Wataru Hida

Chemosensitivity and Perception of Dyspnea in Patients with a History of Near-Fatal Asthma

BACKGROUND Many deaths from attacks of asthma may be preventable. However, the difficulty in preventing fatal attacks is that not all the pathophysiologic risk factors have been identified. METHODS To examine whether dyspnea and chemosensitivity to hypoxia and hypercapnia are factors in fatal asthma attacks, we studied 11 patients with asthma who had had near-fatal attacks, 11 patients with asthma who had not had near-fatal attacks, and 16 normal subjects. Their respiratory responses to hypoxia and hypercapnia, determined by the standard rebreathing technique while the patients were in remission, were assessed in terms of the slopes of ventilation and airway occlusion pressure as a function of the percentage of arterial oxygen saturation and end-tidal carbon dioxide tension, respectively. The perception of dyspnea was scored on the Borg scale during breathing through inspiratory resistances ranging from 0 to 30.9 cm of water per liter per second. RESULTS The mean (+/- SD) hypoxic ventilatory response (0.14 +/- 0.12 liter per minute per percent of arterial oxygen saturation) and airway occlusion pressure (0.05 +/- 0.05 cm of water per percent of arterial oxygen saturation) were significantly lower in the patients with near-fatal asthma than in the normal subjects (0.60 +/- 0.35, P < 0.001, and 0.16 +/- 0.08, P < 0.001, respectively) and the patients with asthma who had not had near-fatal attacks (0.46 +/- 0.29, P = 0.003, and 0.15 +/- 0.09, P = 0.004). The Borg score was also significantly lower in the patients with near-fatal asthma than in the normal subjects, and their lower hypoxic response was coupled with a blunted perception of dyspnea. CONCLUSIONS Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose patients to fatal asthma attacks.

In vivo release of glutamate in nucleus tractus solitarii of the rat during hypoxia.

1. An attempt has been made to test the hypothesis that, in the caudal part of nucleus tractus solitarii (NTS) where carotid sinus nerve (CSN) afferents project, L‐glutamate (Glut) modulates the hypoxic ventilatory response. 2. Unanaesthetized, peripherally chemodenervated (carotid body denervated; CBD) and sham‐operated, freely moving rats were used. During peripheral chemoreceptor stimulation by hypoxia (10% O2 for 30 min) or doxapram (Dox) infusion (2 mg kg‐1 (30 min)‐1), ventilation was recorded and successively, under the same conditions, the extracellular Glut concentration ([Glut]o) in the caudal NTS was measured by in vivo microdialysis. [Glut]o was also measured during hyperoxic hypercapnia (10% CO2‐30% O2 for 30 min). 3. Furthermore, the effects on ventilation of exogenous Glut, the NMDA (N‐methyl‐D‐aspartate) receptor antagonist MK‐801 or the ionotropic receptor antagonist kynurenate microinjected into the caudal NTS were investigated in sham‐operated rats. 4. In sham‐operated rats, both ventilation and [Glut]o in NTS were increased during peripheral chemoreceptor stimulation. On the other hand, no increases in either ventilation or Glut release were observed in CBD rats. In spite of ventilatory augmentation during hypercapnia, no response of [Glut]o to hypercapnia was observed in either group. 5. Local Glut application into NTS increased ventilation. Pretreatment with MK‐801 or kynurenate reduced the hypoxic ventilatory response. This reduction in ventilation was mainly due to the decrease in tidal volume. 6. These results suggest that hypoxia induced the release of Glut in NTS and that this effect was mediated by arterial chemosensory input.

Nitric oxide as a retrograde messenger in the nucleus tractus solitarii of rats during hypoxia.

1. We examined the role of nitric oxide (NO) in respiratory regulation in the nucleus tractus solitarii (NTS), where L‐glutamate release associated with peripheral chemoreceptor activation modulates the hypoxic ventilatory response. 2. Experiments were performed in unanaesthetized freely moving rats. First, the effects on the hypoxic ventilatory response of sodium nitroprusside (SNP, a NO donor) or NG‐monomethyl‐L‐arginine (L‐NMMA, a NO synthase inhibitor), microinjected into the NTS, were investigated. Second, using in vivo microdialysis, changes in extracellular L‐glutamate during hypoxia were examined in the presence of L‐NMMA. Third, the effect of L‐NMMA on ventilatory augmentation by exogenous L‐glutamate was examined. Furthermore, we measured extracellular L‐citrulline concentration changes during hypoxia in the NTS to assess NO formation indirectly and also examined the effect of MK‐801 (an NMDA receptor antagonist) on L‐citrulline levels during hypoxia. 3. SNP increased ventilation during both normoxia and hypoxia. L‐NMMA did not alter ventilation or L‐glutamate levels during normoxia but significantly attenuated the hypoxic ventilatory response and the increase in L‐glutamate during hypoxia. The inhibition by L‐NMMA was blocked by L‐arginine. The ventilatory augmentation by exogenous L‐glutamate was attenuated by L‐NMMA. L‐Citrulline increased during hypoxia, and this increase was inhibited by MK‐801. 4. We provide the first in vivo evidence that, in the NTS, NO works as a retrograde messenger in an L‐glutamate‐releasing positive feedback system contributing to the augmentation of ventilation during hypoxia.

Pulmonary Function and Regional Distribution of Emphysema as Determined by High-Resolution Computed Tomography

In patients with pulmonary emphysema, emphysematous changes are not uniform and vary from minimum alveolar destruction to advanced bullous formation, depending on the lobe or site in the lungs. However, we have little knowledge on whether or how this nonuniformity or localization affects pulmonary function in PE patients. Therefore, we measured the computed tomography (CT) density of divided sites in lungs with high-resolution CT images from 25 PE patients (FEV1.0%, mean ± SD 36 ± 9%, %DLCO 48 ± 16%, all men, 68 ± 4 years) and compared them to various parameters of pulmonary function. The mean CT density of whole lungs correlated with 12 pulmonary function parameters including FEV1.0 and diffusion capacity. When both lung fields were divided into peripheral, intermediate and central portions, the CT density of the central portion correlated with all pulmonary function parameters with which CT density of whole lungs correlated. In contrast, the CT density of the peripheral portion significantly correlated with only 7 parameters with smaller correlation coefficient values than those of the central portion. When divided into upper, middle and lower portions, the CT densities of upper, middle and lower portions correlated with 6, 8 and 10 of the 12 pulmonary function parameters which correlated with the density of whole lungs, respectively. The delta value of CT densities between the upper and lower portions or between the lateral and medial portions correlated with obstructive impairment (FEV1.0 and FEV1.0%). These findings suggest that (1) central rather than peripheral emphysematous changes affect pulmonary function, and (2) uniformity of emphysematous change correlates with the severity of airway obstruction in PE patients.

Nasal continuous positive airway pressure improves quality of life in obesity hypoventilation syndrome.

We studied the quality of life of obesity hypoventilation syndrome (OHS) by comparing it with age- and body mass index-matched patients without hypoventilation and age-matched obstructive sleep apnea (OSA) patients with body mass index (BMI) under 30, and the efficacy of nasal continuous positive airway pressure (CPAP) therapy for 3 to 6 months on the quality of life in these patients. Prospectively recruited patients from six sleep laboratories in Japan were administered assessments of the general health status by the Short-Form 36 Health Survey (SF-36) and subjective sleepiness by the Epworth Sleepiness Scale (ESS). Compared with matched healthy subjects, OHS and OSA patients not yet treated had worse results on the ESS scores and the SF-36 subscales for physical functioning, role limitations due to physical problems, general health perception, energy/vitality, role limitations due to emotional problems, and social functioning. The ESS scores of OHS patients were worse than those of the OSA groups including the age- and BMI-matched OSA patients. In the SF-36 subscales of OHS patients, only the subscale of social functioning showed worse results compared with that of BMI-matched OSA patients. After 3 to 6 months of treatment, ESS scores and these SF-36 subscales in all three patient groups improved to the normal level. These results suggested that the quality of life of OHS before nasal CPAP was significantly impaired and that nasal CPAP for OHS improved the quality of life associated with the improvement of daytime sleepiness to the level of the other OSA patients.

Role of the parabrachial nucleus in ventilatory responses of awake rats.

1. The parabrachial nucleus (PBN) is thought to play an important role in cardiorespiratory control. However, the circumstances under which it affects ventilation are still not known. The purpose of the present study was to investigate how the PBN modulates the ventilatory responses to hypercapnia, hypoxia or a resistive load in awake rats with chemical lesions of the PBN. 2. In three groups of rats (with lateral PBN lesion, with Kölliker‐Fuse nucleus lesion and control), ventilation was measured under various conditions. 3. There was no difference in the breathing of normal room air in any of the groups. However, the lesioned groups showed a reduced ventilatory response to hyperoxic hypercapnia (inspired CO2 fractions (FI,CO2) of 3, 5, 8 and 10%) and to graded hypoxia (inspired O2 fractions (FI,O2) of 16, 12, 10 and 8%) compared with the control group. The control group showed a biphasic response to sustained hypoxia (FI,O2 at 10% for 30 min), known as ‘hypoxic depression’, while the lesioned groups showed moderate ventilatory exaggeration throughout hypoxia. In response to a resistive load, the lateral PBN lesion group showed no change in ventilatory compensation. 4. The PBN appeared to have a considerable influence on ventilation stimulated in various ways during wakefulness.

Induction of Adrenomedullin During Hypoxia in Cultured Human Glioblastoma Cells

Abstract: Adrenomedullin is a potent vasodilator peptide originally isolated from pheochromocytoma. Adrenomedullin is produced by various types of cells including neurons and astrocytes. To explore possible pathophysiological roles of adrenomedullin in hypoxic brain, we studied the effects of hypoxia on the expression of adrenomedullin in T98G human glioblastoma cells by radioimmunoassay and northern blot analysis. Expression levels of adrenomedullin mRNA and immunoreactive adrenomedullin levels in the culture medium were increased by hypoxia about six‐ and about threefold, respectively. Treatment with cobalt chloride increased expression levels of adrenomedullin mRNA about threefold and immunoreactive adrenomedullin levels in the culture medium about threefold in T98G cells. Using actinomycin D, we showed that hypoxia did not cause the stabilization of the adrenomedullin mRNA, suggesting that the increased adrenomedullin mRNA levels in response to hypoxia are caused mainly by increased transcription. Treatment with cycloheximide caused increases in adrenomedullin mRNA levels in both normoxic and hypoxic states, raising the possibility that some protein(s) may act as a suppressor of adrenomedullin gene expression in T98G cells. These findings indicate that adrenomedullin is highly induced during hypoxia in T98G glioblastoma cells and suggest that increased expression of adrenomedullin during hypoxia may be important in the defense against hypoxia or ischemia in the brain.

CO2 response for the brain stem artery blood flow velocity in man

We examined changes in the blood flow velocity of brain stem artery (BSA) and middle cerebral artery (MCA) in response to hypercapnic, normocapnic and hypocapnic hyperventilation in seven awake subjects with a transcranial Doppler to determine if there are differences in blood flow control in regional brain perfused by these respective arteries, and to separate the effects of CO2 and ventilation itself on blood flow velocity during CO2 loading. During hypercapnic hyperventilation, BSA flow velocity increased linearly with an increase in end-tidal partial pressure of CO2 (PETCO2). During hypocapnic hyperventilation, BSA flow velocity decreased linearly with decrease in PETCO2, but did not change during normocapnic hyperventilation. The mean CO2 reactivity of BSA was 2.8%/mmHg. The responses of MCA to these hyperventilations and CO2 reactivity were similar to those of BSA. These findings suggest that CO2 rather than ventilation per se is the important stimulus to changes in brain blood flow velocity and that the CO2 responses of brain arteries are not affected by differences in vascular beds.

Pulmonary hypertension in patients with chronic obstructive pulmonary disease: recent advances in pathophysiology and management.

Abstract: In patients with chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH) is associated with a worse prognosis. Recently, information has been increasing concerning the cellular and molecular aspects of the pathophysiology of PH in COPD. The most striking finding is the role of vascular endothelial cells and endogenous mediators released by these cells. Endothelial cell‐dependent relaxation is impaired in COPD patients with PH. Moreover, vascular remodelling in these patients is mainly responsible for irreversible PH in advanced COPD. Smoking cessation will slow down the progression of the disease process and may prevent the development of PH in COPD. The timing of initiation of long‐term oxygen therapy is important for the effective management of PH in COPD. Research on therapeutic agents for the effective treatment of PH is still needed in the management aspect of patients with COPD. This review focuses on the recent advances in our understanding of the pathophysiology and treatment of PH in COPD.

A new method of inhalation challenge with propranolol: comparison with methacholine-induced bronchoconstriction and role of vagal nerve activity.

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.