Effect of chronic hypoxia on breathing and EMGs of respiratory muscles in awake ponies.

Breathing, diaphragmatic and transversus abdominis electromyograms (EMGdi and EMGta, respectively), and arterial blood gases were studied during normoxia (arterial PO2 = 95 Torr) and 48 h of hypoxia (arterial PO2 = 40-50 Torr) in intact (n = 11) and carotid body-denervated (CBD, n = 9) awake ponies. In intact ponies, arterial PCO2 was 7, 5, 9, and 11 Torr below control (P less than 0.01) at 1 and 10 min and 5 and 24-48 h of hypoxia, respectively. In CBD ponies, arterial PCO2 was 3-4 Torr below control (P less than 0.01) at 4, 5, 6, and 24 h of hypoxia. In intact ponies, pulmonary ventilation, mean inspiratory flow rate, and rate of rise of EMGdi and EMGta changed in a multi-phasic fashion during hypoxia; each reached a maximum during the 1st h (P less than 0.05), declined between 1 and 5 h (P less than 0.05), and increased between 5 and 24-48 h of hypoxia. As a result of the increased drive to the diaphragm, the mean EMGdi was above control throughout hypoxia (P less than 0.05). In contrast, as a result of a sustained reduction in duration of the EMGta, the mean EMGta was below control for most of the hypoxic period. In CBD ponies, pulmonary ventilation and mean inspiratory flow rate did not change during chronic hypoxia (P greater than 0.10). In these ponies, the rate of rise of the EMGdi was less than control (P less than 0.05) for most of the hypoxic period, which resulted in the mean EMGdi to also be less than control (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of increased end-expiratory lung volume on breathing in awake ponies

We studied the changes in breathing and respiratory muscle electromyograms (EMG) during passively induced increases in end-expiratory lung volume (EELV) in awake normal (N), hilar nerve-denervated (HND), carotid body-denervated (CBD), and HND + CBD ponies. EELV was increased by applying continuous negative pressure (-10 and -20 cmH2O) around the torso of the standing pony. In all groups, negative pressure produced sustained increases in EELV that were linearly related to the degree of negative pressure. Elevated EELV decreased breathing frequency (f) in N and CBD ponies but increased f in HND and HND + CBD ponies. When EELV was increased, tidal volume was unchanged or above control in N ponies but was below or near control in the other groups. In all groups during elevated EELV, arterial PCO2 initially decreased but then increased relative to control with isocapnia achieved after approximately 1.5 min. In all groups, the elevated EELV was accompanied by increased stimulation of the diaphragm as indicated by increased rate of rise of the integrated EMG (P less than 0.05). During elevated EELV, the duration of diaphragm EMG was reduced, but only in HND ponies was this reduction significant (P less than 0.05). In N ponies, the major effect of elevated EELV on the expiratory transversus abdominis (TA) muscle was an increase (P less than 0.05) in duration of activity and therefore total activity. The work of breathing was thus presumably shifted more to this muscle during elevated EELV. These changes in TA timing were not observed in HND and HND + CBD ponies during elevated EELV. We conclude that elevation of EELV, which presumably places the diaphragm on a less favorable portion of its length-tension relationship, results in compensatory increased stimulation of the diaphragm that is not critically dependent on hilar and carotid chemoreceptor afferents. However, hilar afferents do contribute to the changes in diaphragm and TA duration of activity during elevated EELV.     

Ventilatory control in peripheral chemoreceptor-denervated ponies during chronic hypoxemia.

The present study was designed to provide further insight into the role of the carotid and aortic chemoreceptors in ventilatory (VE) acclimatization during sojourn at altitude. Measurements were made: 1) on 10 ponies near sea level (SL, 740 Torr) under normal conditions, 2) on 6 of these at SL following chemoreceptor denervation (CD), and 3) subsequently on all 10 during 4 days of hypobaric hypoxia (PaO2 = 40-47 Torr). CD resulteo in hypoventilation at SL (deltaPaCO2 = d8 Torr, P less than 0.05), and it prevented hyperventilation normally observed with injection of NaCN and acute exposure to hypoxia (less than 1 h). In contrast, hyperventilation was evident in normal ponies during acute hypoxia (deltaPaCO2 = -6.7 Torr). Ventilation increased in both groups between the 2nd and 8th h of hypoxia (deltaPaCO2 from 1 h = -4 Torr, P less than 0.05). This change, a common characteristic of acclimatization, persisted throughout 4 days of hypoxia in the normal ponies. However, in the CD ponies this change was evident consistently only through the 12th h and after the 44 h hyperventilation was no longer evident. We conclude that the peripheral chemoreceptors are essential in ponies for normal VE acclimatization to this degree of hypoxemia. Two additional findings in CD ponies suggest the presence of a CNS inhibitory influence on the VE control center during chronic hypoxemia. First, acute hyperoxygenation on the 4th day of hypoxemia induced hyperventilation (deltaPaCO2 = -5 Torr, P less than 0.05). Second, again on the 4th day and during hyperoxygenation, VE responsiveness to CO2 and doxapram HCl was greater than at sea level.     

Independence of exercise hyperpnea and acidosis during high-intensity exercise in ponies

We investigated arterial PCO2 (PaCO2) and pH (pHa) responses in ponies during 6-min periods of high-intensity treadmill exercise. Seven normal, seven carotid body-denervated (2 wk-4 yr) (CBD), and five chronic (1-2 yr) lung (hilar nerve)-denervated (HND) ponies were studied during three levels of constant load exercise (7 mph-11%, 7 mph-16%, and 7 mph-22% grade). Mean pHa for each group of ponies became alkaline in the first 60 s (between 7.45 and 7.52) (P less than 0.05) at all work loads. At 6 min pHa was at or above rest at 7 mph-11%, moderately acidic at 7 mph-16% (7.32-7.35), and markedly acidic at 7 mph-22% (7.20-7.27) for all groups of ponies. Yet with no arterial acidosis at 7 mph 11%, normal ponies decreased PaCO2 below rest (delta PaCO2) by 5.9 Torr at 90 s and 7.8 Torr by 6 min of exercise (P less than 0.05). With a progressively more acid pHa at the two higher work loads in normal ponies, delta PaCO2 was 7.3 and 7.8 Torr by 90 s and 9.9 and 11.4 Torr by 6 min, respectively (P less than 0.05). CBD ponies became more hypocapnic than the normal group at 90 s (P less than 0.01) and tended to have greater delta PaCO2 at 6 min. The delta PaCO2 responses in normal and HND ponies were not significantly different (P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of reducing anatomic dead space on arterial PCO2 during CO2 inhalation

Carotid body-denervated (CBD) ponies have a less than normal increase in arterial PCO2 (PaCO2) when inspired CO2 (PICO2) is increased, even when pulmonary ventilation (VE) and breathing frequency (f) are normal. We studied six tracheostomized ponies to determine whether this change 1) might be due to increased alveolar ventilation (VA) secondary to a reduction in upper airway dead space (VD) or 2) is dependent on an upper airway sensory mechanism. Three normal and three chronic CBD ponies were studied while they were breathing room air and at 14, 28, and 42 Torr PICO2. While the ponies were breathing room air, physiological VD was 483 and 255 ml during nares breathing (NBr) and tracheostomy breathing (TBr), respectively. However, at elevated PICO2, mixed expired PCO2 often exceeded PaCO2; thus we were unable to calculate physiological VD using the Bohr equation. At all PICO2 in normal ponies, PaCO2 was approximately 0.3 Torr greater during NBr than during TBr (P less than 0.05). In CBD ponies this NBr-TBr difference was only evident while breathing room air and at 28 Torr PICO2. At each elevated PICO2 during both NBr and TBr, the increase in PaCO2 above control was always less in CBD ponies than in normal ponies (P less than 0.01). The VE-PaCO2, f-PaCO2, and tidal volume-PaCO2 relationships did not differ between NBr and TBr (P greater than 0.10) nor did they differ between normal and CBD ponies (P greater than 0.10). We conclude that the attenuated increase in PaCO2 during CO2 inhalation after CBD is not due to a relative increase in VA secondary to reducing upper airway VD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle shortening increases sensitivity of fatigue to severe hypoxia in canine diaphragm.

The effects of inspired O2 on diaphragm tension development during fatigue were assessed using isovelocity (n = 6) and isometric (n = 6) muscle contractions performed during a series of exposures to moderate hypoxia [fraction of inspired O2 (FIO2) = 0.13], hyperoxia (FIO2 = 1), and severe hypoxia (FIO2 = 0.09). Muscle strips were created in situ from the canine diaphragm, attached to a linear ergometer, and electrically stimulated (30 Hz) to contract (contraction = 1.5 s/relaxation = 2 s) from optimal muscle length (Lo = 8.9 cm). Isovelocity contractions shortened to 0.70 Lo, resulting in a mean power output of 210 mW/cm2. Fatigue trials of 35 min duration were performed while inspired O2 was sequentially changed between the experimental mixtures and normoxia (FIO2 = 0.21) for 5-min periods. In this series, severe hypoxia consistently decreased isovelocity tension development by an average of 0.1 kg/cm2 (P less than 0.05), which was followed by a recovery of tension (P less than 0.05) on return to normoxia. These responses were not consistently observed in isometric trials. Neither isovelocity nor isometric tension development was influenced by moderate hypoxia or hyperoxia. These results demonstrate that the in situ diaphragm is relatively insensitive to rapid changes in O2 supply over a broad range and that the tension development of the shortening diaphragm appears to be more susceptible to severe hypoxia during fatigue. This may reflect a difference in either the metabolic or blood flow characteristics of shortening contractions of the diaphragm.     

Shivering and cardiorespiratory responses during normocapnic hypoxia in the pigeon

To study the inhibitory effect of hypoxia on the cold defense mechanism, pigeons were exposed at low ambient temperature (5 degrees C) to various inhaled gas mixtures: normoxia [0.21 fractional concentration of O2 (FIO2)], hypoxia (0.07 FIO2), and normocapnic hypoxia (0.07 FIO2 + 0.045 FICO2). Electromyographic (EMG) activity indicative of shivering thermogenesis was inhibited during hypoxia, and body temperature (Tre) fell by 0.09 degrees C/min. Respiratory frequency (f) and minute ventilation (VE) increased by 143 and 135%, respectively, compared with normoxia, but tidal volume (VT) was not changed. PO2, PCO2, and O2 contents in the arterial and mixed venous blood were decreased and pH was enhanced. During normocapnic hypoxia, shivering EMG was present at approximately 50% of the normoxic intensity; Tre fell by only 0.04 degrees C/min. Arterial and mixed venous PCO2 and pH were the same as during normoxia, but VE increased by 430% because of twofold increases in both f and VT. During normocapnic hypoxia, arterial PO2 and O2 content were higher than during hypoxia alone. We conclude that the persistence of shivering during normocapnic hypoxia is due to maintenance of critical levels of arterial PO2 and O2 content.     

Role of carotid chemoreceptors and pulmonary vagal afferents during helium-oxygen breathing in ponies

Our purpose was to assess compensatory breathing responses to airway resistance unloading in ponies. We hypothesized that the carotid bodies and hilar nerve afferents, respectively, sense chemical and mechanical changes caused by unloading, hence carotid body-denervated (CBD) and hilar nerve-denervated ponies (HND) might demonstrate greater ventilatory responses when decreasing resistance. At rest and during treadmill exercise, resistance was transiently reduced approximately 40% in five normal, seven CBD, and five HND ponies by breathing gas of 79% He-21% O2 (He-O2). In all groups at rest, He-O2 breathing did not consistently change ventilation (VE), breathing frequency (f), tidal volume (VT), or arterial PCO2 (PaCO2) from room air-breathing levels. During treadmill exercise at 1.8 mph-5% grade in normal and HND ponies, He-O2 breathing did not change PaCO2 but at moderate (6 mph-5% grade), and heavy (8 mph-8% grade) work loads, absolute PaCO2 tended to decrease by 1 min of resistance unloading. delta PaCO2 calculated as room air minus He-O2 breathing levels at 1 min demonstrated significant changes in PaCO2 during exercise resistance unloading (P less than 0.05). No difference between normal and HND ponies was found in exercise delta PaCO2 responses (P greater than 0.10); however, in CBD ponies, the delta PaCO2 during unloading was greater at any given work load (P less than 0.05), suggesting finer regulation of PaCO2 in ponies with intact carotid bodies. During heavy exercise VE and f increased during He-O2 breathing in all three groups of ponies (P less than 0.05), although there were no significant differences between groups (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperventilation in ponies at the onset of and during steady-state exercise

We studied blood gases in ponies to assess the relationship of alveolar ventilation (VA) to pulmonary CO2 delivery during moderate treadmill exercise. In normal ponies for 1.8, 3, or 6 mph, respectively, partial pressure of CO2 in arterial blood (PaCO2) decreased maximally by 3.1, 4.4, and 5.7 Torr at 30-90 s of exercise and remained below rest by 1.4, 2.3, and 4.5 Torr during steady-state (4-8 min) exercise (P less than 0.01). Partial pressure of O2 in arterial blood (PaO2) and arterial pH, (pHa) also reflected hyperventilation. Mixed venus CO2 partial pressure (PVCO2) decreased 2.3 and 2.9 Torr by 30 s for 3 and 6 mph, respectively (P less than 0.05). In work transitions either from 1.8 to 6 mph or from 6 mph to 1.8 mph, respectively, PaCO2 either decreased 3.8 Torr or increased 3.3 Torr by 45 s of the second work load (P less than 0.01). During exercise in acute (2-4 wk) carotid body denervated (CBD) ponies at 1.8, 3, or 6 mph, respectively, PaCO2 decreased maximally below rest by 9.0, 7.6, and 13.2 Torr at 30-45 s of exercise and remained below rest by 1.3, 2.3, and 7.8 Torr during steady-state (4-8 min) exercise (P less than 0.1). In the chronic (1-2 yr) CBD ponies, the hypocapnia was generally greater than normal but less than in the acute CBD ponies. We conclude that in the pony 1) VA is not tightly matched to pulmonary CO2 delivery during exercise, particularly during transitional states, 2) the exercise hyperpnea is not mediated by PaCO2 or PVCO2, and 3) during transitional states in the normal pony, the carotid bodies attenuate VA drive thereby reducing arterial hypocapnia.     

Ventilatory acclimatization to hypoxia is not dependent on cerebral hypocapnic alkalosis

We previously demonstrated that, in awake goats, 6 h of hypoxic carotid body perfusion during systemic normoxia produced time-dependent hyperventilation that is typical of ventilatory acclimatization to hypoxia (VAH). The hypocapnic alkalosis that occurred could have produced VAH by inducing cerebral vasoconstriction and brain lactic acidosis even though systemic arterial normoxia was maintained. In the present study we tested the hypothesis that hypocapnic alkalosis is a necessary component of VAH. Goats were prepared so that one carotid body could be perfused, from an extracorporeal circuit, with blood in which gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Using this preparation we carried out 4 h of hypoxic carotid body perfusion while maintaining systemic arterial (and brain) normoxia in awake goats. Expired minute ventilation (VE) was measured while CO2 was added to inspired air to maintain normocapnia. Carotid body PCO2 and PO2 were maintained near 40 Torr during the 4-h carotid body perfusion. Control mean VE was 8.65 +/- 0.48 l/min (mean +/- SE). With acute carotid body hypoxia (30 min) VE increased to 21.73 +/- 2.02 l/min (P less than 0.05); over the ensuing 3.5 h of carotid body hypoxia, VE progressively increased to 39.14 +/- 4.14 l/min (P less than 0.05). These data indicate that neither cerebral hypoxia nor hypocapnic alkalosis are required to produce VAH. After termination of the 4-h carotid body stimulation, hyperventilation was not maintained in these studies, i.e., there was no deacclimatization. This suggests that acclimatization and deacclimatization are produced by different mechanisms.     

Brain hypoxia preferentially stimulates genioglossal EMG responses to CO2

Although the dominant respiratory response to hypoxia is stimulation of breathing via the peripheral chemoreflex, brain hypoxia may inhibit respiration. We studied the effects of two levels of brain hypoxia without carotid body stimulation, produced by inhalation of CO, on ventilatory (VI) and genioglossal (EMGgg) and diaphragmatic (EMGdi) responses to CO2 rebreathing in awake, unanesthetized goats. Neither delta VI/delta PCO2 nor VI at a PCO2 of 60 Torr was significantly different between the three conditions studied (0%, 25%, and 50% carboxyhemoglobin, HbCO). There were also no significant changes in delta EMGdi/delta PCO2 or EMGdi at a PCO2 of 60 Torr during progressive brain hypoxia. In contrast, delta EMGgg/delta PCO2 and EMGgg at a PCO2 of 60 Torr were significantly increased at 50% HbCO compared with either normoxia or 25% HbCO (P less than 0.05). The PCO2 threshold at which inspiratory EMGgg appeared was also decreased at 50% HbCO (45.6 +/- 2.6 Torr) compared with normoxia (55.0 +/- 1.4 Torr, P less than 0.02) or 25% HbCO (53.4 +/- 1.6 Torr, P less than 0.02). We conclude that moderate brain hypoxia (50% HbCO) in awake, unanesthetized animals results in disproportionate augmentation of EMGgg relative to EMGdi during CO2 rebreathing. This finding is most likely due to hypoxic cortical depression with consequent withdrawal of tonic inhibition of hypoglossal inspiratory activity.     

Effect of elevated PICO2 on metabolic rate in humans and ponies

The primary purpose of this study was to determine the effect of acute (20-30 min) elevations of inspired CO2 partial pressure (PICO2) on whole-body O2 consumption (VO2). In human subjects, VO2 increased approximately 15 ml.min-1.m-2 with each 7-Torr increment in PICO2 from 0.4 to 28 Torr (P less than 0.05), but VO2 did not change significantly when PICO2 was increased from 28 to 35 and 42 Torr (P greater than 0.05). In ponies, VO2 did not change when PICO2 was increased from 0.7 to 7 Torr (P greater than 0.05), but it increased about 6 ml.min-1.m-2 with each 7-Torr increment in PICO2 from 7 to 28 Torr, and it increased 18 ml.min-1.m-2 when PICO2 was increased from 28 to 42 Torr (P less than 0.05). At low PICO2 the delta VO2/ delta VE was 25 and 7 ml/l for humans and ponies, respectively, where VE is pulmonary ventilation. These values exceeded the expected O2 cost of breathing; hence, some factor, such as shivering or nonshivering thermogenesis, contributed to the elevated VO2. At high PICO2, VE increased without a proportional increase in VO2; thus the delta VO2/ delta VE decreased to about 2.5 ml/l in ponies and to near 0.0 in humans. Accordingly, at high PICO2 some VO2-suppressing factor partially counteracted those factors stimulating VO2. The maximum decrease from control pHa was 0.061 and 0.038 in humans and ponies, respectively. It is questionable whether this mild acidosis was sufficient to suppress VO2. In both species, pulmonary excretion of metabolic CO2 and the respiratory exchange ratio were below control during CO2 inhalation (P less than 0.01), which suggested an increased tissue storage of CO2.     

Differential responses of expiratory muscles to chemical stimuli in awake dogs

We assessed respiratory muscle response patterns to chemoreceptor stimuli (hypercapnia, hypoxia, normocapnic hypoxia, almitrine, and almitrine + CO2) in six awake dogs. Mean electromyogram (EMG) activities were measured in the crural (CR) diaphragm, triangularis sterni (TS), and transversus abdominis (TA). Hypercapnia and normocapnic hypoxia caused mild to marked hyperpnea [2-5 times control inspiratory flow (VI)] and increased activity in CR diaphragm, TS, and TA. When hypocapnia was permitted to develop during hypoxia and almitrine-induced moderate hyperpnea, CR diaphragm activity increased, whereas TS and TA activities usually did not change or were reduced below control. Over time in hypercapnia, CR diaphragm, TS, and TA were augmented and maintained at these levels over many minutes; with hypoxic hyperventilation CR diaphragm, TS, and TA were first augmented but then CR diaphragm remained augmented while TS and, less consistently, TA were inhibited over time. Marked hyperpnea (4-5 times control) due to carotid body stimulation increased TA and TS EMG activity despite an accompanying hypocapnia. We conclude that in the intact awake dog 1) carotid body stimulation augments the activity of both inspiratory and expiratory muscles; 2) hypocapnia overrides the augmenting effect of carotid body stimulation on expiratory muscles during moderate hyperpnea, usually resulting in either no change or inhibition; 3) at higher levels of hyperpnea both chemoreceptor stimulation and stimulatory effects secondary to a high ventilatory output favor expiratory muscle activation; these effects override any inhibitory effects of a coincident hypocapnia; and 4) expiratory muscles of the rib cage/abdomen may be augmented/inhibited independently of one another.     

Fiber types and fiber diameters in canine respiratory muscles

In the present study, we measured fiber types and fiber diameters in canine respiratory muscles and examined regional variation within the diaphragm. Samples of eight diaphragm regions, internal intercostals, external intercostals, transversus abdominis, and triceps brachii were removed from eight adult mongrel dogs, frozen, and histochemically processed for standard fiber type and fiber diameter determinations. The respiratory muscles were composed of types I and IIa fibers; no IIb fibers were identified. Fiber composition differed between muscles (P less than 0.0001). Normal type I percent (+/- SE) were: diaphragm 46 +/- 2, external intercostal 85 +/- 6, internal intercostals 48 +/- 3, transversus abdominis 53 +/- 1, and triceps 33 +/- 7. The diaphragm also contained a type I subtype [6 +/- 1% (SE)] previously thought only to occur in developing muscle. Fiber composition varied between diaphragm regions (P less than 0.01). Most notably, left medial crus contained 64% type I fibers. Fiber size also varied systematically among muscles (P less than 0.025) and diaphragm regions (P less than 0.0005). External intercostal fiber diameter was largest (47-50 microns) and diaphragm was smallest (34 microns). Within diaphragm, crural fibers were larger than costal (P less than 0.05). We conclude that there are systematic differences in fiber composition and fiber diameter of the canine respiratory muscles.     

Central action of tachykinins on activity of expiratory pumping muscles.

The central effects of tachykinins (substance P, neurokinin A, and neurokinin B) on the distribution of the motor activity to rib cage and abdominal expiratory muscles were studied in anesthetized tracheotomized spontaneously breathing dogs and cats. Intracisternal application of substance P (11 dogs) in doses of 10(-5) to 10(-4) M caused diaphragm electrical activity to change insignificantly from 19.3 +/- 1.9 to 24.8 +/- 3.2 units (P greater than 0.05), produced a moderate increase of triangularis sterni activity from 12.6 +/- 2.2 to 19.2 +/- 2.2 units (P less than 0.05), and stimulated a large increase of transversus abdominis activity from 9.4 +/- 2.7 to 28.5 +/- 2.6 units (P less than 0.01). Comparable effects were seen with similar doses of neurokinin A (8 dogs) and neurokinin B (3 dogs) administered intracisternally. Local application of substance P to the ventral medullary surface (5 dogs and 4 cats) also caused expiratory muscle activity to increase more than diaphragm activity, and in addition transversus abdominis activity increased to a larger extent than triangularis sterni activity. Furthermore, administration of the substance P antagonist [D-Pro2,D-Trp7,9]-SP to the ventral medullary surface decreased respiratory motor output, with expiratory muscles activity being attenuated to a greater extent than diaphragm activity. Application of neurotensin and N-methyl-D-asparate to the ventral surface of the medulla produced responses similar to those observed as a result of central administration of tachykinin peptides. The results suggest that 1) mammalian tachykinins are involved in the regulation of thoracic and abdominal expiratory muscle activity, 2) these muscles manifest substantial differences in their electrical responses to excitatory neuropeptides acting centrally, and 3) inputs from modulatory neurons located in this vicinity of the ventral medullary surface seem to be distributed unevenly to different expiratory premotor and/or motoneurons.     

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

Goats were prepared so that one carotid body (CB) could be perfused with blood in which the gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Since one CB is functionally adequate, the nonperfused CB was excised. To determine whether systemic arterial hypoxemia is necessary for ventilatory acclimatization to hypoxia (VAH), the CB was perfused with hypoxic normocapnic blood for 6 h [means +/- SE: partial pressure of carotid body O2 (PcbO2), 40.6 +/- 0.3 Torr; partial pressure of carotid body CO2 (PcbCO2), 38.8 +/- 0.2 Torr] while the awake goat breathed room air to maintain systemic arterial normoxia. In control periods before and after CB hypoxia the CB was perfused with hyperoxic normocapnic blood. Changes in arterial PCO2 (PaCO2) were used as an index of changes in ventilation. Acute hypoxia (0.5 h of hypoxic perfusion) resulted in hyperventilation sufficient to reduce average PaCO2 by 6.7 Torr from control (P less than 0.05). Over the subsequent 5.5 h of hypoxic perfusion, average PaCO2 decreased further, reaching 4.8 Torr below that observed acutely (P less than 0.05). Acute CB hyperoxic perfusion (20 min) following 6 h of hypoxia resulted in only partial restoration of PaCO2 toward control values; PaCO2 remained 7.9 Torr below control (P less than 0.05). The progressive hyperventilation that occurred during and after 6 h of CB hypoxia with concomitant systemic normoxia is similar to that occurring with total body hypoxia. We conclude that systemic (and probably brain) hypoxia is not a necessary requisite for VAH.     

Pulmonary vascular tone is increased by a voltage-dependent calcium channel potentiator

The mechanism of hypoxia-induced pulmonary vasoconstriction remains unknown. To explore the possible dependence of the hypoxic response on voltage-activated calcium (Ca2+) channels, the effects of BAY K 8644 (BAY), a voltage-dependent Ca2+ channel potentiator, were observed on the pulmonary vascular response to hypoxia of both the intact anesthetized dog and the perfused isolated rat lung. In six rat lungs given BAY (1 X 10(-6)M), hypoxia increased mean pulmonary arterial pressure (Ppa) to 30.5 +/- 1.7 (SEM) Torr compared with 14.8 +/- 1.2 Torr for six untreated rat lungs (P less than 0.01). After nifedipine, the maximum Ppa during hypoxia fell 14.1 +/- 2.4 Torr from the previous hypoxic challenge in the BAY-stimulated rats (P less than 0.01). BAY (1.2 X 10(-7) mol/kg) given during normoxia in seven dogs increased pulmonary vascular resistance 2.5 +/- 0.3 to 5.0 +/- 1.2 Torr X 1(-1) X min (P less than 0.05), and systemic vascular resistance 55 +/- 4.9 to 126 +/- 20.7 Torr X 1(-1) X min (P less than 0.05). Systemic mean arterial pressure rose 68 Torr, whereas Ppa remained unchanged. Administration of BAY during hypoxia produced an increase in Ppa: 28 +/- 1.5 to 33 +/- 1.9 Torr (P less than 0.05). Thus BAY, a Ca2+ channel potentiator, enhances the hypoxic pulmonary response in vitro and in vivo. This, together with the effect of nifedipine on BAY potentiation, suggests that increased Ca2+ channel activity may be important in the mechanism of hypoxic pulmonary vasoconstriction.     

Ventilatory response of spinal cord-lesioned subjects to electrically induced exercise

Seven human spinal cord-lesioned subjects (SPL) underwent electrically induced muscle contractions (EMC) of the quadriceps and hamstring muscles for 10 min: 5 min control, 2 min with venous return from the legs occluded, and 3 min postocclusion. Group mean changes in CO2 output compared with rest were +107 +/- 30.6, +21 +/- 25.7, and +192 +/- 37.0 (SE) ml/min during preocclusion, occlusion, and postocclusion EMC, respectively. Mean arterial CO2 partial pressure (PaCO2) obtained from catheterized radial arteries at 15- to 30-s intervals showed a significant (P less than 0.05) hypocapnia (36.2 Torr) during occlusion and a significant (P less than 0.05) hypercapnia (38.1 Torr) postocclusion relative to a group mean preocclusion EMC PaCO2 of 37.5 Torr. Relative to preocclusion EMC, expired ventilation (VE) decreased during occlusion and increased after release of occlusion. However, changes in VE always occurred after changes in end-tidal PCO2 (mean 41 s after occlusion and 10 s after release of occlusion). In the two subjects investigated during hyperoxia, the VE and PaCO2 responses to occlusion and release did not differ from normoxia. We conclude that the data do not support mediation of the EMC hyperpnea in SPL by humoral mechanisms that others have proposed for mediation of the exercise hyperpnea in spinal cord-intact humans.     

Carotid bodies are required for ventilatory acclimatization to chronic hypoxia

We have compared the ventilatory responses of intact and carotid body-denervated (CBD) goats to moderate [partial pressure of O2 in arterial blood; (Pao2) approximately 44 Torr] and severe (Pao2 approximately 33 Torr) many time points for up to 7 days of hypobaria. In the intact group there were significant time-dependent decreases in partial pressure of CO2 in arterial blood (PaCO2) in both moderate and severe hypoxemia (approximately-7 and -11 Torr) that were largely complete by 8 h of hypoxemia and maintained throughout. Acute restoration of normoxia in chronically hypoxic intact animals produced time-dependent increases in Paco2 over 2 h, but hypocapnia persisted relative to sea-level control. Arterial plasma [HCO3-] and [H+] decreased, and [Cl-] increased with a time course and magnitude consistent with developing hypocapnia. Chronic CBD, per se, resulted in a sustained, partially compensated respiratory acidosis, as PaCO2 rose 6 Torr and base excess rose 3 mEq/1, [Cl-] fell 1 mEq/1, and pHa fell 0.01 units. During exposure to identical levels of arterial hypoxemia as in the intact group. CBD animals showed no significant changes in PaCO2, [H+]a, or [HCO3-]a at any time during moderate or severe hypoxemia. Plasma [C1-] remained within the normal range throughout exposure to moderate hypoxia and increased in severe hypoxia. In a few instances some hypocapnia was observed, but this was highly inconsistent and was always less than one-third of that observed in intact goats. In contrast to intact goats, acute restorations of normoxia in the chronically hypoxic CBD goats always caused hyperventilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of arterial O2 on the susceptibility to posthyperventilation apnea during sleep.

To investigate the contribution of the peripheral chemoreceptors to the susceptibility to posthyperventilation apnea, we evaluated the time course and magnitude of hypocapnia required to produce apnea at different levels of peripheral chemoreceptor activation produced by exposure to three levels of inspired P(O2). We measured the apneic threshold and the apnea latency in nine normal sleeping subjects in response to augmented breaths during normoxia (room air), hypoxia (arterial O2 saturation = 78-80%), and hyperoxia (inspired O2 fraction = 50-52%). Pressure support mechanical ventilation in the assist mode was employed to introduce a single or multiple numbers of consecutive, sigh-like breaths to cause apnea. The apnea latency was measured from the end inspiration of the first augmented breath to the onset of apnea. It was 12.2 +/- 1.1 s during normoxia, which was similar to the lung-to-ear circulation delay of 11.7 s in these subjects. Hypoxia shortened the apnea latency (6.3 +/- 0.8 s; P < 0.05), whereas hyperoxia prolonged it (71.5 +/- 13.8 s; P < 0.01). The apneic threshold end-tidal P(CO2) (Pet(CO2)) was defined as the Pet(CO2)) at the onset of apnea. During hypoxia, the apneic threshold Pet(CO2) was higher (38.9 +/- 1.7 Torr; P < 0.01) compared with normoxia (35.8 +/- 1.1; Torr); during hyperoxia, it was lower (33.0 +/- 0.8 Torr; P < 0.05). Furthermore, the difference between the eupneic Pet(CO2) and apneic threshold Pet(CO2) was smaller during hypoxia (3.0 +/- 1.0 Torr P < 001) and greater during hyperoxia (10.6 +/- 0.8 Torr; P < 0.05) compared with normoxia (8.0 +/- 0.6 Torr). Correspondingly, the hypocapnic ventilatory response to CO2 below the eupneic Pet(CO2) was increased by hypoxia (3.44 +/- 0.63 l.min(-1).Torr(-1); P < 0.05) and decreased by hyperoxia (0.63 +/- 0.04 l.min(-1).Torr(-1); P < 0.05) compared with normoxia (0.79 +/- 0.05 l.min(-1).Torr(-1)). These findings indicate that posthyperventilation apnea is initiated by the peripheral chemoreceptors and that the varying susceptibility to apnea during hypoxia vs. hyperoxia is influenced by the relative activity of these receptors.