Potentiation of exercise ventilatory response by airway CO2 and dead space loading.

We examined the effects of different modes of airway CO2 load on the ventilation-CO2 output (VE-VCO2) relationship during mild to moderate exercise. Four young and three older male subjects underwent incremental steady-state treadmill exercise while breathing a mixture of CO2 in O2 (CO2 loading) or 100% O2 with and without a large external dead space [DS loading and control (C), respectively]. During DS loading, the elevated arterial PCO2 (PaCO2) remained constant from rest to mild exercise and began to increase only at higher work rates. To achieve similar chemical drive, the same PaCO2 levels were established during CO2 loading by external PCO2 forcing. In the young group, CO2 loading resulted in a steepening of the VE-VCO2 relationship compared with C, whereas in the older group the reverse pattern was found. DS loading resulted in a consistent increase in the VE-VCO2 slope compared with C and CO2 loading [39.1 +/- 5.6 (mean +/- SD) vs. 24.9 +/- 5.0 and 26.7 +/- 4.4, respectively] in all subjects. The difference in potentiation of VE-VCO2 by CO2 and DS loading was not due to differences in mean chemical drive or changes in breathing pattern. Thus changes in the profile of airway CO2 influx may have an independent influence on ventilatory CO2-exercise interaction. Peripheral chemoreceptors mediation, although important, is not obligatory for this behavior.


Parenchymal stability.

Both continuum and micromechanical models have been used to describe the mechanics of lung parenchyma. Different authors, using different models, have come to different conclusions about parenchymal stability. We show that the continuum model, augmented by bounds on the elastic moduli obtained from recent micromechanical modeling, yields the same conclusions about stability that have been obtained from purely micromechanical modeling: if the lung were homogeneous, it would be stable; local atelectasis would not occur at positive transpulmonary pressure. However, the same analysis yields the prediction that if the surface-to-volume ratio is not uniform throughout the lung, regions of higher surface density collapse if surface tension is large and insensitive to surface area. A micromechanical model that illustrates regional collapse is described.


Acute and chronic pulmonary vasoconstriction after left lung autotransplantation in conscious dogs.

We investigated the acute and chronic effects of left lung autotransplantation (LLA) on the left pulmonary vascular pressure-flow (LP/Q) relationship in conscious dogs. Continuous LP/Q plots were generated in chronically instrumented conscious dogs 2 days, 2 wk, 1 mo, and 2 mo after LLA. Identically instrumented normal conscious dogs were studied at equal time points post-surgery. LLA had little or no effect on baseline systemic hemodynamics or blood gases. In contrast, compared with normal conscious dogs, striking active flow-independent pulmonary vasoconstriction was observed 2 days post-LLA. The slope of the LP/Q relationship was increased from a normal value of 0.275 +/- 0.021 to 0.699 +/- 0.137 mmHg.ml-1.min-1.kg-1 2 days post-LLA. Pulmonary vasoconstriction of similar magnitude was also observed on a chronic basis at 2 wk, 1 mo, and even 2 mo post-LLA. Pulmonary vasoconstriction post-LLA was not due to fixed resistance at the left pulmonary arterial or venous anastomotic sites. Finally, systemic arterial blood gases were unchanged when total pulmonary blood flow was directed to exclusively perfuse the transplanted left lung. Thus, LLA results in both acute and chronic pulmonary vasoconstriction in conscious dogs. LLA should serve as a useful stable experimental model to assess the specific effects of surgical transplantation on pulmonary vascular regulation.


Effects of acute oligohydramnios on respiratory system of fetal sheep.

Prolonged oligohydramnios, or a lack of amniotic fluid, is associated with pulmonary hypoplasia and subsequent perinatal morbidity, but it is unclear whether short-term or acute oligohydramnios has any effect on the fetal respiratory system. To investigate the acute effects of removal of amniotic fluid, we studied nine chronically catheterized fetal sheep at 122-127 days gestation. During a control period, we measured the volume of fluid in the fetal potential airways and air spaces (VL), production rate of that fluid, incidence and amplitude of fetal breathing movements, tracheal pressures, and fetal plasma concentrations of cortisol, epinephrine, and norepinephrine. We then drained the amniotic fluid for a short period of time [24-48 h, 30.0 +/- 4.0 (SE) h] and repeated the above measurements. The volume of fluid drained for the initial studies was 1,004 +/- 236 ml. Acute oligohydramnios decreased VL from 35.4 +/- 2.9 ml/kg during control to 22.0 +/- 1.6 after oligohydramnios (P less than 0.004). Acute oligohydramnios did not affect the fetal lung fluid production rate, fetal breathing movements, or any of the other measured variables. Seven repeat studies were performed in six of the fetuses after reaccumulation of the amniotic fluid at 130-138 days, and in four of these studies the lung volume also decreased, although the overall mean for the repeat studies was not significantly different (27.0 +/- 5.2 ml/kg for control vs. 25.5 +/- 5.5 ml/kg for oligohydramnios). Again, none of the other measured variables were altered by oligohydramnios in the repeat studies.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of thromboxane synthase inhibition on tumor necrosis factor-induced lung injury in sheep.

To examine the role of thromboxane (Tx) A2 in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we tested the effects of OKY-046, a selective thromboxane synthase inhibitor, on pulmonary hemodynamics, lung lymph balance, circulating leukocytes, arterial blood gas analysis, and TxA2 (as TxB2) and prostacyclin (as 6-keto-prostaglandin F1 alpha) levels in plasma and lung lymph after TNF infusion in awake sheep. Infusion of human recombinant TNF (3.5 micrograms/kg) into a chronically instrumented awake sheep caused a transient increase in pulmonary arterial pressure (Ppa). The Ppa peaked within 15 min of the start of TNF infusion from 23.3 +/- 1.1 (SE) cmH2O of baseline to 42.3 +/- 2.3 cmH2O and then decreased toward baseline. The pulmonary hypertension was accompanied by transient hypoxemia, peripheral leukopenia, and the increases in TxB2 in plasma and lung lymph. These changes were followed by an increase in flow of protein-rich lung lymph, consistent with an increase in pulmonary microvascular permeability. OKY-046 significantly prevented the rises of Ppa and TxB2 concentrations in plasma and lung lymph during early phase after TNF infusion. OKY-046, however, did not attenuate the increase of lung lymph flow, transient hypoxemia, and leukopenia. From these data, and by comparison with our previous studies of OKY-046-pretreated sheep during endotoxemia, we conclude that TxA2 has an important role of the increase in the early pulmonary hypertension, but it is not related to the early hypoxemia, leukopenia, and lung lymph balances in TNF-induced lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)


NANC nerve pathways controlling mucus glycoconjugate secretion into feline trachea.

We used autonomic-blocking drugs to define nonadrenergic noncholinergic (NANC) vagus nerve pathways regulating tracheal mucus secretion. In anesthetized cats, mucus glycoconjugates, radiolabeled biosynthetically with [35S]sulfate and [3H]glucose, were washed from a tracheal segment in situ and dialyzed before scintillation counting and chemical assay with periodic acid-Schiff (PAS). Without autonomic blockade, vagal stimulation (9.5 Hz, 10 V, 2-ms pulse width, 10-min duration) increased outputs of radiolabeled and PAS-reactive glycoconjugates repeatably over four stimulation periods. In other animals, vagus nerves were stimulated with administration of autonomic blockers between stimulations. The first stimulation (no blockers) increased glycoconjugate output (delta 35S = 221 +/- 43.3%, delta 3H = 58 +/- 13.8%; delta PAS = +299 +/- 82.7%). Atropine, phentolamine, and propranolol reduced these responses (delta 35S = 67 +/- 15.6%; delta 3H = 26 +/- 5.3%; delta PAS = 88 +/- 25.6%). Guanethidine did not significantly lessen them further, although delta 3H was no longer significant. Ganglion blockade with hexamethonium prevented most of the remaining response to vagal stimulation (P less than 0.05 for diminution of delta 35S and delta PAS), but small effects persisted (delta 35S = 17 +/- 5.6%; delta PAS = 20 +/- 6.8%; P less than 0.05). We conclude that the main NANC vagal pathway controlling tracheal glycoconjugate secretion runs orthodromically.


Variation and limitations in fiber enzymatic and size responses in hypertrophied muscle.

The present study was designed to determine whether the degree and kind of adaptation of a muscle fiber to a functional overload (FO) are determined by properties that are intrinsic to that fiber. The study also addresses the question of the capability of fibers to maintain a normal level of coordination of proteins per fiber as fiber volume changes dramatically. The plantaris muscle of six adult female cats was overloaded for 12 wk by bilateral synergist removal. Plantaris muscle fiber mean size doubled after FO, although some very small fibers that stained dark for adenosinetriphosphatase (ATPase) were observed in some of the FO muscles. There appeared to be no change in total succinate dehydrogenase activity per fiber. A reduction in succinate dehydrogenase activity per unit volume was observed in a substantial number of fibers, reflecting a disproportionate increase in fiber volume relative to mitochondrial volume. In contrast, total alpha-glycerophosphate dehydrogenase activity and actomyosin ATPase activity increased as fiber size increased, whereas there was no change in alpha-glycerophosphate dehydrogenase and ATPase activities per unit volume. Control and FO muscle fibers generally expressed either a fast or slow myosin heavy chain type, but in some cases FO muscle fibers expressed both fast and slow myosin heavy chains. The persistence of variability in fiber sizes and enzyme activities in fibers of overloaded muscles suggests a wide range in the adaptive potential of individual fibers to FO. These data indicate that a severalfold increase in cell size may occur without significant qualitative changes in the coordination of protein regulation associated with metabolic pathways and ATP utilization.


Upper airway anesthesia delays arousal from airway occlusion induced during human NREM sleep.

Six healthy subjects (5 males and 1 female, 26-40 yr old) were studied during non-rapid-eye-movement (NREM) sleep to assess the role of upper airway (UA) afferents in the arousal response to induced airway occlusion. Subjects wore an airtight face mask attached to a low-resistance one-way valve. A valve in the inspiratory circuit allowed instantaneous inspiratory airway occlusion and release; the expiratory circuit remained unoccluded at all times. Each subject was studied during two nights. On one night, occlusions were created during stable stage 2 NREM sleep before and after application of 4% lidocaine to the oral and nasal mucosa. On the other night, the protocol was duplicated with saline ("sham anesthesia") rather than lidocaine. The order of nights was randomized. Occlusions were sustained until electroencephalographic arousal. Three to 12 occlusions were performed in each subject for each of the four parts of the protocol (pre- and post-lidocaine, pre- and post-saline). The auditory threshold for arousal (1,500-Hz tone beginning at 30 dB) was also tested before and after UA lidocaine. For the group, arousal time after UA anesthesia was prolonged compared with preanesthesia arousal time (P less than 0.001); arousal time after sham anesthesia did not significantly increase from before sham anesthesia (P = 0.9). The increase in arousal time with UA anesthesia was greater than the increase with sham anesthesia (P less than 0.001). The auditory arousal threshold did not increase after UA anesthesia. Inspiratory mask pressure, arterial O2 saturation of hemoglobin, and end-tidal PCO2 during occlusions were similar before and after UA anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)


Contrasting effects of prostaglandins E2 and F2 alpha on sensitivity of the human cough reflex.

Prostaglandins have been shown to influence the sensitivity of the cough reflex. To investigate putative mechanisms of this, we examined the effects of inhaled prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) on human cough responses elicited by two challenges, low chloride solution and capsaicin, which may activate different neural pathways. Baseline cough challenges were followed after 2 h by five breaths of PGE2, PGF2 alpha, or citric acid as a control. Cough challenges were repeated after 1 min. Potentiation of capsaicin responses occurred after PGE2 (median increase 2 coughs/min, range 0-7, P less than 0.01) and PGF2 alpha (median increase 8 coughs/min, range -3 to 27, P less than 0.01) compared with control. The effect of PGF2 alpha was greater (P less than 0.05) than that of PGE2. Potentiation of low chloride responses also occurred after PGF2 alpha (median increase 7 coughs/2 min, range -1 to 19, P less than 0.01), but effects of PGE2 were insignificant against this challenge (median change -1 coughs/2 min, range -4 to 13). These data suggest that PGE2 and PGF2 alpha have different effects on the sensitivity of the human cough reflex, which may be relevant during airway disease.


Increased venous pressure causes increased thoracic duct pressure in awake sheep.

The lymph from most organs drains through the thoracic duct and into veins in the neck. We hypothesized that increases in neck vein pressure (Pnv) are reflected through the thoracic duct to the lung lymphatic-thoracic duct junction. To test this, we cannulated the lung lymphatics in the direction of flow in four sheep. We advanced each cannula until it entered the thoracic duct. Thus the pressure at the tip of the lymphatic cannula (Px) was the pressure at the outflow of the lung lymphatics. We also placed a balloon into the superior vena cava. One to two days later, we measured Px in the awake sheep as we inflated the balloon and increased Pnv in steps to 25-45 cmH2O. We found no significant differences in Px and Pnv. Furthermore, Px closely followed Pnv after each step increase in Pnv. These results support our hypothesis that increases in Pnv cause increases in the outflow pressure to lung lymphatics.


Short-duration spaceflight impairs human carotid baroreceptor-cardiac reflex responses.

Orthostatic intolerance is a predictable but poorly understood consequence of space travel. Because arterial baroreceptors modulate abrupt pressure transients, we tested the hypothesis that spaceflight impairs baroreflex mechanisms. We studied vagally mediated carotid baroreceptor-cardiac reflex responses (provoked by neck pressure changes) in the supine position and heart rate and blood pressure in the supine and standing positions in 16 astronauts before and after 4- to 5-day Space Shuttle missions. On landing day, resting R-R intervals and standard deviations, and the slope, range, and position of operational points on the carotid transmural pressure-sinus node response relation were all reduced relative to preflight. Stand tests on landing day revealed two separate groups (one maintained standing arterial pressure better) that were separated by preflight slopes, operational points, and supine and standing R-R intervals and by preflight-to-postflight changes in standing pressures, body weights, and operational points. Our results suggest that short-duration spaceflight leads to significant reductions in vagal control of the sinus node that may contribute to, but do not account completely for, orthostatic intolerance.


Failure of pulmonary acidosis to increase respiratory drive.

Experiments were performed to determine whether increases in acidity isolated to the pulmonary circulation would stimulate hypothesized pulmonary chemoreceptors and increase respiratory drive in the anesthetized paralyzed mechanically ventilated cat (n = 9). Respiratory drive was assessed by measuring the frequency and amplitude of the integrated phrenic neurogram. To create an isolated pulmonary acidosis, blood returning to the lung was acidified by infusion of 0.3 M lactic acid (1.91 ml/min) into the inferior vena cava, while systemic arterial pH was restored to near normal levels by simultaneous infusion of base (0.3 M NaOH) into the left atrium. Six minutes after the start of this dual infusion of acid and base, right ventricular (pulmonary) pH decreased from 7.286 to 7.179 and PCO2 increased 7 Torr. Systemic arterial pH and PCO2 were unchanged from measurements immediately before the infusion. This level of pulmonary acidosis failed to increase respiratory drive as assessed by phrenic activity. To test the sensitivity of the preparation to known systemic arterial chemical stimuli, a combined pulmonary and systemic acidosis was elicited by infusion of 0.3 M lactic acid into the inferior vena cava and 0.3 M NaCl into the left atrium. This infusion significantly lowered both systemic arterial and pulmonary arterial pH (7.343 to 7.155 for systemic arterial pH and 7.286 to 7.067 for pulmonary pH) and increased phrenic efferent activity 45%. We conclude that phrenic efferent activity is unaffected by moderate reductions in the pH of the pulmonary circulation in the absence of a significant systemic arterial acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)


PEEP is necessary for exogenous surfactant to reduce pulmonary edema in canine aspiration pneumonitis.

Alveolar edema inactivates surfactant, and surfactant depletion causes edema by reducing lung interstitial pressure (Pis). We reasoned that surfactant repletion might reduce edema by raising Pis after acute lung injury and that positive end-expiratory pressure (PEEP) might facilitate this effect. One hour after tracheal administration of hydrochloric acid in 18 anesthetized dogs with transmural pulmonary capillary wedge pressure of 8 Torr, the animals were randomized into three groups: in the SURF + PEEP group, 50 mg/kg of calf lung surfactant extract (CLSE) was instilled into each main stem bronchus with 8 cmH2O of PEEP; in the SAL + PEEP group, PEEP was followed by an equal volume of saline (SAL); in the SURF group, CLSE was given without PEEP. After 5 h, edema in excised lungs (wet-to-dry weight ratios) was significantly less in the SURF + PEEP group (9.1 +/- 1.0) than in the other groups (11.3 +/- 1.8 and 11.3 +/- 1.8, respectively). In the SURF + PEEP group, pulmonary venous admixture fell by 6%; this change was different from the 7% increase in the SAL + PEEP group and 40% increase in the SURF group (P less than 0.05). Airway secretions obtained in the SURF + PEEP group had normal minimum surface tensions of 4 +/- 2 mN/m, a value much lower than in SAL + PEEP and SURF groups (32 +/- 4 and 22 +/- 7 mN/m, respectively). We conclude that surfactant normalizes surface tension and decreases transcapillary hydrostatic forces in this lung injury model, thereby reducing edema formation and improving gas exchange. These benefits occur only if surfactant is given with PEEP, allowing surfactant access to the alveoli and/or minimizing its inhibition by edema proteins.


Oxygen radical scavengers protect against eosinophil-induced injury in isolated perfused rat lungs.

The protective effect of oxygen radical scavengers on lung injury induced by activated eosinophils was examined in isolated perfused rat lungs. Eosinophils were obtained by bronchoalveolar lavage from rats infected with Toxocara canis and activated with phorbol myristate acetate (PMA). There were no changes in pulmonary vascular (RT) and airway (Raw) resistances and only minimal changes in vascular permeability assessed using the capillary filtration coefficient (Kf,c) in PMA control lungs and nonactivated eosinophil-treated lungs. In lungs receiving 3 x 10(6) PMA-activated eosinophils, there were significant increases from baseline of 7.3-fold in RT at 30 min, primarily due to the constriction of small arteries and veins; 3.6-fold in Kf,c at 90 and 130 min; and 2.5-fold in Raw. The lungs also became markedly edematous. Both superoxide dismutase and catalase pretreatment prevented the significant increase in Kf,c and lung wet-to-dry weight ratios and partially attenuated the increase in Raw, but did not significantly inhibit the increase in RT induced by activated eosinophils. Heat-inactivated catalase did not attenuate the eosinophil-induced increases in Kf,c, Raw, or RT. Thus, activated eosinophils acutely increased microvascular permeability primarily through production of oxygen free radicals. The free radical scavengers superoxide dismutase and catalase partially attenuated the bronchoconstriction but had no significant effect on the vasoconstriction induced by activated eosinophils.


Role of neutrophil elastase in allergen-induced lysozyme secretion in the dog trachea.

To test our hypothesis that neutrophil elastase plays a role in airway hypersecretion associated with the allergic late-phase response, using an isolated tracheal segment system in vivo and measuring lysozyme activity in the perfusate of the lumen as a marker of submucosal gland secretion over 8 h, we studied the response of five allergic dogs to ragweed. The dogs were exposed on separate occasions to specific allergen, to allergen vehicle, and to allergen in the presence of a selective neutrophil elastase inhibitor, ICI 200,355. Allergen exposure caused a marked increase in lysozyme secretion that was significantly increased at 4, 6, and 8 h compared with controls and ICI 200,355-treated dogs. Neutrophil elastase appeared in the perfusate after allergen exposure and was positively correlated with lysozyme secretion at 8 h. These findings suggest that neutrophil elastase plays an important role as a secretagogue in the allergic late-phase response.


Reductions of neural activities to upper airway muscles after elevations in static lung volume.

We evaluated the hypothesis that the tonic discharge of pulmonary stretch receptors significantly influences the respiratory-modulated activities of cranial nerves. Decerebrate and paralyzed cats were ventilated with a servo-respirator, which produced changes in lung volume in parallel with integrated phrenic activity. Activities of the facial, hypoglossal, and recurrent laryngeal nerves and nerves to the thyroarytenoid muscle and triangularis sterni were recorded. After a stereotyped pattern of lung inflation, tracheal pressure was held at 1, 2, 4, or 6 cmH2O during the subsequent ventilatory cycle. Increases in tracheal pressure caused progressive reductions in both inspiratory and expiratory cranial nerve activities and progressive elevations in triangularis sterni discharge; peak levels of phrenic activity declined modestly. Similar changes were observed in normocapnia and hypercapnia. We conclude that the tonic discharge of pulmonary stretch receptors is an important determinant of the presence and magnitude of respiratory-modulated cranial nerve activity. This reflex mechanism may maintain upper airway patency and also regulate expiratory airflow.


Acute and long-term TNF-alpha administration increases pulmonary vascular reactivity in isolated rat lungs.

Tumor necrosis factor-alpha (TNF-alpha) causes pulmonary hypertension and arterial hypoxemia, but the mechanisms are unknown. We conducted two experiments to test the hypothesis that TNF-alpha alters pulmonary vascular reactivity, which in turn could cause either pulmonary hypertension or arterial hypoxemia. In experiment 1, rats were given acute or long-term injections of TNF-alpha (recombinant human) in vivo. Rats treated acutely received either saline or TNF-alpha (40 micrograms/kg iv in saline) 3 min (TNF-3 min; n = 8), 20 min (TNF-20 min; n = 8), or 24 h (TNF-24 h; n = 5) before the lungs were isolated. Rats treated chronically received injections of either saline or TNF-alpha (250 micrograms/kg ip in saline) two times per day for 7 days (TNF-7 days; n = 9). Lungs were isolated and perfused with Earle's salt solution (+2 g/l NaHCO3 + 4 g/100 ml Ficoll), and vascular reactivity was tested with acute hypoxia (3 min; 3% O2) and angiotensin II (ANG II; 0.025-0.40 micrograms). Pulmonary pressor responses to hypoxia were greater (P less than 0.05) in TNF-20 min and TNF-7 day groups. ANG II responses were increased (P less than 0.05) in TNF-7 day rats. In experiment 2, lungs were isolated and perfused and received direct pulmonary arterial injections of TNF-alpha (0.2, 2.0, and 20 micrograms) or saline, after stable responses to hypoxia and ANG II (0.10 microgram) were attained. Reactivity was not different between control and TNF-alpha rats before the injections, but TNF-alpha increased (P less than 0.05) responses to hypoxia and ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of regular voluntary exercise on resting cardiovascular responses in SHR and WKY pregnant rats.

The purpose of this study was to assess the influence of regular voluntary exercise in pregnant normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats on 1) uteroplacental perfusion and mean arterial pressure in the resting conscious condition and 2) fetal number, fetal weight, and number of fetal resorptions. WKYs and SHRs were randomly assigned to standard cages [CWKY (n = 10); CSHR (n = 6)] or cages with activity wheels [EWKY (n = 7); ESHR (n = 8)]. EWKYs and ESHRs exercised for 12 wk, and then all rats were bred and experiments were conducted on gestational day 17. Resting blood flow (microspheres), heart rate (HR), and mean arterial pressure (Pa) were measured. No significant difference was found in Pa, HR, uterine blood flow (ESHRs 52 +/- 8 ml.min-1.100 g-1; CSHRs 28 +/- 6 ml.min-1.100 g-1), or maternal placental blood flow (ESHRs, 122 +/- 31 ml.min-1.100 g-1; CSHRs 78 +/- 21 ml.min-1.100 g-1) among the groups. Exercise altered the relationship between maternal placental and uterine blood flow and Pa in the SHR; SHRs with lower Pa maintained higher placental and uterine blood flow after training. Before gestation ESHRs ran on average more kilometers per week than EWKYs (43 +/- 3 vs. 34 +/- 4), but during gestation ESHRs averaged fewer kilometers per week than EWKYs (16 +/- 4 vs. 22 +/- 4). Succinate dehydrogenase activity was higher in the white vastus lateralis (1.02 +/- 0.2 mumol cytochrome c reduced.min-1.g wet wt-1) and vastus intermedius (3.1 +/- 0.5 mumol cytochrome c reduced.min-1.g wet wt-1) muscles of ESHRs.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of O2 in regulating tissue respiration in dog muscle working in situ.

This study was designed to investigate the role of tissue oxygenation in some of the factors that are thought to regulate muscle respiration and metabolism. Tissue oxygenation was altered by reductions in O2 delivery (muscle blood flow x arterial O2 content), induced by decreases in arterial PO2 (PaO2). O2 uptake (VO2) was measured in isolated in situ canine gastrocnemius at rest and while working at two stimulation intensities (isometric tetanic contractions at 0.5 and 1 contractions/s) on three separate occasions, with only the level of PaO2 (78, 30, and 21 Torr) being different for each occasion. Muscle blood flow was held constant (pump perfusion) at each work intensity for the three different levels of PaO2. Muscle biopsies were obtained at the end of each rest and work period. Muscle VO2 was significantly less (P less than 0.05) at both stimulation intensities for the hypoxemic conditions, whereas [ATP] was reduced only during the highest work intensity during both hypoxemic conditions (31% reduction at 21 Torr PaO2 and 17% at 30 Torr). For each level of PaO2, the relationships between the changes that occurred in VO2 and levels of phosphocreatine, ADP, and ATP/ADP.P(i) as the stimulation intensity was increased were significantly correlated; however, the slopes and intercepts of these lines were significantly different for each PaO2. Thus a greater change in any of the proposed regulators of tissue respiration (e.g., phosphocreatine, ADP) was required to achieve a given VO2 as PaO2 was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)


Modeling the effects of hypoxia on ATP turnover in exercising muscle.

Most models of metabolic control concentrate on the regulation of ATP production and largely ignore the regulation of ATP demand. We describe a model, based on the results of Hogan et al. (J. Appl. Physiol. 73: 728-736, 1992), that incorporates the effects of ATP demand. The model is developed from the premise that a unique set of intracellular conditions can be measured at each level of ATP turnover and that this relationship is best described by energetic state. Current concepts suggest that cells are capable of maintaining oxygen consumption in the face of declines in the concentration of oxygen through compensatory changes in cellular metabolites. We show that these compensatory changes can cause significant declines in ATP demand and result in a decline in oxygen consumption and ATP turnover. Furthermore we find that hypoxia does not directly affect the rate of anaerobic ATP synthesis and associated lactate production. Rather, lactate production appears to be related to energetic state, whatever the PO2. The model is used to describe the interaction between ATP demand and ATP supply in determining final ATP turnover.


Autoresuscitation: a survival mechanism in piglets.

Piglets were studied to determine 1) the cardiovascular and neurophysiological effects of prolonged laryngeal-induced respiratory inhibition (n = 7) and 2) whether these effects were modulated by autonomic blockade (n = 6). Respiration, electrocardiogram, electroencephalogram (EEG), and blood pressure were recorded, and blood gases were measured. During continuous laryngeal stimulation in the presence of light anesthesia, apnea was interrupted every 1-2.5 min by clusters of two to six breaths. Compared with control, these breaths had a significantly greater tidal volume (430 +/- 30% of control), shorter inspiratory time (87 +/- 5%), and longer expiratory time (124 +/- 15%) and, thus, were of a gasping nature. With each cluster of gasps, arterial PO2 increased from 15 +/- 2 to 56 +/- 5 Torr, heart rate from 84 +/- 7 to 161 +/- 5 beats/min, and mean blood pressure from 48 +/- 4 to 106 +/- 6 mmHg. The EEG became flat by 1 min after the onset of apnea and remained isoelectric throughout the stimulus period. Cyclical gasps were not affected by sympathetic or parasympathetic blockade. These data show that, despite EEG silence, piglets can autoresuscitate by initiating gasps that are not dependent on autonomic integrity. These gasps markedly improve cardiovascular status and may sustain animals for a prolonged period of time.


24-hour homeodynamic states of arterial blood pressure and pulse interval in conscious rats.

In models that describe the homeostasis of the circulation, arterial blood pressure is usually expressed as a single value, which is regarded as the set point in such systems. The aim of the study was to identify in rats from 24-h beat-to-beat recordings the value of blood pressure that describes best such a set point of the cardiovascular system. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), kept on a 12:12-h lights on-off cycle, were instrumented for computerized 24-h beat-to-beat recording of mean arterial pressure (MAP) and pulse interval (PI). Three-dimensional frequency distributions were constructed by plotting for each beat its MAP vs. its PI. During the dark period, the concurrent distribution of MAP and PI showed two distinct modes while during the light period a single mode was found. Comparable patterns were found in SHRs and WKYs. These three different modes were significantly different from the mathematically calculated mean values of MAP and PI over these periods. Thus in rats the 24-h behavior of the cardiovascular system is better described by dynamic shifts between different modes (homeodynamic states) than by a single set point.


Pharyngeal dilation associated with cricothyroid muscle contraction in dogs.

The mechanical function of phasic respiratory-related activity of the cricothyroid muscle of the larynx is poorly understood. We studied five adult cross-bred dogs (weight 14-20 kg) deeply anesthetized with pentobarbitone sodium, mechanically ventilated via a tracheostomy, and placed prone with the mouth open. Bilateral cricothyroid muscle contraction was induced by supramaximal electrical stimulation of the external branches of the superior laryngeal nerve. Computerized axial tomography was used to assess effects of cricothyroid muscle contraction. During cricothyroid muscle contraction, oropharyngeal (tip of epiglottis) cross-sectional area increased by 18.0 +/- 3.0% (SE) (P = 0.008), whereas combined left and right piriform recess cross-sectional area increased by 85 +/- 25% (n = 4; P = 0.02) at the midepiglottic level and by 152 +/- 37% (P = 0.01) at the base of the epiglottis. Furthermore, at the base of the epiglottis the maximum horizontal distance between the alae of the thyroid cartilage increased by 21 +/- 8% (P = 0.05). In contrast, lateral glottic diameter decreased by 52 +/- 2% (n = 4; P = 0.01), whereas dorsoventral glottic diameter increased by 18 +/- 5% (n = 4; P less than 0.02). The cricothyroid muscle, therefore, has the capacity to act simultaneously as a pharyngeal dilator and a glottic constrictor and thus may play a role in the control of oropharyngeal as well as laryngeal patency.


Protein requirements and muscle mass/strength changes during intensive training in novice bodybuilders.

This randomized double-blind cross-over study assessed protein (PRO) requirements during the early stages of intensive bodybuilding training and determined whether supplemental PRO intake (PROIN) enhanced muscle mass/strength gains. Twelve men [22.4 +/- 2.4 (SD) yr] received an isoenergetic PRO (total PROIN 2.62 g.kg-1.day-1) or carbohydrate (CHO; total PROIN 1.35 g.kg-1.day-1) supplement for 1 mo each during intensive (1.5 h/day, 6 days/wk) weight training. On the basis of 3-day nitrogen balance (NBAL) measurements after 3.5 wk on each treatment (8.9 +/- 4.2 and -3.4 +/- 1.9 g N/day, respectively), the PROIN necessary for zero NBAL (requirement) was 1.4-1.5 g.kg-1.day-1. The recommended intake (requirement + 2 SD) was 1.6-1.7 g.kg-1.day-1. However, strength (voluntary and electrically evoked) and muscle mass [density, creatinine excretion, muscle area (computer axial tomography scan), and biceps N content] gains were not different between diet treatments. These data indicate that, during the early stages of intensive bodybuilding training, PRO needs are approximately 100% greater than current recommendations but that PROIN increases from 1.35 to 2.62 g.kg-1.day-1 do not enhance muscle mass/strength gains, at least during the 1st mo of training. Whether differential gains would occur with longer training remains to be determined.


Expression of muscle capillary alkaline phosphatase is affected by hypoxia.

Hypoxia stimulates angiogenesis in some microvascular beds, but no clear angiogenic effect of hypoxia has yet been demonstrated in adult skeletal muscle. In this study the distribution of alkaline phosphatase (APase) was compared with a novel microvascular marker, Griffonia simplicifolia I (GSI), to determine whether the respective markers were expressed by muscle capillaries during hypoxic conditions and to probe for the presence or absence of angiogenesis in response to short-term hypoxia. Mice were exposed to normobaric 8% oxygen for 7 or 21 days. Capillary density in the red and white areas of the gastrocnemius muscle was determined with the use of a double-labeling procedure for both APase and fluorescently tagged GSI. Little change in capillary density was found. Focal reductions in APase activity were observed within 1 wk of hypoxia, but no changes were observed in GSI binding. In controls, 74 and 92% of red and white muscle capillaries, respectively, were APase positive. This percentage declined to 60% in red and 43% in white muscle after 21 days of hypoxia. The results indicate that APase expression is labile under certain conditions and warrant a cautious approach to using the enzyme as a marker. Binding of the GSI lectin to muscle capillaries appeared to be unchanged by the exposure to hypoxia, indicating stability of this marker system. No significant change in the number of capillaries around individual muscle fibers was evident at 21 days when GSI was used to detect capillaries. These results confirm the absence of hypoxia-induced angiogenesis in muscle capillaries during the time period studied.


Modification of bronchial reactivity by physiological concentrations of plasma epinephrine.

Circulating epinephrine concentrations are altered in certain pathophysiological states, but whether such changes in epinephrine concentrations can alter bronchial responsiveness in subjects with asthma has not been studied. We studied 10 subjects with asthma in a double-blind crossover study on 4 nonconsecutive days. After measurement of baseline forced expiratory volume in 1 s (FEV1) and plasma epinephrine concentration, subjects were given placebo or 4, 16, or 64 ng.kg-1.min-1 epinephrine by intravenous infusion for 45 min. Blood was taken for plasma epinephrine concentration before the infusion and at 30 min, when a histamine challenge test was performed. Mean plasma epinephrine concentrations ranged from 0.37 nmol/l on placebo to 3.76 nmol/l with the 64-ng/kg infusion. FEV1 increased progressively with increasing concentrations of infused epinephrine, the mean change ranging from -0.051 on placebo to 0.331 after the highest concentration of epinephrine. The provocative dose of histamine causing a 20% fall in FEV1 increased progressively with increasing concentrations of infused epinephrine, geometric mean values ranging from 0.61 mumol with placebo to 1.7 mumol after the highest dose of epinephrine. Thus epinephrine, at physiological plasma concentrations, can modify bronchial reactivity.


Endotoxin tolerance is associated with altered GTP-binding protein function.

Previous studies have suggested that guanine nucleotide regulatory (G) proteins modulate endotoxin-stimulated peritoneal macrophage arachidonic acid (AA) metabolism. Endotoxin-stimulated metabolism of AA by peritoneal macrophages is decreased in endotoxin tolerance (Rogers et al. Prostaglandins 31: 639-650, 1986). These observations led to a study of G protein function and AA metabolism by peritoneal macrophages in endotoxin tolerance. Endotoxin tolerance was induced by the administration of sublethal doses of endotoxin. AA metabolism was assessed by measurement of thromboxane B2 (TxB2), a cyclooxygenase metabolite. NaF (5 mM), an activator of G proteins, significantly stimulated TxB2 synthesis in control macrophages from 7.7 +/- 0.2 to 19.1 +/- 0.6 (SE) ng/ml (P less than 0.05) at 2 h and was partially inhibited by pertussis toxin, suggesting a G protein-dependent mechanism. Salmonella enteritidis endotoxin (50 micrograms/ml) stimulated a similar increase in TxB2 levels (23 +/- 0.4 ng/ml, P less than 0.05). In contrast to control macrophages, macrophages from endotoxin-tolerant rats stimulated with either NaF or S. enteritidis endotoxin had TxB2 levels that were only 30 and 2% of the respective stimulated control cells. Basal guanosine-triphosphatase (GTPase) activity (33 +/- 6 pmol.mg-1.min-1) in endotoxin-tolerant macrophage membranes was significantly lower (P less than 0.05) than control basal activity (158 +/- 5 pmol.mg-1.min-1). This suppression of macrophage GTPase activity was apparent 48 h after the first in vivo sublethal endotoxin injection (100 micrograms/kg ip). The reduced GTPase activity paralleled in vitro cellular hyporesponsiveness to endotoxin-stimulated TxB2 production.(ABSTRACT TRUNCATED AT 250 WORDS)


Coordination of wingbeat and respiration in the Canada goose. I. Passive wing flapping.

The effects of passive wing flapping on respiratory pattern were examined in decerebrate Canada geese. The birds were suspended dorsally with two spine clamps while the extended wings were continuously moved up and down with a device designed to reproduce actual wing flapping. Passive wing motion entrained respiration over limited ranges by both increasing and decreasing the respiratory period relative to rest. All ratios of wingbeat frequency to respiratory frequency seen during free flight (Soc. Neurosci. Abstr. 15: 391, 1989) were produced during passive wing flapping. In addition, the phase relationship between wingbeat frequency and respiratory frequency, inspiration starting near the peak of wing upstroke, was similar to that seen during free flight and was unaffected by perturbations of the wing-flapping cycle. Removal of all afferent activity from the wings did not affect the ability of continuous passive wing movement to entrain respiration. However, feedback from the wings was required to produce rapid within-breath shifts in the respiratory period in response to single wing flaps. In conclusion, although feedback from the chest wall/lung may be more important in producing entrainment during the stable conditions of passive wing flapping, wing-related feedback may be critically involved in mediating the rapid adjustments in respiratory pattern required to maintain coordination between wing and respiratory movements during free flight.


Coordination of wingbeat and respiration in birds. II. "Fictive" flight.

To determine whether an interaction between central respiratory and locomotor networks may be involved in the observed coordination of wingbeat and respiratory rhythms during free flight in birds, we examined the relationship between wingbeat and respiratory activity in decerebrate Canada geese and Pekin ducks before and after paralysis. Locomotor activity was induced through electrical stimulation of brain stem locomotor regions. Respiratory frequency (fv) was monitored via pneumotachography and intercostal electromyogram recordings before paralysis and via intercostal and cranial nerve IX electroneurogram recordings after paralysis. Wingbeat frequency (fW) was monitored using pectoralis major electromyogram recordings before, and electroneurogram recordings after, paralysis. Respiratory and cardiovascular responses of decerebrate birds during active (nonparalyzed) and "fictive" (paralyzed) wing activity were qualitatively similar to those of a variety of vertebrate species to exercise. As seen during free flight, wingbeat and respiratory rhythms were always coordinated during electrically induced wing activity. Before paralysis during active wing flapping, coupling ratios (fW/fv) of 1:1, 2:1, 3:1, and 4:1 (wingbeats per breath) were observed. After paralysis, fW and fv remained coupled; however, 1:1 coordination predominated. All animals tested (n = 9) showed 1:1 coordination. Two animals also showed brief periods of 2:1 coupling. It is clear that locomotor and respiratory networks interact on a central level to produce a synchronized output. The observation that the coordination between fW and fv differs in paralyzed and nonparalyzed birds suggests that peripheral feedback is involved in the modulation of a centrally derived coordination.


Graphite-like lubrication of mesothelium by oligolamellar pleural surfactant.

Six studies have been completed to reevaluate pleural surfactant as a possible boundary lubricant in mesothelial sliding. It is capable of remarkable antiwear action, giving a mean scar diameter on a standard "four-ball test" comparable to the best commercially available lubricants and reducing friction to values anticipated from lamellated solid lubricants such as graphite. Pleural surfaces displayed appreciable hydrophobicity, which was almost eliminated by rinsing with a lipid solvent from which phospholipid was recovered and quantified. These quantities indicated that equivalent of 7.3 adsorbed monolayers of surface-active phospholipid, which was in general agreement with the number of layers of a graphite-like surface coating visualized by electron microscopy by use of a novel fixation procedure that avoids conventional aldehydes known to destroy hydrophobic surfaces. Graphite-like (dry) lubrication by adsorbed surface-active phospholipid is discussed as an excellent lubrication system available wherever the distribution of fluid allows the pleura to make contact.


Lung and chest wall impedances in the dog in normal range of breathing: effects of pulmonary edema.

We evaluated the effect of pulmonary edema on the frequency (f) and tidal volume (VT) dependences of respiratory system mechanical properties in the normal ranges of breathing. We measured resistance and elastance of the lungs (RL and EL) and chest wall of four anesthetized-paralyzed dogs during sinusoidal volume oscillations at the trachea (50-300 ml, 0.2-2 Hz), delivered at a constant mean airway pressure. Measurements were made before and after severe pulmonary edema was produced by injection of 0.06 ml/kg oleic acid into the right atrium. Chest wall properties were not changed by the injection. Before oleic acid, EL increased slightly with increasing f in each dog but was independent of VT. RL decreased slightly and was independent of VT from 0.2 to 0.4 Hz, but above 0.4 Hz it tended to increase with increasing flow, presumably due to the airway contribution. After oleic acid injection, EL and RL increased greatly. Large negative dependences of EL on VT and of RL on f were also evident, so that EL and RL after oleic acid changed two- and fivefold, respectively, within the ranges of f and VT studied. We conclude that severe pulmonary edema changes lung properties so as to make behavior VT dependent (i.e., nonlinear) and very frequency dependent in the normal range of breathing.


Respiration and measurement of cardiac output by thermodilution and central or peripheral dye dilution.

Cardiac output as measured by indicator dilution methods during artificial ventilation shows differences up to +/- 35%. We studied the influence of spontaneous breathing on measurement of cardiac output by thermodilution (TD) and central (CDD) and peripheral dye dilution (PDD) in seven anesthetized dogs. Injection of indicator was timed at one of five chosen moments in a respiratory cycle. The indicator for TD was also used as solvent for indocyanine green. Results were normalized by the value obtained with injection at inspiratory onset. Results of the central dilution methods showed a slight but not significant difference between values measured with injection at 25 and 75% of the respiratory cycle: 105.7 and 98.0%, respectively, (TD) and 102.3 and 97.2% (CDD). Mean cardiac output determined by TD, CDD, or PDD was not significantly different. We conclude that 1) a reasonable estimate of cardiac output may be obtained by means of a single indicator-dilution curve and 2) the choice of the dilution method may be determined by practical considerations.


Entrainment of respiratory rhythm to respiratory oscillations of arterial PCO2 in vagotomized dogs.

The aim of this study was to demonstrate that the medullary respiratory rhythm generator is capable of entraining to respiratory oscillations of arterial PCO2 (CO2 oscillations). We used 10 anesthetized, paralyzed, vagotomized, and mechanically ventilated dogs. First, rate of mechanical ventilation was manually adjusted so that it matched the dog's spontaneous respiratory rate, which established a constant phase relationship between the mechanical ventilation and the burst of phrenic neurogram (initial phase). Then this phase relationship was temporally disturbed by a brief electrical stimulation of the superior laryngeal nerve (SLN). In the control group, the initial phase and the steady-state phase relationship after SLN stimulation were randomly distributed within the phase plane, implying no interaction between the respiratory center and mechanical ventilation. In contrast, when CO2 output from the lung was increased 2.6-fold above the control level by venous CO2 loading, the initial phase and the steady-state phase after SLN stimulation were locked in such a way that the onset of the burst of phrenic neurogram coincided with the peak of CO2 oscillations. This was not demonstrated when the dog was made hyperoxic. We therefore conclude that the respiratory center could entrain to phasic chemical afferent inputs originating from CO2 oscillations, provided they are considerably amplified.


Influences of NREM sleep on the activity of tonic vs. inspiratory phasic muscles in normal men.

Studies of sleep influences on human pharyngeal and other respiratory muscles suggest that the activity of these muscles may be affected by non-rapid-eye-movement (NREM) sleep in a nonuniform manner. This variable sleep response may relate to the pattern of activation of the muscle (inspiratory phasic vs. tonic) and peripheral events occurring in the airway. Furthermore, the ability of these muscles to respond to respiratory stimuli during NREM sleep may also differ. To systematically investigate the effect of NREM sleep on respiratory muscle activity, we studied two tonic muscles [tensor palatini (TP), masseter (M)] and two inspiratory phasic ones [genioglossus (GG), diaphragm (D)], also measuring the response of these muscles to inspiratory resistive loading (12 cmH2O.l-1.s) during wakefulness and NREM sleep. Seven normal male subjects were studied on a single night with intramuscular electrodes placed in the TP and GG and surface electrodes placed over the D and M. Sleep stage, inspiratory airflow, and moving time average electromyograph (EMG) of the above four muscles were continuously recorded. The EMG of both tonic muscles fell significantly (P less than 0.05) during NREM sleep [TP awake, 4.3 +/- 0.05 (SE) arbitrary units, stage 2, 1.1 +/- 0.2; stage 3/4, 1.0 +/- 0.2. Masseter awake, 4.8 +/- 0.6; stage 2, 3.3 +/- 0.5; stage 3/4, 3.1 +/- 0.5]. On the other hand, the peak phasic EMG of both inspiratory phasic muscles (GG and D) was well maintained.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of training on muscle O2 transport at VO2max.

To quantify the relative contributions of convective and peripheral diffusive components of O2 transport to the increase in leg O2 uptake (VO2leg) at maximum O2 uptake (VO2max) after 9 wk of endurance training, 12 sedentary subjects (age 21.8 +/- 3.4 yr, VO2max 36.9 +/- 5.9 ml.min-1.kg-1) were studied. VO2max, leg blood flow (Qleg), and arterial and femoral venous PO2, and thus VO2leg, were measured while the subjects breathed room air, 15% O2, and 12% O2. The sequence of the three inspirates was balanced. After training, VO2max and VO2leg increased at each inspired O2 concentration [FIO2; mean over the 3 FIO2 values 25.2 +/- 17.8 and 36.5 +/- 33% (SD), respectively]. Before training, VO2leg and mean capillary PO2 were linearly related through the origin during hypoxia but not during room air breathing, suggesting that, at 21% O2, VO2max was not limited by O2 supply. After training, VO2leg and mean capillary PO2 at each FIO2 fell along a straight line with zero intercept, just as in athletes (Roca et al. J. Appl. Physiol. 67: 291-299, 1989). Calculated muscle O2 diffusing capacity (DO2) rose 34% while Qleg increased 19%. The relatively greater rise in DO2 increased the DO2/Qleg, which led to 9.9% greater O2 extraction. By numerical analysis, the increase in Qleg alone (constant DO2) would have raised VO2leg by 35 ml/min (mean), but that of DO2 (constant Qleg) would have increased VO2leg by 85 ml/min, more than twice as much. The sum of these individual effects (120 ml/min) was less (P = 0.013) than the observed rise of 164 ml/min (mean). This synergism (explained by the increase in DO2/Qleg) seems to be an important contribution to increases in VO2max with training.


Periodic hemodynamics in skeletal muscle during local arterial pressure reduction.

The time-dependent features of red blood cell flow were evaluated with laser-Doppler flowmetry (LDF) in the left gastrocnemius muscle of 31 anesthetized New Zealand White rabbits during stepwise arterial occlusion. During the control period with a median femoral pressure of 72 mmHg, 29 animals showed minor irregular fluctuations in LDF blood flow, and only two animals displayed periodic variations of blood flow. Lowering femoral arterial pressure induced maximal periodic blood flow variations at a median pressure of 35 mmHg in all animals with a median frequency of 1.5 cycles/min (termed "slow-wave flow motion"). The median amplitude was 48% of the corresponding average flow. These slow waves disappeared at a median femoral pressure of 20 mmHg. The median LDF flow value was 4.00 arbitrary units (AU) at control pressure and 2.05 AU at maximum slow-wave flow motion. When slow-wave flow motion was seen at several pressure levels, their frequency was identical, which supports the local pacemaker concept. This study promotes a novel concept for the role and physiological significance of periodic hemodynamics in that it is a condition not characteristic for normal control situations but is activated below a specific local arterial blood pressure and flow threshold, which is known to be the lower end of autoregulation in the microcirculation of rabbit skeletal muscle. This also suggests that slow-wave flow motion is primarily under local control mechanisms.


PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats.

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)


A peptidergic component to vagally induced tracheal vasodilation in the dog.

The purpose of the study was to determine the extent that peptidergic afferent and efferent pathways contribute to vagally induced vasodilation in the trachea of the dog. The change in vascular resistance of the tracheal branch of the cranial thyroid artery and the trachealis responses were determined in 28 anesthetized, paralyzed, and mechanically ventilated dogs. After propranolol (2 mg/kg) and phentolamine (1.5 mg/kg), stimulation of the superior laryngeal nerves (NS; 15 Hz, 7 V, 2 ms, 30 s) caused a decrease in vascular resistance of 11.7 +/- 0.8% and a tracheal contraction of 5.2 +/- 4.7 cmH2O. Atropine (1.5 mg/kg) reduced the fall in vascular resistance to 4.7 +/- 0.8% (P less than 0.01), whereas tracheal contraction was abolished. Thiorphan (1.5 mg), a neutral endopeptidase inhibitor, augmented the decrease in vascular resistance (8.8 +/- 0.6%; P less than 0.01) to NS. After hexamethonium (0.5 mg/kg), NS still caused a small decrease in TVR (2.9 +/- 0.9%; P less than 0.05), which was abolished by capsaicin. In atropinized dogs, capsaicin reduced the fall in vascular resistance after NS; the residual vasodilation was virtually abolished by hexamethonium. Acetylcholine (10(-3) mg/kg) decreased vascular resistance (15.7 +/- 3.0%), and the effect was abolished by atropine. We conclude that there is noncholinergic nonadrenergic vagally induced tracheal vasodilation that is peptidergic. The peptidergic vasodilation appears to be mediated by both afferent and efferent pathways.


Neutral endopeptidase inhibitor potentiates endothelin-1-induced airway smooth muscle contraction.

To study the role of neutral endopeptidase (NEP) on endothelin-1-induced contraction of the airway smooth muscle, we examined the contractile effect of endothelin-1 in the isolated guinea pig trachea and human bronchus in the presence or absence of NEP inhibitor phosphoramidon. After incubation with phosphoramidon (10(-8) to 10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the airway tissues in organ baths. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in a concentration-dependent fashion in both guinea pig trachea and human bronchus, and it shifted the concentration-response curves to the left. Because NEP is known to cleave tachykinins, we next studied whether endothelin-1 contracts airway tissues by releasing endogenous tachykinins from bronchial C-fibers. After incubation with phosphoramidon (10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the tissues that were treated with capsaicin to deplete the tachykinins. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in the capsaicin-treated tissues, suggesting that endothelin-1 causes the contraction, at least in part, without releasing tachykinins. In contrast to the effect of phosphoramidon, captopril (an angiotensin-converting enzyme inhibitor), leupeptin (a serine protease inhibitor), and bestatin (an aminopeptidase inhibitor) did not modulate the effect of endothelin-1-induced contraction in both guinea pig trachea and human bronchus. From these results, we conclude that NEP plays an important role in regulating endothelin-1-induced contraction in the guinea pig trachea and human bronchus.


Relationship between body and leg VO2 during maximal cycle ergometry.

It is not known whether the asymptotic behavior of whole body O2 consumption (VO2) at maximal work rates (WR) is explained by similar behavior of VO2 in the exercising legs. To resolve this question, simultaneous measurements of body and leg VO2 were made at submaximal and maximal levels of effort breathing normoxic and hypoxic gases in seven trained male cyclists (maximal VO2, 64.7 +/- 2.7 ml O2.min-1.kg-1), each of whom demonstrated a reproducible VO2-WR asymptote during fatiguing incremental cycle ergometry. Left leg blood flow was measured by constant-infusion thermodilution, and total leg VO2 was calculated as the product of twice leg flow and radial arterial-femoral venous O2 concentration difference. The VO2-WR relationships determined at submaximal WR's were extrapolated to maximal WR as a basis for assessing the body and leg VO2 responses. The differences between measured and extrapolated maximal VO2 were 235 +/- 45 (body) and 203 +/- 70 (leg) ml O2/min (not significantly different). Plateauing of leg VO2 was associated with, and explained by, plateauing of both leg blood flow and O2 extraction and hence of leg VO2. We conclude that the asymptotic behavior of whole body VO2 at maximal WRs is a direct reflection of the VO2 profile at the exercising legs.


Bronchomotor vagal preganglionic cell bodies in the dog: an anatomic and functional study.

A previous study in our laboratory demonstrated that the stimulation with microinjection of DL-homocysteic acid of cell bodies in the rostral portion of the external formation of the nucleus ambiguus (Aext) increased total lung resistance in dogs. In the present study anatomic experiments were conducted in dogs to determine if the rostral Aext contains vagal preganglionic cell bodies that give rise to axons in the pulmonary branches of the vagus nerve. The application of horseradish peroxidase (HRP) to either the pulmonary branches or the vagus at a point between the pulmonary branches and the cardiac branches resulted in retrograde labeling of cell bodies in both rostral Aext and the dorsal motor nucleus of the vagus (DMN). On the other hand, application of HRP to the vagus at a point below the pulmonary branches did not result in any retrogradely labeled cell bodies in rostral Aext but did result in labeled cell bodies in DMN. In another series of experiments DL-homocysteic acid (2.5 nmol in 25 nl) was microinjected at sites in rostral Aext and DMN. As we previously reported the injection of DL-homocysteic acid in rostral Aext increased total lung resistance. In contrast, in the same animals, the injection of DL-homocysteic acid in DMN did not change total lung resistance. We conclude that bronchomotor vagal preganglionic cell bodies are located in rostral Aext but not in DMN. The functional significance of vagal preganglionic cell bodies in DMN whose axons contribute to the pulmonary branches of the vagus nerve remains to be determined.


Accumulated oxygen deficit increases with inclination of uphill running.

This study examined whether accumulated oxygen deficit depends on treadmill grade during uphill running. Oxygen uptake was measured during steady-state submaximal running. By linear extrapolation at each grade, energy demand was estimated for short exhaustive runs. Oxygen deficit was the difference between this estimate and accumulated oxygen uptake. Six subjects ran at grades of 1, 15, and 20% (study I), and five males trained for anaerobic metabolism ran at 1, 10.5, and 15% (study II). Accumulated oxygen deficit was 40 +/- 11 (SD), 72 +/- 20, and 69 +/- 8 ml O2/kg, respectively (study I), and 57 +/- 8, 78 +/- 10, and 100 +/- 7 ml O2/kg (study II). The finding that accumulated oxygen deficit became larger with treadmill inclination could reflect involvement of an increasing muscle mass. However, variation in accumulated oxygen deficit was too large to make this possibility the only explanation. More likely at small treadmill inclinations energy demand for high-intensity running is underestimated by extrapolation from oxygen uptake during submaximal exercise. At high grades of uphill running, accumulated oxygen deficit reached a maximum that may reflect the subjects' anaerobic capacity for running. This hypothesis was substantiated by an enhanced accumulated oxygen deficit in the anaerobically trained subjects during 15%, but not during 1%, uphill running.


Fatigability and blood flow in the rat gastrocnemius-plantaris-soleus after hindlimb suspension.

The purpose of this study was to test the hypothesis that hindlimb suspension increases the fatigability of the soleus during intense contractile activity and determine whether the increased fatigue is associated with a reduced muscle blood flow. Cage-control (C) and 15-day hindlimb-suspended (HS) rats were anesthetized, and either the gastrocnemius-plantaris-soleus (G-P-S) muscle group or the soleus was stimulated (100 Hz, 100-ms trains at 120/min) for 10 min in situ. In the G-P-S preparation, blood flow was measured with radiolabeled microspheres before and at 2 and 10 min of contractile activity. The G-P-S fatigued markedly at this stimulation frequency, and the differences between C and HS animals were not significant until the 9th min of contractile activity. In contrast, the stimulation resulted in faster rates and significantly larger amounts of fatigue in the soleus from HS than from C animals. The atrophied soleus showed significant differences by 1 min of stimulation (C = 70 +/- 1% vs. HS = 57 +/- 2% of peak train force) and remained different at 10 min (C = 64 +/- 4% vs. HS = 45 +/- 2% peak train force). Relative blood flow to the soleus was similar between groups before and during contractile activity (rest: C = 20 +/- 3 vs. HS = 12 +/- 3; 2 min: C = 128 +/- 6 vs. HS = 118 +/- 4; 10 min: C = 123 +/- 11 vs. HS = 105 +/- 11 ml.min-1.100 g-1). In conclusion, these results established that 15 days of HS increased the fatigability of the soleus, but the effect was not caused by a reduced muscle blood flow.


Effects of high-frequency pressure waves applied to upper airway on respiration in central apnea.

We examined the effects of high-frequency (30-Hz) low-pressure oscillations on respiration in nine patients with central sleep apnea. All patients were studied during sleep and wore a nasal mask through which the oscillations were applied. All tests were performed during periods of repetitive central apneas. Respiratory efforts were monitored from the airflow and calibrated Respitrace signals. After several cycles of apnea were monitored, the oscillatory pressures were applied for brief periods (less than 5 s) at the midpoint of the central apneas. All trials in which arousal occurred were discarded, leaving a total of 106 trials in the nine patients. High-frequency oscillation of the upper airway stimulated respiratory effort(s) in 68% of all trials (72 of 106). Apnea length was significantly shortened in four of the nine patients. In one patient with a tracheostomy, the stimulus applied to his isolated upper airway evoked respiratory efforts during central apnea in 13 of 15 trials. We conclude that high-frequency oscillatory pressures applied to the upper airway can stimulate respiratory efforts during central apnea. This response may be mediated by upper airway receptors involved in nonrespiratory airway defense reflexes and may have implications in the treatment of patients with central sleep apnea.


Sensitivity to endotoxin in rabbits is increased after hemorrhagic shock.

The immunoinflammatory response following trauma and hemorrhage may predispose to the development of sepsis and multiple-organ failure syndrome. Cardiac output (CO), arterial pressure, arterial PO2, and pulmonary permeability index were measured. We examined the sensitivity of rabbits to infusions of lipopolysaccharide (LPS) after hemorrhagic shock. Shock was produced by reducing CO to 40% of baseline for 90 min, followed by resuscitation with shed blood and then with lactated Ringer solution to maintain CO near baseline. Animals were assigned to three groups: 1) hemorrhagic shock only, 2) LPS only, and 3) hemorrhagic shock + LPS. Groups 1 and 3 were subjected to hemorrhagic shock on day 1. Escherichia coli LPS was infused (1.0 microgram/kg i.v.) into groups 2 and 3 on day 2. Fluid resuscitation with lactated Ringer solution was continued in an effort to maintain CO at baseline. Five hours after LPS infusion, 125I-albumin was injected intravenously, and rabbits were killed 1 h later for measurement of pulmonary permeability index. LPS infusion after shock (group 3) caused significant decreases in CO, arterial pressure, and PO2 and an increase in pulmonary permeability. These changes were not seen in the groups 1 and 2. We conclude that hemorrhagic shock and resuscitation result in a proinflammatory state, leading to increased sensitivity to subsequent exposure to LPS.


Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure.

We previously showed that when the pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to determine whether some of the ultrastructural changes are rapidly reversible when the capillary pressure is reduced. To test this, the Ptm was raised to 52.5 cmH2O for 1 min of blood perfusion and then reduced to 12.5 cmH2O for 3 min of saline-dextran perfusion, followed by intravascular fixation at the same pressure. In another group of animals, the pressure was elevated for 1 min of blood and 3 min of saline-dextran before being reduced. The results were compared with previous studies in which the capillary pressures were maintained elevated at 52.5 cmH2O during the entire procedure. Control studies were also done at sustained low pressures. The results showed that the number of endothelial and epithelial breaks per millimeter and the total fraction area of the breaks were reduced when the pressure was lowered. For example, the number of endothelial breaks per millimeter decreased from 7.1 +/- 2.1 to 2.4 +/- 0.7, and the number of epithelial breaks per millimeter fell from 11.4 +/- 3.7 to 3.4 +/- 0.7. There was evidence that the breaks that closed were those that were initially small and were associated with an intact basement membrane. The results suggest that cells can move along their underlying matrix by rapid disengagement and reattachment of cell adhesion molecules, causing breaks to open or close within minutes.(ABSTRACT TRUNCATED AT 250 WORDS)


Low-dose dopamine hastens onset of gut ischemia in a porcine model of hemorrhagic shock.

Gut metabolism may become anaerobic before the whole body during progressive phlebotomy in dogs. Because dopamine has selective mesenteric vasodilator effects, we asked whether dopamine could delay onset of bowel ischemia during hemorrhagic shock. We studied whole body and gut O2 consumption (VO2) and O2 delivery (QO2) using progressive phlebotomy in anesthetized pigs. Nine pigs received a dopamine infusion of 2 micrograms.kg-1.min-1, whereas a control group of seven pigs received equivalent saline infusion. Onset of ischemia in whole body and gut was determined as critical O2 delivery (QO2c), the intersection point of biphasic regression on plots of VO2-QO2 relationships. Blood flow and O2 extraction were measured as mechanisms of gut ischemia for entire in situ small and large gut using a superior mesenteric venous fistula. Dopamine hastened onset of gut ischemia relative to onset of whole body ischemia (gut critical point in terms of whole body QO2 9.9 +/- 2.1 ml O2.kg-1.min-1, whole body QO2c 7.8 +/- 0.7 ml O2.kg-1.min-1, P less than 0.01). In contrast, onset of gut ischemia in control animals occurred at same time as onset of whole body ischemia (gut critical point in terms of whole body QO2 7.4 +/- 2.3 ml O2.kg-1.min-1, whole body QO2c 7.1 +/- 2.7 ml O2.kg-1.min-1, P = not significant). Hastening of onset of gut ischemia in dopamine-treated animals was associated with decreased ability of gut to extract O2. Low-dose dopamine was not protective against gut ischemia during shock but rather caused earlier onset of gut ischemia during hemorrhagic shock.


Relationship among running mileage, bone density, and serum testosterone in male runners.

Our purpose was to investigate the relationship between running volume and bone mineral mass in adult male runners. Whole body and regional bone mineral density were determined by dual-photon absorptiometry in 22 sedentary controls and 53 runners who were selected according to their running mileage to fall into a 5- to 10-, 15- to 20-, 25- to 30-, 40- to 55-, or 60- to 75-mile/wk group. All groups were of similar age (20-45 yr) and nutritional status, as determined by 7-day food records. Regional sites for bone density measurements included the trunk, spine, pelvis, thighs, and lower legs. In addition, serum total testosterone was determined in each subject and computed tomography scans were made of the lower legs in 34 subjects to assess bone cross-sectional area. No significant differences were detected for bone density measurements with the exception of the lower legs where it was significantly (P less than 0.05) greater for the 15- to 20-mile/wk group than for the control and 5- to 10-mile/wk groups. With mileage greater than 20 miles/wk, bone density of the lower legs showed no further increase and, in fact, tended to decrease, so that for the 60- to 75-mile/wk group it was similar to that of the controls. Cross-sectional area of the tibia and fibula when normalized to body weight tended to be greater as weekly mileage increased and was significantly greater in the 40- to 55-mile/wk runners than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of temperature on the biaxial mechanics of excised lung parenchyma of the dog.

The influence of temperature on the mechanical properties of excised saline-filled lung parenchyma of the dog was studied at low lung volume. The motivation of this study was to determine whether lung tissue material without the influence of surface tension undergoes a phase transition in the 20-40 degrees C range, as does synthetic elastin studied by Urry in 1984-1986. Dynamic biaxial and uniaxial tensile tests were done, and strain vs. Lagrangian stress curves were recorded during slow cooling and heating between 40 and 10 degrees C. To emphasize the effects of elastin, strains (defined as stretch ratio minus one) were kept below 30%. A slight decrease in compliance occurred with cooling over the entire temperature range. This effect may be attributed to collagen. It was accompanied by a gradual increase in length as the tissue cooled, an effect that may be attributed to elastin. This process was partially reversible with reheating. However, this effect is in contrast with the sudden drastic change in mechanical properties of synthetic elastin described by Urry. Hysteresis, creep, and stress relaxation were small at these low strains. Possible causes of these effects are discussed.


Optimized estimation of respiratory impedance by signal averaging in the time domain.

The spontaneous breathing of a subject during measurements of respiratory impedance (Zrs) by the forced oscillation technique (FOT) induces errors that result in biased impedance estimates, especially at low frequencies. Although in standard measurements this bias may be avoided by using special impedance estimators, there are two applications of FOT for which such estimators are not useful: when a head generator is used and when measurements are made during intubation. In this paper we describe a data-processing procedure for unbiased impedance estimation for all FOT setups. The proposed estimator (Z) was devised for pseudorandom excitation and is based on time-domain signal averaging before frequency analysis. The performance of estimator Z was first analyzed by computer simulation of a head generator setup and a setup including an endotracheal tube to measure (2-32 Hz) a resistance-inertance-elastance model mimicking Zrs of a healthy subject. Second, Z was assessed during real measurements in 16 healthy subjects. The results obtained in the simulation (e.g., error in elastance was reduced from 15.6% with most conventional estimators to 3.3% with Z in simulation of head generator setup) and in the measurements in subjects (differences of less than 1.6% between Z and a reference) confirmed the theoretical lack of bias of Z and its practical suitability for the different FOT setups. In addition to its applicability in the situations in which no other unbiased estimators are available, estimator Z is also advantageous in most conventional applications of FOT, since it requires much less computing time and thus allows on-line Zrs measurements.


A method for analysis of pulmonary arterial and venous occlusion data.

Recently, we presented a compartmental model of the pulmonary vascular resistance (R) and compliance (C) distribution with the configuration C1R1C2R2C3 (J. Appl. Physiol. 70: 2126-2136, 1991). This model was used to interpret the pressure vs. time data obtained after the sudden occlusion of the arterial inflow (AO), venous outflow (VO), or both inflow and outflow (DO) from an isolated dog lung lobe. In the present study, we present a new approach to the data analysis in terms of this model that is relatively simple to carry out and more robust. The data used to estimate the R's and C's are the steady-state arterial [Pa(0)] and venous [Pv(0)] pressures, the flow rate (Q), the area (A2) encompassed by Pa(t) after AO and the equilibrium pressure (Pd) after DO, and the average slope (m) of the Pa(t) and Pv(t) curves after VO. The following formulas can then be used to calculate the 2 R's and 3 C's: [Pa(0) - Pv(0)]/Q = R1 + R2 = RT, R1C1 congruent to to A2/[Pa(0) - Pd], R1 congruent to [Pa(0) - Pd]/Q, Q/m = C1 + C2 + C3 = CT, and C2 = CT - (RTC1/R2).


On the purported discovery of the bronchial circulation by Leonardo da Vinci.

Among modern physiologists and anatomists, there has been a nearly universal acceptance that Leonardo da Vinci was the first to identify the anatomy of the bronchial circulation. However, because of certain ambiguities in both his anatomic drawing that was supposed to have shown this circulation and the accompanying descriptive text, we questioned whether he really could have been the first to discover this small but important vasculature. To address this question, we set out to repeat Leonardo's dissections in the ox. We reasoned that perhaps the normally tiny bronchial vessels would be considerably more noticeable in this very large species. Our dissections, however, failed to provide any evidence that Leonardo's drawing was that of the bronchial circulation. Furthermore we observed a set of distinct small pulmonary veins to the left upper and right middle lobes that Leonardo, given his lack of understanding of the function of the lung and its circulation, could have easily mistaken for a separate circulation. We thus conclude that Leonardo da Vinci did not describe the anatomy of the bronchial circulation. We believe that the first person to clearly and unequivocally describe the anatomy of this circulation was the Dutch Professor of Anatomy and Botany, Frederich Ruysch.


Hypoxic bronchodilation.

Recent advances in computed tomographic imaging provide a unique method to serially and directly visualize acute physiological response in the lung. To directly investigate the airway response to hypoxia, high-resolution computed tomographic scans of the lungs of eight intact anesthetized minipigs were serially repeated before, during, and after ventilation with a hypoxic gas mixture (inspired fraction of O2 congruent to 0.07). This approach demonstrated an acute reversible 56 +/- 8% (SE) dilation in large airways (greater than 2 mm diam) and a 90 +/- 15% dilation in small airways (less than 1.99 mm diam) with decreased inspired O2 tension. Of the airways studied, 70 of 76 dilated. Hypoxic bronchodilation may interact with hypoxic pulmonary vasoconstriction in the fundamental physiological process of ventilation-perfusion matching in the lung.


Intrinsic properties of pharyngeal and diaphragmatic respiratory motoneurons and muscles.

Breathing is a complex act requiring the coordinated activity of multiple groups of muscles. Thoracic and abdominal respiratory muscles expand and contract the lungs, whereas pharyngeal and laryngeal respiratory muscles maintain upper airway patency and regulate upper airway resistance. An appreciation of the importance of the latter muscle group in maintaining ventilatory homeostasis and in the pathophysiology of sleep apnea has led to extensive studies examining the neural regulation of pharyngeal dilator muscles. The present review examines the role of heterogeneity in motoneuron and muscle properties in determining the diversity in the electrical and mechanical behaviors of thoracic compared with pharyngeal muscle groups. Specifically, phrenic and hypoglossal motoneuron electrophysiological properties influence whether and the extent to which these neurons will fire in response to a given synaptic input arising from chemo- and mechanoreceptors and from respiratory and nonrespiratory pattern generators. Furthermore, thoracic and pharyngeal muscle properties determine the mechanical response to motoneuronal activity, including the speed of contraction, relationships between motoneuron firing frequency and force production, and whether force is maintained during repetitive activation. Heterogeneity in the functional capabilities of these motoneurons and muscles is in turn determined by diversity of their structural and biochemical properties. Thus, intrinsic properties of respiratory motoneurons and muscles act in concert with neuronal drives in defining the complex electrical and mechanical behavior of pharyngeal and thoracic respiratory motor systems.


Effects of growth hormone on diaphragmatic recovery from malnutrition.

A 25% weight loss was induced in adult Fisher 344 rats by nutritional deprivation. Subsequently, normal feeding was resumed. Refed animals were divided into three groups and received recombinant human growth hormone (rhGH) injections during 5 wk of refeeding, saline injections during 5 wk of refeeding, or 9 wk of refeeding without injections. The effects of nutritional deprivation and the various refeeding protocols on the cross-sectional areas (CSA) of each of the four types of myofibers [typed immunohistochemically with antibodies against four myosin heavy chain (MHC) isoforms known to be present in the rat diaphragm] were determined. Malnutrition decreased the CSA of myofibers containing MHC2X, MHC2B, and MHC2A (i.e., fast myofibers), with the greatest effect on muscle mass being due to the atrophy of fibers containing MHC2X. Fibers containing MHC beta/slow failed to undergo malnutrition-induced atrophy. Whereas refeeding for 5 wk in the absence of rhGH allowed the recovery of CSA of fibers containing MHC2A, fibers containing MHC2B and MHC2X remained smaller than fibers of similar type in control animals. In contrast, 5 wk of refeeding supplemented with rhGH returned all fiber CSAs to control values. Even when refeeding alone was extended to 9 wk to allow for weight stabilization, the CSA of the fibers containing MHC2B and MHC2X remained smaller than similar fibers in control muscle. Serum insulin-like growth factor, a marker of malnutrition (R. Reeves and J. Elders, J. Nutr. 109: 613-620, 1979), was significantly decreased after nutritional deprivation and returned to normal after 5 wk of refeeding and GH supplementation.


Differences in metabolic response of dog and goat latissimus dorsi muscle to chronic stimulation.

The latissimus dorsi (LD) muscle is considered suitable to assist ventricular mechanical function in either cardiomyoplasty or extra-aortic-assist devices. Such application requires that this mixed-type skeletal muscle be transformed into a fatigue-resistant muscle, the adaptation of which can be elicited by chronic stimulation. In this study the LD muscles of dog and goat were subjected in situ to 12 wk of continuous electrical stimulation through intramuscular electrodes, and their myofibrillar and metabolic adaptations were compared. A gradual increase in the contraction rate of the muscle (in 10 wk from 30 to 80 contractions/min) caused the proportion of immunohistochemically identified type I fibers to increase in dog muscle from 30 to 74% and in goat muscle from 21 to 99%. Correspondingly, the anaerobic-glycolytic activity (fructose-6-phosphate kinase and lactate dehydrogenase activities) decreased by approximately 75% in both dog and goat muscles, whereas the oxidative capacity (fatty acid oxidation and citrate synthase activity) increased two- to threefold in goat LD muscle but remained unaltered in dog LD muscle. Muscular contents of high-energy phosphates and endogenous substrates were maintained, but the L-carnitine content decreased by 43% in both dog and goat. Our data further indicate that, for the monitoring of the metabolic adaptation of skeletal muscle, the ratio of activities of the oxidative and anaerobic-glycolytic pathways (e.g., citrate synthase to fructose-6-phosphate kinase activities) is a useful parameter in both dog and goat.(ABSTRACT TRUNCATED AT 250 WORDS)


Compensatory muscle fiber hypertrophy in elderly men.

Muscle strength and muscle morphology have been studied three times during a period of 11 yr in nine elderly men. On the last occasion the average age was 80.4 (range 79-82) yr. Body cell mass decreased by 6% and muscle strength for knee extension, measured by means of isometric and concentric isokinetic (30-60 degrees/s) recordings, declined by 25-35% over the 11-yr period. Between 76 and 80 yr of age only the isokinetic strength for 30 degrees/s decreased significantly. Muscle fiber composition in the vastus lateralis did not change between 69 and 76 yr of age, but there was a significant reduction in the proportion of type IIb fibers from 76 to 80 yr. The decrease in type II fiber areas was not significant between 69 and 76 yr of age (as in a larger sample from the same population), but a significant increase in both type I and type II fiber areas was recorded from 76 to 80 yr of age and biceps brachii showed similar tendencies. In the same period, the enzymatic activities of myokinase and lactate dehydrogenase subsided in the vastus lateralis, but there was no change for triose phosphate dehydrogenase, 3-hydroxy-CoA-dehydrogenase, and citrate synthase. The muscle fiber hypertrophy in this group of elderly men with maintained physical activity between 76 and 80 yr of age is interpreted as a compensatory adaptation for the loss of motor units. In addition, the adaptation with respect to oxidative capacities seems to be maintained at this age.


Distribution of injury and microdosimetry of ozone in the ventilatory unit of the rat.

The distribution of ozone-induced injury across ventilatory units of the lungs was determined and compared with the predicted distribution of ozone dose across the same units to evaluate dose-response relationships. Sprague-Dawley rats were exposed to either 0.98 ppm ozone 8 h/day for 90 days or to filtered air only. En bloc microdissection was used to identify and isolate in longitudinal profile the bronchiole-alveolar duct junction, first pair of alveolar duct generations, and intervening bifurcation ridge. The first alveolar outpocketing along the bronchiolar wall of each isolation was used to identify the center of a series of concentric arcs radiating outward at 100-microns intervals across each ventilatory unit. The intercept lengths of each arc with the tissue of alveolar septal tips (edges) and alveolar walls were measured and expressed as a function of distance into the ventilatory unit. Relative ozone dose across the ventilatory unit was estimated using the geometry of the tracheobronchial tree and the volume and surface area distribution within individual ventilatory units. This mathematical model of ozone dose demonstrated a high degree of correlation to this measured tissue injury response. The findings of this study demonstrate that microdosimetry and microtoxicology can be used to determine dose-response relationships within the ventilatory unit and to assess questions of tissue sensitivity in ozone-induced lung injury.


Oxygen cost of resistive-loaded breathing in quadriplegia.

We hypothesized that, in quadriplegia, chest wall distortion would increase the energy cost of ventilation. To assess this, we measured the oxygen cost of breathing (VO2 resp) and changes in chest wall configuration during inspiratory resistive-loaded breathing tasks in five quadriplegic and five normal subjects. Each subject performed three breathing tasks that spanned a range of work rates (Wtot). Configurational changes of the abdomen and upper, lower, and transverse rib cage were assessed with magnetometers. We found that 1) in both groups, VO2resp increased linearly with Wtot over the range of tasks performed, 2) the mean slope of the regression line of VO2resp vs. Wtot was greater for quadriplegic than for normal subjects (3.7 +/- 0.8 vs. 2.0 +/- 0.7 ml O2/J, P less than 0.01), 3) efficiency of breathing (Wtot/VO2resp) was less for quadriplegic than for normal subjects (1.9 +/- 0.6 vs. 3.5 +/- 1.4%, P less than 0.001), 4) during inhalation, upper and lower rib cages behaved similarly in the two groups, but the quadriplegic subjects had a decrease in transverse rib cage and a much greater increase in abdomen than normal subjects, and 5) functional residual capacity decreased in normal but not in quadriplegic subjects during the breathing tasks. We conclude that the lesser efficiency of breathing in quadriplegia may be related to the elastic work of chest wall distortion, shorter mean operational diaphragm length, and possibly differences between normal and quadriplegic subjects in mechanical advantage of available inspiratory muscles.


Decrease in lung volume-related feedback enhances laryngeal reflexes to negative pressure.

Negative pressure applied to the upper airway has an excitatory effect on the activity of upper airway muscles and an inhibitory effect on thoracic inspiratory muscles. The role of lung volume feedback in this response was investigated in 10 anesthetized spontaneously breathing adult rabbits. To alter lung volume feedback, the lower airway was exposed to SO2 (250 ppm for 15 min), thereby blocking slowly adapting receptors (SARs). Negative pressure pulses (5, 10, and 20 cmH2O, 300-ms duration) were applied to the functionally isolated upper airway before and after SAR blockade. Tracheal airflow and electromyogram (EMG) of the genioglossus and alae nasi were recorded. Peak EMG, peak inspiratory flow, tidal volume, and respiratory timing of control breaths (3 breaths immediately preceding test) and test breaths were determined. Analysis of variance was used to determine the significance of the effects. Negative pressure pulses increased peak EMG of genioglossus and alae nasi and inspiratory duration and decreased peak inspiratory flow. These effects were larger after SAR blockade. We conclude that a decrease in volume feedback from the lung augments the response to upper airway pressure change.


Erythropoietin response to acute normobaric hypoxia in humans.

Hypoxia causes an increased production of erythropoietin (EPO), but the time course of the EPO response in humans has not been well characterized. This study examines the relationship between the duration of normobaric hypoxic exposure and plasma EPO levels in healthy human subjects. Six volunteers breathed a gas mixture of 10.5% O2-89.5% N2 continuously for 5, 60, and 120 or intermittently for 240 min. O2 saturations were maintained between 75 and 85% during the exposure. Arterial pH was 7.467 +/- 0.019, PO2 37.05 +/- 2.43 Torr, and PCO2 36.69 +/- 2.05 Torr. O2 half-saturation pressures of hemoglobin were normal for all subjects. Plasma EPO was measured every 30 min for 360 min by radioimmunoassay. No increase in EPO was seen after the 5- and 60-min exposures. However, a 50% increase was seen 240 min after the initiation of the 120-min hypoxic exposure (P less than 0.01). Intermittent exposure resulted in an increase of EPO by 52% 360 min after the onset of exposure (P less than 0.05). Therefore, exposing humans continuously to an inspiratory O2 fraction of 0.105 for 120 min or intermittently for 240 min provides a sufficient stimulus to increase production of EPO.


Late potentials in an ovine model of acute transmural myocardial infarction.

The development of slow conduction during the first hours of acute transmural myocardial infarction (ATMI) was studied by signal-averaged electrocardiograms (SAE) in 19 adult anesthetized sheep. SAEs were recorded before and after intravenous infusions of lidocaine and bretylium were begun and 10, 30, and 60 min after ATMI produced by ligation of the left anterior descending and second diagonal coronary arteries. Four sheep died promptly of ventricular tachyarrhythmias; two others developed sustained ventricular arrhythmias, which precluded additional data. Biphasic changes in QRS duration, root mean square voltage of the terminal 40 ms of the QRS complex, and duration of terminal low-amplitude (less than 30 microV) signal were observed. Peak changes in conduction occurred 30 min after infarction and regressed toward baseline thereafter. At 30 min, all animals developed late potentials, which were defined as signals that exceeded both after-drug QRS duration and duration of terminal low-amplitude signal less than 30 microV by more than two standard deviations. At 60 min, only 3 of 13 (23%) animals had late potentials. Conduction is slowest 30 min after ATMI in sheep but may not be related to development of ventricular arrhythmias. In five of six sheep (83%), ventricular arrhythmias occurred within 15 min of infarction before peak slowing was observed by SAE.


Ventilatory and metabolic responses to cold and hypoxia in intact and carotid body-denervated rats.

The effects of hypoxia on thermoregulation and ventilatory control were studied in conscious rats before and after carotid denervation (CD). Measurements of metabolic rate (VO2), ventilation (V), shivering intensity (SI), and colonic temperature (Tc) were made in groups of eight rats subjected to three protocols. In protocols 1 and 2, at ambient temperature (Ta) of 25 and 5 degrees C, respectively, rats were exposed to normoxia and hypoxia [inspired O2 fraction (FIO2) 0.13-0.11]. In protocol 3, Ta was decreased from 25 to 5 degrees C in 30-min steps of 5 degrees C. Recordings were made in normoxia and hypoxia (FIO2 0.12). The results show that in both intact and CD rats 1) in normoxia, cold exposure increased VO2, V, and SI, and these increases were proportional to the decrease in Ta; 2) hypoxia induced only a transient decrease in SI, and, for a given Ta, VO2 was reduced whereas V and SI were increased; and 3) in CD rats, V increased less during cold exposure in both normoxia and hypoxia; VO2 and Tc were more depressed during hypoxia. It is concluded that 1) the interaction between Ta and FIO2 in the control of V is partly dependent on the carotid body afferents, 2) shivering thermogenesis may be transiently affected by hypoxia independently of the carotid body afferents, and 3) nonshivering thermogenesis may be directly inhibited by hypoxia, especially during cold exposure.


Relative contribution of bronchial flow to subpleural region in dog lung.

The bronchial flow is approximately 1% of the total pulmonary flow. Anastomosis between the bronchial and pulmonary vessels occurs primarily at the microcirculatory level. It is assumed that bronchopulmonary anastomoses are present in a homogeneous manner throughout lung parenchyma. To investigate this issue, an in situ blood-perfused left lower lung lobe (500 ml/min) was prepared in a live dog. The bronchial flow rate in the entire lobe was monitored using the rate of volume gain in the reservoir while the pulmonary and bronchial flow in the subpleural region was monitored using laser-Doppler flowmetry. The results were expressed as ratio of bronchial to pulmonary flow rate for the entire lobe and for the subpleural region. We found that, for the entire lobe, bronchial flow was 1.0% of pulmonary flow, while for the subpleural region this ratio was much higher, with an average of 12%. In two different experimental conditions that were imposed to affect the global bronchial flow, these ratios changed in the same direction as the global bronchial flow. After transfusion of blood into the animal, bronchial flow increased to 1.7%, while the subpleural bronchial flow increased to 18% of the subpleural pulmonary flow. During elevation of venous pressure, bronchial flow decreased to 0.6%, while the subpleural bronchial flow decreased to 10% of the subpleural pulmonary flow. The differences in the ratios between the global and subpleural region may be explained by having low pulmonary blood flow in the periphery compared with the interior regions of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)


Aerosol bolus dispersion and convective mixing in human and dog lungs and physical models.

The dispersion of aerosol boluses in the lung is a probe for convective mixing and has been proposed as a marker for abnormal lung function. To better understand the factors underlying this phenomenon, aerosol dispersion was compared in human subjects, dogs, and various physical models. In all systems, dispersion increased with the volumetric penetration of the aerosol bolus. The rate of this increase was 83% greater in humans compared with dogs. Dispersion in dogs was close to that in a packed bed with beads of 2.5 mm. Aerosol dispersion decreased with increasing flow rate in human subjects. An artificial larynx inserted into the straight tube caused a 33% increase in dispersion. In humans, aerosol dispersion was significantly correlated with forced expired flow between 25 and 75% of vital capacity. A 2-s pause between inspiration and expiration increased dispersion 23-58% in three isolated dog lungs but did not affect dispersion in the packed bed. The data suggest that lung geometry, flow rate, particle mobility, and the larynx all significantly affect aerosol dispersion by influencing the reversibility of aerosol transport between inspiration and expiration.