In this study, Fos immunohistochemistry was used to map brainstem neuronal pathways activated during hypercapnia and hypoxia. Conscious rats were exposed to six different gas mixtures: (a) air; (b) 8% CO2 in air; (c) 10% CO2 in air; (d) 15% CO2 in air; (e) 15% CO2 + 60% O2, balance N2; (f) 9% O2, balance N2. Double-staining was performed to show the presence of tyrosine hydroxylase. Hypercapnia, in a dose-dependent way caused Fos expression in the following areas: caudal nucleus tractus solitarius (NTS), with few labeled A2 noradrenergic neurons; noradrenergic A1 cells and noncatecholaminergic neurons in the caudal ventrolateral medulla; raphe magnus and gigantocellular nucleus pars alpha (GiA); many noncatecholaminergic (and relatively few C1) neurons in the lateral paragigantocellular nucleus (PGCl), and in the retrotrapezoid nucleus (RTN); locus coeruleus (LC), external lateral parabrachial and Kölliker-Fuse nuclei, and A5 noradrenergic neurons at pontine level; and in caudal mesencephalon, the ventrolateral column of the periaqueductal gray (vlPAG). In most of these nuclei, hypoxia also induced Fos expression, albeit generally less than after hypercapnia. However, hypoxia did not cause labeling in RTN, juxtafacial PGCl, GiA, LC, or vlPAG. After normoxic hypercapnia, more labeled cells were present in NTS and PGCl than after hyperoxic hypercapnia. Part of the observed labeling could be caused by stress- or cardiovascular-related sequelae of hypoxia and hypercapnia. Possible implications for the neural control of breathing are also discussed, particularly with regard to the finding that several nuclei, not belonging to the classical brainstem respiratory centres, contained labeled cells.

SUMMARY1. The ventilatory response to isoxic square-wave challenges in end-tidal Pco2 was investigated at three levels of end-tidal PO2 (PET, 02) in nine healthy male subjects.2. Twenty-seven responses against a background of mild hypoxia (PET 0,. 10 kPa), sixty-seven against a background of normoxia (PET, 02 14-5 kPa) and seventy-six against a background of hyperoxia (PET,02 ? 70 kPa) were collected. 3. The breath-to-breath data were partitioned into a fast and a slow ventilatory component using a two-compartment model.4. In the normoxic and hypoxic experiments the CO2 sensitivity of the fast component averaged to about 30 and 40 % of the total CO2 sensitivity, respectively. In the hyperoxic experiments three subjects had no fast component in their response while in three others the CO2 sensitivity of the fast component averaged to about 24 % of the total CO2 sensitivity. In the remaining three subjects the presence of a fast component was doubtful.5. We argue that the fast component is due to the peripheral chemoreflex loop and the slow component to the central chemoreflex loop.6. The central CO2 sensitivity and the apnoeic threshold (extrapolated end-tidal CO2 at zero ventilation in the steady state) were 15% smaller in hyperoxia than those in normoxia and hypoxia. In normoxia and mild hypoxia the central CO2 sensitivities were not significantly different.7. We argue, that apart from peripheral oxygen-carbon dioxide interaction, there is evidence for central oxygen-carbon dioxide interaction in human subjects.8. We conclude that in general there is a contribution to ventilation of the peripheral chemoreceptors during hyperoxia in man.

3. In all subjects the ventilatorv C(2 sensitivities obtained with the rebreathing method (Sr) were appreciably larger than the steady-state CO2 sensitivities (S). The ratio Sr/Ss ranged from t 40 to 2 59 with a mean value of tP85.4. We argue that these results can be explained by considering the effect of changes in cerebral blood flow upon increasing the arterial CO2 tension during rebreathing and the steady state.5. AVe conclude that in general the CO2 sensitivity obtained with Read's rebreathing method does not represent the steady-state CO2 sensitivity.

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