Effects of adenosine and xanthine derivatives on breathing during acute hypoxia in the anesthetized newborn piglet

Neonates of animals and humans exhibit a paradoxical ventilatory response to hypoxia characterized by an initial increase in minute ventilation followed by a late, sustained decrease. Exogenous adenosine analogues cause respiratory depression, and the xanthine derivative aminophylline, a competitive inhibitor of adenosine receptors, decreases the amount of hypoxic ventilatory depression in the newborn piglet. Other xanthine derivative such as enprofylline are weak adenosine antagonists. The purpose of this report is to test the hypothesis that enprofylline would not reverse ventilatory depression caused by hypoxia, supporting the suggestion that adenosine contributes to hypoxic ventilatory depression. To confirm the weak adenosine antagonism of enprofylline, L-N6-(phenylisopropyl)adenosine (PIA) was administered to six newborn piglets until respiratory depression was achieved. Either aminophylline or enprofylline was then administered. Aminophylline, but not enprofylline, reversed the respiratory depression caused by PIA. In seven additional piglets, respiratory depression was first produced by 10% oxygen breathing and the ability of saline, aminophylline, and enprofylline to reverse the decrease in ventilation was evaluated. The administration of either saline or enprofylline produced little change in minute ventilation (9.8% +/- 3.7% and -11.7% +/- 7.7%, respectively), whereas aminophylline consistently produced an increase (43.5% +/- 7.3% [P less than 0.001]). Both aminophylline and enprofylline increased heart rate (P less than 0.01), whereas saline produced no significant change. Blood pressure was increased by enprofylline but not by aminophylline or saline. These findings suggest that, in the anesthetized newborn piglet, adenosine contributes to ventilatory depression caused by hypoxia.     

Ventilation, EELV and diaphragmatic activity in rats during chronic normobaric hypoxia.

We determined the effects of chronic hypoxia on end-expiratory lung volume (EELV), end-expiratory diaphragmatic activity (DE) and ventilation (VE) in 27 intact (awake and anesthetized) and six carotid body-denervated (CBD; anesthetized) rats. Twenty-nine control animals were also studied. Recordings were made during hypoxia and normoxia before and after 2 or 3 weeks of hypoxia (+3 days of recovery from chronic hypoxia). In awake rats, 2 weeks of chronic hypoxia increased only normoxic VE, while 3 weeks of chronic hypoxia did not change VE or DE. In anesthetized intact rats, after both exposures, hypoxic and normoxic VE tended to decrease, DE did not change and hypoxic and normoxic EELV were enlarged. In CBD animals, 2 weeks of chronic hypoxia did not affect hypoxic VE but decreased normoxic ventilation and enlarged EELV similar to the intact animals. After 3 days of recovery in normoxia, all parameters except EELV were restored to prehypoxic values. Also, transition from hypoxia to normoxia induced parallel changes in EELV and DE while chronic hypoxia increased only EELV. Therefore, chronic normobaric hypoxia induced, (1) an increase in normoxic ventilation reflecting a process of acclimatization; (2) an enlargement of EELV that did not depend on changes in DE and carotid chemoreceptors.     

Metabolic and ventilatory rates in newborn kittens during acute hypoxia

Newborns respond to acute hypoxia with a brief increase in ventilation (VE) followed by a decline toward the normoxic value. We asked to what extent this biphasic pattern is determined by changes in metabolic rate. In newborn awake kittens within the first week after birth we measured VE by the barometric method, oxygen consumption (VO2) and CO2 production (VCO2) by manometric techniques during air breathing and after 10 min of 10% O2 breathing. In hypoxia, VO2 and VCO2 dropped (about 45% and 35%, respectively) with a slight decrease in body temperature. VE was as in normoxia and, from the changes in breathing pattern, a drop in alveolar ventilation was calculated. Since the drop in VCO2 exceeded that in calculated alveolar ventilation (VA), a decrease in PACO2 (estimated at about 5 mm Hg) was expected. This decrement was confirmed by measurements of transcutaneous PCO2, which dropped an average of 3.3 mm Hg in the hypoxic kittens, even when VE was below the normoxic value. Hence, despite the decline in VE and VA during the biphasic response, the newborn continued to hyperventilate with respect to CO2 production, lowering PCO2. The strategy of dropping VO2 instead of maintaining the energetic requirements by increasing VE was not determined by mechanical constraints, since all kittens hyperventilated when exposed to CO2, either in air or hypoxia. Several implications of the tight coupling between ventilation and metabolism are discussed, including a possible role in the genesis of periodic breathing in hypoxia.     

Ventilation, EELV and diaphragmatic activity in rats during the early phase of normobaric hypoxia.

We tested whether the enhancement of end-expiratory activity of the diaphragm (DE) induced by acute hypoxia persists during long-lasting hypoxia and participates in the enlargement of end-expiratory lung volume (EELV). We thus measured these two parameters together with ventilation (VE) in 30 rats, either awake or anesthetized, exposed to (1) poikilocapnic hypoxia sustained for 2 or 3 h; or (2) chronic normobaric hypoxia for 7 days interrupted by short episodes of normoxia. Twelve control animals were also studied. (1) Sustained hypoxia induced a stable increase in DE, VE and EELV. (2) In awake rats, chronic hypoxia induced a transient increase in VE after 1 day of hypoxia, and an increase persisting during acute normoxia throughout the exposure. DE followed the same, although less pronounced, course as VE. In anesthetized animals, only EELV was increased in both chronic hypoxia and acute normoxia, but its enlargement in normoxia was not associated with a concomitant increase in DE. The transition from hypoxia to normoxia always induced a decrease in DE and EELV. Therefore, (1) during hypoxia sustained for 2 or 3 h, the ventilatory and diaphragmatic responses were stable; (2) during chronic hypoxia lasting 1 week, a ventilatory acclimatization was expressed by a transient increase in hypoxic VE and a hyperventilation continuing during acute normoxia; (3) EELV enlargement in chronic hypoxia was partly related to changes in DE and partly due to another mechanism possibly involving morphological adaptations.     

Ventilation and oxygen consumption during acute hypoxia in newborn mammals: a comparative analysis

We asked whether the lack of sustained hyperventilation during acute hypoxia, often reported to occur in the infant, is a common characteristic among newborn mammalian species, and to which extent inter-species differences may be accounted for by differences in metabolic responses. Ventilation (VE) and breathing pattern have been measured by flow-plethysmography or by the barometric method in normoxia and after 10 min of 10% O2 breathing in newborn mammals of 17 species over a 3 g to 20 kg range in body size. In 14 of these species oxygen consumption (VO2) has also been measured by a manometric technique or by calculation from the changes in chamber O2 pressure. VE and VO2 changed in proportion, among species, both in normoxia and hypoxia. In hypoxia, VE was higher, similar, or even lower than in normoxia, with some relation to the degree of maturity of the species at birth. In general, the small or absent VE responses to hypoxia resulted from small or no increase in tidal volume, while breathing frequency stayed elevated. The few departures from this pattern could be explained by interspecies differences in hypoxic sensitivity, since additional experiments in kittens and puppies indicated that, with more severe hypoxia, the pattern changed from rapid and shallow to deep and slow. In all cases, irrespective of the magnitude of the VE response, the VE/VO2 (and the mean inspiratory flow/VO2) increased during hypoxia, because the drop in VE, when present, was accompanied by an even larger drop in VO2. In fact, VO2 in hypoxia decreased in most species, although to variable degrees. Body temperature either did not change or decreased slightly, possibly indicating a trend toward a decrease of the set point of thermoregulation during hypoxia. In conclusion, the analysis gave further support to the concept that, during acute hypoxia, changes in metabolic rate play a paramount role in the ventilatory response of the newborn mammal.     

Aminophylline has little positive inotropic effect and a slightly negative diastolic effect on the left ventricle during hypoxic conditions in dogs

We examined the effect of aminophylline on left ventricular (LV) mechanics and central hemodynamics under normoxic and hypoxic conditions in respective groups of dogs. In an open-chest preparation, LV end-systolic and diastolic dimensions were measured with ultrasonic crystal transducers seated subendocardially along the anterior to posterior and apex to base axes. In the group studied during hypoxia, measurements were obtained during 3 conditions: normoxia; hypoxia to a PO2 of 30 mm Hg; and during hypoxia when aminophylline was infused to a blood level of about 15 mg/L. In the group studied under normoxic conditions, measurements were initially obtained during normoxia after which aminophylline was also infused to a blood level of 15 mg/L. Intravascular volume was given or removed to maintain LV filling pressures at about 10 mm Hg during all conditions. In the normoxic group, aminophylline caused an increase in stroke volume (SV) and had a positive inotropic effect on the LV. End-systolic dimensions were reduced, while end-diastolic dimensions did not change with aminophylline. On the other hand, under hypoxic conditions, aminophylline did not have a positive inotropic effect: SV did not increase and end-systolic dimensions remained unchanged. Under hypoxic conditions, moreover, aminophylline caused a slight decrease in end-diastolic dimensions by augmenting hypoxia-induced increases in myocardial resting tension. Our results indicate that unlike normoxic conditions, aminophylline may have little beneficial effect on LV performance during hypoxic conditions.     

Carotid bodies and ventilatory response to hypoxia in aminophylline-treated piglets

Peripheral chemoreceptors may be immature in neonatal animals, exhibiting maturational changes in the perinatal period. Even though methylxanthines are respiratory stimulants, many premature neonates do not respond to them. Thus, we hypothesized that carotid body activity is necessary for aminophylline to reverse hypoxia-induced respiratory depression. We exposed 16 anesthetized newborn piglets (age 2-7 days) to hypoxia (inhalation of 12% oxygen) for 5 min. Aminophylline (15 mg/kg iv) was administered either prior to (11 piglets) or following (5 piglets) carotid body denervation (CBD). Before CBD, hypoxia elicited transient initial increases in tidal volume (from 79 ± 4 to 99 ± 1% of maximum, mean ± SE), minute ventilation (from 64 ± 5 to 93 ± 4%), and peak phrenic electroneurogram (from 63 ± 8 to 91 ± 6%, all P < 0.05). This was followed by a decrease in tidal volume, minute ventilation and phrenic electroneurogram (all P < 0.05). Prior to CBD, aminophylline pretreatment prevented the decrease in all the measures of respiratory output during late hypoxia. After CBD, hypoxia induced an initial and sustained depression of ventilation (tidal volume from 100 to 33 ± 14%; frequency from 94 ± 4 to 42 ± 17%; minute ventilation from 100 to 32 ± 14%, all P < 0.05)and phrenic electroneurogram (peak phrenic from 100 to 47 ± 18%; minute phrenic from 85 ± 6 to 55 ± 21%, both P < 0.05). Administration of aminophylline after CBD did not prevent the profound respiratory depression elicited by hypoxia in the chemodenervated piglets. We conclude that aminophylline prevents respiratory depression during late hypoxia, however, in the absence of afferent input generated by the carotid bodies, aminophylline does not reverse respiratory depression induced by hypoxia in anesthetized newborn piglets. Pediatr Pulmonol. 1995; 20:94–100 . © 1995 Wiley-Liss, Inc.     

Effects of gas density on experimentally obstructed ventilation during acute hypoxia

When patients with obstructive lung disease breathe helium-oxygen mixtures, their arterial PCO2, is lowered towards normal, indicating more effective ventilation. However, there is a lack of detailed respiratory data from clinical cases, so that the mechanisms remain unclear. To study relevant variables during hypoxemia and obstruction in the absence of disease, we undertook experiments with healthy subjects breathing normoxic and hypoxic gas mixtures of differing densities (air, 13.7% O2 in N2 and 13.7% O2 in helium) through an experimental obstruction (resistive airway loading). This increased airway resistance was twice that reported from the ambient-pleural pressure differences in patients with moderately severe emphysema. Without imposed resistance the total ventilation (VE) increased 27% on both hypoxic mixtures. With normoxia, the obstruction increased tidal volume but decreased frequency so that VE and alveolar ventilation (VA) were essentially unchanged. With hypoxia, breathing pattern changed similarly, but now VE decreased while VA was maintained. Helium returned the breathing patterns toward normal. Obstruction lowered the rapid increase in VE from two or three breaths of N2, but the decrease from two or three breaths of O2 was unchanged. We detected an increase in metabolic rate with obstructed breathing that was reduced by the helium mixtures. The remarkable finding was that despite the obstruction being markedly uncomfortable because of the high resistance, we did not find any substantial disturbance in gas exchange, compared to hypoxia with no obstruction. Thus, the main mechanisms responsible for improved blood gases in patients breathing helium mixtures were outside the scope of our experiment and likely related to disease factors.     

Effects of bronchoconstriction on breathing during normoxia and hypoxia in anesthetized cats

The effect of an increase in bronchomotor tone on control of breathing during both normoxia and hypoxia, and the role of vagal afferents in regulating these responses were studied in 15 anesthetized cats. Minute ventilation (VE) was measured with a pneumotachograph connected in series with a tracheal cannula. Total diaphragmatic EMG activity per minute (means p X f, peak EMG moving average X respiratory frequency) was measured to assess the central inspiratory drive. Bronchoconstriction was generated by inhalation of methacholine aerosol (10-30 breaths, 0.5% solution) which increased total lung resistance to approximately 400% of the control value. Transient hypoxia was induced by allowing the cats to rebreathe a hypoxic gas mixture (4.5% O2 balanced N2) for approximately 1 min. During normoxia, bronchoconstriction increased VE from a baseline of 100 to 129 +/- 7% (mean +/- SEM; P less than 0.05) and increased (means p X f) from 100 to 174 +/- 16% (P less than 0.01). During hypoxia, the response of (means p X f) to bronchoconstriction (404 +/- 40%) was still greater than without bronchoconstriction (306 +/- 35%; P less than 0.01), but the responses of VE were not significantly different between these two conditions (P greater than 0.05). After sectioning both vagus nerves the bronchoconstriction-induced increase in central inspiratory drive was either reduced (during normoxia) or abolished (during hypoxia). These results suggest that stimulation of vagal bronchopulmonary afferents are involved in regulating the ventilatory responses to bronchoconstriction. Other non-vagal factors, such as intrinsic properties and reflex responses of the respiratory muscles, may also contribute, in part, to the observed responses.     

Adenosine is a pulmonary vasodilator in newborn lambs.

We investigated the systemic and pulmonary vascular effects of adenosine and determined plasma adenosine levels in pulmonary circulation in 12 newborn lambs during normoxia and during alveolar hypoxia (10% O2, 5% CO2, and 85% N2). Lambs were instrumented at 7 days of age with catheters in the descending aorta, main pulmonary artery, and right and left atria, and a flow transducer around the main pulmonary artery, and were studied following a 3-day recovery. Adenosine or an equal volume of normal saline (control) was infused into the right atrial line in doses ranging from 0.01 to 2.5 mumol/kg/min. In normoxic lambs, adenosine caused a significant decrease in pulmonary vascular resistance and increase in heart rate in doses of 0.15 to 2.5 mumol/kg/min and a decrease in systemic vascular resistance, with increase in cardiac output in doses of 0.3 to 2.5 mumol/kg/min. Baseline plasma adenosine levels in pulmonary artery and left atrium decreased significantly during alveolar hypoxia. Adenosine infusion in hypoxic lambs caused decreases in pulmonary artery pressure and pulmonary vascular resistance at all the doses tested. Aortic pressure and systemic vascular resistance decreased, and heart rate and cardiac output increased at doses greater than or equal to 0.3 mumol/kg/min in hypoxic lambs during adenosine infusion. The pulmonary vascular effects of adenosine in hypoxic lambs were attenuated by prior treatment of animals with aminophylline. Thus, adenosine appears to be an important regulator of pulmonary vascular response to hypoxia in newborn lambs. Its vasodilator effects were specific for pulmonary circulation when it was infused in doses less than or equal to 0.15 mumol/kg/min into the right atrium and appear to be mediated by P1 purinergic receptors.     

Role of catecholamines and beta-receptors in ventilatory response during hypoxic exercise.

The ventilatory response to moderate exercise in hypoxia is potentiated in goats, decreasing PaCO2 more than in normoxic exercise. We investigated the hypothesis that this potentiation results from a ventilatory stimulus provided by increased levels of circulating catecholamines (norepinephrine and/or epinephrine), acting via beta-receptors. Plasma norepinephrine [NE] and epinephrine [E] concentrations, arterial blood gases and ventilation were measured in normoxia and hypoxia (PaO2 = 34-38 Torr) at rest and during moderate exercise (5.6 kph; 5% grade) in seven female goats. PaCO2 decreased from rest to exercise in normoxia (2.9 +/- 0.7 Torr; P less than 0.01), and decreased significantly more from rest during hypoxic exercise (6.4 +/- 0.6 Torr; P less than 0.01). [NE] increased in both normoxic (1.1 +/- 0.4 ng/ml; P less than 0.05) and hypoxic exercise (2.5 +/- 0.5 ng/ml; P less than 0.01); the [NE] increase in hypoxia was significantly greater (P less than 0.01). [E] increased in normoxic (0.3 +/- 0.1 ng/ml; P less than 0.05) but not hypoxic exercise (0.6 +/- 0.5 ng/ml; P greater than 0.2). Experiments were repeated following administration of the beta-adrenergic receptor blocker, propranolol (2 mg/kg, i.v.). After beta-blockade, PaCO2 decreases from rest to exercise in normoxia (3.2 +/- 0.7 Torr; P less than 0.01) and hypoxia (8.1 +/- 0.7 Torr; P less than 0.001) were not significantly different from control. The data indicate that beta-adrenergic receptor stimulation is not necessary for a greater decrease in PaCO2 during hypoxic versus normoxic exercise. The greater rise in [NE] suggests a possible role in ventilatory control during hypoxic exercise, perhaps via alpha-adrenergic receptors. However, recent evidence suggests that NE is inhibitory in goats, and that NE is unlikely to mediate extra ventilatory stimulation during hypoxic exercise.     

The ventilatory response to hypoxia in the newborn lamb after carotid body denervation

Neonates of various species including lambs respond to hypoxia by a transient hyperventilation followed by a VE depression (diphasic response). To better delineate the role of the carotid chemoreceptors and that of the central depressive/inhibitive effect of hypoxia on minute ventilation, we have studied the VE response of 4-day-old carotid body-deprived lambs (CBD) during successive exposure to moderate and severe (0.12 and 0.07 FIO2) hypoxia. The carotid body denervation was done to abolish most of the chemoreceptor stimulating effect on VE during hypoxia and to allow for central depression/inhibition of VE during hypoxia. In the CBD lambs, baseline VE was 461 +/- 81 (SE) ml X (kg X min)-1. It increased to 532 +/- 79 ml X (kg X min)-1 and to 541 +/- 75 ml X (kg X min)-1, to 0.12 FIO2 and 0.07 FIO2. These VE increases did not reach level of significance (P greater than 0.05). After 2-5 min of both levels of hypoxia VE dropped respectively to 460 +/- 60 ml X (kg X min)-1 and to 459 +/- 38 ml X (kg X min)-1. No marked ventilatory depressions were noted but VE had only returned to baseline. It is concluded that, in the denervated newborn lamb, the centrally mediated depressive effect of hypoxia is small and not sufficient to explain the diphasic VE response of the intact lamb to steady state hypoxia. Analysis of the magnitude of the hyperventilation and the VE damping pre-hypoxic levels occurring with sustained hypoxia in newborns of various species suggests that the immaturity of the O2-sensitive chemoreceptor rather than the central effect of hypoxia is the determinant factor of the diphasic response of newborn mammals to hypoxic hypoxia.     

Fluoromisonidazole. A metabolic marker of myocyte hypoxia

Fluoromisonidazole is metabolically trapped in viable hypoxic cells in vitro. This property is the basis for the hypothesis that [18F]fluoromisonidazole can be used to detect hypoxic tissues noninvasively using positron emission tomography. To assess the potential usefulness of this compound as a marker for hypoxic myocardium, we measured the accumulation of [3H]fluoromisonidazole in isolated adult rat myocytes under normoxic, hypoxic (5,000 ppm O2), and anoxic conditions. Both anoxia and hypoxia caused a marked increase in [3H]fluoromisonidazole accumulation. Relative to uptake during normoxia, uptake during anoxia was increased by 8.4-fold at 60 minutes and 26.5-fold at 180 minutes (p less than 0.001). During hypoxia, uptake was increased by 4.4-fold at 60 minutes and by 15.3-fold at 180 minutes (p less than 0.0001) and occurred in the absence of significant cell injury as measured by release of creatine kinase and changes in cell morphology. Additional studies demonstrated a slow oxygen-insensitive efflux of fluoromisonidazole or labeled metabolite(s) from myocytes reincubated in drug-free medium. We conclude that fluoromisonidazole is avidly retained in hypoxic myocytes and thus may be suitable for noninvasive detection of hypoxic myocardium using positron emission tomography.     

Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets

Low tidal volume/inspiratory pressure ventilator strategies result in hypercapnia, which has been shown to increase pulmonary vasomotor tone. This may be particularly detrimental in infants and children with preexistent pulmonary hypertension. In this study, a piglet model of chronic hypoxia-induced pulmonary hypertension was used to test the hypotheses that: 1) the effects of hypercapnic acidosis are exaggerated by preexistent pulmonary hypertension; and 2) the pulmonary hemodynamic effects of hypercapnic acidosis are attenuated by normalizing pH. Pulmonary hypertension was induced by 2 weeks of hypoxia. Hemodynamic responses were measured in control and pulmonary hypertensive piglets during both normoxia and hypoxia under normocapnic, hypercapnic acidotic, and compensated hypercapnic conditions. We found that: 1) hypercapnic acidosis increased both normoxic and hypoxic pulmonary vascular resistance index (PVRI) in control piglets; 2) the pressor effects of hypercapnia were not attenuated by infusing bicarbonate to normalize the pH; and 3) piglets with chronic hypoxia-induced pulmonary hypertension had elevated baseline normoxic and hypoxic PVRI, but responded to hypercapnic acidosis and compensated hypercapnia in a similar way to control piglets. These data suggest that acute hypercapnic acidosis may have deleterious effects on the pulmonary hemodynamics of normal and pulmonary hypertensive subjects which may not be acutely reversed by buffering the pH.     

Chemoreflex drive and the dynamics of ventilation and gas exchange during exercise at hypoxia

We tested the hypothesis that the promotion of hypoxic ventilatory responsiveness (HVR) and/or hypercapnic ventilatory responsiveness (HCVR) mostly acting on the carotid body with a changing work rate can be attributed to faster hypoxic ventilatory dynamics at the onset of exercise. Eleven subjects performed a cycling exercise with two repetitions of 6 minutes while breathing at FIO(2) = 12%. The tests began with unloaded pedaling, followed by three constant work rates of 40%, 60%, and 80% of the subject's ventilatory threshold at hypoxia. Reference data were obtained at the 80% ventilatory threshold work rate during normoxia. Using three inhaled 100% O(2) breath tests, a comparison of hypoxia and normoxia revealed an augmentation of HVR in hypoxia, which then significantly increased proportionally with the increase in work rate. In contrast, HCVR using three inhaled 10% CO(2) breath tests was unaffected by the difference in work rate at hypoxia but did exceed its level at normoxia. The decrease in the half-time of hypoxic ventilation became significant with an increase in work rates and was significantly lower than at normoxia. Using a multiregression equation, HVR was found to account for 63% of the variance of hypoxic ventilatory dynamics at the onset of exercise and HCVR for 9%. O(2) uptake on-kinetics and off-kinetics under hypoxic conditions were significantly slower than under normoxic conditions, whereas they were not altered by the changing work rates at hypoxia. These results suggest that the faster hypoxic ventilatory dynamics at the onset of exercise can be mostly attributed to the augmentation of HVR with an increase in work rates rather than to HCVR. Otherwise, O(2) uptake dynamics are affected by the lower O(2), not by the changing work rates under hypoxic conditions.     

Ontogeny of plasma, CSF and brainstem ACTH in piglets: effects of hypoxia and anesthesia

This study was designed to assess the postnatal maturation of adrenocorticotropin (ACTH) levels in piglets under basal conditions and in response to single, acute stressors. ACTH levels were measured by radioimmunoassay in plasma, cerebrospinal fluid (CSF) and in a dorsal medullary slice containing the nucleus tractus solitarii (dmscNTS) of young and older piglets (1.5-6 and 35-43 days old, respectively) under the following experimental conditions: (1) normoxia (both groups); (2) hypoxia, 10% O2/N2 for greater than or equal to 30 min (both groups); (3) sham anesthesia, i.p. saline in normoxia (young group); (4) anesthesia, 25 mg/kg i.p. pentobarbital in normoxia (young group), and (5) anesthesia combined with hypoxia (young group). During normoxia, ACTH levels in young, as compared to older piglets, were higher in CSF (p less than 0.01) and plasma (0.05 less than p less than 0.10) and not different in dmscNTS. Hypoxia produced no ACTH changes in CSF, increased ACTH in plasma of young (p = 0.03) and older piglets (p = 0.09), and decreased ACTH in dmscNTS of older (p = 0.01) and young piglets (p = 0.07). As compared to sham anesthesia, anesthesia did not alter any ACTH levels. Combined hypoxia and anesthesia increased ACTH levels in plasma when compared to normoxia (p less than 0.05), sham anesthesia (p less than 0.05) or anesthesia alone (p less than 0.05), but not when compared to hypoxia alone. We conclude that neonatal swine have high basal ACTH levels and mount significant plasma ACTH responses to a single, acute hypoxic stressor. The presence of ACTH in the region of the NTS supports its possible role as a neuromodulator in the brain.     

Ventilatory responses to hyperkalemia and exercise in normoxic and hypoxic goats

The ventilatory response to moderate exercise is potentiated during hypoxia in goats, causing PaCO2 to decrease more from rest to exercise than in normoxia. We investigated the hypothesis that this response is due to the ventilatory stimulus provided by an interaction between exercise induced hyperkalemia and hypoxia. Plasma potassium concentration ([K+]), arterial blood gases and ventilation were measured in normoxia and hypoxia (PaO2 = 34-38 Torr) at rest and during steady-state exercise (5.6 kph; 5% grade) in seven goats. PaCO2 decreased during normoxic exercise (2.9 +/- 0.7 Tor; P less than 0.01), and decreased significantly more during hypoxic exercise (6.4 +/- 0.6 Torr; P less than 0.01). [K+] increased in both normoxic (1.0 +/- 0.1 mEq/L; P less than 0.01) and hypoxic (0.9 +/- 0.2 mEq/L; P less than 0.01) exercise, but these changes were not significantly different from each other. On a different day, resting goats were infused intravenously with 200 mM KCl for 5 min at a rate sufficient to obtain [K+] similar to exercise (8.6-12 ml/min) in normoxia and hypoxia. Hyperkalemia at rest caused similar PaCO2 decreases in normoxia (1.7 +/- 0.7 Torr; P less than 0.05) and hypoxia (1.7 +/- 0.5 Torr; P less than 0.01), but had no statistically significant effect on ventilation in either condition. These data indicate that hyperkalemia, at levels approximating those during moderate exercise, has a mild stimulatory effect on alveolar ventilation; however, hypoxia does not affect this response. We conclude that hyperkalemia does not provide sufficient ventilatory stimulation to account for exercise hyperpnea, nor does hypoxia potentiate the ventilatory stimulation from hyperkalemia at rest.     

The effects of unilateral carotid body excision on ventilatory control in goats

The purpose of this study was to determine whether or not unilateral carotid body excision (UCBE) alters normal respiratory control in awake and otherwise intact goats. We measured resting VE and blood gas tensions and pH and ventilatory responses (VR) to NaCN, dopamine and Doxapram in awake goats before and after UCBE. Resting ventilation, blood gas tensions and pH, and the VR to the above stimuli were not altered by UCBE. During exposure to hypoxia in a hypobaric chamber (PB = 450 torr), PaCO2 decreased in UCBE goats over the first hour, indicating acute hypoxic hyperventilation. During the subsequent 8 h, PaCO2 decreased an additional 5-6 torr, suggesting ventilatory acclimatization to chronic hypoxia (VACH). The response was similar to that observed in intact goats. Acute normoxia following 6 and 8 hr did not completely alleviate the hypocapnia of prolonged hypoxia, further suggesting VACH. We conclude that sufficient redundancy exists in the inputs from the paired carotid body chemoreceptors so that normal ventilatory responsiveness to acute and chronic stimuli is present in goats possessing only a single carotid body.     

Effect of hypoxia on the sensation of dyspnea during hypercapnic ventilatory response in normal subjects]

We examined, in 32 normal adults, the effect of hypoxia on the sensation of dyspnea during hypercapnic ventilatory response (HCVR). The tests were conducted under two different levels of inspiratory O2 content, either hyperoxia (PETO2 greater than 150 Torr) or hypoxia (PETO2 50-55 Torr), with simultaneous assessment of dyspnea sensation by visual analogue scaling (VAS). The sensation was evaluated either in relation to VE standardized by predicted MVV (the slope of VAS-VE regression line or VAS at VE 40%) or in relation to PETCO2 (the slope of VAS-PETCO2 line or VAS at PETCO2 55 Torr). Concomitant hypoxia significantly enhanced both the mean value of delta VE/delta PETCO2 and that of delta P0.1/delta PETCO2. The sensation of dyspnea did not differ between the two conditions when it was evaluated in relation to ventilation, whereas it was markedly greater during hypoxic HCVR when it was evaluated in relation to PETCO2. The hypoxic augmentation of the sensation, compared at PETCO2 55 Torr, could be explained by increase of the motor output from the respiratory center, since it was positively correlated with the relative change of VE, VTTI, and delta P0.1/delta PETCO2 (r = 0.70, p less than 0.0001; r = 0.63, p less than 0.0001; r = 0.40, p less than 0.05, respectively). From these findings, we conclude that hypoxia does not have a direct dyspnogenic effect, at least in normal subjects.     

Effect of alveolar pressure on pulmonary artery pressure in chronically hypoxic rats

The effect on pulmonary artery pressure of a rise in alveolar pressure differed in chronically hypoxic rats (10% O2 for 3-5 weeks) compared with control rats. Chronically hypoxic rats have newly muscularised walls in arterioles in the alveolar region. Isolated lungs of chronically hypoxic and control rats were perfused with blood under conditions in which alveolar pressure was greater than left atrial pressure during both normoxia and hypoxia. Alveolar pressure was the effective downstream pressure. Pressure-flow lines were measured at low and high alveolar pressure (5 and 15 mmHg). During normoxia pressure-flow lines of chronically hypoxic rats had a steeper slope (higher resistance) and greater extrapolated intercept on the pressure axis (effective downstream pressure) than control rats. In both groups of rats the change from low to high alveolar pressure during normoxia caused an approximately parallel shift in the pressure-flow line similar to the change in alveolar pressure. During hypoxia, which led to an increase in slope and intercept in both groups of rats, the effect of a rise in alveolar pressure differed in chronically hypoxic from control rats. In control rats there was a small parallel shift in the pressure-flow line that was much less than the increase in alveolar pressure; in chronically hypoxic rats there was a large parallel shift in the pressure-flow line that was greater than the increase in alveolar pressure. Thus in chronically hypoxic rats hypoxic vasoconstriction probably occurred mainly in muscular alveolar vessels, whereas in control rats it probably occurred upstream in extra-alveolar vessels. At constant blood flow the relation between pulmonary artery pressure and alveolar pressure was measured while alveolar pressure was reduced from approximately 15 mmHg to zero during both normoxia and hypoxia. In control and chronically hypoxic rats the slope of this line was less than 1. At an alveolar pressure of 2-3 mmHg there was an inflection point below which the line was nearly horizontal in control but negative in chronically hypoxic rats. During hypoxia the inflection point increased in control but not in chronically hypoxic rats, whereas the preinflection slope became negative. Apart from a rise in pulmonary artery pressure at all values of alveolar pressure, which occurred in both groups of rats, there was no change in the form of the curve in chronically hypoxic rats during hypoxia. These results also suggest constriction of extra-alveolar vessels in control rats and alveolar vessels in chronically hypoxic rats during hypoxia.