Altered breathing mechanics and ventilatory response during exercise in children born extremely preterm.

BACKGROUND: Extreme preterm birth confers risk of long-term impairments in lung function and exercise capacity. There are limited data on the factors contributing to exercise limitation following extreme preterm birth. This study examined respiratory mechanics and ventilatory response during exercise in a large cohort of children born extremely preterm (EP). METHODS: This cohort study included children 8-12 years of age who were born EP (≤28 weeks gestation) between 1997 and 2004 and treated in a large regionalised neonatal intensive care unit in western Canada. EP children were divided into no/mild bronchopulmonary dysplasia (BPD) (ie, supplementary oxygen or ventilation ceased before 36 weeks gestational age; n=53) and moderate/severe BPD (ie, continued supplementary oxygen or ventilation at 36 weeks gestational age; n=50). Age-matched control children (n=65) were born at full term. All children attempted lung function and cardiopulmonary exercise testing measurements. RESULTS: Compared with control children, EP children had lower airway flows and diffusion capacity but preserved total lung capacity. Children with moderate/severe BPD had evidence of gas trapping relative to other groups. The mean difference in exercise capacity (as measured by oxygen uptake (VO2)% predicted) in children with moderate/severe BPD was -18±5% and -14±5.0% below children with no/mild BPD and control children, respectively. Children with moderate/severe BPD demonstrated a potentiated ventilatory response and greater prevalence of expiratory flow limitation during exercise compared with other groups. Resting lung function did not correlate with exercise capacity. CONCLUSIONS: Expiratory flow limitation and an exaggerated ventilatory response contribute to respiratory limitation to exercise in children born EP with moderate/severe BPD.

AltitudeOmics: exercise-induced supraspinal fatigue is attenuated in healthy humans after acclimatization to high altitude.

AIMS: We asked whether acclimatization to chronic hypoxia (CH) attenuates the level of supraspinal fatigue that is observed after locomotor exercise in acute hypoxia (AH). METHODS: Seven recreationally active participants performed identical bouts of constant-load cycling (131 ± 39 W, 10.1 ± 1.4 min) on three occasions: (i) in normoxia (N, PI O2 , 147.1 mmHg); (ii) in AH (FI O2 , 0.105; PI O2 , 73.8 mmHg); and (iii) after 14 days in CH (5260 m; PI O2 , 75.7 mmHg). Throughout trials, prefrontal-cortex tissue oxygenation and middle cerebral artery blood velocity (MCAV) were assessed using near-infrared-spectroscopy and transcranial Doppler sonography. Pre- and post-exercise twitch responses to femoral nerve stimulation and transcranial magnetic stimulation were obtained to assess neuromuscular and corticospinal function. RESULTS: In AH, prefrontal oxygenation declined at rest (Δ7 ± 5%) and end-exercise (Δ26 ± 13%) (P < 0.01); the degree of deoxygenation in AH was greater than N and CH (P < 0.05). The cerebral O2 delivery index (MCAV × Ca O2 ) was 19 ± 14% lower during the final minute of exercise in AH compared to N (P = 0.013) and 20 ± 12% lower compared to CH (P = 0.040). Maximum voluntary and potentiated twitch force were decreased below baseline after exercise in AH and CH, but not N. Cortical voluntary activation decreased below baseline after exercise in AH (Δ11%, P = 0.014), but not CH (Δ6%, P = 0.174) or N (Δ4%, P = 0.298). A twofold greater increase in motor-evoked potential amplitude was evident after exercise in CH compared to AH and N. CONCLUSION: These data indicate that exacerbated supraspinal fatigue after exercise in AH is attenuated after 14 days of acclimatization to altitude. The reduced development of supraspinal fatigue in CH may have been attributable to increased corticospinal excitability, consequent to an increased cerebral O2 delivery.

Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects.

Twenty-one subjects with asthma underwent treadmill exercise to exhaustion at a workload that elicited approximately 90% of each subject's maximal O2 uptake (EX1). After EX1, 12 subjects experienced significant exercise-induced bronchospasm [(EIB+), %decrease in forced expiratory volume in 1.0 s = -24.0 +/- 11.5%; pulmonary resistance at rest vs. postexercise = 3.2 +/- 1.5 vs. 8.1 +/- 4.5 cmH2O.l(-1).s(-1)] and nine did not (EIB-). The alveolar-to-arterial Po2 difference (A-aDo2) was widened from rest (9.1 +/- 6.7 Torr) to 23.1 +/- 10.4 and 18.1 +/- 9.1 Torr at 35 min after EX1 in subjects with and without EIB, respectively (P < 0.05). Arterial Po2 (PaO2) was reduced in both groups during recovery (EIB+, -16.0 +/- -13.0 Torr vs. baseline; EIB-, -11.0 +/- 9.4 Torr vs. baseline, P < or = 0.05). Forty minutes after EX1, a second exercise bout was completed at maximal O2 uptake. During the second exercise bout, pulmonary resistance decreased to baseline levels in the EIB+ group and the A-aDo2 and PaO2 returned to match the values seen during EX1 in both groups. Sputum histamine (34.6 +/- 25.9 vs. 61.2 +/- 42.0 ng/ml, pre- vs. postexercise) and urinary 9alpha,11beta-prostaglandin F2 (74.5 +/- 38.6 vs. 164.6 +/- 84.2 ng/mmol creatinine, pre- vs. postexercise) were increased after exercise only in the EIB+ group (P < 0.05), and postexercise sputum histamine was significantly correlated with the exercise PaO2 and A-aDo2 in the EIB+ subjects. Thus exercise causes gas-exchange impairment during the postexercise period in asthmatic subjects independent of decreases in forced expiratory flow rates after the exercise; however, a subsequent exercise bout normalizes this impairment secondary in part to a fast acting, robust exercise-induced bronchodilatory response.

Respiratory pattern generator model using Ca++-induced Ca++ release in neurons shows both pacemaker and reciprocal network properties.

There are two contradictory explanations for central respiratory rhythmogenesis. One suggests that respiratory rhythm emerges from interaction between inspiratory and expiratory neural semicenters that inhibit each other and thereby provide reciprocal rhythmic activity (Brown 1914). The other uses bursting pacemaker activity of individual neurons to produce the rhythm (Feldman and Cleland 1982). Hybrid models have been developed to reconcile these two seemingly conflicting mechanisms (Smith et al. 2000; Rybak et al. 2001). Here we report computer simulations that demonstrate a unified mechanism of the two types of oscillator. In the model, we use the interaction of Ca(++)-dependent K+ channels (Mifflin et al. 1985) with Ca(++)-induced Ca++ release from intracellular stores (McPherson and Campbell 1993), which was recently revealed in neurons (Hernandez-Cruz et al. 1997; Mitra and Slaughter 2002a,b; Scornik et al. 2001). Our computations demonstrate that uncoupled neurons with these intracellular mechanisms show conditional pacemaker properties (Butera et al. 1999) when exposed to steady excitatory inputs. Adding weak inhibitory synapses (based on increased K+ conductivity) between two model neural pools surprisingly synchronizes the activity of both neural pools. As inhibitory synaptic connections between the two pools increase from zero to higher values, the model produces first dissociated pacemaker activity of individual neurons, then periodic synchronous bursts of all neurons (inspiratory and expiratory), and finally reciprocal rhythmic activity of the neural pools.

Endogenous excitatory drive to the respiratory system in rapid eye movement sleep in cats.

A putative endogenous excitatory drive to the respiratory system in rapid eye movement (REM) sleep may explain many characteristics of breathing in that state, e.g. its irregularity and variable ventilatory responses to chemical stimuli. This drive is hypothetical, and determinations of its existence and character are complicated by control of the respiratory system by the oscillator and its feedback mechanisms. In the present study, endogenous drive was studied during apnoea caused by mechanical hyperventilation. We reasoned that if there was a REM-dependent drive to the respiratory system, then respiratory activity should emerge out of the background apnoea as a manifestation of the drive. Diaphragmatic muscle or medullary respiratory neuronal activity was studied in five intact, unanaesthetized adult cats who were either mechanically hyperventilated or breathed spontaneously in more than 100 REM sleep periods. Diaphragmatic activity emerged out of a background apnoea caused by mechanical hyperventilation an average of 34 s after the onset of REM sleep. Emergent activity occurred in 60 % of 10 s epochs in REM sleep and the amount of activity per unit time averaged approximately 40 % of eupnoeic activity. The activity occurred in episodes and was poorly related to pontogeniculo-occipital waves. At low CO2 levels, this activity was non-rhythmic. At higher CO2 levels (less than 0.5 % below eupnoeic end-tidal percentage CO2 levels in non-REM (NREM) sleep), activity became rhythmic. Medullary respiratory neurons were recorded in one of the five animals. Nineteen of twenty-seven medullary respiratory neurons were excited in REM sleep during apnoea. Excited neurons included inspiratory, expiratory and phase-spanning neurons. Excitation began about 43 s after the onset of REM sleep. Activity increased from an average of 6 impulses s-1 in NREM sleep to 15.5 impulses s-1 in REM sleep. Neuronal activity was non-rhythmic at low CO2 levels and became rhythmic when levels were less than 0.5 % below eupnoeic end-tidal levels in NREM sleep. The level of CO2 at which rhythmic neuronal activity developed corresponded to eupnoeic end-tidal CO2 levels in REM sleep. These results demonstrate an endogenous excitatory drive to the respiratory system in REM sleep and account for rapid and irregular breathing and the lower set-point to CO2 in that state.

Mu and delta opioid receptor regulation of pro-opiomelanocortin peptide secretion from the rat neurointermediate pituitary in vitro.

We investigated the ability of selective opioid agonists and antagonists to influence pro-opiomelanocortin peptide secretion from the rat neurointermediate lobe in vitro. The mu-opioid agonist DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkephalin) significantly stimulated beta-endorphin and alpha-melanocyte-stimulating hormone release relative to controls early (30 min) in the incubation period. Similar effects on beta-endorphin secretion were observed with the selective mu-opioid agonist dermorphin. The delta-opioid receptor agonist DPDPE ([D-Pen(2,5)]enkephalin) weakly inhibited beta-endorphin secretion relative to controls while the kappa-opioid receptor agonist U50488 had no effect. The mu-opioid selective antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) inhibited basal beta-endorphin secretion while kappa- and delta-opioid receptor antagonists had no effect. Our data support a role for local mu-opioid receptor control of intermediate lobe pro-opiomelanocortin peptide secretion. Peptide secretion from melanotropes appears to be tonically stimulated by activation of mu-opioid receptors in the absence of intact neuronal innervation to the intermediate lobe.

alpha-melanocyte-stimulating hormone and habituation of prey-catching behavior in the Texas toad, Bufo speciosus.

We investigated dose-dependent effects of alpha-melanocyte-stimulating hormone (alpha-MSH) on habituation in the Texas toad, Bufo speciosus. Additionally, we determined changes in plasma and brain levels of alpha-MSH following peripheral administration of the peptide or following exposure to an ether stressor. The ability of alpha-MSH to facilitate acquisition of habituation was dose dependent. Plasma alpha-MSH concentrations were elevated within 5 min of dorsal lymph sac injection and remained elevated up to 600% over controls after 30 min. Administration of 50 microgram alpha-MSH had no effect on plasma corticosterone levels. Radiolabeled alpha-MSH was detected in cerebrospinal fluid microdialysates within minutes of peripheral injection. Concentrations of alpha-MSH in the telencephalon and preoptic area were significantly lowered after ether exposure, whereas levels in the optic tectum, thalamus/hypothalamus, brainstem, and plasma were unchanged. We conclude that alpha-MSH administered peripherally facilitates habituation in a dose-dependent fashion. Our results confirm that the effects of alpha-MSH are independent of corticosterone secretion. The peptide is cleared rapidly into the bloodstream and enters the cerebrospinal fluid after dorsal lymph sac injection. Neuronal alpha-MSH may help toads gather information about their environment when exposed to certain stressors.

Alterations in brain and pituitary beta-endorphin content in genetically epilepsy-prone rats.

We measured beta-endorphin concentrations in the anterior and neurointermediate lobes of the pituitary gland and in microdissected brain regions of moderate-seizure genetically epilepsy-prone rats (GEPR-3), severe-seizure GEPR-9s and Sprague-Dawley non-epileptic control rats. Plasma concentrations of beta-endorphin and beta-melanocyte-stimulating hormone (alpha-MSH) were also measured as indicators of pituitary POMC-peptide secretion. Concentrations of beta-endorphin in the anterior lobe of GEPR-3s were 53% higher compared to controls and 57% higher compared to GEPR-9s. There were no differences in neurointermediate lobe beta-endorphin concentrations between control and either GEPR strain. Plasma beta-endorphin concentrations were significantly lower in GEPR-9s than controls. Plasma levels of alpha-MSH did not differ between control and GEPRs. In the hypothalamus of GEPR-9s beta-endorphin concentrations in the arcuate nucleus were significantly greater than in GEPR-3s. Concentrations of beta-endorphin in the central amygdala of GEPR-9s were two- to threefold greater than in control or GEPR-3s. Beta-Endorphin concentrations in the central gray of GEPR-3s were 58% lower than control or GEPR-9s. These data suggest that anterior lobe beta-endorphin secretion is reduced in GEPR-9s. Furthermore, brain endorphinergic pathways appear to be differentially altered in GEPR-3s and GEPR-9s. Alterations in pituitary beta-endorphin secretion and brain endorphinergic systems may contribute to seizure susceptibility in GEPRs and to differences in seizure severity between GEPR-3s and GEPR-9s.