L.C. Ou

Ventilatory response of decorticate and decerebrate cats to hypoxia and CO2.

The steady state ventilatory response of normal, fully awake cats was studied under graded hypoxia (at PAO2 = 110, 55, 45 torr) with PACO2 controlled throughout at the resting, normoxic level and at +5 torr. Subsequently, either a mid-collicular decerebration or a decortication was performed, and the ventilatory studies were repeated. Respiratory frequency, tidal volume, and ventilation in the decerebrate state responded to hypoxia and hypercapnia in a manner indistinguishable from the control. The decorticate cats, however, exhibited an exaggerated response to hypoxia, principally the result of increased frequency. The negative hypoxic, hypercapnic interaction, characteristic of awake cats, was demonstrable in both the decerebrate and decorticate animals. The findings are interpreted as revealing coupled descending influences on the medullary respiratory centers in hypoxia--one that is facilitatory and originates in the diencephalon, and the other, inhibitory, from the cerebrum. The significance of this suprapontine system in normal hypoxic ventilatory control is discussed.

Properties of mitochondria from hearts of cattle acclimatized to high altitude.

Abstract Hearts of domestic cattle from two groups, one born and raised at sea level and the other born and raised at an altitude of 4250 m, were studied to determine whether any mitochondrial adaptations to high altitude could be demonstrated. Direct counts of mitochondrial number revealed a 40 % increase in the high altitude hearts, but mitochondrial size was the same as at sea level. Measurements of enzyme content indicated an individual mitochondrial increase in electron transport system; and oxygen uptake and cytochrome a oxidase, per mitochondrion, were increased in the same proportion. These changes are discussed as an intracellular mechanism which would serve to preserve oxidative metabolism in hypoxia, particularly under exercising conditions. The effective conservation of oxygen pressure head by this means is probably less than one mm Hg.

Physiological evidence for increased tissue capillarity in rats acclimatized to high altitude

Abstract A feature of fully acclimatized animals is an increase in tissue capillary density, but existing evidence is morphological. The present experiments sought to provide physiological evidence, and to that end a measure of “tissue diffusing capacity” was developed, based on the uptake rate of low concentrations of CO from subcutaneous gas pockets in rats. On that basis it was determined that three weeks of acclimatization to an equivalent altitude of 5600 m resulted in a roughly doubled uptake rate. When corrections for the contribution of the secondary polycythemia were made, and using certain simplifying assumptions, it was deduced that acclimatization resulted in a 50 % increase of capillary number. The effect of this change on P O 2 in the most distal sites of a diffusion cylinder have been calculated on the assumption that gas pocket P O 2 represents regional venous P O 2 . The value is more than 10 mm Hg below sea level control at 5600 m but is still well above zero, which would not be the case without increase of capillarity. Experiments to test the effect of acclimatization to lesser altitudes indicated no effect on capillarity in a three week period when the altitude was below 4100 m.

Exogenous erythropoietin fails to augment hypoxic pulmonary hypertension in rats

In two rat strains (H and M) with differing susceptibilities to chronic hypoxia we examined the role of polycythemia in the differing hypoxic pulmonary hemodynamic responses. We hypothesized that augmentation of hematocrit (Hct) during hypoxia in the resistant M strain would render cardiopulmonary responses similar to those obtained in the susceptible H strain. Administration of human recombinant erythropoietin (EPO) in doses of 100, 250 and 500 U.kg-1 s.c. thrice weekly for three weeks raised Hct similarly in both strains indicating that normoxic rats had similar sensitivities to EPO. In rats exposed to hypobaric hypoxia (0.5 atm) for 21 days, EPO (500 U.kg-1 thrice weekly) significantly increased Hct and whole blood viscosity as expected. Surprisingly, right ventricular (RV) to body weight (BW) ratio as an index of right ventricular hypertrophy (RVH) and RV peak systolic pressure did not increase in EPO-injected rats of either strain compared to hypoxic controls. Among hypoxic animals, Hct correlated highly with viscosity but not with RV/BW. We conclude, contrary to our hypothesis, that polycythemia does not appear to be responsible for the strain difference in RVH and pulmonary hypertension.

Ventilatory responses and blood gases in susceptible and resistant rats to high altitude

On exposure to a stimulated altitude of 5500 m (18 000 ft), the Hilltop (H) strain of Sprague-Dawley rats develops signs of chronic mountain sickness (CMS) (severe polycythemia, severe pulmonary hypertension and right ventricular hypertrophy) associated with a high mortality rate. In contrast, the Madison (M) strain of Sprague-Dawley rats remains healthy with less severe cardiopulmonary and hematological responses. We tested the hypothesis that hypoventilation in the H rats relative to the M rats, leading to greater alveolar hypoxia or hypoxemia, could account for the different hematological and cardiopulmonary responses between the two strains. Ventilatory responses and blood gases were compared under normoxia and acute and chronic hypoxia in fully awake and unrestrained animals of the two strains. There were no differences in VE, Pao2, PaCO2, pHa, P-vO2, PvCO2 and pH-v under either acute or chronic hypoxia between the two strains of rats. It is concluded that relative hypoventilation does not contribute to altitude susceptibility in H rats.

Hypoxia and carbon dioxide as separate and interactive depressants of ventilation

The respiratory frequency, tidal volume and ventilization responses of 20 conscious cats to hypoxia, at controlled levels of alveolar CO2, revealed a characteristic steady state response in the majority of animals which indicated a negative interaction of stimuli on tidal volume and minute volume of ventilation, but a positive interaction on frequency. Another series of studies, conducted on seven conscious cats, sought to identify hypoxic response thresholds and depression thresholds, by determining responses over a wide range of hypoxic stimulus intensities, and at different controlled alveolar PCO2. Response threshold was at about 65 torr PAO2. Under eucapnic conditions, ventilation began to fail at PAO2 about 30 torr due to failure of tidal volume. The frequency continued to increase even in the lowest range of PAO2. With hypocapnia no failure of ventilation, frequency, or tidal volume was seen even at the lowest PAO2, but with hypercapnia, the tidal volume began to fail at PAO2 about 50 torr. The minute volume however, continued to increase into the lowest range of PAO2, because the frequency continued to respond at a rate greater than the tidal volume was failing. The results are discussed in terms of interactive depression manifest through the coupled responses of peripheral and central mechanisms.

Acute and chronic pulmonary pressor responses to hypoxia: The role of blunting in acclimatization

We studied two strains of Sprague-Dawley rats: the Madison (M) that acclimatizes successfully to high altitude; and the Hilltop (H), that manifests signs of chronic mountain sickness at high altitude and has a high mortality rate. Awake, chronically instrumented animals were tested at sea level, at intervals during 30 days at a simulated altitude of 5500 m, and during 10 to 15 days of recovery at sea level. Mean pulmonary artery pressure (PAP) rose at high altitude to reach 60 mm Hg in H and 40 mm Hg in M, but the acute pressor response to hypoxia at sea level was much more pronounced in M than H. Depression of PAP by normoxic exposures in H rats at high altitude was slightly early in the period of stay but was enhanced with further prolongation of high altitude residence. The M rats, in contrast, had a blunted response (normoxia had very little depressant effect on PAP) after the first 24 h at high altitude, and it remained so for the duration of the stay. On return to sea level the response of H rats remained unchanged for 7 days, but the blunted response of the M rats at high altitude reversed at sea level to become exaggerated. We conclude: that responses of PAP to acute hypoxia do not forecast what the chronic response will be; that the appearance of an unidentified mechanism during chronic hypoxia in the M strain attenuates the vasoreactivity of the pulmonary vessels to hypoxia; and that the absence of such a blunting mechanism in H leads to the higher PAP in this strain and its morbid consequences. The hypothesis is put forward that the existence of such a blunting mechanism is an important factor in the adaptability of species to high altitude.

Responses of blood volume and red cells mass in two strains of rats acclimatized to high altitude

Two strains of rats, one that adapts successfully to high altitude (HA) (Madison = M) and the other that adapts poorly and suffers a high mortality rate at high altitude (Hilltop = H) were studied during 40 days of exposure to a simulated altitude of 18 000 ft (5450 m; PB = 175). The time rate of change of blood volume (TBV), red cell volume (RBCV), plasma volume (PV) and hematocrit (Hct), and the interrelationships of these variables, particularly emphasizing TBV, PV and Hct as functions of RBCV, were compared in the M and H strains. Sea level control values in the two strains were not different, but by the 5th day at HA RBCV and TBV had expanded to a greater extent in H than M - a difference that was maintained throughout the 40 days - but PV decreased similarly in the two strains. By 30 days the inter-strain differences of RBCV, TBV, and Hct became more pronounced but still no difference of PV was noted. The most significant feature was the greater polycythemic response of H, which at the extreme range was not associated with any further decrease of PV and therefore resulted in rapid expansion of TBV. The probable effects of these responses on cardiovascular function and oxygen transport are discussed, comparing the differences of H and M strains, which became maladaptive in H. The similarity of the responses in H to those of man with chronic mountain sickness is noted.

The role of brief hypocapnia in the ventilatory response to CO2 with hypoxia

In conscious cats the ventilatory response curve to physiological range of CO2 is displaced upward by hypoxia (about 45 torr), but it rises, either parallel with, or convergent on, the normoxic curve. Thus, a positive interaction of hypoxia and hypercapnic stimuli is not observed under these circumstances. However, if during the hypoxic exposure, hypocapnia is allowed to develop, the subsequently determined CO2 ventilatory response curve will shift to the left, rise steeply, particularly in the early phase, and demonstrate a positive hypoxic hypercapnic interaction. A demonstrable interactive effect was dependent on a conditioning period of hypocapnia, and this was shown to be associated with an elevated level of lactic acid to a greater degree in cerebral venous blood than in CSF or arterial blood. The interpretation is discussed without reaching a firm conclusion of mechanism, but the results emphasize how a minor change of experimental protocol affects a basic phenomenon in the chemical control of breathing.

Post-prandial rise in alveolar CO2 and ventilatory response in cats☆

Abstract Awake, unrestrained cats showed an average 4-5-torr increase of alveolar P CO 2 after eating. Ventilation, on the other hand, did not change, and it was concluded that the rise of alveolar P CO 2 i was a consequence of an increase of metabolism without proportional change of alveolar ventilation. Ventilatory response to CO 2 and to hypoxia, determined in the pre- and post-prandial states, showed curves with parallel displacement but no change of slope. A comparison is drawn against other situations of ventilatory response with increase of metabolism, but in all cases the mechanisms remain obscure.