Respiratory Modulation Research Articles

Motor Unit Recruitment in Human Genioglossus Muscle in Response to Hypercapnia

single motor unit recordings of the genioglossus (GG) muscle indicate that GG motor units have a variety of discharge patterns, including units that have higher discharge rates during inspiration (inspiratory phasic and inspiratory tonic), or expiration (expiratory phasic and expiratory tonic), or do not modify their rate with respiration (tonic). Previous studies have shown that an increase in GG muscle activity is a consequence of increased activity in inspiratory units. However, there are differences between studies as to whether this increase is primarily due to recruitment of new motor units (motor unit recruitment) or to increased discharge rate of already active units (rate coding). Sleep-wake state studies in humans have suggested the former, while hypercapnia experiments in rats have suggested the latter. In this study, we investigated the effect of hypercapnia on GG motor unit activity in humans during wakefulness. sleep research laboratory. sixteen healthy men. each participant was administered at least 6 trials with P(et)CO(2) being elevated 8.4 (SD = 1.96) mm Hg over 2 min following a 30-s baseline. Subjects were instrumented for GG EMG and respiratory measurements with 4 fine wire electrodes inserted subcutaneously into the muscle. One hundred forty-one motor units were identified during the baseline: 47% were inspiratory modulated, 29% expiratory modulated, and 24% showed no respiratory related modulation. Sixty-two new units were recruited during hypercapnia. The distribution of recruited units was significantly different from the baseline distribution, with 84% being inspiratory modulated (P < 0.001). Neither units active during baseline, nor new units recruited during hypercapnia, increased their discharge rate as P(et)CO(2) increased (P > 0.05 for all comparisons). increased GG muscle activity in humans occurs because of recruitment of previously inactive inspiratory modulated units.

Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiac vagal outflow in the rat

BackgroundCardiac vagal preganglionic neurons (CVPN) are responsible for the tonic, reflex and respiratory modulation of heart rate (HR). Although CVPN receive GABAergic and glutamatergic inputs, likely involved in respiratory and reflex modulation of HR respectively, little else is known regarding the functions controlled by ionotropic inputs. Activation of g-protein coupled receptors (GPCR) alters these inputs, but the functional consequence is largely unknown. The present study aimed to delineate how ionotropic GABAergic, glycinergic and glutamatergic inputs contribute to the tonic and reflex control of HR and in particular determine which receptor subtypes were involved. Furthermore, we wished to establish how activation of the 5-HT1A GPCR affects tonic and reflex control of HR and what ionotropic interactions this might involve.ResultsMicroinjection of the GABAA antagonist picrotoxin into CVPN decreased HR but did not affect baroreflex bradycardia. The glycine antagonist strychnine did not alter HR or baroreflex bradycardia. Combined microinjection of the NMDA antagonist, MK801, and AMPA antagonist, CNQX, into CVPN evoked a small bradycardia and abolished baroreflex bradycardia. MK801 attenuated whereas CNQX abolished baroreceptor bradycardia. Control intravenous injections of the 5-HT1A agonist 8-OH-DPAT evoked a small bradycardia and potentiated baroreflex bradycardia. These effects were still observed following microinjection of picrotoxin but not strychnine into CVPN.ConclusionsWe conclude that activation of GABAA receptors set the level of HR whereas AMPA to a greater extent than NMDA receptors elicit baroreflex changes in HR. Furthermore, activation of 5-HT1A receptors evokes bradycardia and enhances baroreflex changes in HR due to interactions with glycinergic neurons involving strychnine receptors. This study provides reference for future studies investigating how diseases alter neurochemical inputs to CVPN.

Effect of baroreceptor stimulation on the respiratory pattern: Insights into respiratory–sympathetic interactions

Sympathetic nerve activity (SNA) is modulated by respiratory activity which indicates the existence of direct interactions between the respiratory and sympathetic networks within the brainstem. Our experimental studies reveal that T(E) prolongation evoked by baroreceptor stimulation varies with respiratory phase and depends on the pons. We speculate that the sympathetic baroreceptor reflex, providing negative feedback from baroreceptors to the rostral ventrolateral medulla and SNA, has two pathways: one direct and independent of the respiratory-sympathetic interactions and the other operating via the respiratory pattern generator and is hence dependent on the respiratory modulation of SNA. Our experimental studies in the perfused in situ rat preparation and complementary computational modelling studies support the hypothesis that baroreceptor activation during expiration prolongs the T(E) via transient activation of post-inspiratory and inhibition of augmenting expiratory neurones of the Bötzinger Complex (BötC). We propose that these BötC neurones are also involved in the respiratory modulation of SNA, and contribute to the respiratory modulation of the sympathetic baroreceptor reflex.

Acute intermittent hypoxia in ratin vivoelicits a robust increase in tonic sympathetic nerve activity that is independent of respiratory drive

Acute intermittent hypoxia (AIH) elicits long-term increases in respiratory and sympathetic outflow (long-term facilitation, LTF). It is still unclear whether sympathetic LTF is totally dependent on changes in respiration, even though respiratory drive modulates sympathetic nerve activity (SNA). In urethane-anaesthetized, vagotomized mechanically ventilated Sprague-Dawley rats, we investigated the effect of ten 45 s episodes of 10% O2-90% N(2) on splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PNA). We then tested whether or not hypoxic sympathetic chemoreceptor and baroreceptor reflexes were changed 60 min after AIH. We found that 17 animals manifested a sustained increase of sSNA (+51.2+/-4.7%) 60 min after AIH, but only 10 of these rats also expressed phrenic LTF compared with the time controls (rats not exposed to hypoxia, n=5). Inspiratory triggered averages of integrated sSNA showed respiratory modulation of SNA regardless of whether or not phrenic LTF had developed. The hypoxic chemoreceptor reflex was enhanced by 60 min after the development of AIH (peak change from 76.9+/-13.9 to 159.5+/-24.9%). Finally, sympathetic baroreceptor reflex sensitivity increased after sympathetic LTF was established (Gainmax from 1.79+/-0.18 to 2.60+/-0.28% mmHg1). Our findings indicate that respiratory-sympathetic coupling does contribute to sympathetic LTF, but that an additional tonic increase of sympathetic tone is also present that is independent of the level of PNA. Sympathetic LTF is not linked to the change in baroreflex function, since the baroreflex appears to be enhanced rather than impaired, but does play an important role in the enhancement of the hypoxic chemoreflex.

An implicit measure of olfactory performance for non-human primates reveals aversive and pleasant odor conditioning

We have little understanding of how odorants are processed in neural networks of the primate brain. Because chemo-stimuli are harder to control than physical stimuli (e.g. vision, audition), such research was limited by the temporal resolution, accuracy, and reliability of olfactometers (odor producing machines). Recent advances were able to create olfactometers that overcome these limitations, allowing their use together with neuroimaging techniques in humans. From the behavioral point of view, olfaction research requires a behavioral measure that can be used to quantify olfactory performance. This becomes a real problem when working with animals, where, unlike humans, explicit measures are harder to obtain. Furthermore, because odorants are powerful primitive reinforcers, such implicit measures can be beneficial to use in learning paradigms. Here we describe an olfactometer suitable for use in non-human primates, and an end-port design that allows the accurate measure of real-time respiratory modulations that are elicited in response to odor presentation. We demonstrate that this implicit measure is differentially modulated when experiencing pleasant or aversive odors. We then present an experimental paradigm in which monkeys learn to associate tones with odors, and show that the time delay from the conditioned stimuli to the next breath can be used to measure learning and memory expression in this paradigm. Using this construct, we reveal olfactory performance during acquisition and extinction of odor conditioning. These techniques can be used in electrophysiological recordings from relevant brain areas to shed light on neural networks involved in odor processing and reinforcement-learning.

Is augmented central respiratory–sympathetic coupling involved in the generation of hypertension?

Respiratory modulation of autonomic neural activity, with consequent phasic alteration of cardiac and vascular function, has been observed in many species including humans and is considered an index of cardiovascular health. Whilst many factors contribute to this modulation, including for example baroreceptor reflex feedback, it is accepted that a significant component is derived from an interaction within the central nervous system. Functional links between the brainstem circuitry generating the respiratory rhythm and neurons responsible for generate sympathetic and parasympathetic activity to the cardiovascular system have long been hypothesized, although the detailed understanding of these interactions is incomplete. There are several proposed physiological functions for these interactions including the matching of ventilation to cardiac output and tissue blood flow. However, recent observations suggest that altered central respiratory coupling may play a role in the development of hypertension and in the maintenance of elevated levels of sympathetic vasomotor activity in disease. The focus of this review article is to discuss these observations and place them within the context of current understanding of the neural substrates that might be responsible for respiratory-sympathetic coupling.

Autonomic and cardiovascular responses to chemoreflex stress in apnoea divers

Sleep apnoea, with repeated periods of hypoxia, results in cardiovascular morbidity and concomitant autonomic dysregulation. Trained apnoea divers also perform prolonged apnoeas accompanied by large lung volumes, large reductions in cardiac output and severe hypoxia and hypercapnia. We tested the hypothesis that apnoea training would be associated with decreased cardiovagal and sympathetic baroreflex gains and reduced respiratory modulation of muscle sympathetic nerve activity (MSNA; microneurography). Six trained divers and six controls were studied at rest and during asphyxic rebreathing. Despite an elevated resting heart rate (70 ± 14 vs. 56 ± 10 bpm; p = 0.038), divers had a similar cardiovagal baroreflex gain (−1.22 ± 0.47 beats/mmHg) as controls (−1.29 ± 0.61; NS). Similarly, though MSNA burst frequency was slightly higher in divers at rest (16 ± 4 bursts/min vs. 10 ± 5 bursts/min, p = 0.03) there was no difference in baseline burst incidence, sympathetic baroreflex gain (−3.8 ± 2.1%/mmHg vs. −4.7 ± 1.7%/mmHg) or respiratory modulation of MSNA between groups. Resting total peripheral resistance (11.9 ± 2.6 vs. 12.3 ± 2.2 mmHg/L/min) and pulse wave velocity (5.82 ± 0.55 vs. 6.10 ± 0.51 m/s) also were similar between divers and controls, respectively. Further, the sympathetic response to asphyxic rebreathing was not different between controls and divers (−1.70 ± 1.07 vs. −1.74 ± 0.84 a.u./% desaturation). Thus, these data suggest that, unlike patients with sleep apnoea, apnoea training in otherwise healthy individuals does not produce detectable autonomic dysregulation or maladaption.

Respiratory modulation of premotor cardiac vagal neurons in the brainstem.

The respiratory and cardiovascular systems are highly intertwined, both anatomically and physiologically. Respiratory and cardiovascular neurons are often co-localized in the same brainstem regions, and this is particularly evident in the ventral medulla which contains presympathetic neurons in the rostral ventrolateral medulla, premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus, and the ventral respiratory group, which includes the pre-Botzinger complex. Anatomical studies of respiratory and cardiovascular neurons have demonstrated that many of these neurons have projections and axon collateral processes which extend into their neighboring cardiorespiratory regions providing an anatomical substrate for cardiorespiratory interactions. As other reports in this Special Issue of Respiratory Physiology & Neurobiology focus on interactions between the respiratory network and baroreceptors, neurons in the nucleus tractus solitarius, presympathetic neurons and sympathetic activity, this report will focus on the respiratory modulation of parasympathetic activity and the neurons that generate parasympathetic activity to the heart, cardiac vagal neurons.

Heritability of abnormalities in cardiopulmonary coupling in sleep apnea: use of an electrocardiogram-based technique.

Studies of the genetics of obstructive sleep apnea may be facilitated by identifying intermediate traits with high heritability that quantify etiological pathways, such as those related to respiratory control. Electrocardiogram (ECG)-based sleep spectrograms, measuring the coupling between respiratory modulation of ECG QRS-wave amplitude and heart rate variability, may provide measures of sleep state and ventilatory dynamics during sleep. We evaluated the familial aggregation of distinctive spectrographic biomarkers of unstable sleep, related to elevated-low frequency cardiopulmonary coupling (e-LFC), to assess their utility in genetic studies. 622 participants from 137 families from the Cleveland Family Study underwent standardized polysomnography (PSG). From the ECG signal on the PSG, the interbeat interval time series and the corresponding ECG-derived respiratory signal were extracted, and the low frequency (0.01-0.1 Hz) component of their coupling was computed using a fully automated method. Narrow sense heritability of e-LFC was calculated using variance component methods. A spectral marker of abnormal low frequency cardiopulmonary coupling (e-LFC) demonstrated moderate correlation with apnea hypopnea index (AHI; r = 0.35, P < 0.0001). The heritability estimate for e-LFC, after adjusting for age and sex was 0.32 (P < 10-5) and remained unchanged after additionally adjusting for body mass index or AHI. In biological relatives of those with sleep apnea, a related marker of e-LFC was more prevalent than in controls (P = 0.05). Approximately 30% of the variability of e-LFC, measured from a continuous ECG during sleep, is explained by familial factors other than BMI. ECG-based spectrographic measures of cardiopulmonary coupling may provide novel phenotypes for characterizing subgroups of individuals with different propensities and genetic etiologies for sleep apnea or for other conditions associated with sleep fragmentation.

Respiratory and Mayer wave-related discharge patterns of raphé and pontine neurons change with vagotomy

Previous models have attributed changes in respiratory modulation of pontine neurons after vagotomy to a loss of pulmonary stretch receptor "gating" of an efference copy of inspiratory drive. Recently, our group confirmed that pontine neurons change firing patterns and become more respiratory modulated after vagotomy, although average peak and mean firing rates of the sample did not increase (Dick et al., J Physiol 586: 4265-4282, 2008). Because raphé neurons are also elements of the brain stem respiratory network, we tested the hypotheses that after vagotomy raphé neurons have increased respiratory modulation and that alterations in their firing patterns are similar to those seen for pontine neurons during withheld lung inflation. Raphé and pontine neurons were recorded simultaneously before and after vagotomy in decerebrated cats. Before vagotomy, 14% of 95 raphé neurons had increased activity during single respiratory cycles prolonged by withholding lung inflation; 13% exhibited decreased activity. After vagotomy, the average index of respiratory modulation (eta(2)) increased (0.05 +/- 0.10 to 0.12 +/- 0.18 SD; Student's paired t-test, P < 0.01). Time series and frequency domain analyses identified pontine and raphé neuron firing rate modulations with a 0.1-Hz rhythm coherent with blood pressure Mayer waves. These "Mayer wave-related oscillations" (MWROs) were coupled with central respiratory drive and became synchronized with the central respiratory rhythm after vagotomy (7 of 10 animals). Cross-correlation analysis identified functional connectivity in 52 of 360 pairs of neurons with MWROs. Collectively, the results suggest that a distributed network participates in the generation of MWROs and in the coordination of respiratory and vasomotor rhythms.

Elevated sympathetic activity precedes the arterial hypertension in the Goldblatt model

Despite the extensive use of the Goldblatt model of hypertension (two kidney one clip, 2K1C) sympathetic mechanisms responsible for both the development and maintenance of the elevated blood pressure remain unclear. We tested the hypothesis that sympathetic nerve activity (SNA) is elevated by the third week after clipping and before development of hypertension. Using the in situ working heart brainstem preparation, male Wistar rats were divided into three groups: Sham (n=7), and 2K1C (3 weeks) of which some were hypertensive (2K1C‐H, n=6) or and others normotensive (2K1C‐N, n=9) as determined a priori. At comparable perfusion rates, pressures were higher in both 2K1C groups (2K1C‐H: 76 ± 1; 2K1C‐N: 74 ± 3 vs Sham: 60 ± 2 mmHg, p&lt; 0.05). The respiratory modulation of SNA was significantly elevated in both 2K‐1C groups (e.g. 2K1C‐H: 47.7 ± 6.1; 2K1C‐N: 32.8 ± 2.8 vs Sham: 20.5 ± 2.5 μV, p&lt; 0.05). Pre‐collicular transection reduced SNA in all rat groups (2K1C‐H: 32.5 ± 7.5, 2K1C‐NH: 48 ± 6.9 vs Sham: 13.2 ± 1%, p&lt; 0.05). Subsequent transection at the medullary‐spinal cord abolished SNA in Sham and 2K1C‐N but decreased it by 57± 5.5% in 2K1C‐H. We conclude, SNA can be raised prior to onset of hypertension by the 3rd week after clipping and this, in part, originates from enhanced respiratory modulation. Supported by CAPES and British Heart Foundation.

Increased intrinsic excitability of muscle vasoconstrictor sympathetic preganglionic neurones in neonatal spontaneously hypertensive rats

Young, spontaneously hypertensive (SH) rats show an increased level of sympathetic activity that predates the development of hypertension (Simms et al 2009 J Physiol).We have examined the properties of muscle vasoconstrictor sympathetic preganglionic neurones (MVC‐SPN) in neonatal SH and Wistar rats. Whole‐cell recordings were obtained from SPN (Wistar n=169, SH n=76; aged p9–14) in T3–4 segment of the working heart‐brainstem preparation.SPN of SH rats showed a higher firing frequency (1.7 vs 3.0Hz) and smaller AHP amplitude. When analysed by functional subgroup it was apparent that these difference were secondary to changes in the excitability of MVC‐SPN. These showed significantly higher firing frequencies (2.2 vs 3.5Hz) with increased respiratory modulation. Additionally, the SH MVC‐SPN had shorter, smaller AHPs, lower input resistances and a weaker transient rectification (IA).Voltage clamp analysis of spontaneous excitatory synaptic events in MVC‐SPN showed similar frequencies and amplitudes of EPSCs. There was a modest preponderance of large EPSCs in SH rats (&gt;30pA, &lt;0.3Hz) which alone did not account for the increased spike discharge.In summary, the MVC SPN of neonatal SH rats are intrinsically more excitable. These changes occur prior to, and may play a causal role in, the development of hypertension.

Assessment of vasomotor oscillations with Fourier analysis of biological tissue impedance

Fourier analysis revealed a number of periodicities in small variations of bioimpedance of human finger including the major spectrum peaks at the frequencies of heart beats, respiration, and Mayer wave (0.1 Hz). These periodic variations of bioimpedance were detected under the normal conditions and during blood flow arrest in the hand by a pneumatic cuff placed on the arm. They are explained by periodic variations in systemic blood pressure and by oscillations of regional vascular tone resulted from neural vasomotor control. During normal blood flow, the greatest variations in bioimpedance were observed at the heart rate, and their amplitude surpassed by an order of magnitude the amplitudes of respiratory oscillations and Mayer wave. In contrast, during blood arrest, the largest amplitude of rhythmical changes of the impedance characterized the oscillations at respiration rate, while the amplitude of oscillations at the heart rate was the smallest. During normal respiration and circulation, two side cardiac peaks were revealed in bioimpedance amplitude spectrum which disappeared during respiration arrest and thought to reflect the amplitude respiratory modulation of the cardiac output via sympathetic influences. During normal breathing, the second and the third harmonics of the cardiac spectrum peak were split reflecting frequency respiratory modulation of the heart rate by parasympathetic influences. The results favour applicability of Fourier analysis of bioimpedance variations in assessment of regional neural influences and neurogenic modulation of cardiac activity.

Central CO2chemoreception in cardiorespiratory control

Central CO₂chemoreception in cardiorespiratory control

Erratum to: A Numerical Model of the Respiratory Modulation of Pulmonary Shunt and PaO2 Oscillations for Acute Lung Injury

Erratum to: A Numerical Model of the Respiratory Modulation of Pulmonary Shunt and PaO2 Oscillations for Acute Lung Injury

Investigating fractal property and respiratory modulation of human heartbeat time series using empirical mode decomposition

The human heartbeat interval reflects a complicated composition with different underlying modulations and the reactions against environmental inputs. As a result, the human heartbeat interval is a complex time series and its complexity can be scaled using various physical quantifications, such as the property of long-term correlation in detrended fluctuation analysis (DFA). Recently, empirical mode decomposition (EMD) has been shown to be a dyadic filter bank resembling those involved in wavelet decomposition. Moreover, the hierarchy of the extracted modes may be exploited for getting access to the Hurst exponent, which also reflects the property of long-term correlation for a stochastic time series. In this paper, we present significant findings for the dynamic properties of human heartbeat time series by EMD. According to our results, EMD provides a more accurate access to long-term correlation than Hurst exponent does. Moreover, the first intrinsic mode function (IMF 1) is an indicator of orderliness, which reflects the modulation of respiratory sinus arrhythmia (RSA) for healthy subjects or performs a characteristic component similar to that decomposed from a stochastic time series for subjects with congestive heart failure (CHF) and atrial fibrillation (AF). In addition, the averaged amplitude of IMF 1 acts as a parameter of RSA modulation, which reflects significantly negative correlation with aging. These findings lead us to a better understanding of the cardiac system.

Pulse wave analysis during instructed breathing as an indicator of significant coronary artery disease

Previous studies indicated that fluctuations in photoplethysmograph (PPG) amplitude may predict coronary artery disease (CAD). The respiratory modulation response (RMR) is derived from spectral analysis of the PPG signal during instructed breathing. We sought to evaluate the RMR obtained from the fingertip as a predictor of significant CAD. RMR was calculated as the relative change in the respiratory modulation of the PPG, in response to breathing at 0.1Hz. RMR results of 97 consecutive patients (age 62+/-12 years, 77% male) were compared with their angiograms. Coronary lesions with diameter stenosis >50% that required revascularisation were classified significant. RMR was analysed after 20 sec. of spontaneous breathing, followed by 70 sec. of breathing at 0.1Hz. The test was repeated post procedure in 76 patients. RMR was lower in patients with significant CAD compared to those with non-significant (16.3+/-20.1; n=66 vs. 40.6+/-16.9; n=31, P<0.001). It improved after successful angioplasty (from 15.0+/-19.0 to 40.0+/-18.9; P<0.001) and did not change after diagnostic catheterisation. Using receiver operating characteristic analysis, we identified RMR<30% (sensitivity 79%, specificity 87%; positive predictive value 93%; negative predictive value 66%) to be the optimal cutoff for predicting significant CAD. The RMR is a novel, non-invasive parameter for the assessment of significant CAD.

Central CO2 chemoreception and integrated neural mechanisms of cardiovascular and respiratory control

In this review, we examine why blood pressure (BP) and sympathetic nerve activity (SNA) increase during a rise in central nervous system (CNS) P(CO(2)) (central chemoreceptor stimulation). CNS acidification modifies SNA by two classes of mechanisms. The first one depends on the activation of the central respiratory controller (CRG) and causes the much-emphasized respiratory modulation of the SNA. The CRG probably modulates SNA at several brain stem or spinal locations, but the most important site of interaction seems to be the caudal ventrolateral medulla (CVLM), where unidentified components of the CRG periodically gate the baroreflex. CNS P(CO(2)) also influences sympathetic tone in a CRG-independent manner, and we propose that this process operates differently according to the level of CNS P(CO(2)). In normocapnia and indeed even below the ventilatory recruitment threshold, CNS P(CO(2)) exerts a tonic concentration-dependent excitatory effect on SNA that is plausibly mediated by specialized brain stem chemoreceptors such as the retrotrapezoid nucleus. Abnormally high levels of P(CO(2)) cause an aversive interoceptive awareness in awake individuals and trigger arousal from sleep. These alerting responses presumably activate wake-promoting and/or stress-related pathways such as the orexinergic, noradrenergic, and serotonergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have brainwide projections that contribute to the CO(2)-induced rise in breathing and SNA by facilitating neuronal activity at innumerable CNS locations. In the case of SNA, these sites include the nucleus of the solitary tract, the ventrolateral medulla, and the preganglionic neurons.

Acute temperature resistance threshold in heart mitochondria: Febrile temperature activates function but exceeding it collapses the membrane barrier

Purpose: Molecular mechanisms underlying hyperthermia-induced cellular injury are not fully understood. The aim of this study was to identify the components of mitochondrial oxidative phosphorylation affected by mild hyperthermia and to quantify the contribution of each component to changes in system behaviour.Methods: Temperature effects on the oxidative phosphorylation in isolated rat-heart mitochondria were assessed using modular kinetic analysis. Mitochondrial H2O2 production and lipid peroxidation were measured for estimation of temperature-induced oxidative damage.Results: The increase of temperature in the febrile range (40°C) slightly activated mitochondrial function through stimulation of the respiratory module, without affecting the kinetics of the proton leak and phosphorylation modules. At 42°C, state 3 respiration rate remained unchanged, the proton leak across the inner mitochondrial membrane was substantially increased, the respiratory module slightly inhibited, leading to decreased membrane potential (Δψ) and diminished ATP synthesis (16% lower phosphorylation flux). Increase of temperature above 42°C caused dissipation of Δψ and abolishment of ATP synthesis indicating complete uncoupling of oxidative phosphorylation. The changes in mitochondrial functions induced by incubation at 42°C were completely reversible in contrast to only partial recovery after incubation at higher temperature (45°C). Furthermore, hyperthermia stimulated the production of H2O2 and membrane lipid peroxidation with maximal rates observed at 40°C.Conclusions: We demonstrated for the first time that febrile temperature (40°C) activates mitochondrial energy supplying functions, whereas further temperature increase by only a few degrees leads to severe impairment of mitochondrial ability to maintain ΔΨ and synthesise ATP.

A Numerical Model of the Respiratory Modulation of Pulmonary Shunt and PaO2 Oscillations for Acute Lung Injury

It is an accepted hypothesis that the amplitude of the respiratory-related oscillations of arterial partial pressure of oxygen (DeltaPaO2) is primarily modulated by fluctuations of pulmonary shunt (Deltas), the latter generated mainly by cyclic alveolar collapse/reopening, when present. A better understanding of the relationship between DeltaPaO2, Deltas, and cyclic alveolar collapse/reopening can have clinical relevance for minimizing the severe lung damage that the latter can cause, for example during mechanical ventilation (MV) of patients with acute lung injury (ALI). To this aim, we numerically simulated the effect of such a relationship on an animal model of ALI under MV, using a combination of a model of lung gas exchange during tidal ventilation with a model of time dependence of shunt on alveolar collapse/opening. The results showed that: (a) the model could adequately replicate published experimental results regarding the complex dependence of DeltaPaO2 on respiratory frequency, driving pressure (DeltaP), and positive end-expiratory pressure (PEEP), while simpler models could not; (b) such a replication strongly depends on the value of the model parameters, especially of the speed of alveolar collapse/reopening; (c) the relationship between DeltaPaO2 and Deltas was overall markedly nonlinear, but approximately linear for PEEP>or=6 cmH2O, with very large DeltaPaO2 associated with relatively small Deltas.