were somewhat less than those of C. The HCVR of HL and C were indistinguishable (2.68 +/- 0.28 versus 2.71 +/- 0.22 L/min/mm Hg, respectively). The increment of mouth occlusion pressure (delta Pm0.1/delta CO2), however, was markedly greater in HL (P much less than 0.01). The three male groups also had equivalent HCVR, and again, the HL had an increased delta Pm0.1/delta CO2. HL men exhibited larger increments of VT and decreased frequency responses during CO2 rebreathing than did male C and H, although these differences were statistically significant only in the comparison between the transplant groups. We conclude that HL with normal spirometry have appropriate HCVR, despite pulmonary denervation. Pm0.1 responses of these subjects are increased, however, reflecting either a compensatory response to greater respiratory impedances or an occult alteration of ventilatory mechanics. Moreover, compared with subjects with similar pulmonary function, e.g., heart transplant recipients, the breathing pattern of HL during progressive hypercarbia is consistent with the absence of vagal-mediated inflation inhibition.     

Effect of naloxone on the respiratory responses to hypoxia in chronic obstructive pulmonary disease

Ventilatory and airway occlusion pressure responses to hypoxia were measured in 7 subjects with chronic obstructive pulmonary disease (COPD). Paired responses were obtained after the administration of saline or naloxone and, on separate days, in 5 of the 7 subjects, after 2 saline injections. Naloxone increased (p less than 0.05) the mean inspiratory flow and the ventilatory and airway occlusion pressure responses to hypoxia when compared with the saline responses. Resting ventilation and tidal volume also increased, but not significantly. Involvement of endogenously generated opioid substances in the control of breathing of patients with COPD is further suggested by this study.