巽 浩一郎

We investigated how signals arising from peripheral chemoreceptors could affect pulmonary vasculature in rats. Effects of the hypoxic exposure (10%) on mean pulmonary arterial pressure (mPAP), abdominal aortic flow (Q) and the estimated total pulmonary vascular resistance (mPAP/Q) were determined in anesthetized, artificially ventilated, carotid sinus nerve intact or chemodenervated rats. The pressor response of PAP to hypoxia seen in intact rats changed to the depressor response after chemodenervation. Hypoxia elicited a decrease in Q and an increase in mPAP/Q in both intact and chemodenervated rats. Selective carotid body stimulation by the intra-carotid injection of sodium cyanide (NaCN) in normoxia elicited an immediate but transient increase in PAP and Q before and after bilateral vagotomy. The peak change in PAP slightly preceded that in Q. These responses to NaCN were completely abolished by chemodenervation. These results indicate that the immediate chemoreflex contributes to the short-term regulation of pulmonary vasculature in rats. Copyright (C) 1998 Elsevier Science B.V.

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

It is estimated that approximately one million Japanese suffer from disorders of sleep and wakefulness such as sleep apnea the majority of those affected remain undiagnosed and untreated, although we do not know how many of them should be treated. The consequences of sleep disorders are significant and include reduced productivity, lowered cognitive performance, increased likelihood of accidents, higher morbidity and mortality and impaired quality of life. Despite their wide spread distribution and impact upon our society, sleep-related problems are not recognized as a public health issue. We should recognize and respond effectively to sleep-related issues. In the United States National Commission on Sleep Disorders Research estimates that 95 percent of patients with sleep disorders remain undiagnosed and that the cost of these untreated sleep disorders is astronomical in terms of reduced quality of life, lower productivity in school and the workplace, and the loss of life due to accidents caused by excessive sleepiness. That may be the case in Japan. The most successful and commonly used medical treatment of obstructive sleep apnea (OSA) in the United States is nasal continuous positive airway pressure (CPAP), a mask-like device and pump that together act to keep the airway open with air pressure. In our country several approaches have been reported to treat OSA patients these approaches include CPAP, mechanical devices such as orthodontic appliances, and surgical procedures such as uvulopalatopharyngoplasty (UPPP). However, considerably more information will be needed before any of these physical interventions may be recommended for general use.

We prospectively examined the survival rate of 67 chronic obstructive pulmonary disease (COPD) and 74 late sequelae of pulmonary tuberculosis (TB seq) patients to clarify whether nocturnal oxy hemoglobin desaturation (NOD) could be one of the independent factors determining their mortality. The sleep monitoring of arterial oxygen saturation (SpO2) and pulmonary function tests were assessed in all patients at the time of registration. Forty % of COPD and 24% of TB seq died as the direct result of deterioration of chronic respiratory failure during the 7-year observation period. Cox's proportional hazards analysis showed that NOD was an independent prognostic factor in both groups, and this was especially prominent when evaluated in terms of sleep lowest SpO2 in COPD and 85% desaturation time in TB seq. No significant prognostic factor was observed among age, vital capacity percent predicted (%VC), forced expiratory volume in one second (FEV1.0%) and partial pressure of carbon dioxide (PaCO2). We conclude that the degree of NOD can affect mortality in COPD and TB seq.

Effective alveolar ventilation and hypoxic ventilatory response (HVR) are higher in females than in males and after endogenous or exogenous elevation of progesterone and estrogen. The contribution of normal physiological levels of ovarian hormones to resting ventilation and ventilatory control and whether their site(s) of action is central and/or peripheral are unclear. Accordingly, we examined resting ventilation, HVR, and hypercapnic ventilatory responses (HCVR) before and 3 wk after ovariectomy in five female cats. We also compared carotid sinus nerve (CSN) and central nervous system translation responses to hypoxia in 6 ovariectomized and 24 intact female animals. Ovariectomy decreased serum progesterone but did not change resting ventilation, end-tidal PCO2, or HCVR (all P = NS). Ovariectomy reduced the HVR shape parameter A in the awake (38.9 ± 5.5 and 21.2 ± 3.0 before and after ovariectomy, respectively, P &lt 0.05) and anesthetized conditions. The CSN response to hypoxia was lower in ovariectomized than in intact animals (shape parameter A = 22.6 ± 2.5 and 54.3 ± 3.5 in ovariectomized and intact animals, respectively, P &lt 0.05), but central nervous system translation of CSN activity into ventilation was similar in ovariectomized and intact animals. We concluded that ovariectomy decreased ventilatory and CSN responsiveness to hypoxia, suggesting that the presence of physiological levels of ovarian hormones influences hypoxic chemosensitivity by acting primarily at peripheral sites.

Monocrotaline (MCT) is bioactivated in liver cytochrome P-450s to MCT pyrrole (MCTP), which primarily injures the lung endothelium to result in the development of pulmonary hypertension (PH) in rats. However, whether there is a relation between the degree of PH and the activity of liver cytochrome P- 450 to convent MCT to MCTP remains unclear. To examine the relation between these physiological and biochemical changes, we first measured the severity of MCT-induced (20 mg/kg) PH in male, female, castrated male, and phenobarbital (PB, liver P-450s inducer)-pretreated male rats. The degree of right ventricular hypertrophy was more severe in PB-pretreated male than in control male rats. It was also more severe in male than in either female or castrated male rats, suggesting that sex-specific P-450s could be involved in the metabolic pathways of MCT in the liver. Further to explore which of the isozymes (2A2, 2C11, and 3A) of P-450s in the liver is responsible for the bioactivation of MCT, we measured the rate of MCTP production in hepatic microsomes by a modified Mattock's method. Treatment of male rats with PB and pregnenolone 16α-carbonitrile (PCN), which is the specific inducer of P-450 3A, increased the rate of MCTP production, suggesting that P-450 3A may contribute to the conversion to pyrrole. Therefore we measured the amount of P-450 3A protein by immunoblotting and attempted to inhibit MCT metabolism by using antibodies to P-450 3A. P-450 3A was significantly induced by PCN (6.5- fold) and PB (4.6-fold) treatment and reduced by castration (0.38-fold). The amount of P-450 3A was closely correlated with the production of MCTP, and the conversion of MCT to MCTP was strongly inhibited by antibodies against P- 450 3A. These results indicated that P-450 3A was predominantly responsible for the metabolism of MCT to MCTP in rat liver and suggested a tight linkage between the degree of PH and the activity of liver P-450 3A.

Thirty-eight patients with late sequelae of pulmonary tuberculosis (TB seq.) were studied to clarify the characteristics of sleep desaturation in comparison with 40 patients with chronic obstructive pulmonary disease (COPD). While awake, the TB seq. group had a lower % VC and a higher PaCO2. In both groups, the sleep lowest SaO2 was positively correlated with the awake SaO2. The regression line between the sleep lowest SaO2 and the awake baseline SaO2 in the TB seq. group was located below that in the COPD group. Awake PaCO2 was negatively related to the sleep lowest SaO2 only in the TB seq. group. These results indicate that the sleep lowest SaO2 values were lower in TB seq. than in COPD patients with the same levels of SaO2 while awake. Sleep studies are necessary to reveal the indication for nocturnal oxygen therapy in TB seq. patients, especially when they are hypercapnic in spite of their good awake oxygenation.

Previously we showed that prolonged exposure to severe hypoxia produces decreased peripheral chemoreceptor responsiveness to hypoxia and attenuates central nervous system (CNS) chemosensory translation, which together may contribute to the decreased hypoxic ventilatory response (HVR) in chronic hypoxia. In this study, we sought to determine whether the central or peripheral activity of endogenous dopamine modulates this decreased HVR. We examined the effects of peripheral and central dopamine receptor blockade on HVR and carotid sinus nerve (CSN) response to hypoxia in controls and in cats exposed to a simulated altitude of 5500 m for 3 weeks. Domperidone increased CSN response to hypoxia in hypoxic cats to levels similar to those observed in controls. HVR was also augmented by domperidone in hypoxic cats, but remained below that of controls. As a result, the CNS chemosensory translation remained reduced in hypoxic animals. We further treated animals with haloperidol. However, this combined treatment with domperidone and haloperidol led to no further increase in CSN or ventilatory responses to hypoxia, or in CNS chemosensory translation in hypoxic cats. Thus, decreased HVR in hypoxic cats is mediated both by depression of hypoxic sensitivity of the carotid body, which is largely dopaminergic, and by decreased CNS chemosensory translation which must involve non-dopaminergic mechanisms. © 1995.

A 38-year-old woman was referred to our hospital for severe pulmonary hypertension (pulmonary arterial pressure 63/36 mmHg). Digital subtraction angiography showed complete obstruction of the right main pulmonary artery and severe stenosis of the left main pulmonary artery. Although there were no symptoms or signs of systemic arterial lesions, the initial diagnosis was aortitis syndrome with pulmonary arterial involvement, and prednisolone therapy was started (60 mg/day). Pulmonary arterial pressure decreased to 53/12 mmHg. At a dosage of 20 mg/day, however, multiple nodular shadows were present on the X-ray film of the chest, but they disappeared after the dosage was increased. The level of anti-myeloperoxidase antibodies in her serum changed at almost the same time as multiple nodular shadows appeared on the chest X-ray film. Because anti-MPO antibodies have been never detected in patients with aortitis syndrome, polyangitis overlap syndrome was suspected. However, we found no evidence of systemic vasculitis that is, vasculitis in other organs, including the kidney and the skin. Therefore, we made a diagnosis of idiopathic pulmonary arteritis with positive anti-MPO antibodies.

Thirty-eight patients with late sequelae of pulmonary tuberculosis (TB seq.) were studied to clarify whether or not nocturnal oxyhemoglobin desaturation (NOD) could relate to acute exacerbation of chronic respiratory failure (AE). All patients had been untreated with home oxygen therapy, because they were not severely hypoxic. We performed sleep studies, pulmonary function tests and arterial blood gas analysis and investigated past history about AE in each patient. Twelve patients had experienced AE with right heart failure and they were classified as CHF (congestive heart failure) group. The rest was classified as Non-CHF group. These two groups were compared as for each variable examined. There was no difference between the two groups in age, body weight, %VC, FEV(1.0%), and awake Pa(O2). Awake Pa(CO2) was significantly higher in CHF group. Although no difference was observed in baseline Sa(O2), the degree of NOD was significantly greater in CHF group when evaluated by lowest Sa(O2) during sleep and 85% desaturation time (total time spent with Sa(O2) less than 85%). Moreover, 21 of Non-CHF and 6 of CHF were studied for cardiac parameters using right side cardiac catheterization. While the differences of mean pulmonary arterial pressure and cardiac output between the two groups were not significant, pulmonary arteriolar resistance was higher in CHF group. We concluded that NOD in TB seq. had a major role in AE with right heart failure. We speculated that AE might be caused, at least partly, by pulmonary vasopressor response to recurrent NOD.

18歳から59歳までの男性約7,000名を対象とした疫学調査により, いびきの程度と, 年齢, 肥満, いびきの家族歴, 日中の傾眠, 高血圧, 喫煙, アルコール摂取, 交通事故との関連を検討した. 毎晩往復の大いびきをかく人, ないし毎晩大いびきで時に息が止まる人を重度のいびき群とした. 加齢, 肥満, 喫煙, アルコール摂取はすべていびきの増悪因子であることが認められた. また重度のいびき群では, いびきの家族歴があり, 日中の傾眠および高血圧の既往歴, もしくは治療中の人の割合が有意に多かった. 交通事故との関連は認められなかった. アンケートにて重度のいびき群の中で, 40歳以上で肥満を伴い, かつ日中の傾眠および起床時の頭痛があるというすべてに解答した被検者は全体の0.25%であった.

In an open, prospective, multicenter trial the clinical efficacy of imipenem/cilastatin sodium (IPM/CS) for the treatment of 14 cases with aspiration pneumonia was investigated. The mean age was 75.4 years old. Diseases of central nervous system were present in 11 cases, cardiovascular diseases, pulmonary diseases and diabetes mellitus in 2 cases each respectively. Seven cases were community-acquired and another seven were hospital-acquired. Six cases were moderate and 8 cases were severe. Causative organisms were determined in 9 cases (64.3%),multiple causative organisms were isolated in 3 cases. Isolated organisms were Staphylococcus aureus (4),Pseudomonas aeruginosa (3), Klebsiella pneumoniae (3), Escherichia coli (1), Acinetobacter calcoaceticus (1). Detection of anaerobes was not attempted. Clinical effects of IPM/CS were excellent in 3, good in 8, fair in 2, poor in 1, the efficacy rate was thus 78.6%. P. aeruginosa was isolated from 2 out of 3 cases in which therapy with IPM/CS failed. Monotherapy with IPM/CS appears to be highly effective for cases of aspiration pneumonia, but the disease due to IPM-resistant P. aeruginosa is an exception. © 1990, Japan Antibiotics Research Association. All rights reserved.

In an open, prospective, multicenter trial we investigated the clinical efficacy of Imipenem/cilastatin sodium (IPM/CS) for the treatment of pulmonary infection. Out of 129 cases collected, 103 could be evaluated for utility of IPM/CS: 83 with pneumonia (49 moderate and 34 severe cases), 6 with lung abscess, 5 with empyema, 9 with chronic bronchial infection caused by Pseudomonas aeruginosa. In 83 cases of pneumonia, the mean age was 67.6 years old, significant underlying diseases were present in 87.9%, and 21 cases (25.3%) were hospital-acquired. Causative organisms were determined in 36 cases (43.4%), and multiple causative organisms were isolated in 5 cases. The principal pathogens were Streptococcus pneumoniae (8), Staphylococcus aureus (8), P. aeruginosa (8), Haemophilus influenzae (6), Klebsiella pneumonia (6). The efficacy rate of the cases of pneumonia in monotherapy with IPM/CS was 84.6%: moderate 87.2%, severe 80.6%, community-acquired 91.7%, and hospital-acquired 61.1%. Monotherapy with IPM/CS was highly effective in cases of aspiration pneumonia. The efficacy rate in cases in which the causative organism was P. aeruginosa was low (50.0%). The efficacy rate of the cases of lung abscess was 100% and of empyema was 50.0%. Of 9 cases of chronic bronchial infection due to P. aeruginosa, in 5 cases treated with IPM/CS combined with tobramycin and I case treated combined with amikacin, the efficacy rate was 66.6% and the eradication rate 33.3%. We consider monotherapy with IPM/CS to be highly effective in cases of moderate and severe pneumonia, with the exception of disease due to imipenem-resistant P. aeruginosa. © 1990, Japanese Society of Chemotherapy. All rights reserved.

男性呼吸器不全患者を対象にテストステロン (T) 分泌動態を検討した. 症例をPaO₂の値により3群に分け検討を行った結果, PaO₂が60Torr 以下の呼吸不全を呈した群では, PaO₂が70Torr を越えるコントロール群と比較して, 尿中および血中T値の有意な低下が認められた. またLHRH負荷試験において, 呼吸不全を呈した群ではコントロール群と比較して, 30分後のLHの増加率の低下および個々の症例の検討でLHのピーク値出現の遅延が高率に認められた. 一方HCG負荷試験では48時間後の値に差は認められなかった. T生合成に関する17α水酸化酵素の活性を, 17α水酸化プロゲステロン/プロゲルテロンの比より推定したが, この値は低酸素血症の程度に伴い低下するのが認められた. 以上より男性呼吸不全患者においては, PaO₂低下に伴いアンドロジェン活性の低下および17α水酸化酵素活性の低下が起り, これは視床下部-下垂体系の機能低下に起因していることが示唆された.

Twelve healthy men were studied to determine the effect of ventilatory stimulation with chlormadinone acetate (CMA), a potent synthetic progesterone, in small doses (5 mg/day), on arterial blood gas levels. Using a randomized, double-blind, crossover trial, one week of CMA administration caused a significant reduction in arterial CO2 tension (PaCO2) by 4.1 ± 2.9 (SD) mm Hg. The magnitude of the fall in PaCO2 was about the same as that obtained with dose of 50 mg per day in our previous study. These results indicate that the dosages of progestin and the effect of the drug on ventilation were not in parallel, and it may provide the idea that larger doses of progestin would not necessarily be required to stimulate ventilation.

We studied hypoxic and hypercapnic ventilatory drives in 22 eucapnic obese subjects (14 female and eight male subjects) referred for weight reduction therapy and 23 normal subjects (eight female and 15 male subjects). In the female subjects, both occlusion pressure, currently used as an indicator of ventilatory drive, and ventilatory responses to hypoxia, as well as occlusion pressure response to hypercapnia, were significantly greater in the obese than in the normal subjects however, no significant differences in these responses between male obese and male normal subjects were observed, except for the hypoxic occlusion pressure response. We also studied breathing during sleep in the obese subjects, and male predominance in abnormal breathing and oxygen desaturation was noted. These results showed that obese female subjects increased their hypoxic and hypercapnic chemosensitivities against their body mass loading, which was not evident in obese male subjects. The relatively depressed chemosensitivities of the latter may be related to disordered breathing and oxygen desaturation during sleep.

There is as yet no convincing evidence that acetazolamide, a carbonic anhydrase inhibitor, is effective in obstructive sleep apnoea. A study was therefore designed to examine the effect of acetazolamide (250 mg/day) on sleep events and ventilatory control during wakefulness in nine patients with the sleep apnoea syndrome. In eight of the nine patients the apnoea index and the total duration of apnoea were reduced by acetazolamide, and the mean (SEM) apnoea index of all patients changed from 25.0 (6.7) to 18.1 (5.8) episodes an hour. Furthermore, the total time of arterial oxygen desaturation (SaO2) - more than 4% depression SaO2 from the baseline sleeping level - divided by total sleep time was also significantly decreased and its mean (SEM) value improved from 24.1 (7.9) to 13.6 (4.8)% of total sleep time. Five of the seven patients with varying degrees of daytime hypersomnolence had their symptoms obviously improved. There was no patient whose predominant type of apnoea was converted from the obstructive to the central type, or vice versa. In the studies of wakefulness, metabolic acidosis, an increase of arterial oxygen tension (PaO2) and a decrease of arterial carbon dioxide tension (PaCO2) were observed. The slopes of the occlusion pressure response and the ventilatory response to carbon dioxide increased, and the carbon dioxide ventilatory response line shifted to the left. It is suggested that acetazolamide cannot remove apnoea completely but has a beneficial effect in mild cases of obstructive sleep apnoea through an augmentation of central (CO2, H+) drive and a stabilising effect on ventilatory control.

Ten healthy young males were studied with a double-blind, cross-over trial to determine whether or not chlormadinone acetate (CMA), a potent synthetic progesterone, augments hypoxic chemosensi-tivity. Seven days after CMA administration, inspiratory minute volume (Vi) and tidal volume (FT) significantly increased. PaCo2 decreased by 3.0 ± 2.6 (S.D.) Torr (p&lt 0.05) and plasma bicarbonate decreased by 2.9±1.1 mM (p&lt 0.01). During CMA administration, the atmospheric hypoxic ventilatory response (HVR), assessed by minute ventilatory (ΔVt/ΔSaO2), and occlusion pressure responses (Δp2/ΔsaO2), significantly increased about 1.9 (p&lt 0.05) and 1.6 times (p&lt 0.01) compared to the placebo response, respectively. The calculated normocapnic HVR (ΔVt/ΔSaO2) increased about 2.3 times the placebo run. Hypoxic response evaluated by the withdrawal test, which represents the peripheral chemo-sensitivity without involving the influence due to secondary hypoxic depression, was about 1.7 times the placebo response (p&lt 0.05). We conclude that CMA augments hypoxic respiratory chemosensitivity. © 1987, PHYSIOLOGICAL SOCIETY OF JAPAN. All rights reserved.

We studied the effect of acetazolamide, a potent inhibitor of carbonic anhydrase, on pulmonary functions, blood gas analysis and ventilatory responses to hypoxia and hypercapnia in healthy male subjects. The following are the data obtained at 4 days after acetazolamide administration (500 mg/day), and compared with those before administration. There is no significant difference in VC, FRC, FEV(1.0%) and D(LCO). Pa(CO2), pH and (HCO3 -) decreased and Pa(O2) increased. On the average, arterial Pa(CO2) is expected to change by 1.51 Torr for a 1-meq/l chronic change in (HCO3 -). V̇1 and V(T) at rest increased while f, T1/T(TOT), V̇(CO2) and V̇(O2) at rest did not change. V(T)/T1 showed increasing tendency without statistical significance. Normocapnic hypoxic ventilatory response (HVR) increased significantly, but there was no significant change in hypocapnic HVR. Hypercapnic ventilatory response (HCVR) increased significantly in both unloaded and loaded conditions.

Recent studies have demonstrated that oxygen desaturation occurs during sleep in some patients with chronic obstructive pulmonary disease (COPD). The degree of sleep hypoventilation in COPD may be related to an inadequate chemical control of ventilation. To investigate this relationship, we compared maximal sleep changes in arterial oxygen saturation (SaO2) with the hypercapnic and hypoxic ventilatory control during wakefulness in 24 patients with COPD. Both hypercapnic and hypoxic ventilatory responses were inversely correlated with the degree of maximal sleep desaturation in rapid-eye-movement (REM) sleep. Furthermore, the level of baseline SaO2 during wakefulness was also negatively related to the magnitude of sleep desaturation. Patients with insufficient chemical control of breathing appear to have larger falls in SaO2, particularly if they have lower baseline SaO2.

A 49-year-old male was admitted with recurrent infected pulmonary cystic lesion. Chest X-ray film showed an infiltrative shadow with an air-fluid level in the right lower lobe and CT-scan showed a polycystic lesion. No arterial abnormality was found on aortography. Right lower lobectomy was carried out and pathologically, the lesion was intralobar sequestration without arterial abnormality. This case seems to support the theory that pulmonary sequestration should be considered as a bronchovascular anomaly.