H. V. Forster

Effects of acute through life-long hypoxic exposure on exercise pulmonary gas exchange.

Abstract The adequacy, efficiency and control of pulmonary gas exchange during exercise was compared among groups who were exposed for various durations of time to moderate hypoxia (3100 m altitude, P i O2 100 mm Hg. These groups included native lowlanders during acute, shortterm (4 to 45 days) and long-term (1–16 yr) exposure and native highlanders of 1 to 3 generations exposure. The working sojourner depended almost entirely on his ventilatory adaptation for maintaining adequate pulmonary and systemic O2 transport at 3100 m. Exercise D lco , VC, (A-a) DO2 and Hb concentration were unchanged from acute through 21 days exposure, although (A-a) DO2 widened after 45 days at 3100 m. In contrast to the sojourner, the resident of 3100 m hypoventilated during exercise and maintained PaCO2 at or above resting levels. He depended on a high O2 carrying capacity and most importantly on an increased D lco and Vc and narrowed (A-a) D o2 for his enhanced systemic O2 delivery during work. No differences in the pulmonary response to work were found among long-term and native residents of 3100 m. Hence, the highlander avoided the high levels of ventilatory work and exertional dyspnea experienced by the sojourner without compromising systemic O2 delivery.

Ventilatory Acclimatization to Moderate Hypoxemia in Man: THE ROLE OF SPINAL FLUID [H+]

This study has assessed the regulation of arterial blood and cerebrospinal fluid (CSF) pH and thereby their contribution to the control of breathing in normal man during various stages of ventilatory acclimatization to 3,100 m altitude. CSF acid-base status was determined: (a) from measurements of lumbar spinal fluid during steady-state conditions of chronic normoxia (250 m altitude) and at + 8 h and + 3-4 wk of hypobaric hypoxia; and (b) from changes in cerebral venous P(CO2) at + 1 h hypoxic exposure. After 3-4 wk at 3,100 m, CSF [H(+)] remained significantly alkaline to values obtained in either chronic normoxia or with 1 h hypoxic exposure and was compensated to the same extent ( approximately 66%) as was arterial blood [H(+)]. Ventilatory acclimatization to 3,100 m bore no positive relationship to accompanying changes in arterial P(O2) and pH and CSF pH: (a) CSF pH either increased or remained constant at 8 h and at 3-4 wk hypoxic exposure, respectively, coincident with significant, progressive reductions in Pa(CO2); (b) arterial P(O2) and pH increased progressively with time of exposure; and (c) in the steady-state of acclimatization to 3,100 m the combination of chemical stimuli present, i.e. Pa(O2) = 60 mm Hg, pHa and pH(CSF) = + 0.03-0.04 > control, was insufficient to produce the observed hyperventilation (Pa(CO2) = 32 mm Hg). It was postulated that ventilatory acclimatization to 3,100 m altitude was mediated by factors other than CSF [H(+)] and that the combination of chronic hypoxemia and hypocapnia of moderate degrees provided no mechanisms for the specific regulation of CSF [H(CO3) (-)] and hence for homeostasis of CSF [H(+)].

Control of exercise hyperpnea under varying durations of exposure to moderate hypoxia

Abstract Ventilation and arterial acid-base status at rest and during steady-state work at P i O 2 100, 145 and 250 mm Hg, were studied in: (1) lowlanders at sea level and after 4, 21 and 45 days sojourn at 3100 m altitude; (2) lowlanders residing for 2–15 years at 3100 m; and (3) native altitude residents. The total ventilatory changes at rest and work in the sojourner between ambient conditions at 250 and 3100 m altitudes were attributed: (a) to (acute) hypoxia alone, particularly during moderate to severe exercise; and (b) to the secondary effects of altitude sojourn which accounted for most of the final levels of hyperventilation achieved under all conditions of rest and work, and were complete after 4 days sojourn. Because of: (a) the absence of a significant respiratory alkalosis in response to acute hypoxia at rest, and (b) the normal ventilatory acclimatization to altitude in a lowlander subject who was non-responsive to hypercapnic-hypoxic stimuli combinations, it was reasoned that current theories based on a restoration of CSF [H + ] were not sufficient to explain the hyperventilation obtained upon sojourn to 3100 m. In residents of 3100 m: (a) Exercise e was significantly lower, Pa CO 2 higher (PIo2100), and the Δe with removal of hypoxemia less than in the sojourner at 3100 m, but similar to the sojourners results obtained during acute hypoxic exposure at sea-level; and (b) native residents and resident low-landers were similar in all respects. Sojourner-resident differences in hypoxic exercise hyperpnea at 3100 m were attributed primarily to the acquired hyper-responsiveness in the sojourner and to a lesser extent to some degree of subnormal ventilatory chemosensitivity in the resident.

Depression of ventilation by dopamine in goats — effects of carotid body excision

Dopamine (DA) given IV by bolus injection (5, 10, 20 micrograms/kg) and by slow IV infusion (20 micrograms . kg . min) depressed VE significantly in awake normoxic goats. These responses were attenuated but not eliminated during hypoxia (FIO2 = 0.14) and hyperoxia (FIO2 = 1.0). After administering haloperidol (0.3 mg/kg) or removing the carotid bodies (CBE) there was greater attenuation of the response to DA. In normal goats haloperidol also caused a significant increase in ventilatory response to acute hypoxia and exaggerated depression of VE after 3--5 breaths O2 during steady-state hypoxia. After CBE haloperidol caused mild hypoventilation (delta PaCO2 = +2.5 Torr). CBE induced hypoventilation in goats (delta PaCO2 = +7.8 Torr) and reduced, but did not totally eliminate, peripheral chemoreceptor responses to acute stimuli (NaCN injection, transient N2 and transient O2 breathing). Attempted aortic body denervation did not eliminate these residual responses. We conclude: (1) DA may function as a modulator of carotid body (CB) function in the goat, (2) there may be central excitatory DA receptors in the goat, (3) the CB is important in regulating resting ventilation in the goat.

Carotid body hypercapnia does not elicit ventilatory acclimatization in goats

The carotid body (CB) perfusion model utilizes surgical vascular ligations to allow isolated blood supply to a single in situ CB in awake goats. The contralateral CB was excised. By use of an extracorporeal pump-oxygenator system the blood gas composition perfusing the CB can be controlled independently from that of the systemic arterial system including the brain. Using this model we compared the responses of systemically normoxic goats to CB hypercapnia and CB hypoxia. In 6 goats CB stimulation with hypercapnic-normoxic blood (mean PcbCO2 = 78 Torr, mean PcbO2 congruent to 100 Torr) produced acute hyperventilation (mean decrease in PaCO2 of 5.2 Torr, P less than 0.05) which remained constant over the 4-h perfusion period. Lack of a progressively increasing hyperventilation indicates that ventilatory acclimatization did not occur with hypercapnic CB perfusion. Hypoxic-normocapnic CB stimulation (mean PcbO2 = 40 Torr, mean PcbCO2 = 39 Torr) produced an acute mean decrease in PaCO2 of 5.5 Torr (P less than 0.05) in 6 additional goats. In contrast to CB hypercapnia, the acute hyperventilation induced by CB hypoxia was followed by a progressive time-dependent additional mean decrease in PaCO2 of 5.6 Torr (P less than 0.05) over a 4-h period (ventilatory acclimatization). These data are compatible with the concept of separate receptor mechanisms for hypercapnia and hypoxia in the CB and suggest that the early phase of ventilatory acclimatization to hypoxia in goats may result from a time-dependent increase in CB afferent output.

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.

Respiratory Influences on Acid-Base Status and Their Effects on O2 Transport during Prolonged Muscular Work

During exercise of short duration in healthy man, the increase in alveolar ventilation is precisely matched to the increased tissue CO2 production. Hence arterial is closely regulated near resting levels and the only change in pH is secondary to an uncompensated metabolic acidosis.

Differences between three inbred rat strains in number of K+ channel-immunoreactive neurons in the medullary raphé nucleus

Ventilatory sensitivity to hypercapnia is greater in Dahl salt-sensitive (SS) rats than in Fawn Hooded hypertensive (FHH) and Brown Norway (BN) inbred rats. Since pH-sensitive potassium ion (K(+)) channels are postulated to contribute to the sensing and signaling of changes in CO(2)-H(+) in chemosensitive neurons, we tested the hypothesis that there are more pH-sensitive K(+) channel-immunoreactive (ir) neurons within the medullary raphé nuclei of the highly chemosensitive SS rats than in the other two strains. Medullary tissues from male and female BN, FHH, and SS rats were stained with cresyl violet or with antibodies targeting TASK-1, K(v)1.4, and Kir2.3 channels. K(+) channel-ir neurons were quantified and compared with the total neurons in the region. The total number of neurons in the medullary raphé 1) was greater in male FHH than the other male rats, 2) did not differ among the female rats, and 3) did not differ between sexes. The average number of K(+) channel-ir neurons per section was 30-60 neurons higher in the male SS than in the other rat strains. In contrast, for the females, the number of K(+) channel-ir neurons was greatest in the BN. We also found significant differences in the number of K(+) channel-ir neurons between sexes in SS (males > females) and BN (females > males) rats, but not the FHH strain. Our findings support the hypothesis for males but not for females, suggesting that both genetic background and sex are determinants of K(+) channel immunoreactivity of medullary raphé neurons, and that the expression of pH-sensitive K(+) channels in the medullary raphé does not correlate with the ventilatory sensitivity to hypercapnia.

The Role of the Carotid Body in Acclimatization to Hypoxia

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increasing hyperventilation that occurs during prolonged exposure to hypoxia. The carotid chemoreceptors are responsible for the acute ventilatory response to hypoxia and they are recognized as critical to at least the initiation of VAH (Forster et al., 1976, 1981: Smith et al., 1984). Beyond the initial acute hypoxic hyperventilation the mechanism of VAH has been controversial. Several mechanisms associated with brain hypoxia have been proposed previously, e.g., acidification of cerebral interstitial fluid in the environment of the central chemoreceptors (Fencl et al., 1979), changes in brain monoamine metablolism (Olson et al., 1983) and suprapontine facilitation of respiratory activity (Tenney and Ou, 1977). It is clear that brain hypoxia alone cannot initiate VAH since it does not proceed normally in the absence of the carotid chemoreceptors (Forster et al., 1976, 1981: Smith et al., 1984). However, it remains unclear as to the role brain hypoxia and acid-base changes play in VAH. Similarly the role of the peripheral chemoreceptors remains unclear. Therefore, we asked the following questions: l) Is brain hypoxia a necessary component of the mechanism of VAH? 2) Does hypocapnic alkalosis play a critical role in VAH? and 3) Can VAH be induced by different modes of carotid body (CB) stimuli?