Intermittent hypoxia suppresses adiponectin secretion by adipocytes.

Obstructive sleep apnea (OSA), characterized by cyclic intermittent hypoxia (IH) during sleep, is an independent risk factor for cardiovascular disease. Adiponectin (APN), an adipocytokine secreted exclusively by adipocytes, possesses antiatherogenic properties. Low levels of APN, particularly the high-molecular-weight (HMW) form, are associated with an increased risk of cardiovascular disease. Here, we hypothesized that IH would result in the dysregulation of APN expression and secretion. 3T3-L1 adipocytes were exposed to IH at 12 cycles/h for 6 h/d to simulate the IH condition similar to that encountered in OSA. Control adipocytes were exposed to 21% O(2) under identical conditions. After 48 h of incubation, IH caused a decrease in the secretion of total and HMW APN in spite of a significant upregulation of APN mRNA expression by adipocytes. This study suggested a novel mechanism of how the cyclic hypoxemia in OSA predisposes OSA patients to cardiovascular disease through the dysregulation of secretion of APN by adipocytes. Further studies are needed to determine the exact molecular mechanism how IH reduces the release of APN by adipocytes.

The utility of neural network in the diagnosis of Cheyne-Stokes respiration.

The aim of this study was to design a diagnostic model to identify patients with Cheyne-Stokes respiration (CSR-CSA) based on indices of oximetric spectral analysis. A retrospective analysis of oximetric recordings of 213 sleep studies conducted over a one-year period at a Veterans Affairs medical facility was performed. A probabilistic neural network (PNN) was developed from salient features of the oximetric spectral analysis, desaturation events and the delta index. A fivefold cross-validation was used to assess the accuracy of the neural network in identifying CSR-CSA. When compared to overnight polysomnography, the PNN achieved a sensitivity of 100% (95% confidence interval [CI] 85%-100%) and a specificity of 99% (95% 97%-100%) with a corresponding area under the curve of 99% (95% CI 99%-100%). When combined with overnight pulse oximetry, PNN offers an accurate and easily applicable tool to detect CSR-CSA.

Opioidergic modulation of ventilatory response to sustained hypoxia in obese Zucker rats.

OBJECTIVE: To determine whether altered central and/or peripheral opioidergic mechanisms contribute to the altered ventilatory response to sustained hypoxia in obese Zucker rats. RESEARCH METHODS AND PROCEDURES: Eight lean (176 +/- 8 [SEM] g) and eight obese (225 +/- 12 g) Zucker rats were studied at 6 weeks of age. Pulmonary ventilation ((E)), tidal volume (V(T)), and breathing frequency (f) at rest and in response to sustained (30 minutes) hypoxic (10% O(2)) challenges were measured on three separate occasions by the barometric method after the randomized, blinded administration of equal volumes of saline (control), naloxone methiodide (N(M); 5 mg/kg, peripheral opioid antagonist), or naloxone hydrochloride (N(HCl); 5 mg/kg, peripheral and central opioid antagonist). RESULTS: Administration of N(M) and N(HCl) in lean animals had no effect on (E) either at rest or during 30 minutes of sustained exposure to hypoxia. Similarly, N(M) failed to alter (E) in obese rats. In contrast, N(HCl) significantly (p < 0.05) increased (E) and V(T) both at rest and during 2 to 10 minutes of hypoxic exposure in obese rats. After 20 to 30 minutes of hypoxic exposure, V(T) remained elevated with N(HCl), but the earlier elevation of (E) seemed to be attenuated due to a decrease in f at 20 minutes of exposure to hypoxia. DISCUSSION: Thus, endogenous opioids modulate both resting (E) and the ventilatory response to sustained hypoxia in obese, but not in lean, Zucker rats by acting specifically on opioid receptors located within the central nervous system.

Serotonergic modulation of ventilation and upper airway stability in obese Zucker rats.

To elucidate the role of serotonin in the maintenance of normal breathing and upper airway (UA) patency in obesity, we studied the effects of systemic administration of ritanserin, a serotonin (5-HT) 2A and 2C receptor antagonist, on ventilation (V E) during room air breathing and during hypoxic (10% O2) and hypercapnic (4% CO2) ventilatory challenges in awake young (6-8 wk) and older (7-8 mo) obese and lean Zucker (Z) rats. Older obese Z rats adopted a more rapid shallow breathing pattern compared with older lean rats. The administration of ritanserin (1 mg/kg intraperitoneally) to older obese rats resulted in a reduction in V E (439 +/- 35 [SD] to 386 +/- 41 ml/kg/min, p < 0.01), a decrease in respiratory rate, a prolongation of inspiratory time, and an increase in V O2 (16.4 +/- 1.7 to 18.2 +/- 1.9 ml/kg(0.75)/min, p < 0.05) during room air breathing. By comparison, it had little effect on ventilation in young lean and obese Z or older lean Z rats. Ritanserin also had no effect on ventilatory responses to either hypoxia or hypercapnia in young or older lean and obese Z rats. The collapsibility of the isolated UA was examined in older Z rats. The pharyngeal critical pressure (Pcrit) of older obese rats was significantly greater than that of lean rats (p < 0.05), indicating that obese rats have more collapsible UA than lean rats. The administration of ritanserin significantly increased Pcrit in older obese rats (-1.6 +/- 0.3 to -0.8 +/- 0.2 cm H2O, p < 0.01) and in lean rats (-3.1 +/- 1.0 to -2.4 +/- 0.6 cm H2O, p < 0.05). We suggest that the 5-HT(2A/2C) receptor subtype plays an important role in the maintenance of UA stability and normal breathing in obesity, and we speculate that older obese Z rats may have augmented serotonergic control of UA dilator muscles as a mechanism to prevent pharyngeal collapse.

Comparison of cervical magnetic and transcutaneous phrenic nerve stimulation before and after threshold loading.

Brief supramaximal stimulation of the phrenic nerves (twitch) is considered a promising technique to detect diaphragmatic fatigue in humans. However, the most commonly employed methodology (transcutaneous stimulation) is technically difficult. Cervical magnetic stimulation is a recently described technique that is potentially simpler and may obviate some of the problems inherent with transcutaneous stimulation. The purpose of this study was to determine the ability of cervical magnetic stimulation to evaluate diaphragmatic function. Accordingly, we measured transdiaphragmatic pressure (Pdi) during transcutaneous and cervical magnetic stimulation of the phrenic nerves before and after a potentially fatiguing task; inspiratory threshold loading to task failure. During threshold loading, subjects generated approximately 60% of their maximal esophageal pressure with each breath until they could no longer reach the target pressure. At least 10 twitches were obtained during both transcutaneous and magnetic stimulation before and 10, 30, 60, and 120 min after threshold loading. Control twitch Pdi was significantly larger during magnetic stimulation compared with transcutaneous stimulation: 39.3 +/- 3.0 (mean +/- SE) versus 27.4 +/- 2.3 cm H2O, p < 0.0005. This increase in twitch Pdi was solely due to the esophageal component. Following threshold loading, a significant reduction in transcutaneous twitch Pdi was seen in only three of the 10 subjects. Mean transcutaneous twitch Pdi fell only slightly from 27.4 +/- 2.3 during control to 25.1 +/- 2.2 cm H2O at 10 min after loading (p < 0.004). In contrast, magnetic twitch Pdi was significantly reduced in nine of the 10 subjects following threshold loading. Mean magnetic twitch Pdi fell from 39.3 +/- 3.0 during control to 31.1 +/- 3.0 cm H2O at 10 min after loading (p < 0.0001). The average fall in twitch Pdi post-loading (expressed as a percentage of the control value) was significantly greater for magnetic stimulation compared with transcutaneous stimulation: 21.0 +/- 3.1 versus 7.8 +/- 2.9%, p < 0.0001. In summary: (1) in the fresh state, twitch Pdi is larger with magnetic stimulation compared with transcutaneous stimulation, and (2) transcutaneous and cervical magnetic twitch Pdi are affected differently by threshold loading to task failure.

Reproducibility of Borg scale measurements of dyspnea during exercise in patients with COPD.

The purpose of this study was to evaluate the moderate term (5 weeks) reproducibility of Borg scale ratings of the effort to breathe (Borge) and the degree of discomfort evoked by breathing (Borgd) in patients with COPD during exercise. Six subjects with moderately severe COPD (FEV1, 1.42 +/- 0.50 L) underwent progressive incremental exercise (15 W/min) on a cycle ergometer to a symptom-limited maximum every week for 6 weeks (first week used as practice session). Minute ventilation (VE), oxygen consumption (VO2), and Borg ratings were obtained every minute during exercise. Borge and Borgd were highly correlated in each subject (r = 0.99 +/- 0.01). Borg scores were not significantly different across study days during both maximal and submaximal exercise. The within-subject coefficient of variation (CV) for Borge during maximal exercise was 13.9 +/- 9.0% (range, 6 to 31%) which was not significantly different from that observed for the physiological indices: 8.2 +/- 4.1% (range, 4 to 15%) for VE and 5.2 +/- 3.4% (range, 1 to 10%) for VO2. In contrast, at 66% of the maximum workload, the within-subject CV for Borge was 25.0 +/- 13.6% (range, 12 to 50%) which was significantly greater than that observed for the physiologic indices: 5.8 +/- 2.0% (range, 3 to 9%) for VE and 4.6 +/- 1.1% (range, 3 to 6%) for VO2. In every subject, Borge was linearly correlated with VE, VO2, and workload. However, within an individual subject, the slope of these relationships varied between trials; within-subject CV for the slope of the Borge/VE relationship was 20.2 +/- 8.0% (range, 12 to 32%). In conclusion, during incremental exercise Borg ratings of dyspnea are not as reproducible as physiologic indices in patients with COPD.

Determination of gas exchange threshold by nonparametric regression.

The gas exchange threshold (GET) has been used an an index of anaerobic threshold because it can be measured noninvasively. GET is estimated from a breakpoint in breath by breath values of carbon dioxide uptake (Vco2) and oxygen uptake (Vo2) obtained during a progressive exercise test. Three methods of estimating GET were evaluated: (1) the original V slope method (OVS) using two adjoining standard linear regressions, (2) the modified V slope method (MVS) where the breakpoint is detected by visual inspection, and (3) a new method that we developed with nonparametric regression (NPM) using cubic splines. Simulated data were used because the existence of a breakpoint is known with certainty. Detection accuracy for OVS and MVS never exceeded 63% because of a low specificity. The detection accuracy of NPM ranged between 50 and 89% depending on the amount of noise and abruptness of the threshold, and exceeded that of OVS and MVS at low levels of noise. NPM was significantly more accurate (p < 0.05) than OVS and MVS for detecting GET except with high levels of noise. Both NPM and OVS have similar degrees of numerical accuracy and are superior to the currently used MVS method in this respect. All three methods gave similar results on 20 exercise tests. We conclude from the simulated data that NPM is more accurate than OVS and MVS at detecting GET. NPM can be applied to human data and it provides results that are consistent with OVS and MVS.

Twitch potentiation following voluntary diaphragmatic contraction.

The purpose of this study was to determine whether twitch potentiation (a transient augmentation of twitch tension following vigorous muscular contraction) occurs in the human diaphragm in vivo. Six healthy subjects were studied. To determine whether twitch potentiation occurs, the subjects attempted to maximally activate their diaphragm by performing the combined Mueller-expulsive maneuver with visual feedback (Pdi max maneuver). Twitches were obtained before, at 10 s after the transdiaphragmatic pressure (Pdi) maneuver, and at intervals over the ensuing 10 min. We also determined whether twitch potentiation would occur following submaximal voluntary diaphragmatic contractions (33 and 66% of Pdi max). In addition, we examined whether repeated voluntary contractions would result in greater twitch potentiation compared with that observed after a single voluntary contraction. Twitch potentiation was observed in every subject. The number of maximal voluntary contractions (MVC) (one, two, or four) had no significant effect on the degree of twitch potentiation. The increase in twitch amplitude (expressed as a percentage of the control value) averaged 63 +/- 35% (SD)(pooled data from one, two, and four contraction trials). Twitch potentiation decayed in a monoexponential fashion (r = 0.99) with a time constant of 125 s (95% Cl = 100 to 160 s). Twitch potentiation was also observed after submaximal voluntary diaphragmatic contractions. Again, the number of voluntary contractions (one or four) had no significant effect on the degree of twitch potentiation. After submaximal diaphragmatic contractions of 66% of Pdi max, the degree of twitch potentiation was not significantly different, 61 +/- 36% (pooled data from one and four contraction trials) from that observed following the maximal voluntary contraction maneuvers.(ABSTRACT TRUNCATED AT 250 WORDS)

Diaphragmatic fatigue after exercise in healthy human subjects.

The purpose of this study was to determine whether diaphragmatic fatigue occurs after high-intensity constant-load whole-body exercise to volitional exhaustion. Ten sedentary subjects with a maximal oxygen uptake of 2.52 +/- 0.47 L/min were studied. Subjects exercised on a bicycle ergometer at 80% of their maximal working capacity until volitional exhaustion. Minute ventilation during the last minute of exercise was 89.9 +/- 13.6 L/min, which represented 50 +/- 6% of the subjects' 12-s maximal voluntary ventilation. During the last minute of exercise, mean inspiratory esophageal pressure was 18.1 +/- 5.3 cm H2O, which represented only 15 +/- 4% of the subjects' maximal static inspiratory pressure. Bilateral transcutaneous supramaximal phrenic nerve stimulation was performed before and 10, 30, 45 and 60 min after exercise. Twitch diaphragmatic pressure (twitch Pdi) was significantly decreased after exercise in seven of the 10 subjects. For the group as a whole, twitch Pdi fell from 28.9 +/- 3.7 cm H2O during control to 23.9 +/- 5.1 cm H2O at 10 min after exercise (p < 0.005). The fall in twitch Pdi was due to a significant decrease in twitch esophageal pressure from 19.6 +/- 4.3 cm H2O during control to 15.5 +/- 4.9 cm H2O (p < 0.001). Twitch gastric pressure was not significantly different: 8.7 +/- 4.0 cm H2O, compared with 9.2 +/- 3.8 cm H2O during control. Twitch Pdi recovered to 93 +/- 7% of control values at 60 min after exercise. The fall in twitch Pdi after exercise indicates that diaphragmatic fatigue can occur following heavy endurance exercise in sedentary healthy persons.