The effects of arginine vasopressin (AVP) and amiloride were studied in 16 unanesthetized fetal sheep (129–135 days of age) with indwelling catheters. Secretion was measured by an impermeant tracer technique. Control fetuses showed no change in lung liquid secretion over a 5-h period with an average secretion rate of 3.6 +/- 0.31 ml.kg-1.h-1. Infusion of AVP (23.4 +/- 2.23 mU.kg-1.min-1) in seven fetuses (134–140 days of age) produced significant decreases (from control) in the secretion rate over a 5-h period: the secretion rate decreased by 68% in the last hour. Amiloride placed in the lung liquid during infusion of AVP, but after AVP effects had taken place, reversed the AVP-induced decrease in lung liquid secretion. AVP in conjunction with other hormones that are elevated during the stress of birth (epinephrine and cortisol) may be important in the removal of lung fluid at birth.
Autologous serum with or without platelet-activating factor (PAF) was instilled into one lung lobe of an anesthetized cat, and changes in the regional lung water content were monitored for 4 h with proton nuclear magnetic resonance (NMR) images and relaxation time measurements. With serum as an instillate, water was cleared with a half time of approximately 670 min; after 4 h, 86 +/- 6% of that instilled remained. With PAF added to the instillate, clearance was biphasic with an initial clearance half time of approximately 30 min followed by clearance similar to that observed after serum instillation; after 4 h, 35 +/- 4% of that instilled remained. In contrast, 4 h after instillation of serum or serum plus PAF, 91 +/- 3% and 82 +/- 5%, respectively, of the instilled 125I-labeled albumin remained in the lung (P = 0.06). From transverse magnetization relaxation curves we were able to resolve two relaxation components, which we have attributed to the instilled fluid in the air spaces (relaxation time = 177 +/- 7 ms) and the tissue-bound fluid (relaxation time = 25 +/- 1 ms).
Effects of experimental exposure to O3 (0.33 ppm) or filtered air on regional lung function were assessed in nine healthy male subjects. Immediately after 2-h chamber exposures, regional ventilation and particle dosimetry were measured by gamma camera imaging. The vertical distributions of a radiolabeled gas (133Xe) and aerosol (3.5-microns-diam insoluble 99mTc-tagged Fe2O3 particles) were quantitated for upper, middle, and lower lung regions; distribution data were corrected for regional differences in lung volume and tissue attenuation. Indexes of mechanical function, inspiratory capacity, and mid-maximal expiratory flow rates were significantly reduced after O3, but functional residual capacity remained unchanged. Exposure to O3 significantly enhanced the fraction of respired aerosol retained by the lung and altered the distribution pattern of deposited aerosol by increasing particle deposition to the middle lung region (P < 0.05). Aerosol penetration indexes, i.e., ratio of particle deposition in central lung regions to that in peripheral lung regions, and particle retention 24 h postinhalation (an index of aerosol deposition within alveoli and slowly clearing bronchioles) indicated that particle filtration efficiency had increased for tracheobronchial and parenchymal lung regions. For seven of the nine subjects, regional ventilation after O3 was reduced by 14% to the lung base and enhanced by 8 and 6% to the upper and middle lung regions, respectively; these changes were significant (P < 0.02) compared with ventilation after filtered air.(ABSTRACT TRUNCATED AT 250 WORDS)
The present study assessed the effects of 40 min of tail shock stress (1-s shock, 0.2 mA every 30 s) on renal and cardiovascular function in swim-trained (T), water-immersed (IM), and untrained (UT) borderline hypertensive rats (BHR). T BHR swam for 2 h/day 5 days/wk for 10–12 wk, whereas IM BHR on the same schedule were placed in water at neck level and were not permitted to swim. Age-matched sedentary controls were paired one each with the exercise group (group 1) and the immersion group (group 2). Heart rate was significantly greater in UT than in T BHR (P = 0.09) during baseline (rest). Heart rate responses during stress were not different between UT and IM BHR (group 2). Systolic and diastolic blood pressures during stress and recovery were not different between UT BHR and T or IM BHR. Urine flow rate was significantly increased from baseline during the first 20 min of stress in UT and IM BHR only. Changes in glomerular filtration rate were not consistent across studies. Renal blood flow decreased significantly from baseline during tail shock stress in UT but not T BHR. Plasma glucose levels were significantly increased above baseline during the second 20 min of stress in UT BHR only and were significantly greater than those in the T BHR. Plasma insulin levels in UT BHR were significantly decreased from baseline during tail shock stress and recovery but were unchanged from baseline in T BHR. These observations suggest that swim training independent of water immersion alters the effect that stress exerts on renal and cardiovascular function in BHR, which results in better fluid and electrolyte conservation in T BHR.
To determine whether nicotine is involved in evoking the irritant effects of cigarette smoke in airways, we studied the responses to inhalation of a single puff (30 ml) of three types of smoke (high nicotine, low nicotine, and gas phase) in healthy male nonsmokers. After the upper airways were locally anesthetized, the subjects, breathing through a mouthpiece, were instructed to signal the detection and the intensity of airway irritation with a push-button device. Inhalation of high-nicotine smoke consistently triggered an intense airway irritation in the lower neck and upper chest region; the total number of push-button signals generated in the first 5 s was 6.61 +/- 0.87 (mean +/- SE, n = 12), with a detection latency of 0.93 +/- 0.11 s. By contrast, inhalation of low-nicotine and gas phase smoke either was not detected or caused only very mild irritation (0.89 +/- 0.4 and 0.36 +/- 0.22, respectively). In addition, the intensity of smoke-induced airway irritation was markedly reduced after premedication with aerosolized hexamethonium, a nicotinic receptor antagonist (P < 0.01, n = 8). Furthermore, inhalation of nicotine aerosol also immediately evoked intense airway irritation and coughs (n = 5). Thus we conclude that the airway irritation evoked by inhaling cigarette smoke results from an activation of sensory endings located in the central airways and nicotine is the primary agent responsible for this action.
The kinetics of oxygen uptake (VO2) were observed at the onset of submaximal cycling exercise in seven men and one woman [mean age 22.6 +/- 0.9 (SE) yr] in the upright and supine positions and the supine position with -40 mmHg lower body negative pressure (LBNP). There was no significant difference for peak VO2 and ventilatory threshold between the supine (3,081 +/- 133 and 1,954 +/- 138 ml/min, respectively) and the supine + LBNP positions (3,062 +/- 152 and 1,973 +/- 122 ml/min); however, both were reduced compared with upright exercise (3,483 +/- 200 and 2,353 +/- 125 ml/min). Kinetic analysis applied to six repetitions by each subject indicated a slowing from a mean total lag time (time required to achieve 63% of the difference in VO2 between baseline and new steady state) of 36.3 +/- 2.7 s in upright exercise to 44.1 +/- 3.5 s in the supine position. However, total lag time for the supine + LBNP position (36.0 +/- 2.8 s) did not differ from upright exercise but was significantly faster than supine exercise. These data have been interpreted in support of an O2 transport limitation to VO2 kinetics at the onset of supine exercise that is countered by LBNP, likely through a more rapid increase in perfusion to the exercising muscle at these submaximal work rates.
To test the hypothesis that native high-altitude residents have less beta-sympathetic and more parasympathetic tone than newcomers, we compared the effects of beta-sympathetic and parasympathetic blockade in 10 Tibetan and 9 Han acclimatized male residents of Lhasa, Tibet Autonomous Region, China (elevation 3,658 m). Each subject was studied during cycle ergometer exercise at 70, 132, and 191 W after placebo (normal saline), beta-sympathetic (propranolol, 0.2 mg/kg iv), or parasympathetic (atropine, 0.04 mg/kg iv) blockade in random order on different days. At rest, the fall in resting heart rate with propranolol and the rise with atropine were equal in Tibetan and Han subjects. During exercise, the fall in heart rate with propranolol relative to placebo values was greater in the Han than in the Tibetan group, whereas the rise in heart rate with atropine was greater in the Tibetans. Propranolol or atropine administration did not change minute ventilation per unit O2 consumption in either group. At the highest level of exercise on the placebo day, the Tibetans achieved a higher work load and level of O2 consumption than the Han subjects. Propranolol or atropine reduced O2 consumption and work load similarly in the two groups at the highest exercise level. The results supported our hypothesis that native Tibetan residents of high altitude exhibit more para-sympathetic and less beta-sympathetic tone during exercise. Neither relatively greater parasympathetic nor less sympathetic activation appeared implicated in the greater exercise capacity of Tibetans compared with that of acclimatized newcomer residents of high altitude.
Systemic and lower limb skeletal muscle lactate metabolism was studied in 10 men with congestive heart failure by use of a primed continuous intravenous infusion of L-(+)-[U-14C]lactate. Arterial and deep femoral venous blood samples were obtained at rest and during 30 min of submaximal exercise. Systemic lactate metabolic turnover rate (Rd) was determined using Steele's isotopic steady-state equation (Rd = isotopic infusion rate/arterial specific activity). Plasma lactate concentrations in the artery and deep femoral vein did not change significantly from resting values during exercise (1.11 +/- 0.13 vs. 1.26 +/- 0.12 and 1.27 +/- 0.12 vs. 1.30 +/- 0.12 mM, respectively), whereas Rd increased from 22.5 +/- 1.8 to 41.6 +/- 4.8 mumol.kg-1.min-1 (P < 0.005). Rd did not significantly correlate with arterial lactate concentration during rest or exercise. Because of simultaneous uptake and release of lactate in skeletal muscle, arterial and deep femoral venous lactate concentrations are not closely related to either systemic or lower limb skeletal muscle lactate metabolism in patients with congestive heart failure.
Time to onset of hyperbaric oxygen-induced convulsions was measured in mice and rats exposed to hyperbaric oxygen (515–585 kPa) under conditions of low humidity (dry gas, < 10% relative humidity) or in a humidified environment (60% relative humidity). At all pressures tested, the duration of convulsive activity was markedly increased (P < 0.001), because of the earlier onset of severe generalized convulsions, in the groups of rodents exposed to the higher humidity. Pulmonary oxygen poisoning was determined by increases in lung wet and dry weights. Such pulmonary damage was also significantly (P < 0.001) increased in the humidified groups. Hyperoxic toxicity was also measured in rats and mice exposed to approximately 100% oxygen (normobaric hyperoxia) under conditions of 30 or 62% relative humidity. In contrast to the results obtained with hyperbaric oxygen exposure, there was slightly less toxicity in the rodents maintained at 62% compared with 30% humidity in normobaric hyperoxia.
In animals subjected to hemorrhage, plasma arginine vasopressin concentrations increase to levels sufficient to cause vasoconstriction, thus attenuating the hypotensive response. The purpose of this study was to examine the contribution of vasopressin to blood pressure regulation during hypotension in humans. Hypotension was induced in twelve normal subjects by lower body negative pressure (LBNP) before and after intravenous administration of vasopressin V1 receptor antagonist. Before drug administration, LBNP reduced systolic blood pressure from 125 +/- 4 to 78 +/- 12 mmHg (P < 0.01) as vasopressin concentration increased from 2.9 +/- 0.6 to 17 +/- 6 pg/ml (P < 0.05). After administration of the vasopressin antagonist, LBNP reduced systolic blood pressure from 128 +/- 3 to 89 +/- 11 mmHg (P < 0.01). The hypotensive response to LBNP was not potentiated by inhibiting vasopressin's vasoconstrictive effects (P = NS). Thus hypotension causes marked increases in plasma vasopressin concentration. In contrast to findings in animal studies, however, vasopressin does not contribute to the maintenance of blood pressure during hypotension in humans.
The influence of exercise training on left ventricular function at rest (R), at anaerobic threshold (AT), and during peak exercise (PE) was evaluated in 12 healthy untrained and 13 trained (T) subjects who underwent Doppler echocardiography at R and radionuclide ventriculography at R and during exercise. The end-diastolic volume and stroke volume were significantly higher in the T group than in the untrained group at R. The ejection fraction rose significantly from R to AT and from AT to PE (80.0 +/- 0.84 vs. 83.6 +/- 0.91%), but no significant difference was observed between groups. The peak diastolic filling rate rose significantly during exercise, with a further significant increase observed in the T group (AT, 6.38 +/- 0.40 vs. 5.01 +/- 0.16 end-diastolic counts/s; PE, 8.24 +/- 0.42 vs. 7.15 +/- 0.35 end-diastolic counts/s). The percent variation of minimal systolic counts fell significantly at AT and PE in relation to R. Our data demonstrate that exercise training produces a significant increase in peak diastolic filling rate but no change in systolic function during exercise and that metabolic acidosis caused by exercise does not limit systolic function.
Interaction among mediators such as bradykinin (BK), histamine (H), and prostaglandin (PG) D2 may contribute to reduction in airway caliber in asthma. Ten stable asthmatic subjects took part in a study to investigate possible mediator interaction. The provocative concentration of mediator required to reduce forced expiratory volume in 1 s (FEV1) by 12.5% from the starting baseline value (PC12.5) and that required to reduce the fall in FEV1 from 12.5 to 25% (PC25–12.5) of H, BK, and PGD2 were determined. On three subsequent occasions, subjects inhaled either the vehicle plus BK PC12.5 or the vehicle plus H or PGD2 PC25–12.5, and FEV1 was measured at regular time intervals up to 40 min. Predicted time course curves were calculated from these results. On two additional occasions, interactive time course studies were undertaken when the subject inhaled BK PC12.5 followed by H or PGD2 PC25–12.5. On a further three visits, the time courses of individual mediators were studied. When BK was combined with H and PGD2, the maximum fall in FEV1 and the rate of recovery after inhalation of the second mediator were not significantly different from those values of predicted time course responses for the same combination of mediator. Thus, by employing pharmacologically active concentrations of inhaled BK, H, and PGD2, which act through separate receptor mechanisms, we were unable to demonstrate any pharmacological interaction on airway caliber in asthma.
We have designed and implemented a computer-controlled system that uses an adaptive control algorithm (generalized minimum variance) to buffer the breath-by-breath variations of the end-tidal CO2 fraction (FETCO2) that occur spontaneously or are exaggerated in certain experimental protocols (e.g., induced hypoxia, any type of induced variations in the ventilatory pattern). Near the end of each breath, FETCO2 of the following breath is predicted and the inspired CO2 fraction (FICO2) of the upcoming breath is adjusted to minimize the difference between the predicted and desired FETCO2 of the next breath. The one-breath-ahead prediction of FETCO2 is based on an adaptive autoregressive with exogenous inputs (ARX) model: FETCO2 of a given breath is related to FICO2, FETCO2 of the previous breath, and inspiratory ventilation. Adequacy of the prediction is demonstrated using data from experiments in which FICO2 was varied pseudorandomly in wakefulness and sleep. The algorithm for optimally buffering changes in FETCO2 is based on the coefficients of the ARX model. We have determined experimentally the frequency of FETCO2 variations that can be buffered adequately by our controller, testing both spontaneous variations in FETCO2 and variations induced by hypoxia in young awake human subjects. The controller is most effective in buffering variations of FETCO2 in the frequency range of <0.1 cycle/breath. Some potential applications are discussed.
To investigate heterogeneity of airway smooth muscle response, we studied strips of large and small branches from third- to sixth-generation bronchi obtained from ragweed antigen-sensitized and control dogs. The response to electrical field stimulation and carbamylcholine chloride was greater in strips from larger branches of the same generation when expressed as "tissue stress" (force per unit cross-sectional area of the whole tissue), whereas no difference emerged with use of the more appropriate "smooth muscle stress" (force per unit cross-sectional area of the muscle tissue). The response to histamine was significantly higher in small branches than in large ones, and histamine sensitivity [mean effective concentration (EC50)] was 7.79 x 10(-6) [geometric standard error of the mean (GSEM) 1.20] and 1.49 x 10(-5) M (GSEM 1.14), respectively (P < 0.01). Strips from control and sensitized animals at each site and strips from different generations did not show any significant difference. When we clustered our preparations according to dimensions, the response to histamine was significantly higher in small bronchi than in large ones and histamine EC50 was 8.95 x 10(-6) (GSEM 1.17) and 1.57 x 10(-5) M (GSEM 1.18), respectively (P < 0.05). We conclude that evaluation of muscle response in different tissues requires appropriate normalization. Furthermore, classification into generations is inadequate to study bronchial responsiveness, inasmuch as major differences originate from airway size.
In the breath-hold model described by S. Godfrey and E. J. M. Campbell (Respir. Physiol. 5: 385–400, 1968), chemical and nonchemical stimuli are independent. Because these two factors are time dependent, the effect of each could not be measured by breath-holding time (BHT). The aim of this study is to dissociate chemical and nonchemical stimuli and to assess the effects of BHT and PCO2 on respiratory center output by measurement of occlusion pressure (P0.1) and mean inspiratory flow (VI). Nine well-trained divers (age 36.5 +/- 5.0 yr) took part in the study. Each subject had to hold his breath at 75% of vital capacity for 30, 50, and 70 s of BHT. Before each breath hold, the subject inspired successively two vital capacities of the same CO2-O2 gas mixture. P0.1 and VI were measured during the first reinspiration after the breath hold. For the same BHT, we observed good linear relationships between P0.1 or VI and alveolar PCO2. The slopes of these relationships increased with BHT. For alveolar PCO2 of > 50 Torr, P0.1 increased linearly with BHT. These results indicate that, during breath holding, chemical and nonchemical stimuli acted linearly on respiratory motoneuron activity, but they were not independent.
Using a theoretical model, we studied spreading of a bolus of insoluble surfactant deposited on a thin liquid layer of a model airway. Applications include instillation of exogenous surfactant as a treatment for neonatal respiratory distress syndrome, the use of surfactant carriers to deliver drugs via the lung, and the movement of liquid along the airway tree due to naturally occurring gradients of surface tension. The time-dependent governing equations were solved numerically for longitudinal axisymmetric surfactant spreading. We examined the influences of the resident liquid layer (thickness, viscosity, endogenous surfactant, airway radius), of the bolus (volume and surfactant content), and of gravity. The gradient in surface tension drives the flow toward the region of higher surface tension, ultimately creating a shocklike wave of nearly twice the initial lining thickness. Pressure gradients due to interfacial curvature (capillarity) have little effect on the rate of surfactant spread. The presence of an endogenous resident surfactant greatly augments the rate of spreading while inhibiting development of the shock. In all cases studied, the effect of circumferential curvature was negligible, indicating that the liquid layer can be treated as if it were spreading over a flat surface. Our results reveal that the surfactant spreads as time to the one-third power. Accordingly, a surfactant deposited in the trachea of a neonate would spread to the periphery in approximately 12 s.
The observed low frequencies of action potentials observed in medullary respiratory neurons of immature opossums (Didelphis virginiana) could occur because these cells are incapable of achieving higher sustained firing rates. Nonsustainability of firing might also help explain why the inspired breath is brief (approximately 0.1 s) in the youngest opossums and rises very slowly during postnatal life. Firing frequencies of medullary respiratory neurons were examined in spontaneously breathing thiobarbiturate-anesthetized opossums before and after stimulation by the glutamate agonists, N-methyl-D-aspartate (NMDA; 20 mM) or kainic acid (KA; 0.5 mM). Drugs were applied using progressively larger pressure injections through a micropipette; animals were tested from the 5th postnatal wk to adulthood. With a sufficient injection volume, stimulation of cell firing would be followed by apparent suppression of action potentials. A maximum "sustained" firing frequency was obtained from the last injection where discharge remained elevated for at least 0.5 s. Inspiratory and expiratory neurons tested with either drug showed the lowest rates of firing in opossums at 5–9 wk of age compared with 10- to 14-wk-old animals and/or adults. Despite higher rates of discharge in 10- to 14-wk-old animals and/or adults, maximum sustained neuronal firing in the youngest animals was at a higher frequency than during spontaneous breathing and, at least in the cell population tested, does not represent a limitation that might affect breathing pattern.
To determine growth patterns of the lung and airways in adolescents, we analyzed maximal expiratory flow-volume curves, closing capacity, and residual volume. They were obtained every 6 mo for up to 7 yr in 430 boys and 125 girls (11–19 yr), of whom 143 boys and 36 girls were classified as symptomatic; symptoms were most often minor and limited to childhood. Development of flows vs. volumes was used to investigate growth of the airways relative to lung size. A model of isotropic growth of the airways and air spaces (J. Appl. Physiol. 65: 822–828, 1988) was modified for increasing elastic recoil pressure with growth. Growth of airways relative to volume occurred faster in teenage boys than in teenage girls and was compatible with isotropic growth in 92% of asymptomatic boys and in 44% of asymptomatic girls: dysanaptic growth in teenage girls seems to be a normal phenomenon and not a unique characteristic of symptomatic subjects. Subjects with respiratory symptoms in childhood and/or adolescence have lower flows for a given lung size and airway closure at a greater lung volume when they enter adulthood. However, no difference in patterns of lung growth was observed in association with the presence of respiratory symptoms.
The effects of resuscitation with 21 or 100% O2 on cerebral blood flow (CBF) and somatosensory evoked potentials (SEPs) were studied in 19 newborn pigs anesthetized with pentobarbital sodium. They were ventilated with 8% O2 until base excess reached -20 mmol/l and then were randomly reoxygenated with 21% O2 (n = 10) or 100% O2 (n = 9) for 25 min followed by 21% O2. Mean duration of hypoxemia in the two groups was 57 +/- 6 (SE) and 59 +/- 6 min, respectively. CBF determined by radioactive microspheres was significantly increased in all areas in both groups after 5 and 20 min of reoxygenation. At 5 min of reoxygenation forebrain O2 uptake (CMRo2) had increased significantly compared with baseline values in the 21% O2 group (2.5 +/- 0.1 to 3.2 +/- 0.2 ml.100 g-1.min-1) but not in the 100% O2 group. There were, however, no significant differences between the two groups in CBF or CMRo2 at any time, and by 60 min of reoxygenation both had returned to baseline levels. SEPs were not significantly different in the two groups. We conclude that, as judged by CBF, CMRo2, and SEP, 21% O2 is not inferior to 100% O2 when hypoxemic newborn pigs are reoxygenated.
This study determined the receptors responsible for mediating bradykinin's effect on skeletal muscle afferents that cause the pressor reflex in anesthetized cats. In eight cats, 1 microgram of bradykinin was injected intra-arterially into the gracilis muscle before and after intravenous injection of a kinin B2-receptor antagonist (NPC 17731, 20 micrograms/kg). Initial injection of bradykinin reflexly increased mean arterial pressure by 23 +/- 7 mmHg, maximal change in pressure over time by 439 +/- 272 mmHg/s, and heart rate by 11 +/- 4 beats/min. The hemodynamic response to bradykinin was abolished by kinin B2-receptor blockade. Similar injection of the kinin B1-receptor agonist des-Arg9-bradykinin caused no cardiovascular responses (n = 6). In eight different animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses to 30 s of electrically stimulated hindlimb contraction were attenuated by 50 +/- 6, 55 +/- 7, and 41 +/- 8%, respectively, after kinin B2-receptor blockade. In eight other animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses were reduced by 58 +/- 8, 66 +/- 6, and 40 +/- 12%, respectively, after inhibition of prostaglandin synthesis with indomethacin (2.5–3 mg/kg iv) and were then abolished by subsequent B2-receptor blockade. These data suggest that bradykinin contributes to the exercise pressor reflex through its action on kinin B2 receptors located on the nerve endings of the muscle afferents.(ABSTRACT TRUNCATED AT 250 WORDS)
Perfusion redistribution (PR) after acute oleic acid (OA) lung injury may be the result of changes in the tissue concentration ratio of thromboxane (Tx) and prostacyclin (A. H. Stephenson et al. J. Appl. Physiol. 73: 2126–2134, 1992). We tested this hypothesis by determining whether the Tx mimetic U-46619 would mimic PR caused by cyclooxygenase inhibition with meclofenamate and whether the Tx receptor antagonist ONO-3708 would inhibit PR even in the presence of meclofenamate. Measurements of regional pulmonary blood flow (PBF) and lung water concentration were made with the nuclear medicine imaging technique of positron emission tomography. Measurements were made at baseline and 2 h after OA. At baseline, the spatial distribution of PBF was similar in all experimental groups. Two hours after OA, fractional PBF was reduced to the edematous lung in all groups given OA, but the magnitude of change was greater in those groups receiving meclofenamate or U-46619 compared with the change in the group given OA only. Thus, although the Tx mimetic produced the same amount of PR as meclofenamate, Tx inhibition did not prevent PR after meclofenamate. Therefore, the ratio of Tx to prostacyclin per se is not the critical determinant of PR.
The purpose of this study was to examine the inability of paraplegic (P) subjects to redistribute fluid below the spinal cord lesion during arm exercise, with emphasis on the role of the sympathetic system in this redistribution failure. Fifteen male P and 15 male able-bodied [control (C)] subjects performed arm cranking exercise, and volume changes in the calf were measured by strain gauge plethysmography before, during, and after exercise. Muscle pump activity in the legs of C subjects was eliminated. The rate of calf volume decrease at the beginning and halfway points of the exercise period, the total volume decrease during exercise, and the volume increase during recovery were significantly lower in P than in C subjects. Whereas completeness of the lesion had no influence on leg volume changes, the rate of calf volume decrease at the beginning of exercise and the total volume decrease during exercise were significantly correlated with the level of the spinal cord lesion. This study confirms that P subjects are unable to redistribute fluid effectively below the spinal cord injury during arm exercise, which is partly caused by a loss of sympathetically induced vasoconstriction and which appears to be independent of the completeness of the lesion but dependent on its level.
Upper airway obstruction during sleep is characterized by inspiratory airflow limitation and reductions in maximal inspiratory airflow (VImax). To determine how mechanical factors modulate VImax, we analyzed pressure-flow relationships obtained in the isolated upper airway of paralyzed cats. VImax and its determinants, the pharyngeal critical pressure (Pcrit) and the nasal resistance (Rn) upstream to the flow-limiting site (FLS), were measured as caudal tracheal displacement, neck position, and airway length were systematically varied. As the proximal tracheal stump was displaced caudally, graded increases in VImax from 145.3 +/- 90.8 (SD) to 285.9 +/- 117.5 ml/s (P < 0.02) and decreases in Pcrit from -3.0 +/- 3.0 to -9.5 +/- 3.4 cmH2O (P < 0.002) were seen without any significant change in Rn. During neck flexion, significant decreases in VImax from 192.1 +/- 68.5 to 87.2 +/- 48.4 ml/s (P = 0.001), increases in Pcrit from -5.3 +/- 2.03 cmH2O to -1.6 +/- 1.4 cmH2O (P < 0.001), and decreases in Rn from 29.7 +/- 12.2 cmH2O.l-1.s to 16.2 +/- 8.9 cmH2O.l-1.s (P < 0.001) were noted compared with the neutral or extended neck position. Relative to the neutral airway length, upper airway length was found to decrease by 1.15 +/- 0.14 cm during neck flexion and to lengthen by 0.45 +/- 0.12 cm during neck extension. When tracheal displacement and neck position were altered, VImax and Rn correlated directly and Pcrit correlated inversely with airway length (P < 0.001). We conclude that alterations in airflow mechanics with caudal tracheal displacement and changes in neck positions are primarily due to alterations in airway length.
Previous studies suggested that phrenic motor output is largely refractory to afferent stimuli during gasping. We tested this concept by electrically stimulating the carotid sinus nerve (CSN) or the superior laryngeal nerve (SLN) of anesthetized peripherally chemodenervated vagotomized ventilated cats during eupnea or gasping induced by hypoxia. During eupnea, phrenic neurogram amplitude (PNA) increased by 110% during 30 s of supramaximal CSN stimulation, but burst frequency did not change. Progressive hypoxia caused gasping after arterial O2 content was reduced by 75%. During gasping, CSN stimulation caused premature onset of gasp in 12 of 13 trials, shortened intergasp interval [6.3 +/- 0.9 vs. 14.8 +/- 2.5 (SE) s], and resulted in a small (20%) but significant increase in PNA. Intensity of SLN stimulation was adjusted to abolish phrenic activity during the 30-s eupneic stimulation period. During gasping, SLN stimulation of the same intensity tended to delay onset of the next gasp, increased intergasp interval (16.9 +/- 1.9 vs. 13.3 +/- 1.2 s), and reduced PNA by 32%. Thus the respiratory burst pattern formation circuitry responds to afferent stimuli during gasping, albeit in a manner different from the eupneic response. These observations suggest that gasping is the output of a modified eupneic burst pattern formation circuit.
Maternal corticosteroid treatments augment lung function in the human preterm infant. However, not all fetuses respond, the response requires > or = 48 h of exposure, and multiple maternal doses expose the mother to potential risks. To evaluate the potential of direct fetal therapy, we used ultrasound to direct fetal intramuscular or intravascular injections of corticosteroids or saline in sheep and subsequently delivered the preterm lambs at 128 days gestational age to assess postnatal lung function. Relative to saline-injected controls, 0.5 or 2 mg/kg betamethasone given as a single intramuscular dose 48 h before delivery increased compliance and the efficiency of ventilation (as measured by an indicator that included ventilatory pressures and CO2 values) nearly twofold (P < 0.05). Lung volumes, measured from deflation pressure-volume curves, also increased (P < 0.05). However, the 2 mg/kg dose caused severe pulmonary interstitial emphysema in 5 of 13 lambs, suggesting adverse effects. An intravascular fetal dose of 12.5 mg/kg hydrocortisone or an intramuscular dose of 0.1 mg/kg betamethasone had no effect on postnatal lung function. In separate studies, the 2 mg/kg dose improved all indicators of lung function almost twofold after only 24 h of fetal exposure and delivery at 128 days gestational age (P < 0.01). There was a dose-dependent suppression of the postnatal cortisol surge in treated animals, although fetal treatment did not alter cord cortisol levels. Single-dose fetal hormone treatments can cause large and rapid improvements in postnatal lung function in preterm lambs.
Pulmonary vascular distensibility has an important influence on pulmonary hemodynamics. Although many measurements of distensibility have been made on large pulmonary vessels, there is less information on microvascular distensibility. We have measured the distensibility of the smallest (< 70-microns-diam) precapillary arterioles and postcapillary venules. Isolated dog lobes, at 2.5 cmH2O transpulmonary pressure, were perfused at low flows, which caused the arteriovenous pressure gradient to be very small and thereby permitted accurate estimation of microvascular pressure. As microvascular pressure was systematically varied between 0 and 30 mmHg, subpleural microvascular diameters were determined from computer-enhanced images obtained by videomicroscopy. Arteriolar and venular distensibilities were not different from each other. The microvascular pressure-diameter relationship was alinear with distensibility coefficients of 1–3% mmHg-1, values that are of the same order of magnitude as previously measured distensibilities of 100- to 1,000-microns-diam canine pulmonary vessels.
The role of the epithelium and cyclooxygenase products was investigated in the responses of isolated airways to sudden stretch. Strips of guinea pig trachea, in some of which the epithelium had been removed mechanically, were suspended in organ chambers; isometric tension was recorded. After rapid stretching to their optimal tension, the preparations (with and without epithelium) relaxed initially and then contracted to a level close to the imposed tension. Afterward, tissues with epithelium maintained this level of tension, but those without epithelium relaxed. After treatment with papaverine or isoproterenol (at concentrations causing maximal relaxation), stretch was followed only by a decrease in tension; a similar response to stretch was also obtained in tissues treated with indomethacin or acetylsalicylic acid (inhibitors of cyclooxygenase). Dazmegrel (an inhibitor of thromboxane synthase) and SQ-29548 (an antagonist of prostaglandin H2 or thromboxane A2 receptors) did not affect the response of tissues with epithelium but abolished the stretch-induced contraction in those without epithelium. Tranylcypromine, which inhibits prostacyclin synthase, and tetrodotoxin, which blocks local reflexes, did not significantly affect the responses of the tissues to stretch. These observations suggest that thromboxane may mediate the epithelium-independent contraction and that another product of cyclooxygenase contributes to the maintenance of tension on stretching observed in tissues with epithelium.
Increased retropalatal airway resistance may be caused by a sleep-induced loss of palatal muscle activity and a diminished ability of these muscles to respond to the increasing intrapharyngeal negative pressure that develops during sleep. To investigate these possibilities, in six normal subjects, we determined the effect of non-rapid-eye-movement sleep on 1) the tensor palatini (TP) electromyogram (EMG) response to rapid-onset negative-pressure generations (NPG) in the upper airway and 2) the collapsibility of the retropalatal airway during these NPGs. During wakefulness, the change in TP EMG from basal to peak levels (during NPG) was 19.8 +/- 3.2 arbitrary units (P < 0.005). This was markedly reduced during sleep (3.6 +/- 1.5 arbitrary units; P < 0.001). The latency of the TP EMG response was 48.5 +/- 5.6 ms during wakefulness but was prolonged during sleep (105.0 +/- 12.2 ms; P < 0.02). The peak transpalatal pressure during NPG (a measure of airway collapse) was 2.1 +/- 0.7 cmH2O during wakefulness and increased to 5.3 +/- 0.8 cmH2O during sleep (P < 0.05). We conclude that the brisk reflex response of the TP muscle to negative pressure during wakefulness is markedly reduced during non-rapid-eye-movement sleep, in association with a more collapsible retropalatal airway. We speculate that the reduction in this TP reflex response contributes to retropalatal airway narrowing during sleep in normal subjects.
To examine effects of aging and endurance training on human muscle metabolism during exercise, 31P magnetic resonance spectroscopy was used to study the metabolic response to exercise in young (21–33 yr) and older (58–68 yr) untrained and endurance-trained men (n = 6/group). Subjects performed graded plantar flexion exercise with the right leg, with metabolic responses measured using a 31P surface coil placed over the lateral head of the gastrocnemius muscle. Muscle biopsy samples were also obtained for determination of citrate synthase activity. Rate of increase in P(i)-to-phosphocreatine ratio with increasing power output was greater (P < 0.01) in older untrained [0.058 +/- 0.022 (SD) W-1] and trained men (0.042 +/- 0.010 W-1) than in young untrained (0.038 +/- 0.017 W-1) and trained men (0.024 +/- 0.010 W-1). Plantar flexor muscle cross-sectional area and volume (determined using 1H magnetic resonance imaging) were 11–12% (P < 0.05) and 16–18% (P < 0.01) smaller, respectively, in older men. When corrected for this difference in muscle mass, age-related differences in metabolic response to exercise were reduced by approximately 50% but remained significant (P < 0.05). Citrate synthase activity was approximately 20% lower (P < 0.001) in older untrained and trained men than in corresponding young groups and was inversely related to P(i)-phosphocreatine slope (r = -0.63, P < 0.001). Age-related reductions in exercise capacity were associated with an altered muscle metabolic response to exercise, which appeared to be due to smaller muscle mass and lower muscle respiratory capacity of older subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
The current Canadian Recommended Nutrient Intake (RNI) for protein (0.86 g.kg-1.day-1) makes no allowance for an effect of habitual physical activity. In addition, Tarnopolsky et al. (J. Appl. Physiol. 68: 302–308, 1990) showed that males may catabolize more protein than females consequent to endurance exercise. We examined nitrogen (N) balance and leucine kinetics during submaximal endurance exercise to determine the adequacy of the current Canadian RNI for protein for male and female endurance athletes. Athletes were matched for equal training volume, competitive status, and conditioning and were fed diets isoenergetic with their habitual intake, containing protein at the Canadian RNI. Subjects were adapted to the diet for 10 days before completing a 3-day measurement of N balance. N balance showed that the RNI was inadequate for females (-15.9 +/- 6.0 mg.kg-1.day-1) and males (-26.3 +/- 11.0 mg.kg-1.day-1). Leucine kinetics during exercise were determined for each subject on day 3 of the N balance experiment by use of a primed continuous infusion of L-[1–13C]leucine and the reciprocal pool model. Exercise resulted in a significant (P < 0.01) increase in leucine oxidation for both groups. Males oxidized a greater amount of leucine during the infusion than females (P < 0.01). Leucine flux also increased significantly (P < 0.01) during exercise in both groups. We conclude that the current Canadian RNI for protein is inadequate for those who chronically engage in endurance exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
In 19 normal subjects in the supine posture, we compared accuracy and precision of calibration methods that utilized different ranges of tidal volumes and thoracoabdominal partitioning: spontaneous quiet breathing (QB), isovolume maneuvers, and voluntary efforts to breathe with variable tidal volume and thoracoabdominal partitioning. Thoracic and abdominal movements were measured with the respiratory area fluxometer. Calibration methods utilizing one or more types of respiratory efforts were applied to three measurement situations: QB, variable breathing (volume and thoracoabdominal partitioning), and simulated obstructive apnea (isovolume efforts). Qualitative diagnostic calibration (QDC) included QB data only. The isovolume method (ISOCAL) included isovolumetric efforts at end expiration (functional residual capacity) and QB. Multilinear regression analyses were performed on data sets that included 1) voluntary efforts to breathe with variable volume and thoracoabdominal partitioning (CAL 1), 2) QB in addition to variable volume and partitioning (CAL 2), and 3) isovolume maneuvers in addition to QB and variable volume and partitioning efforts (CAL 3). When calibration data included a wide range of tidal volume, variable thoracoabdominal partitioning, and isovolume efforts (CAL 3), a stable calibration with small bias and scatter during all respiratory patterns was obtained. Excluding isovolume maneuvers (CAL 2) and QB (CAL 1) did not diminish accuracy. Limiting data to isovolume efforts at functional residual capacity plus QB (ISO-CAL) caused a significant increase in scatter during variable breathing patterns. Limiting calibration data to that portion of QB with small variation in the uncalibrated sum of thoracic and abdominal movements (QDC) caused significant increases in scatter in both isovolume efforts and variable breathing.
The effects of an exhaustive bout of eccentric exercise on insulin secretion and action were determined using the hyperglycemic clamp technique. Clamps were performed on eight healthy men after 7 days of inactivity and approximately 36 h after a bout of eccentric exercise. Eccentric exercise consisted of 10 sets of 10 repetitions of combined knee extensions and flexions for each leg at a mean torque 84 +/- 5% of peak concentric torque. During the hyperglycemic clamp procedure, plasma glucose concentration was acutely raised to 10 mmol/l and was maintained near this level for 120 min. Arterialized blood samples were obtained from a heated hand vein to determine plasma glucose and insulin concentrations. Eccentric exercise appeared to produce marked muscle damage, as indicated by a 50-fold increase in plasma creatine phosphokinase (100 +/- 17 vs. 5,209 +/- 3,811 U/l, P < 0.001) and subjective reports of muscle soreness. Peak insulin response during the early phase (0–10 min) of the hyperglycemic clamp was higher after eccentric exercise (183 +/- 38 microU/ml) than after the control clamp (100 +/- 23 microU/ml, P < 0.005). Late-phase (10- to 120-min) insulin response was not altered after eccentric exercise. Peak plasma C-peptide concentrations were higher during the early phase (5.0 +/- 0.7 vs. 4.3 +/- 0.8 ng/ml, P < 0.05) and the late phase (7.5 +/- 0.9 vs. 5.4 +/- 0.6 ng/ml, P < 0.05). Prior eccentric exercise had no significant effect on whole body glucose disposal or glucose disposal rate adjusted for prevailing plasma insulin concentration. These data provide evidence that a single bout of eccentric exercise causes an increase in pancreatic beta-cell insulin secretion in response to hyperglycemia.
Both sides of the nasal vasculature of the dog in vivo were perfused separately, with measurement of vascular resistance responses to stimulation of various nerves. Stimulation of the central end of a cut superior laryngeal nerve caused an ipsilateral vasodilation (-4.98%) and a contralateral vasoconstriction (+3.96%), the difference being statistically significant (P < 0.01). Stimulation of a glossopharyngeal nerve caused vasodilation on both sides, the ipsilateral (-17.52%) being greater than the contralateral (-6.33%) response (P < 0.05). Mechanical stimulation of the nasal mucosa caused little ipsilateral change (+0.47%) and a weak contralateral vasoconstriction (+3.78%; P < 0.01). Stimulation of the central end of a cervical vagus nerve caused vasodilations on both sides, the ipsilateral (-9.75%) being greater than the contralateral (-5.73%) change (P < 0.05). With bilateral perfusions of the cervical tracheal arteries, stimulation of a superior laryngeal nerve caused vasodilation on both sides, the ipsilateral (-10.1%) being greater than the contralateral (-7.4%) response (P < 0.05). Stimulation of the central end of a vagus nerve caused vasoconstrictions on both the sides, the ipsilateral (+37.4%) being greater than the contralateral (+10.8%) change (P < 0.05). Thus various nervous inputs from the nose, pharynx, larynx, and vagal distribution cause asymmetric vascular responses both in the nose and in the cervical trachea.
To examine the effect of chronological age on thermoregulation during passive heat exposure, six older (O, 61 +/- 1 yr) and six young (Y, 26 +/- 2 yr) men sat at rest during a 30-min baseline period (dry-bulb temperature = 28 degrees C), a 60-min thermal transient (28–46 degrees C by 2 degrees C steps every 5 min), and 30 min at 46 degrees C dry-bulb temperature. Subjects were matched for maximal O2 consumption, anthropometry, and body composition. Testing was repeated after a 9-day active heat acclimation protocol. There were no age differences in rectal (Tre), mean skin (Tsk), or mean body temperature (Tb = 0.8Tre + 0.2Tsk) before or after acclimation, but heart rate was lower (P < 0.01) in the O group in both acclimation states. Heat acclimation resulted in a significantly lower baseline Tre and Tb in both groups, which remained lower throughout the passive heat stress (P < 0.05). To examine the effects of age and acclimation on thermoregulatory effector function, forearm blood flow (by venous occlusion plethysmography) and chest sweating rate (SRch, by dew-point hygrometry) were plotted against Tb. The slope of the forearm blood flow-Tb relationship was significantly (P < 0.05) lower in the O group before and after acclimation. A lower maximal SRch (P < 0.05) was achieved by the O group, but neither the slope of SRch-Tb relationship nor the Tb threshold for sweating was affected by age. Predictably, acclimation resulted in a lower Tb threshold for the onset of sweating and skin vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
The exogenous carbohydrate (CHO) oxidation of naturally enriched [13C]CHO sources with different solubilities was studied during cycling exercise (150 min, 60% maximum work output). Moreover, the effect of adding a 13C tracer with different physical properties than the tracee on exogenous CHO oxidation was investigated. Test solutions (28.5 ml/kg body wt) were water for control of 13C background, 15% soluble partially hydrolyzed corn starch (SOL), 15% insoluble corn starch (In-SOL), and 15% InSOL with [13C6]glucose as tracer. Both the mean and peak exogenous oxidation rates were significantly greater (P < 0.05) in the SOL trial than in the InSOL trial (mean oxidation rate, 0.84 +/- 0.21 and 0.50 +/- 0.15 g/min, respectively; peak oxidation rate, 1.10 +/- 0.18 and 0.81 +/- 0.25 g/min, respectively). The amount of the ingested CHO that was oxidized was significantly higher (P < 0.05) in the SOL trial (126 +/- 31 g) than in the InSOL trial (75 +/- 25 g). When we added an extrinsic tracer ([13C]glucose), the apparent mean and peak oxidation rates of the trial with InSOL and [13C6]glucose were significantly (P < 0.05) higher (0.91 +/- 0.30 and 1.23 +/- 0.41, respectively) than the InSOL values. These results 1) indicate that the addition of the soluble [13C]glucose tracer to an insoluble starch tracee leads to overestimation of the exogenous CHO oxidation rates and 2) suggest that soluble CHO is oxidized at a higher rate during exercise than isocaloric insoluble CHO.
Arteries to the cervical trachea were perfused at constant flow in anesthetized sheep. Perfusion pressures (PP), blood pressure (BP), and changes in tracheal smooth muscle tone (Ptr) were measured. Stimulation of pulmonary C-fiber receptors decreased PP (-6.5%) and BP (-16.8%) and increased Ptr (+61.5%), changes prevented by vagotomy and therefore reflex. Stimulation of cardiac receptors and slowly adapting pulmonary stretch receptors decreased PP (-7.9%) and BP (-21.0) and increased Ptr (+19.0%), changes reversed by vagotomy and therefore reflex. Stimulation and inhibition of slowly adapting pulmonary stretch receptors had no vagal-dependent effect on PP and BP, but inflation decreased (-20.3%) and deflation increased Ptr (+35.2%), effects abolished by vagotomy and therefore reflex. Systemic hypoxia increased PP and BP before and after vagotomy (+12.2 and +40.3%), effects greatly reduced by cutting the carotid body nerves; it increased Ptr (+29.8%), an effect abolished by vagotomy and cutting the carotid body nerves. Systemic hypercapnia increased PP (+16.9%), BP (+20.5%), and Ptr (+36.2%), the first two responses being unaffected by vagotomy and the last almost abolished. Stimulation of carotid body chemoreceptors by KCN increased PP (+22.5%), BP (+104.7%), and Ptr (+8.5%), all responses prevented by cutting the carotid body nerves. Responses to intravenous injections of KCN were similar.
Although episodes of prolonged limb skeletal muscle ischemia followed by periods of reperfusion and reoxygenation are known to elicit free radical-mediated injury, the susceptibility of the diaphragm to this form of injury is not known. The purpose of the present study was to determine the effects of a period of severe partial ischemia, followed by reperfusion, on diaphragm contractile function. We also examined the effect of administration of a free radical scavenger, dimethyl sulfoxide (DMSO), on the diaphragmatic response to ischemia-reperfusion. Experiments were performed on three groups of anesthetized dogs in which a vascularly isolated strip of diaphragm was dissected in situ: 1) a control group in which the diaphragm was perfused at the ambient systemic pressure, 2) a group in which the diaphragm was made ischemic for 3 h and reperfused for 1 h, and 3) a group given DMSO before periods of ischemia and reperfusion. In all groups, we measured diaphragm strip strength and fatigability; we also assessed diaphragm blood flow at several levels of contractile activity. Periods of ischemia, followed by reperfusion, were found to produce a downward shift of the diaphragm force-frequency relationship and also to markedly increase diaphragm fatigability. Diaphragm blood flow at rest and at low levels of contractile activity was unaffected by ischemia-reperfusion, but the flow achieved during fatiguing contractions was appreciably lower than that in nonischemic control animals. DMSO administration protected the diaphragm from the effects of ischemia-reperfusion, preventing alterations in fatigability and strength. Diaphragm flow in DMSO-treated animals was similar to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Inspiratory muscle fatigue, a common event in patients in the intensive care unit, is under multifactorial control. To test the hypothesis that systemic oxygenation is a factor in this event, we subjected five healthy males (age 42 +/- 3 yr) to continuous inspiratory pressure (75% of maximal inspiratory pressure, -95 +/- 5 cmH2O) with the use of a controlled breathing pattern while they breathed normoxic (21% O2), hyperoxic (30% O2), and hypoxic (13% O2) mixtures. Inspiratory muscle endurance (IME; time that pressure could be maintained) and other cardiorespiratory parameters were monitored. Room air IME (3.3 +/- 0.4 min) was shortened (P < 0.05) during 13% O2 breathing (1.6 +/- 0.4 min) but was unaffected during 30% O2 breathing (4.0 +/- 0.6 min). Inspiratory loading lowered the respiratory exchange ratio (RER) during the 21 and 30% O2 trials (1.02 +/- 0.01 to 0.80 +/- 0.03% and 1.05 +/- 0.05 to 0.69 +/- 0.01%, respectively) but not during the 13% O2 trials (1.03 +/- 0.03 to 1.06 +/- 0.07%). At the point of fatigue during the 13% O2 trials, RER was lower compared with the same time point during the 21 and 30% O2 trials. A significant relationship was observed between IME and RER (r = -0.73, P = 0.002) but not between IME and any of the other measured variables. We conclude that 1) hypoxemia impairs the ability of the inspiratory muscles to sustain a mechanical challenge and 2) substrate utilization of the respiratory muscles shifts toward a greater reliance on lipid metabolism when O2 is readily available; this shift was not observed when the O2 supply was reduced.
Injection of water into a lobar bronchus stimulates airway C-fibers and rapidly adapting receptors and evokes airway defense reflexes. To determine whether this stimulus also evokes a reflex increase in bronchial blood flow (Qbr), we injected 1–2 ml of water into a lobar bronchus in anesthetized dogs. Injection decreased arterial pressure but increased Qbr from 9 +/- 1 to 21 +/- 3 ml/min. The increase had a latency of 6–8 s and reached a peak after approximately 20 s; Qbr returned to control after 60–90 s. Airway mucosal blood flow, measured by colored microspheres, increased in proportion to Qbr. In contrast, flow in an adjacent intercostal artery that did not supply the airway decreased slightly. Injection of isosmotic saline had little effect. In 13 of 16 dogs, the water-induced increase in Qbr was abolished by cutting or cooling the cervical vagus nerves and hence was entirely dependent on centrally mediated vagal pathways. When the vagus nerves were intact, about one-third of the vasodilator response remained after pharmacological blockade of muscarinic and adrenergic receptors. We conclude that in dogs the defense response to water in the lower airways includes a large increase in Qbr that is partly due to activation of nonadrenergic noncholinergic autonomic pathways.
The influence of 14 days of spaceflight on cancellous bone of male Wistar rats was assessed by histomorphometric analysis. In proximal tibia, no difference was found between flight, synchronous, vivarium, and basal groups for epiphyseal bone volume or trabecular arrangement. In metaphysis, primary spongiosa width was reduced in flight rats, suggesting an alteration in bone longitudinal growth. In flight rats, secondary spongiosa evidenced a trend toward decreased bone mass, trabecular number and thickness, and osteoid surfaces, whereas there was a tendency toward increased osteoclast number compared with vivarium control but not with synchronous rats. In femoral fossa trochanteri, an area facing deep muscular insertions, no changes in bone volume or structure were noted among the different groups. However, a reduction of osteoid surfaces was seen in flight and synchronous groups compared with the other groups. Resorption activity was increased in flight rats compared with control rats. In thoracic vertebral body, osteoblastic surfaces decreased similarly in flight and synchronous rats. In lumbar vertebral body, decreased osteoblastic surfaces and increased osteoclastic parameters were observed in flight and synchronous rats. The more striking effects of spaceflight were the decrease in tibial primary spongiosa width and the increase in resorption activity of the femoral fossa trochanteri. In all other sites, cellular alterations appeared similar in flight and synchronous rats, suggesting a role for physiological stress. The time course of events would depend on initial growth and turnover rates of bone, its weight-bearing function on earth, and the presence of muscular insertions.
Findings from studies of the effects of aging on the human respiratory controller are equivocal. This study assessed the ventilatory response to CO2 in hyperoxia and hypoxia in groups of younger (YS) and older (OS) humans. Two protocols were used. In the first, end-tidal PCO2 (PETCO2) was clamped at 1–2 Torr above rest (eucapnia), and, in the second, PETCO2 was clamped at 7–8 torr above resting PETCO2 (moderate hypercapnia). End-tidal PO2 was clamped at 100 Torr throughout except for two 2-min periods at 500 and 50 Torr. The ventilatory responses for each subject at each PO2 were fitted to the linear equation, VE = S(PETCO2 - B), where VE is minute ventilation, S is the response curve slope, and B is the response curve threshold. In eucapnia, there were no differences in hypoxic and hyperoxic VE between YS and OS. In hypercapnia, hypoxic VE was 24% lower in OS [39.93 +/- 2.71 (SE) l/min] than in YS (52.16 +/- 3.17 l/min). In hypoxia, S was significantly lower in OS (3.25 +/- 0.38 l.min-1.Torr-1) than in YS (4.76 +/- 0.37 l.min-1.Torr-1). We conclude that, in older humans, VE is lower in hypoxia during moderate hypercapnia, resulting mainly from a decreased peripheral chemoreflex CO2 sensitivity.
During exercise, as heart rate (HR) increases, the QT interval of the electrocardiogram shortens. The mechanism(s) involved in this QT shortening has not been clearly defined. To distinguish the influence of increased circulating catecholamines from myocardial efferent stimulation, the relationship between HR and QT interval was investigated during exercise and cardiovascular reflex stimulation in cardiac transplant patients and normal control subjects. Because of cardiac denervation, increases in HR in these patients are solely due to circulating catecholamines and thus allow isolation of their effect on the QT interval. Twenty-one cardiac transplant patients were studied and compared with 16 normal control subjects. The QT-HR relationship was determined according to an exponential model during treadmill exercise in both groups [QT = 0.12 + 0.492e(-0.008.HR) and QT = 0.12 + 0.459e(-0.007.HR) in normal subjects and transplant patients, respectively] and was statistically similar between groups, suggesting similar QT interval shortening in both groups. During cold pressor and Valsalva maneuvers, HR increased significantly in normal subjects only, whereas QT interval changed minimally in both groups. These results suggest that during exercise the QT interval is influenced predominantly by increases in circulating catecholamines rather than by neurally mediated reflex autonomic changes.
Cell-free hemoglobin (Hb) preparations have been shown to alter vascular tone in vitro and in vivo. The high affinity of Hb for nitric oxide, the putative endothelium-derived relaxing factor (EDRF), may be primarily responsible for this activity, but the contribution of tissue-damaging oxygen-derived free radicals has not been established. We investigated the effects of human Hb interdimerically cross-linked with bis-(3,5-dibromosalicyl)fumarate (alpha alpha Hb) on the coronary vasomotor response to acetylcholine (ACh) in isolated perfused rabbit hearts. Infusion of 0.1 g/dl alpha alpha Hb altered the dose-dependent response to ACh, decreasing the calculated IC50 (ACh concn at which coronary pressure is 50% of its maximal value) from 3.96 +/- 0.34 to 0.85 +/- 0.06 microM (P < 0.01). This augmented sensitivity to ACh was only partially reversed upon washout of alpha alpha Hb (IC50 1.93 +/- 0.13 microM). Simultaneous infusion of 60 microM deferoxamine mesylate with alpha alpha Hb attenuated this response (IC50 decreased from 3.86 +/- 0.27 to 1.73 +/- 0.38 microM), which was completely reversed after removal of alpha alpha Hb (IC50 3.41 +/- 0.17 microM). NG-nitro-L-arginine methyl ester (50 microM) and cross-linked cyanomethemoglobin (CNmet alpha alpha Hb, 0.1 g/dl) induced a significant (P < 0.05) increase in ACh-induced vasoconstriction accompanied by a reduction in myocardial functions in the same range as that caused by alpha alpha Hb. Infusion of deferoxamine mesylate (60 microM) with CNmet alpha alpha Hb completely prevented the reduction in IC50 elicited by the infusion of CNmet alpha alpha Hb alone. These data demonstrate that alpha alpha Hb can alter coronary vasomotor responsiveness and suggest the involvement of at least two mechanisms, one that is related to an accessible ferrous heme and is reversible and another that does not require an open heme site and is irreversible.
We measured electromyographic activity of the diaphragm (EMGdi) and scalene (EMGsc) during isocapnic progressive hypoxic ventilatory responses in five normal males in the supine and upright seated positions. The slope of the regression line relating EMGdi expressed as a percentage of maximum to percent fall in arterial oxyhemoglobin saturation was 93% steeper upright than supine (P < 0.005), whereas the slope of EMGdi activity to minute volume of ventilation was 73% higher upright than supine (P < 0.05). In addition, the slope of EMGsc activity relative to percent fall in arterial oxyhemoglobin saturation and minute ventilation was greater upright than supine (151%, P < 0.001 and 61%, P = 0.056, respectively). Greater EMGsc activity upright than supine was similar to findings during hypercapnic rebreathing. However, the greater EMGdi activity upright than supine stands in contrast to hypercapnic rebreathing where it was previously shown that EMGdi activity was not affected by a change in body position. We conclude that during hypoxic ventilatory responses both EMGdi and EMGsc activities are more pronounced upright than supine. Diaphragmatic activation during progressive hypoxia in response to a change in body position is different from that seen during progressive hypercapnia.
Assessment of changes in airway dimensions during bronchoconstriction is conventionally based on measurements of respiratory mechanics. We evaluated the efficacy of ultrafast high-resolution computed tomography (UHRCT) to directly determine the dynamic changes in cross-sectional area (CSA) of airways in response to methacholine (MCh). UHRCT scans were obtained at functional residual capacity before (baseline) and after intravenous bolus injections of MCh (10(-8.5)-10(-7.0) mol/kg) to seven mechanically ventilated pigs. Changes in CSA of bronchi of varying baseline size (1–10 mm diam) were determined by using a customized image processing software package (VIDA) based on a user-directed computer-adjusted edge-finding algorithm. MCh induced dose-dependent decreases in CSA, which were paralleled by increases in airway opening pressure at higher doses of MCh; at lower doses of MCh, decreases in CSA of smaller airways were detected without concomitant changes in airway opening pressure. Changes in CSA were heterogeneous and variable, especially in the smaller airway ranges. The results of the present study support the concept that UHRCT can be used in conjunction with bolus challenges to effectively determine dose-response changes in airway caliber in both large and small airways. This technique provides data that may not be reflected by conventional lung function measurements and, hence, is a useful tool to study airway reactivity.
We tested whether moderate dynamic exercise alters baroreflex control of heart rate (HR) in conscious dogs and whether the autonomic mechanisms mediating arterial baroreflex control of HR differ in the two settings of rest and exercise. Conscious, chronically instrumented dogs were studied during rest and moderate treadmill exercise (6.4 kpm, 10% grade). Sustained changes in mean arterial pressure (MAP) were induced by graded intravenous infusions of phenylephrine and nitroglycerine. Baroreflex HR sensitivity was assessed as the slope of the linear regression between MAP and HR. Responses to increases and decreases in MAP were analyzed separately. Studies were repeated after muscarinic (atropine, 0.2 mg/kg iv) or beta-adrenergic (propranolol, 2.0 mg/kg iv) blockade during rest and exercise. During control experiments both at rest and during exercise, baroreflex changes in HR were greater in response to decreases than to increases in MAP. Experiments performed after separate cardiac autonomic blockade revealed that at rest baroreflex-induced bradycardia occurs via parasympathetic activation but tachycardia occurs via a combined parasympathetic inhibition-sympathetic activation. During exercise, whereas the magnitude of baroreflex responses was unchanged compared with rest, the autonomic mechanisms mediating the baroreflex changes in HR were altered. In this setting, baroreflex tachycardia and bradycardia occur via modulation of both parasympathetic and sympathetic tone.
Passing galvanic current across the skin (known as "tap water iontophoresis" or TWI) inhibits sweating; however, its mechanism of action is unclear. Using improved methods, we confirmed that anodal current has more of an inhibitory effect than cathodal current, water is superior to saline, and the inhibitory effect is a function of the amperage used. To address the importance of current flowing through the pores, a layer of silicone grease was placed on the skin to reduce the shunt pathway across the epidermis. With silicone, total skin conductance decreased 60% without the sweat pores being occluded, swelling of the stratum corneum and collapse of the poral lumen was prevented, and current-induced inhibition of sweating was enhanced, most likely because of an increase in current density in the pores. The pH of anodal water, but not of saline, dropped to 3, whereas that of cathodal water increased to 10 during passage of current through the skin. Acidified anodal water was superior to alkaline water. Sweat glands isolated from TWI-induced anhidrotic palmar skin responded to methacholine in vitro, but the sweat rate and pharmacological sensitivity were slightly lowered. Thus the strong acidity generated by hydrolysis of water in the anodal bath and the further accumulation of H+ in the sweat duct by anodal current may be responsible for TWI-induced inhibition of sweating due to an unknown lesion(s) in the duct or sweat pore. The secretory coil function may also be altered because of exposure to intense acidity during TWI. The importance of H+ movement into the sweat pore for inhibition of sweating could be further exploited to develop new strategies for the control of sweating.
Determinants of lengthening velocity have not been investigated in the diaphragm muscle. This study was undertaken to define the mechanical determinants of isotonic relaxation rate over the entire load continuum in isolated rat diaphragm (n = 30). We tested the hypothesis that the determinants of lengthening could include loading conditions, namely, preload and afterload; abrupt changes of load during the contraction phase; end-shortening muscle length (ESL); extent of shortening (delta L); time; stimulation mode; and stimulation frequency. In afterloaded contractions preloaded at optimal initial length and stimulated in tetanus at 30 Hz, peak lengthening velocity (+dL/dtmax) was linearly related to delta L, ESL, and/or total load. Varying initial muscle length, ESL, afterload, or the load imposed on the muscle during the isotonic lengthening process did not modify +dL/dtmax vs. delta L relationship, whereas +dL/dtmax vs. load and +dL/dtmax vs. ESL relationships were modified by these procedures. For a given delta L, +dL/dtmax could be modified when lengthening was delayed by reversing the relaxation sequence and when twitch and tetanus modes were compared. In conclusion, our results demonstrate that in isolated diaphragm muscle, delta L is the main determinant of +dL/dtmax over a wide range of loads and under various experimental conditions, independent of ESL and initial muscle length and independent of the load imposed on the muscle during the lengthening process. Time and stimulation mode were also shown to modulate the lengthening rate in diaphragm muscle.
An anatomically accurate, x20 enlarged scale model of a healthy right human adult nasal cavity was constructed from computerized axial tomography scans for the study of nasal airflow patterns. Detailed velocity profiles for inspiratory and expiratory flow through the model and turbulence intensity were measured with a hot-film anemometer probe with 1 mm spatial resolution. Steady flow rates equivalent to 1,100, 560, and 180 ml/s through one side of the real human nose were studied. Airflows were determined to be moderately turbulent, but changes in the velocity profiles between the highest and lowest flow rates suggest that for normal breathing laminar flow may be present in much of the nasal cavity. The velocity measurements closest to the model wall were estimated to be inside the laminar sublayer, such that the slopes of the velocity profiles are reasonably good estimates of the velocity gradients at the walls. The overall longitudinal pressure drop inside the nasal cavity for the three inspiratory flow rates was estimated from the average total shear stress measured at the central nasal wall and showed good agreement with literature values measured in human subjects.
Peak O2 uptake (VO2) has traditionally been compared among individuals differing in body composition by dividing measured values (1/min) by fat-free mass (FFM) (i.e., ratio method). However, the ability of the ratio method to mathematically remove the confounding influence of FFM from peak VO2 has recently been questioned. Therefore, we compared the effectiveness of the ratio method vs. regression modeling to normalize peak VO2 in a large cohort of males and females for differences in FFM. Regression modeling adjusts peak VO2 according to the relationship derived from the regression of peak VO2 on FFM. Results showed that peak VO2 was 60% higher in males (3.53 +/- 1.01/min) than in females (2.22 +/- 0.6 l/min; P < 0.01). With the ratio method (i.e., peak VO2/FFM), peak VO2 was 15% higher in males (54.6 +/- 12 ml.kg FFM-1.min-1) than in females (47.4 +/- 11 ml.kg FFM-1.min-1; P < 0.01). In contrast, when a regression-based approach was employed to normalize values, no significant difference in adjusted peak VO2 was observed between males and females (3.04 +/- 0.9 vs. 3.01 +/- 1.0 l/min). In conclusion, dividing peak VO2 by FFM can produce spurious results, because this approach does not take into account the nonzero intercept. Therefore, a regression-based approach should be used to normalize peak VO2.
We used numerical solutions of a system of equations to simulate gas exchanges of bubbles after a decompression, with particular attention to the effect of number of bubble formation sites per unit of tissue. If many bubbles grow, they deplete the excess dissolved gas in the tissue. The consequences are as follows: 1) the many individual bubbles do not become as large as they would if fewer were competing for gas; 2) more gas is evolved when there are many sites; 3) the bubbles are absorbed sooner than the bigger bubbles that grow with few sites; 4) after diffusion into many bubbles causes N2 partial pressure in the tissue to fall immediately to a low level, N2 partial pressure in the tissue and the exiting blood remain "clamped" to this low level because dissolved N2 removed by blood is replenished by diffusion out of the bubbles; and 5) as long as many bubbles persist, the long-term removal of inert gas from the total system (tissue plus bubbles) follows a straight-line time course rather than an exponential course.
The Bohr/Riley model of CO2 homeostasis describes the relationship between CO2 production, ventilation, and arterial PCO2 and assumes that ventilation and CO2 delivery to the lung are both anatomically and temporally well matched. In contrast to normal breathing, periodic patterns of ventilation show temporal mismatch of ventilation to CO2 delivery. We developed a computer model of lung CO2 clearance that uses CO2 transfer equations to generate iterative solutions for PCO2 in multiple body compartments as a function of time. During continuous ventilatory patterns our model predicts steady-state arterial PCO2 identical to that of the Bohr model. During periodic ventilation, we predict mean PCO2 will be elevated unless mean ventilation is increased above that required by the Bohr model. Waxing and waning tidal volumes, low functional residual capacity, and low capillary blood volume potentiate the hypercapnia. However, if cardiac output oscillates in phase with breathing, hypercapnia is minimized. This analysis suggests a new mechanism for the development of sustained hypercapnia, separate from absolute hypoventilation or the presence of lung disease.
Frequency-domain analyses of R-R intervals are used widely to estimate levels of autonomic neural traffic to the human heart. Because respiration modulates autonomic activity, we determined for nine healthy subjects the influence of breathing frequency and tidal volume on R-R interval power spectra (fast-Fourier transform method). We also surveyed published literature to determine current practices in this burgeoning field of scientific inquiry. Supine subjects breathed at rates of 6, 7.5, 10, 15, 17.1, 20, and 24 breaths/min and with nominal tidal volumes of 1,000 and 1,500 ml. R-R interval power at respiratory and low (0.06–0.14 Hz) frequencies declined significantly as breathing frequency increased. R-R interval power at respiratory frequencies was significantly greater at a tidal volume of 1,500 than 1,000 ml. Neither breathing frequency nor tidal volume influenced average R-R intervals significantly. Our review of studies reporting human R-R interval power spectra showed that 51% of the studies controlled respiratory rate, 11% controlled tidal volume, and 11% controlled both respiratory rate and tidal volume. The major implications of our analyses are that breathing parameters strongly influence low-frequency as well as respiratory frequency R-R interval power spectra and that this influence is largely ignored in published research.
Continuous recording of plasma K+ concentration ([K+]) during exercise would be valuable in determining K+ fluxes associated with muscle activation. Pliable polyvinyl chloride electrodes were constructed by incorporation of valinomycin into a polyvinyl chloride membrane attached to the end of a catheter with a 1 mm outer diameter. Through an outer catheter the electrode was inserted into the femoral vein of human subjects. The setup allowed easy in vivo calibration, and rapid changes of femoral venous [K+] of < 0.1 mmol/l could easily be detected. Drift over 1 h amounted to < 3 mV and was corrected for by analysis of blood samples. Rapid changes in femoral venous [K+] occurred during and after dynamic exercise, short and prolonged isometric contractions, and repetitive isometric contractions of the quadriceps muscle. Combined with arterial blood sampling and flow measurements, the electrodes will allow good approximation of 1) cellular K+ efflux rate associated with increased electrical activity, 2) rate of intramuscular reuptake of K+ mediated by the Na(+)-K+ pump, and 3) rate of K+ loss to or uptake from the circulation by the muscle.
The effect of papaverine on the albumin permeability-surface area product (PS), reflection coefficient (sigma), and capillary filtration coefficient (Kf) was examined in isolated rabbit lungs. Because PS and Kf are functions of vascular surface area and permeability, we also compared papaverine with two other means of maximizing lung surface area: isoproterenol (1 x 10(-7) M) and a mild increase in vascular pressure. Only lungs perfused with 0.1 mg/ml papaverine were significantly different from control. PS increased from control (2.80 +/- 0.16 to 5.53 +/- 0.20 ml.min-1.g dry lung-1 x 10(-2), whereas sigma decreased from control (0.92 +/- 0.01 to 0.78 +/- 0.03). Kf after papaverine was significantly lower than baseline predrug Kf (5.60 +/- 0.78 to 4.56 +/- 0.53 ml.s-1.cmH2O-1.g dry lung-1 x 10(-3). However, this group's predrug Kf was higher than that of any other group. Our results indicate that papaverine increases albumin permeability and decreases endothelial selectivity. The isolated perfused lung appears fully recruited, because Kf and PS did not increase with isoproterenol or increased vascular pressure. Papaverine should be used with caution in the Ringer-perfused lung.
Endothelium-derived nitric oxide (NO) appears to be involved in the regulation of pulmonary vascular tone by O2. We hypothesized that the ability of blood to inhibit the vasodilation caused by NO would vary inversely with the saturation of hemoglobin by O2. To test this hypothesis, we used the pulmonary circulation of the unanesthetized fetal lamb as a bioassay for NO-induced vasodilation. Two to 3 days before the experiment, the main pulmonary artery, left atrium, carotid artery, and trachea of the fetus were catheterized and an ultrasonic blood flow transducer was placed around the proximal portion of the left pulmonary artery. On the day of the experiment, NO solution was prepared by bubbling 10% NO-90% N2 gas mixture in saline. This solution was injected into the fluid-filled potential air spaces of the fetal lungs via the trachea. At the highest dose (0.8 mumol), NO increased pulmonary blood flow fourfold and decreased pulmonary vascular resistance similarly. The dose-response curve for NO was similar to those obtained from isolated pulmonary blood vessels and gas-ventilated animals. Mixing NO solution with maternal arterial blood before injection decreased the effect of NO, and mixing it with venous blood virtually eliminated the effect. The decrease in fetal pulmonary vascular resistance caused by NO was inhibited by blood in inverse proportion to the saturation of hemoglobin with O2 in the blood (R2 = 0.93, P < or = 0.0001), confirming our hypothesis.
A new technique for the sodium dodecyl sulfate-polyacrylamide gel electrophoretic separation of rat skeletal muscle myosin heavy-chain (MHC) isoforms is presented. This technique allows for the separation of the four identified MHC isoforms known to be present in adult rat skeletal muscle. These types of MHC are commonly called I, IIa, IIx or IId, and IIb. The procedure can be performed using minigel electrophoresis systems and does not involve preparation of gradient-separating gels or the use of special cooling devices. The procedure accommodates both silver and Coomasie Blue staining. Thus the procedure is simple to perform and highly repeatable, providing high-resolution separation of MHC protein isoforms. The percent composition of the four adult MHCs in rat soleus, medial gastrocnemius, diaphragm, and levator ani muscles by use of this procedure and Coomasie Blue staining is similar to that previously reported. This new technique provides a novel and easy-to-perform method for the separation of rat skeletal muscle MHC isoforms.