心源性睡眠呼吸异常：心衰患者睡眠期间陈-施呼吸 机制探讨的初步报告*

目的: 探讨心衰患者陈施呼吸的发生率及发生机制。方法: 连续入选2015年3月~2015年5月于阜外医院行睡眠呼吸监测的患者56例,分为心衰组和非心衰组。结果: 两组睡眠呼吸暂停的发生率均较高,心衰组11例患者中呼吸暂停低通气指数（AHI）>5的有10例,平均AHI指数23.93±14.63;非心衰组45例患者中AHI>5的有33例,平均AHI指数16.20±18.76;心衰组中枢性睡眠呼吸暂停（CSA）次数占睡眠呼吸暂停总数的比例明显大于非心衰组病人,分别为80.21%±30.55%和27.16%±35.71%,P<0.01。结论: 心脏的循环功能和肺脏的呼吸功能是联合一体化,相互联系、互为因果而又互相影响。慢性心力衰竭的循环障碍促成了潮式呼吸的发生,所以称之为心源性呼吸睡眠异常。     

Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog.

Periodic breathing is commonly observed in chronic heart failure (CHF) when pulmonary capillary wedge pressure is abnormally high and there is usually concomitant tachypneic hyperventilation. We hypothesized that acute pulmonary hypertension at pressures encountered in CHF and involving all of the lungs and pulmonary vessels would predispose to apnea/unstable breathing during sleep. We tested this in a chronically instrumented, unanesthetized dog model during non-rapid eye movement (NREM) sleep. Pulmonary hypertension was created by partial occlusion of the left atrium by means of an implanted balloon catheter in the atrial lumen. Raising mean left atrial pressure by 5.7 +/- 1.1 Torr resulted immediately in tachypneic hyperventilation [breathing frequency increased significantly from 13.8 to 19.9 breaths/min; end-tidal P(CO2) (P(ET(CO2))) fell significantly from 38.5 to 35.9 Torr]. This tachypneic hyperventilation was present during wakefulness, NREM sleep, and rapid eye movement sleep. In NREM sleep, this increase in left atrial pressure increased the gain of the ventilatory response to CO2 below eupnea (1.3 to 2.2 l.min(-1).Torr(-1)) and thereby narrowed the CO2 reserve [P(ET(CO2)) (apneic threshold) - P(ET(CO2)) (eupnea)], despite the decreased plant gain resulting from the hyperventilation. We conclude that acute pulmonary hypertension during sleep results in a narrowed CO2 reserve and thus predisposes toward apnea/unstable breathing and may, therefore, contribute to the breathing instability observed in CHF.     

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans.

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O(2) saturation nadir 81.4 +/- 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 +/- 11 to 159 +/- 21 units/min (P = 0.001) and mean blood pressure from 92.1 +/- 2.9 to 95.5 +/- 2.9 mmHg (P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O(2) (Fi(O(2))) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 +/- 4 vs. +49 +/- 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (Fi(O(2)) 0.5, for 5 min) were not changed significantly (P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.     

Chemoreflex control of breathing during wakefulness in healthy men and women.

This study used a modified CO(2) rebreathing procedure to examine the effect of gender on the chemoreflex control of breathing during wakefulness in healthy men (n = 14) and women (n = 14). Women were tested in the follicular phase of the menstrual cycle. During rebreathing trials, subjects hyperventilated to reduce the partial pressure of end-tidal CO(2) (Pet(CO(2))) below 25 Torr and were then switched to a rebreathing bag containing a normocapnic hypoxic or hyperoxic gas mixture. During the trial, Pet(CO(2)) increased, while O(2) was maintained at a constant level. The point at which ventilation began to rise as Pet(CO(2)) increased was identified as the ventilatory recruitment threshold (VRT). Ventilation below the VRT was measured, and the slope of the ventilatory response above the VRT was determined. Gender had no effect on the hyperoxic or hypoxic VRT for CO(2). Central chemoreflex sensitivity was significantly greater in men than women but not after correction for forced vital capacity. Measures of peripheral chemoreflex sensitivity were similar between genders. However, the slope of the tidal volume (Vt) response to hyperoxic and hypoxic CO(2) rebreathing (corrected and uncorrected) was greater in men than women, respectively. We conclude that central chemoreflex sensitivity is greater in men compared with women as reflected by differences in ventilatory (uncorrected) and Vt (corrected and uncorrected) responses to CO(2). However, gender has no significant effect on the central chemoreflex VRT for CO(2). The peripheral chemoreflex control of breathing during wakefulness is similar between men and women.     

Increased propensity for apnea via dopamine-induced carotid body inhibition in sleeping dogs.

We determined the effects of specific carotid body chemoreceptor inhibition on the propensity for apnea during sleep. We reduced the responsiveness of the carotid body chemoreceptors using intravenous dopamine infusions during non-rapid eye movement sleep in six dogs. Then we quantified the difference in end-tidal Pco(2) (Pet(CO(2))) between eupnea and the apneic threshold, the "CO(2) reserve," by gradually reducing Pet(CO(2)) transiently with pressure support ventilation at progressively increased tidal volume until apnea occurred. Dopamine infusions decreased steady-state eupneic ventilation by 15 +/- 6%, causing a mean CO(2) retention of 3.9 +/- 1.9 mmHg and a brief period of ventilatory instability. The apneic threshold Pet(CO(2)) rose 5.1 +/- 1.9 Torr; thus the CO(2) reserve was narrowed from -3.9 +/- 0.62 Torr in control to -2.7 +/- 0.78 Torr with dopamine. This decrease in the CO(2) reserve with dopamine resulted solely from the 20.5 +/- 11.3% increase in plant gain; the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal. We conclude that specific carotid chemoreceptor inhibition with dopamine increases the propensity for apnea during sleep by narrowing the CO(2) reserve below eupnea. This narrowing is due solely to an increase in plant gain as the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal control. These findings have implications for the role of chemoreceptor inhibition/stimulation in the genesis of apnea and breathing periodicity during sleep.     

Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs

Chronic exposure to intermittent hypoxia (CIH) has been used in animals to mimic the arterial hypoxemia that accompanies sleep apnea. Humans with sleep apnea and animals exposed to CIH have elevated blood pressures and augmented sympathetic nervous system responses to acute exposures to hypoxia. To test the hypothesis that exposure to CIH alters neurons within the nucleus of the solitary tract (NTS) that integrate arterial chemoreceptor afferent inputs, we measured whole cell currents induced by activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in enzymatically dispersed NTS neurons from normoxic (NORM) and CIH-exposed rats (alternating cycles of 3 min at 10% O2 followed by 3 min at 21% O2 between 8 AM and 4 PM for 7 days). To identify NTS neurons receiving carotid body afferent inputs the anterograde tracer 4- (4-(dihexadecylamino)styryl-N-methylpyridinum iodide (DiA) was placed onto the carotid body 1 wk before exposure to CIH. AMPA dose-response curves had similar EC50 but maximal responses increased in neurons isolated from DiA-labeled CIH (20.1 +/- 0.8 microM, n = 9) compared with NORM (6.0 +/- 0.3 microM, n = 8) rats. NMDA dose-response curves also had similar EC50 but maximal responses decreased in CIH (8.4 +/- 0.4 microM, n = 8) compared with NORM (19.4 +/- 0.6 microM, n = 9) rats. These results suggest reciprocal changes in the number and/or conductance characteristics of AMPA and NMDA receptors. Enhanced responses to AMPA receptor activation could contribute to enhanced chemoreflex responses observed in animals exposed to CIH and humans with sleep apnea.     

Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure.

The present study aimed to determine whether peripheral and/or central chemoreflex function is altered in chronic heart failure (CHF) and whether altered chemoreflex function contributes to sympathetic activation in CHF. A rabbit model of pacing-induced CHF was employed. The development of CHF (3-4 wk of pacing) was characterized by an enlarged heart, an attenuated contractility, and an elevated central venous pressure. Renal sympathetic nerve activity (RSNA) and minute volume (MV) of ventilation in response to stimulation of peripheral chemoreceptors by isocapnic/hypoxic gases were measured in the conscious state. It was found that the baseline RSNA at normoxia was higher in CHF rabbits than in sham rabbits (35. 00 +/- 4.03 vs. 20.75 +/- 2.87% of maximum, P < 0.05). Moreover, the magnitudes of changes in RSNA and MV in response to stimulation of the peripheral chemoreceptors and the slopes of RSNA-arterial PO2 and MV-arterial PO2 curves were greater in CHF than in sham rabbits. Inhibition of the peripheral chemoreceptors by inhalation of 100% O2 decreased RSNA in CHF but not in sham rabbits. The central chemoreflex function, as evaluated by the responses of RSNA and MV to hyperoxic/hypercapnic gases, was not different between sham and CHF rabbits. These data suggest that an enhancement of the peripheral chemoreflex occurs in the rabbit model of pacing-induced CHF and that the enhanced peripheral chemoreflex function contributes to the sympathetic activation in the CHF state.     

Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.     

Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans

Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA, both of which likely play an important role in the development of hypertension in these patients. Additionally, short-term exposure to intermittent hypoxic apneas can produce a sustained elevation of MSNA. Therefore, we tested the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Twenty-one subjects were randomly assigned to one of three groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia). Subjects were exposed to 30 s of the perturbation every minute for 20 min. Chemoreflex control of MSNA was assessed during baseline, 1 min posttreatment, and every 15 min throughout 180 min of recovery by the MSNA response to a single hypoxic apnea. Recovery hypoxic apneas were matched to a baseline hypoxic apnea with a similar nadir oxygen saturation. A significant main effect for chemoreflex control of MSNA was observed after 20 min of intermittent hypoxic apneas (P <0.001). The MSNA response to a single hypoxic apnea was attenuated 1 min postexposure compared with baseline (P <0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (P <0.05). Comparison of treatment groups revealed no differences in the chemoreflex control of MSNA during recovery (P=0.69). These data support the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Furthermore, this response appears to be mediated by hypoxia.     

Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea

Patients with obstructive sleep apnea (OSA) are frequently obese and are predisposed to weight gain. They also have heightened sympathetic drive. We reasoned that noradrenergic activation of beta(3)-receptors on adipocytes would inhibit leptin production, predisposing to obesity in sleep apnea. We therefore tested the hypothesis that obesity and predisposition to weight gain in OSA are associated with low levels of plasma leptin. We prospectively studied 32 male patients (43 +/- 2 yr) with OSA who were newly diagnosed and never treated and who were free of any other diseases. Control measurements were obtained from 32 similarly obese closely matched male subjects (38 +/- 2 yr). Leptin levels were 13.7 +/- 1.3 and 9.2 +/- 1.2 ng/ml in patients with OSA and controls, respectively (P = 0.02). Weight gain over the year before diagnosis was 5.2 +/- 1.7 and 0.5 +/- 0.9 kg in sleep apnea patients and similarly obese control subjects, respectively (P = 0.04). Muscle sympathetic activity was 46 +/- 4 and 30 +/- 4 bursts/min in patients with OSA (n = 16) and control subjects (n = 18), respectively (P = 0.01). Plasma leptin levels are elevated in newly diagnosed otherwise healthy patients with untreated sleep apnea beyond the levels seen in similarly obese control subjects without sleep apnea. Higher leptin levels in OSA, independent of body fat content, suggest that OSA is associated with resistance to the weight-reducing effects of leptin.     

Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits.

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Downregulation of nitric oxide (NO) synthase (NOS) in the carotid body (CB) is involved in this effect. However, it remains poorly understood whether carbon monoxide (CO) also contributes to the altered peripheral chemoreflex sensitivity in CHF. This work highlights the effect of NO and CO on renal sympathetic nerve activity (RSNA) in response to graded hypoxia in conscious rabbits. Renal sympathetic nerve responses to graded hypoxia were enhanced in CHF rabbits compared with sham rabbits. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1.2 microg x kg(-1) x min(-1)) and the CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)(3)Cl(2)](2), 3.0 microg x kg(-1) x min(-1)} each attenuated hypoxia-induced RSNA increases in CHF rabbits (P < 0.05), but the degree of attenuation of RSNA induced by SNAP or [Ru(CO)(3)Cl(2)](2) was smaller than that induced by SNAP + [Ru(CO)(3)Cl(2)](2). Conversely, treatment with the NOS inhibitor N(omega)-nitro-L-arginine (30 mg/kg) + the heme oxygenase (HO) inhibitor Cr (III) mesoporphyrin IX chloride (0.5 mg/kg) augmented the renal sympathetic nerve response to hypoxia in sham rabbits to a greater extent than treatment with either inhibitor alone and was without effect in CHF rabbits. In addition, using immunostaining and Western blot analyses, we found that expression of neuronal NOS, endothelial NOS, and HO-2 protein (expressed as the ratio of NOS or HO-2 expression to beta-tubulin protein expression) was lower in CBs from CHF (0.19 +/- 0.04, 0.17 +/- 0.06, and 0.15 +/- 0.02, respectively) than sham (0.63 +/- 0.04, 0.56 +/- 0.06, and 0.27 +/- 0.03, respectively) rabbits (P < 0.05). These results suggest that a deficiency of NO and CO in the CBs augments peripheral chemoreflex sensitivity to hypoxia in CHF.     

Selected contribution: Ventilatory response to CO2 in high-altitude natives and patients with chronic mountain sickness.

The ventilatory responses to CO(2) of high-altitude (HA) natives and patients with chronic mountain sickness (CMS) were studied and compared with sea-level (SL) natives living at SL. A multifrequency binary sequence (MFBS) in end-tidal Pco(2) was employed to separate the fast (peripheral) and slow (central) components of the chemoreflex response. MFBS was imposed against a background of both euoxia (end-tidal Po(2) of 100 Torr) and hypoxia (52.5 Torr). Both total and central chemoreflex sensitivity to CO(2) in euoxia were higher in HA and CMS subjects compared with SL subjects. Peripheral chemoreflex sensitivity to CO(2) in euoxia was higher in HA subjects than in SL subjects. Hypoxia induced a greater increase in total chemoreflex sensitivity to CO(2) in SL subjects than in HA and CMS subjects, but peripheral chemoreflex sensitivity to CO(2) in hypoxia was no greater in SL subjects than in HA and CMS subjects. Values for the slow (central) time constant were significantly greater for HA and CMS subjects than for SL subjects.     

Effects of human pregnancy on the ventilatory chemoreflex response to carbon dioxide

This study examined the effects of human pregnancy on the central chemoreflex control of breathing. Subjects were two groups (n=11) of pregnant subjects (PG, gestational age, 36.5+/-0.4 wk) and nonpregnant control subjects (CG), equated for mean age, body height, prepregnant body mass, parity, and aerobic fitness. All subjects performed a hyperoxic CO2 rebreathing procedure, which includes prior hyperventilation and maintenance of iso-oxia. Resting blood gases and plasma progesterone and estradiol concentrations were measured. During rebreathing trials, end-tidal Pco2 increased, whereas end-tidal Po2 was maintained at a constant hyperoxic level. The point at which ventilation (Ve) began to rise as end-tidal Pco2 increased was identified as the central chemoreflex ventilatory recruitment threshold for CO2 (VRTco2). Ve levels below (basal Ve) and above (central chemoreflex sensitivity) the VRTco2 were determined. The VRTco2 was significantly lower in the PG vs. CG (40.5+/-0.8 vs. 45.8+/-1.6 Torr), and both basal Ve (14.8+/-1.1 vs. 9.3+/-1.6 l/min) and central chemoreflex sensitivity (5.07+/-0.74 vs. 3.16+/-0.29 l.min-1.Torr-1) were significantly higher in the PG vs. CG. Pooled data from the two groups showed significant correlations for resting arterial Pco2 with basal Ve, central chemoreflex sensitivity, and the VRTco2. The VRTco2 was also correlated with progesterone and estradiol concentrations. These data support the hypothesis that pregnancy decreases the threshold and increases the sensitivity of the central chemoreflex response to CO2. These changes may be due to the effects of gestational hormones on chemoreflex and/or nonchemoreflex drives to breathe.     

Effect of gender on the development of hypocapnic apnea/hypopnea during NREM sleep.

We hypothesized that a decreased susceptibility to the development of hypocapnic central apnea during non-rapid eye movement (NREM) sleep in women compared with men could be an explanation for the gender difference in the sleep apnea/hypopnea syndrome. We studied eight men (age 25-35 yr) and eight women in the midluteal phase of the menstrual cycle (age 21-43 yr); we repeated studies in six women during the midfollicular phase. Hypocapnia was induced via nasal mechanical ventilation for 3 min, with respiratory frequency matched to eupneic frequency. Tidal volume (VT) was increased between 110 and 200% of eupneic control. Cessation of mechanical ventilation resulted in hypocapnic central apnea or hypopnea, depending on the magnitude of hypocapnia. Nadir minute ventilation in the recovery period was plotted against the change in end-tidal PCO(2) (PET(CO(2))) per trial; minute ventilation was given a value of 0 during central apnea. The apneic threshold was defined as the x-intercept of the linear regression line. In women, induction of a central apnea required an increase in VT to 155 +/- 29% (mean +/- SD) and a reduction of PET(CO(2)) by -4.72 +/- 0.57 Torr. In men, induction of a central apnea required an increase in VT to 142 +/- 13% and a reduction of PET(CO(2)) by -3.54 +/- 0.31 Torr (P = 0.002). There was no difference in the apneic threshold between the follicular and the luteal phase in women. Premenopausal women are less susceptible to hypocapnic disfacilitation during NREM sleep than men. This effect was not explained by progesterone. Preservation of ventilatory motor output during hypocapnia may explain the gender difference in sleep apnea.     

Effect of testosterone on the apneic threshold in women during NREM sleep.

The hypocapnic apneic threshold (AT) is lower in women relative to men. To test the hypothesis that the gender difference in AT was due to testosterone, we determined the AT during non-rapid eye movement sleep in eight healthy, nonsnoring, premenopausal women before and after 10-12 days of transdermal testosterone. Hypocapnia was induced via nasal mechanical ventilation (MV) for 3 min with tidal volumes ranging from 175 to 215% above eupneic tidal volume and respiratory frequency matched to eupneic frequency. Cessation of MV resulted in hypocapnic central apnea or hypopnea depending on the magnitude of hypocapnia. Nadir minute ventilation as a percentage of control (%Ve) was plotted against the change in end-tidal CO(2) (Pet(CO(2))); %Ve was given a value of zero during central apnea. The AT was defined as the Pet(CO(2)) at which the apnea closest to the last hypopnea occurred; hypocapnic ventilatory response (HPVR) was defined as the slope of the linear regression Ve vs. Pet(CO(2)). Both the AT (39.5 +/- 2.9 vs. 42.1 +/- 3.0 Torr; P = 0.002) and HPVR (0.20 +/- 0.05 vs. 0.33 +/- 0.11%Ve/Torr; P = 0.016) increased with testosterone administration. We conclude that testosterone administration increases AT in premenopausal women, suggesting that the increased breathing instability during sleep in men is related to the presence of testosterone.     

Comparison of chemoreflex gains obtained with two different methods in cats

This study investigates the correspondence between results of the ventilatory response to CO2 obtained using the technique of dynamic end-tidal CO2 forcing (DEF) and results obtained using the technique of artificial brain stem perfusion (ABP). The DEF technique separates the dynamic ventilatory response into a slow and fast component with gains g1 and g2 as well as the extrapolated CO2 tension at zero ventilation (Bk). The ABP technique results in steady-state central (Sc) and peripheral (Sp) chemoreflex gains and extrapolated CO2 tension at zero ventilation (B). Experiments were performed on 14 alpha-chloralose-urethan anesthetized cats. A wide range of relative peripheral chemosensitivities was obtained by subjecting eight cats to normoxic and three cats to hypoxic CO2 challenges and three cats to both conditions. Statistical analysis of the experimental data showed that the vectors (g1, g2, Bk) and (Sc, Sp, B) for each cat did not differ significantly (P = 0.56). This was also the case for the vectors [g2/(g1 + g2), Bk] and [Sp/(Sc + Sp), B] (P = 0.21). We conclude that in the DEF experiments the slow ventilatory response to isoxic changes in end-tidal CO2 can be equated with the central chemoreflex loop and the faster ventilatory response to the peripheral chemoreflex loop. The agreement between the two techniques is good.     

Almitrine bismesylate and the central and peripheral ventilatory response to CO2

Effects of almitrine bismesylate on the peripheral and central chemoreflex to a CO2 challenge during normoxia were studied in nine alpha-chloralose-urethan anesthetized cats. With the dynamic end-tidal CO2 forcing technique the ventilatory response after a square-wave change in end-tidal PCO2 (PETCO2) was partitioned into a central and a peripheral part using a two-compartment model. With almitrine administered intravenously (0.6 mg/kg followed by a maintenance dose of 0.4 mg.kg-1 X h-1) the CO2 sensitivity of the peripheral chemoreflex increased on the average from 0.315 to 0.564 l.min-1 X kPa-1 (P less than 0.001, 6 cats, 73 runs), whereas the CO2 sensitivity of the central chemoreflex remained the same (P = 0.87). The extrapolated PETCO2 at zero ventilation (apneic threshold) of the (total) steady-state response curve decreased on the average from 3.50 to 2.36 kPa (P less than 0.001). With the artificial brain stem perfusion technique it was confirmed that almitrine did not affect ventilation by administering it to the blood perfusing the brain stem. We conclude that almitrine bismesylate during normoxia enhances the CO2 sensitivity of the peripheral chemoreflex loop and decreases the apneic threshold due to an action located outside the brain stem.     

Blunted muscle vasodilatation during chemoreceptor stimulation in patients with heart failure

Chemoreflex control of sympathetic nerve activity is exaggerated in heart failure (HF) patients. However, the vascular implications of the augmented sympathetic activity during chemoreceptor activation in patients with HF are unknown. We tested the hypothesis that the muscle blood flow responses during peripheral and central chemoreflex stimulation would be blunted in patients with HF. Sixteen patients with HF (49 +/- 3 years old, Functional Class II-III, New York Heart Association) and 11 age-paired normal controls were studied. The peripheral chemoreflex control was evaluated by inhalation of 10% O(2) and 90% N(2) for 3 min. The central chemoreflex control was evaluated by inhalation of 7% CO(2) and 93% O(2) for 3 min. Muscle sympathetic nerve activity (MSNA) was directly evaluated by microneurography. Forearm blood flow was evaluated by venous occlusion plethysmography. Baseline MSNA were significantly greater in HF patients (33 +/- 3 vs. 20 +/- 2 bursts/min, P = 0.001). Forearm vascular conductance (FVC) was not different between the groups. During hypoxia, the increase in MSNA was significantly greater in HF patients than in normal controls (9.0 +/- 1.6 vs. 0.8 +/- 2.0 bursts/min, P = 0.001). The increase in FVC was significantly lower in HF patients (0.00 +/- 0.10 vs. 0.76 +/- 0.25 units, P = 0.001). During hypercapnia, MSNA responses were significantly greater in HF patients than in normal controls (13.9 +/- 3.2 vs. 2.1 +/- 1.9 bursts/min, P = 0.001). FVC responses were significantly lower in HF patients (-0.29 +/- 0.10 vs. 0.37 +/- 0.18 units, P = 0.001). In conclusion, muscle vasodilatation during peripheral and central chemoreceptor stimulation is blunted in HF patients. This vascular response seems to be explained, at least in part, by the exaggerated MSNA responses during hypoxia and hypercapnia.     

Long-lasting ventilatory response of humans to a single breath of hypercapnia in hyperoxia.

It has often been assumed that under normoxia, closed-loop ventilatory responses to transient CO2 stimulation (i.e., lasting for 1-3 breaths) are less likely to be mediated by the slow-responding central (medullary) chemoreflex. This assumption, however, has not been quantitatively examined in humans. We hypothesized that in the closed-loop respiratory chemical feedback system [in which the centrally mediated ventilatory response to transient changes in the arterial PCO2 levels (PaCO2) will in turn affect the pulmonary CO2 and hence PaCO2], the contribution of the central chemoreflex pathways to brief disturbances in blood gases may be more important than considered previously. Using the technique of pseudorandom binary CO2 stimulation, we quantified the ventilatory response of normal humans to brief disturbances in arterial CO2 during hyperoxia. Tidal volume (VI), inspiratory ventilation (VI), inspiratory time (TI), expiratory time (TE), and end-tidal CO2 fraction (FETCO2) were measured in subjects who inhaled a mixture that was pseudorandomly switched between 95% O2-5% CO2 and 100% O2 (63 breath sequences). From these data, we calculated the responses of VI, VI, TI, TE, and FETCO2 to a single-breath inhalation of 1% CO2 in O2. Our results showed that in response to a brief increase of 0.75 Torr in alveolar CO2, VI showed a transient increase (average peak response of 0.12 1/min) that persisted for greater than or equal to 80 s in every subject. The response of VI was similar to that of VI, whereas TI and TE showed no consistent changes. Using these results we calculated that central chemoreflex pathways may contribute significantly to typical transient CO2 stimulation tests in hyperoxic and normoxic humans.     

Postevent ventilation as a function of CO(2) load during respiratory events in obstructive sleep apnea.

Maintenance of eucapnia during sleep in obstructive sleep apnea (OSA) requires a balance between CO(2) loading during apnea and CO(2) elimination. This study examines individual respiratory events and relates magnitude of postevent ventilation to CO(2) load during the preceding respiratory event in 14 patients with OSA (arterial PCO(2) 42-56 Torr). Ventilation and expiratory CO(2) and O(2) fractions were measured on a breath-by-breath basis during daytime sleep. Calculations included CO(2) load during each event (metabolic CO(2) production - exhaled CO(2)) and postevent ventilation in the 10 s after an event. In 12 of 14 patients, a direct relationship existed between postevent ventilation and CO(2) load during the preceding event (P < 0.05); the slope of this relationship varied across subjects. Thus the postevent ventilation is tightly linked to CO(2) loading during each respiratory event and may be an important mechanism that defends against development of acute hypercapnia in OSA. An inverse relationship was noted between this postevent ventilatory response slope and the chronic awake arterial PCO(2) (r = 0.90, P < 0.001), suggesting that this mechanism is impaired in patients with chronic hypercapnia. The link between development of acute hypercapnia during respiratory events asleep and maintenance of chronic awake hypercapnia in OSA remains to be further investigated.