Ventilatory response to 2-h sustained hypoxia in humans

We used two protocols to determine if hypoxic ventilatory decline (HVD) involves changes in slope and/or intercept of the isocapnic HVR (hypoxic ventilatory response, expressed as the increase in VI per percentage decrease in SaO2). Isocapnia was defined as 1.5 mmHg above hyperoxic PET(CO2). HVD was recorded in protocol I during two sequential 25 min exposures to isocapnic hypoxia (85 and 75% SaO2, n=7) and in protocol II during 14 min of isocapnic hypoxia (90% SaO2, FIO2=0.13, n=15), extended to 2 h of hypoxia with CO2-uncontrolled in eight subjects. HVR was measured by the step reduction to sequentially lower levels of SaO2 in protocol I and by 3 min steps to 80% SaO2 at 8, 14 and 120 min in protocol II. The intercept of the HVR (VI predicted at SaO2=100%) decreased after 14 and 25 min in both protocols (P<0.05). Changes in slope were observed only in protocol I at SaO2=75%, suggesting that the slope of the HVR is more sensitive to depth than duration of hypoxic exposure. After 2 h of hypoxia the HVR intercept returned toward control value (P<0.05) with still no significant changes in the HVR slope. We conclude that HVD in humans involves a decrease in hyperoxic ventilatory drive that can occur without significant change in slope of the HVR. The partial reversal of the HVD after 2 h of hypoxia may reflect some components of ventilatory acclimatization to hypoxia.     

Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients

RATIONALE: Methadone is a long-acting mu-opioid and is an effective treatment for heroin addiction. Opioids depress respiration, and patients receiving methadone maintenance treatment (MMT) have higher mortality than the general population. Few studies have investigated ventilatory responses to both hypercapnia and hypoxia in these patients. STUDY OBJECTIVES: We measured hypercapnic ventilatory response (HCVR) and hypoxic ventilatory response (HVR) and investigated possible factors associated with both in clinically stable patients receiving MMT. DESIGN AND SETTING: Patients receiving long-term, stable doses of methadone recruited from a statewide MMT program, and normal, non-opioid-using subjects matched for age, sex, height, and body mass index were studied with HCVR and HVR. RESULTS: Fifty MMT patients and 20 normal subjects were studied, and significantly decreased HCVR and increased HVR were found in MMT patients compared to normal subjects (HCVR [mean +/- SD], l.27 +/- 0.61 L/min/mm Hg vs 1.64 +/- 0.57 L/min/mm Hg [p = 0.01]; HVR, 2.14 +/- 1.58 L/min/% arterial oxygen saturation measured by pulse oximetry [Sp(O2)] vs 1.12 +/- 0.7 L/min/% Sp(O2) [p = 0.008]). Respiratory rate and not tidal volume changes were the major physiologic responses contributing to both HCVR and HVR differences between the groups. Variables associated with HCVR in the MMT patients are as follows: obstructive sleep apnea/hypopnea index (t = 5.1, p = 0.00001), Pa(CO2) (t = - 3.6, p = 0.001), body height (t = 2.6, p = 0.01) and alveolar-arterial oxygen pressure gradient (t = 2.5, p = 0.02). Variables associated with HVR in MMT patients are body height (t = 3.2, p = 0.002) and Pa(CO2) (t = - 2.8, p = 0.008). CONCLUSIONS: Stable long-term MMT patients have blunted central and elevated peripheral chemoreceptor responses. The mechanisms and clinical significance of these findings need further investigation.     

Changes in dopamine D(2)-receptor modulation of the hypoxic ventilatory response with chronic hypoxia

Modulation of the hypoxic ventilatory response (HVR) by dopamine D(2)-receptors (D(2)-R) in the carotid body (CB) and central nervous system (CNS) are hypothesized to contribute to ventilatory acclimatization to hypoxia. We tested this with blockade of D(2)-R in the CB or CNS in conscious rats after 0, 2 and 8 days of hypoxia. On day 0, CB D(2)-R blockade significantly increased VI and frequency (fR) in hyperoxia (FI(O(2))=0.30), but not hypoxia (FI(O(2))=0.10). CNS D(2)-R blockade significantly decreased fR in hypoxia only. On day 2, neither CB nor CNS D(2)-R blockade affected VI or fR. On day 8, CB D(2)-R blockade significantly increased hypoxic VI and fR. CNS D(2)-R blockade significantly decreased hypoxic VI and fR. CB and CNS D(2)-R modulation of the HVR decreased after 2 days of hypoxia, but reappeared after 8 days. Changes in the opposing effects of CB and CNS D(2)-R on the HVR during chronic hypoxia cannot completely explain ventilatory acclimatization in rats.     

Sleep deprivation and the control of ventilation

Sleep deprivation is common in acutely ill patients because of their underlying disease and can be compounded by aggressive medical care. While sleep deprivation has been shown to produce a number of psychological and physiologic events, the effects on respiration have been minimally evaluated. We therefore studied resting ventilation and ventilatory responses to hypoxia and hypercapnia before and after 24 h of sleeplessness in 13 healthy men. Hypoxic ventilatory responses (HVR) were measured during progressive isocapnic hypoxia, and hypercapnic ventilatory responses (HCVR) were measured using a rebreathing technique. Measures of resting ventilation, i.e., minute ventilation, tidal volume, arterial oxygen saturation, and end-tidal gas concentrations, did not change with short-term sleep deprivation. Both HVR and HCVR, however, decreased significantly after a single night without sleep. The mean hypoxic response decreased 29% from a slope of 1.20 +/- 0.22 (SEM) to 0.85 +/- 0.15 L/min/% saturation (p less than 0.02), and the slope of the HCVR decreased 24% from 2.07 +/- 0.17 to 1.57 +/- 0.15 L/min/mmHg PCO2 (p less than 0.01). These data indicate that ventilatory chemosensitivity may be substantially attenuated by even short-term sleep deprivation. This absence of sleep could therefore contribute to hypoventilation in acutely ill patients.     

Almitrine increases the steady-state hypoxic ventilatory response in hypoxic chronic air-flow obstruction

Almitrine, a peripheral chemoreceptor agonist, exerts beneficial effects on blood gases in patients with hypoxic chronic air-flow obstruction, but as these patients exhibit poor ventilatory responses to hypoxia, the mechanism for this improvement is not clear. The effect of a 100-mg dose of almitrine given orally on ventilation and the steady-state hypoxic ventilatory response (HVR) were measured in a randomized, double-blind, placebo-controlled manner in 7 patients with severe hypoxic chronic air-flow obstruction. The isocapnic HVR (delta VE/delta SaO2) was calculated from the changes in ventilation and SaO2 from breathing 60% O2 to breathing air with the addition of CO2 to maintain isocapnia (as estimated from a transcutaneous CO2 electrode). Resting ventilation while breathing air and isocapnic HVR were measured before and 3 h after almitrine or placebo. Almitrine caused no significant change in resting ventilation. There was, however, a large increase in HVR after almitrine (almitrine: -1.5 L/min/%SaO2; range, -0.5 to -3.1; control: -0.4; range, -0.3 to -1.3), but no change after placebo. Almitrine is a powerful stimulant of chemosensitivity and of the hypoxic ventilatory response in chronic hypoxemia, with potential benefit to patients with chronic air-flow obstruction in respiratory failure.     

Possible role of dopamine in ventilatory acclimatization to high altitude

Ventilatory acclimatization to high altitude is accompanied by increased hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses which may reflect increased carotid body chemosensitivity. Dopamine is an inhibitory neuromodulator of the carotid body and its activity may be reduced by hypoxic exposure. To determine whether decreased dopaminergic activity could account for the increased chemosensitivity of acclimatization, we examined the response to peripheral dopamine receptor (D₂) blockade with domperidone on HVR and HCVR in awake cats before and after exposure to simulated altitude of 14000 ft for 2 days. During anesthesia, we also examined the effects of domperidone on carotid body responses to hypoxia and hypercapnia in acclimatized and low altitude cats. Two days' exposure to hypobaric hypoxia produced an increase in HVR and HCVR. Before acclimatization, domperidone augmented HVR and HCVR, but there was no effect after acclimatization. In anesthetized low altitude cats, domperidone increased carotid body responses to hypoxia and hypercapnia, but had no effect in acclimatized cats. These results indicate that decreased endogenous dopaminergic activity may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia and hypercapnia during hypoxic ventilatory acclimatization.     

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

We previously reported that acute intermittent hypoxia (IH) confers delayed cardioprotection against a prolonged ischemic insult in the rat, via the involvement of nitric oxide synthase and K(ATP) channels. In the present study, we investigated the role of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), stress activated p38 MAP kinase (MAPK) and extracellular signal-regulated kinase (ERK1/2) using selective inhibitors of these pathways. Adult male rats were exposed to 1-min cycles of IH (10% O(2), 40 s)/normoxia (21% O(2), 20 s) during 4 h or to normoxic cycles. 24 h later, isolated hearts were perfused in Langendorff mode and subjected to a 30-min global ischemia followed by 120 min of reperfusion. Compared to normoxic conditions, IH significantly reduced infarct size (22.2+/-2.4% vs. 33.8+/-2.6%, p<0.05), improved coronary flow and decreased the contracture at reperfusion. When administered before sustained ischemia, chelerythrine (a PKC inhibitor) abolished both the IH-induced reduction in infarct size (36.1+/-4.9%) and improvement in hemodynamic parameters. In contrast, chelerythrine administration 10 min before IH, did not modify the delayed cardioprotective response. Similarly, wortmannin (a PI3K inhibitor) administration 10 min before IH was unable to block the cardioprotective effects. However, administration of SB203580 (a p38 MAPK inhibitor) and PD98059 (an Erk1/2 inhibitor), 30 min before IH abolished its delayed infarct-sparing effect (32.2+/-3.4% and 33.9+/-2.9%, respectively). In addition, 24 h after IH, a significant increase in p38 MAPK and Erk1/2 phosphorylation was observed by Western blot. These results suggest that the delayed preconditioning induced by intermittent hypoxia does not involve the PI3K signalling pathway and that is mediated by PKC and triggered by p38 MAPK and Erk1/2.     

Respiratory effects of gestational intermittent hypoxia in the developing rat

Intermittent hypoxia (IH), one of the hallmarks of obstructive sleep apnea, occurs more frequently during pregnancy. We hypothesized that IH may lead to persistent postnatal changes in respiratory responses to acute hypoxia and may also lead to adverse effects on spatial function learning as revealed by the Morris water maze. To examine this issue, time-pregnant Sprague-Dawley rats were exposed to IH and room air (IHRA; 21 and 10% O2 alternations every 90 seconds) or to normoxia (RARA) until delivery. Ventilatory and metabolic responses to a 20-minute acute hypoxic challenge (10% O2) were conducted at postnatal ages 5, 10, 15, and 30 days. In addition, spatial task learning was assessed in the water maze at 1 and 4 months of age. Normoxic ventilation was higher at all time points in IHRA rats than in RARA rats (p < 0.01). Peak hypoxic ventilatory responses were attenuated in IHRA rats at 5 days of age and hypoxic ventilatory depression was accentuated at this age as well. However, ventilatory equivalents (minute ventilation/oxygen consumption) revealed significant reductions in peak hypoxic ventilatory responses of IHRA rats and hypoxic ventilatory depression at all postnatal ages (p < 0.01). Acquisition and retention of a spatial task were similar in the IHRA and RARA groups at both 1 and 4 months of age. We conclude that gestational intermittent hypoxia elicits long-lasting alterations in the control of breathing. We postulate that such IH-induced respiratory plasticity may create selective vulnerability to hypoxia during development.     

Ventilatory control in normal man following five minutes' exposure to hypoxia

Ventilatory control was studied in normal subjects following brief (5 min) exposure to hypoxia (inhalation 7-8% O2). The ventilatory response to rebreathing CO2 (hyperoxic) was assessed 20 min before and after 5 min exposure to (a) 7-8% O2, (b) 7-8% O2 rebreathing CO2, (c) rebreathing CO2 during hyperoxia, and (d) 10% O2, normocapnic. The slope of the V-PCO2 response (S) was increased for up to 40 min following (a) and (b) by 25-34%, but was unchanged following (c) and (d). Resting ventilation was unchanged throughout. The ventilatory response to normocapnic progressive hypoxia was measured as the slope of the V-Hb% SaO2 relationship (H); this was increased by 26%. The mechanism underlying this change in ventilatory control in man is unknown; it may relate to the process of acclimatization to hypoxia whereby chronic hypoxia is a greater stimulus to ventilation than acute hypoxia.     

Effect of treatment with nasal continuous positive airway pressure on ventilatory response to hypoxia and hypercapnia in patients with sleep apnea syndrome

BACKGROUND: The increase in peripheral chemoreflex sensitivity in patients with obstructive sleep apnea (OSA) is associated with activation of autonomic nervous system and hemodynamic responses. Nasal CPAP (nCPAP) is an effective treatment for OSA, but little is known on its effect on chemoreflex sensitivity. OBJECTIVES: To assess the effect of nCPAP treatment or placebo (sham nCPAP) on ventilatory control in patients with OSA. SETTING: Sleep laboratory of Azienda Ospedaliera Garibaldi. PATIENTS: Twenty-five patients with moderate-to-severe OSA. DESIGN AND MEASUREMENTS: Patients were randomly assigned to either therapeutic nCPAP (use of optimal pressure, n = 15) or sham nCPAP (suboptimal pressure of 1 to 2 cm H2O, n = 10) in a double-blind fashion and treated for 1 month. A rebreathing test to assess ventilatory response to normocapnic hypoxia and normoxic hypercapnia was performed at basal condition and after 1 month of treatment. RESULTS: The use of therapeutic nCPAP or sham nCPAP did not affect daytime percentage of arterial oxygen saturation (SaO2%) or end-tidal P(CO2). The normocapnic hypoxic ventilatory response was reduced after 1 month of treatment with nCPAP (the slope was 1.08 +/- 0.02 L/min/SaO2% at basal condition and 0.53 +/- 0.07 L/min/SaO2% after 1 month of treatment, p = 0.008) [mean +/- SD], but not in patients treated with sham nCPAP (slope, 0.83 +/- 0.09 L/min/SaO2% and 0.85 +/- 0.19 L/min/SaO2% at basal condition and after 1 month, respectively). The normoxic hypercapnic ventilatory response remained unchanged after 1 month in both groups. No changes in ventilatory response to either hypoxia or hypercapnia were observed after a single night of nCPAP treatment. CONCLUSION: The ventilatory response to hypoxia is reduced during regular treatment, but not after short-term treatment, with nCPAP. Readjusted peripheral oxygen chemosensitivity during nCPAP treatment may be a side effect of both reduced sympathetic activity and increased baroreflex activity, or a possible continuous positive airway pressure-related mechanism leading to a reduced activation of autonomic nervous system per se.     

内皮细胞在不同间歇缺氧方式时核因子κB和细胞间黏附分子1的变化

目的测定人脐静脉内皮细胞可传代细胞株ECV304在不同间歇缺氧（IH）程度、频率、时段和恢复时段下核因子κB（NF-κB）和细胞间黏附分子1（ICAM-1）的变化。方法在自制细胞培养舱中程控产生预置的IH／ROX（再氧合）暴露环境，将ECV304细胞暴露于该环境共60次循环。暴露时按IH／ROX时段将细胞分为11组，每组样本数为12。A组：采用21％O215s／21％O2 3分钟45秒（即间歇正常氧）方案；B组：置于标准孵箱中不加暴露（标准孵育）；C组：采用1．5％O2 15s／21％O2 3分钟45秒方案；D组：采用10％O2 15s／21％O2 3分钟45秒方案；以下固定IH方案为1．5％O2 15s和ROX程度21％O2不变，IH／ROX循环频率分别为12S／h（C组）、9S／h（E组）、6S／h（F组）、20S／h（G组）和40S／h（H组）；I组：采用1．5％O2 30s／21％O23分钟45秒方案；C组完成暴露后放回标准孵箱中60min为J组，120min为K组。分别采用酶联免疫吸附（ELISA）法和细胞表面ELISA法测定细胞裂解液中总NF-κB水平和细胞表面ICAM-1浓度，并测定总蛋白含量。结果C组NF-κB和ICAM-1水平分别为（0．82±0．28）、（1562±56）pg／ml，A组分别为（0．37±0.07）、（768±80）pg／ml，两组比较差异有统计学意义（D值分别为225．00、176．04，P分别〈0．01、〈0．05）；D组分别为（0．66±0．22）、（1113±76）pg／ml，与C组比较差异有统计学意义（U值分别为25．00、0．00，P均〈0.01）；I组分别为（0．45±0.16）、（1155±19）pg／ml，与C组比较差异有统计学意义（U值分别为27．00、0．00，P均〈0.01）；同时C组的NF-κB和ICAM-1水平在C、E、F、G和H这5个不同IH频率组的比较亦是相对最高的（X^2分别为35．63、56．89，P均〈0.01）；J组NF-κB水平[（0．6233±0.0534）]与C组比较差异无统计学意义（D=36．00，P〉0．05），而K组NF-κB水平[（0．3050±0．0013）]与C组比较差异有统计学意义（D=234．00，P〈0．01）。结论IH／ROX可对内皮细胞造成程度依赖的炎性损伤且不易恢复，中度频率的IH／ROX将选择性激活细胞炎性通道。而过高频率和过长时段的IH反而激活细胞适应性通道。     

Comparative human ventilatory adaptation to high altitude

Studies of ventilatory response to high altitudes have occupied an important position in respiratory physiology. This review summarizes recent studies in Tibetan high-altitude residents that collectively challenge the prior consensus that lifelong high-altitude residents ventilate less than acclimatized newcomers do as the result of acquired 'blunting' of hypoxic ventilatory responsiveness. These studies indicate that Tibetans ventilate more than Andean high-altitude natives residing at the same or similar altitudes (PET[CO(2)]) in Tibetans=29.6+/-0.8 vs. Andeans=31.0+/-1.0, P<0.0002 at approximately 4200 m), a difference which approximates the change that occurs between the time of acute hypoxic exposure to once ventilatory acclimatization has been achieved. Tibetans ventilate as much as acclimatized newcomers whereas Andeans ventilate less. However, the extent to which differences in hypoxic ventilatory response (HVR) are responsible is uncertain from existing data. Tibetans have an HVR as high as those of acclimatized newcomers whereas Andeans generally do not, but HVR is not consistently greater in comparisons of Tibetan versus Andean highland residents. Human and experimental animal studies demonstrate that inter-individual and genetic factors affect acute HVR and likely modify acclimatization and hyperventilatory response to high altitude. But the mechanisms responsible for ventilatory roll-off, hyperoxic hyperventilation, and acquired blunting of HVR are poorly understood, especially as they pertain to high-altitude residents. Developmental factors affecting neonatal arterial oxygenation are likely important and may vary between populations. Functional significance has been investigated with respect to the occurrence of chronic mountain sickness and intrauterine growth restriction for which, in both cases, low HVR seems disadvantageous. Additional studies are needed to address the various components of ventilatory control in native Tibetan, Andean and other lifelong high-altitude residents to decide the factors responsible for blunting HVR and diminishing ventilation in some native high-altitude residents.     

Ventilatory response to sustained eucapnic hypoxia in the adult conscious dog.

The ventilatory response to 20 min sustained isocapnic hypoxia (SaO2, 80 +/- 2%) was examined in 5 trained unanesthetized adult dogs breathing through an endotracheal tube. End tidal PCO2 was maintained at the resting levels. The dogs' conscious status was monitored by recording EEG and EOG on a chart recorder. The room temperature was kept between 19 and 21 degrees C. All tests were repeated in each dog on 2 occasions: (1) unloaded tracheal breathing or (2) resistive loaded breathing. During unloaded tracheal breathing, the average ventilation in response to sustained hypoxia rose from a control of 5.1 +/- 0.3 L/min (mean +/- within-dog SE) to 19.2 +/- 1.1 L/min at the initial stage of hypoxia. Ventilation remained at 20.7 +/- 1.3 L/min at 10 min, and then 19.7 +/- 1.4 L/min at the completion of the 20 min hypoxic exposure. There was no ventilatory adaptation observed (P greater than 0.05). After release from hypoxia, the ventilation fell abruptly to 7.6 +/- 0.8 L/min, which was higher than the resting baseline level (P less than 0.05), and then gradually returned to the resting baseline within 10 min. Experiments exposing the dogs to 40 min sustained hypoxia also failed to elicit significant adaptation. During resistive loading, the pattern of average ventilation in response to sustained hypoxia was similar to that observed in unloaded breathing tests. But the ventilatory recovery was longer than unloaded breathing, returning to the resting baseline within 20 min. Again, there was no ventilatory adaptation observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypercapnic and hypoxic ventilatory responses in parents and siblings of children with congenital central hypoventilation syndrome

Children with congenital central hypoventilation syndrome (CCHS) have abnormal ventilatory responses to metabolic stimuli. As there is a genetically determined component of chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted ventilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory responses and hypoxic ventilatory responses in six mothers, four fathers, and five siblings (6 to 49 yr of age) of seven children with CCHS and compared them with 15 age- and sex-matched control subjects (5 to 47 yr of age). Pulmonary function tests were not different between relatives of children with CCHS and control subjects. To measure hypercapnic ventilatory responses, subjects rebreathed 5% CO2/95% O2 until PACO2 reached 60 to 70 mm Hg. To measure hypoxic ventilatory responses (L/min/% SaO2), subjects rebreathed 14% O2/7% CO2/balance N2 at mixed venous PCO2 until SaO2 fell to 75%. All tests were completed in less than 4 min. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory timing/total respiratory cycle timing) were calculated on a breath-by-breath basis. Hypercapnic ventilatory responses were 1.97 +/- 0.32 L/min/mm Hg PACO2 in children with CCHS relatives and 2.23 +/- 0.23 L/min/mm Hg PACO2 in control subjects. Hypoxic ventilatory responses were -1.99 +/- 0.37 L/min/% SaO2 in the relatives and -1.54 +/- 0.25 L/min/% SaO2 in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ventilatory responses to hyperkalemia and exercise in normoxic and hypoxic goats

The ventilatory response to moderate exercise is potentiated during hypoxia in goats, causing PaCO2 to decrease more from rest to exercise than in normoxia. We investigated the hypothesis that this response is due to the ventilatory stimulus provided by an interaction between exercise induced hyperkalemia and hypoxia. Plasma potassium concentration ([K+]), arterial blood gases and ventilation were measured in normoxia and hypoxia (PaO2 = 34-38 Torr) at rest and during steady-state exercise (5.6 kph; 5% grade) in seven goats. PaCO2 decreased during normoxic exercise (2.9 +/- 0.7 Tor; P less than 0.01), and decreased significantly more during hypoxic exercise (6.4 +/- 0.6 Torr; P less than 0.01). [K+] increased in both normoxic (1.0 +/- 0.1 mEq/L; P less than 0.01) and hypoxic (0.9 +/- 0.2 mEq/L; P less than 0.01) exercise, but these changes were not significantly different from each other. On a different day, resting goats were infused intravenously with 200 mM KCl for 5 min at a rate sufficient to obtain [K+] similar to exercise (8.6-12 ml/min) in normoxia and hypoxia. Hyperkalemia at rest caused similar PaCO2 decreases in normoxia (1.7 +/- 0.7 Torr; P less than 0.05) and hypoxia (1.7 +/- 0.5 Torr; P less than 0.01), but had no statistically significant effect on ventilation in either condition. These data indicate that hyperkalemia, at levels approximating those during moderate exercise, has a mild stimulatory effect on alveolar ventilation; however, hypoxia does not affect this response. We conclude that hyperkalemia does not provide sufficient ventilatory stimulation to account for exercise hyperpnea, nor does hypoxia potentiate the ventilatory stimulation from hyperkalemia at rest.     

The ventilatory effects of sustained isocapnic hypoxia during exercise in humans.

To investigate how the ventilatory response to isocapnic hypoxia is modified by steady-state exercise, five subjects were studied at rest and performing 70 W bicycle exercise. At rest, isocapnic hypoxia (end-tidal PO2 50 Torr) for 25 min resulted in a biphasic response: an initial increase in ventilation was followed by a subsequent decline (HVD). During exercise, an end-tidal PO2 of 55-60 Torr was used. The magnitude of the initial ventilatory response to isocapnic hypoxia was increased from a mean +/ SE of 1.43 +/- 0.323 L/min per % arterial desaturation at rest to 2.41 +/- 0.424 L/min per % during exercise (P less than 0.05), but the magnitude of the HVD was reduced from 0.851 +/- 0.149 L/min per % at rest to 0.497 +/- 0.082 L/min per % during exercise (P less than 0.05). The ratio of HVD to the acute hypoxia response was reduced from 0.696 +/- 0.124 at rest to 0.202 +/- 0.029 during exercise (P less than 0.01). We conclude that while exercise augments the ventilatory sensitivity to hypoxia, it also has a direct effect on the mechanisms by which sustained hypoxia depresses peripheral chemosensitivity.     

Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension

We reported previously that simulating sleep apnea in rats by exposing them 7 hours per day to intermittent hypoxia/hypercapnia (IH) elevates plasma endothelin-1 and causes hypertension, which is reversed by an endothelin-1 antagonist. We hypothesized that in this model of sleep apnea-induced hypertension, vascular sensitivity to endothelin-1 is increased in combination with the elevated plasma endothelin-1 to cause the endothelin-1-dependent hypertension. In small mesenteric arteries with endothelial function disabled by passing air through the lumen, diameter and vessel wall [Ca2+] were recorded simultaneously. IH arteries demonstrated increased constrictor sensitivity to endothelin-1 (percentage max constriction 100+/-0% IH versus 80+/-10% Sham; P<0.05). This was accompanied by increased calcium sensitivity of IH arteries. In contrast, constrictor sensitivity and increases in vessel wall [Ca2+] to KCl and phenylephrine were not different between IH and Sham arteries. We have shown previously that endothelin-1 constriction in mesenteric arteries is mediated by endothelin A receptors. In the current study, the selective increase in endothelin-1 constriction in IH resistance arteries was accompanied by increased expression of endothelin A receptor expression (densitometry units 271+/-23 IH versus 158+/-25 Sham; P<0.05). Thus, IH hypertension appears to cause alterations in signaling components unique to endothelin-1 at the receptor level and in postreceptor signaling that increases calcium sensitivity during endothelin A activation. Future studies will determine the specific changes in vascular smooth muscle signaling in IH hypertension causing this augmented contractile phenotype.     

阻塞性睡眠呼吸暂停低通气综合征患者呼吸调节的家族聚集性研究

目的　探讨呼吸调节异常是否是引起阻塞性睡眠呼吸暂停低通气综合征 (OSAHS)家族聚集性的原因。方法　对 10例重度OSAHS患者、其一级亲属 16名及单纯肥胖者 14例进行睡眠监测并测定低氧通气反应 (HVR)、高碳酸通气反应 (HCVR)。对OSAHS患者进行持续气道正压通气(CPAP)治疗 ,在治疗的第 1、2、3个月复查HVR和HCVR。结果　 (1)OSAHS患者亲属的呼吸暂停及低通气指数 (AHI)为 (2 8 4± 39 1)次 /h ,出现习惯性打鼾、白天嗜睡的比例分别为 10 0 %和 90 % ,与对照组相比明显增高 (分别为P <0 0 5 ,P <0 0 1,P <0 0 1)。 (2 )亲属中无论是否有OSAHS ,其HVR、HCVR分别为 (- 19± 2 4 )cmH2 O、(0 31± 0 35 )cmH2 O/mmHg ,与对照组比较差异无显著性 (P >0 0 5 )。 (3)经CPAP治疗后 ,OSAHS患者的HVR、HCVR恢复正常。结论　OSAHS有家族聚集性 ,但这一聚集性与遗传性呼吸调节异常无关     

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

To elucidate the role of chemoresponsiveness in determining postapneic ventilation in sleep-disordered periodic breathing, we measured ventilatory response associated with apnea-induced arterial oxygen desaturation during sleep and compared it with the awake hypoxic ventilatory response (HVR) in 12 male patients with obstructive sleep apnea (OSA). Awake HVR was measured at a slight hypocapnic level (end-tidal PCO2 = 37 +/- 1 mm Hg, mean +/- SEM), and separately at a PCO2 of 45 mm Hg. During non-REM sleep both the ventilatory rate (VE) and the average respiratory frequency (f) in the ventilatory phase between apneic episodes were inversely correlated with the nadir of arterial oxygen saturation (nSaO2) produced by the preceding apneic phase in all patients (VE versus nSaO2; r = -0.74 +/- 0.03, mean +/- SEM; f versus nSaO2, r = -0.56 +/- 0.04). The average tidal volume (VT) also was correlated with nSaO2 in 10 of the patients (r = -0.56 +/- 0.05). During REM sleep VE was correlated with nSaO2 in 11 patients (r = -0.75 +/- 0.03, p less than 0.02). The response of VE to nSaO2 (delta VE/delta nSaO2) varied widely among the patients (non-REM, 0.52 to 2.16; REM, 0.29 to 1.44 L/min/%) and was significantly lower during REM than non-REM sleep (p less than 0.01). The value of delta VE/delta nSaO2 during both non-REM and REM sleep was correlated with awake HVR at an end-tidal PCO2 of 45 mm Hg (non-REM, r = 0.83, p less than 0.02; REM, r = 0.76, p less than 0.05) but not with that at the hypocapnic level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat

Intermittent hypoxia (IH) during sleep, a critical feature of sleep apnea, induces significant neurobehavioral deficits in the rat. Cyclooxygenase (COX)-2 is induced during stressful conditions such as cerebral ischemia and could play an important role in IH-induced learning deficits. We therefore examined COX-1 and COX-2 genes and COX-2 protein expression and activity (prostaglandin E2 [PGE2] tissue concentration) in cortical regions of rat brain after exposure to either IH (10% O2 alternating with 21% O2 every 90 seconds) or sustained hypoxia (10% O2). In addition, the effect of selective COX-2 inhibition with NS-398 on IH-induced neurobehavioral deficits was assessed. IH was associated with increased COX-2 protein and gene expression from Day 1 to Day 14 of exposure. No changes were found in COX-1 gene expression after exposure to hypoxia. IH-induced COX-2 upregulation was associated with increased PGE2 tissue levels, neuronal apoptosis, and neurobehavioral deficits. Administration of NS-398 abolished IH-induced apoptosis and PGE2 increases without modifying COX-2 mRNA expression. Furthermore, NS-398 treatment attenuated IH-induced deficits in the acquisition and retention of a spatial task in the water maze. We conclude that IH induces upregulation and activation of COX-2 in rat cortex and that COX-2 may play a role in IH-mediated neurobehavioral deficits.