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Chronically prepared fetal sheep were subjected to 48 h infusions of theophylline, an adenosine antagonist, enprofylline, a xanthine without adenosine antagonism, or saline. Theophylline increased mean (+/- SD) incidence of REM sleep from 49.3 +/- 8.3% to 57.3 +/- 6.7% (p0.02) and wakefulness from 1.3 +/- 1.4% to 8.1 +/- 7.1% (p0.01). On the first day of theophylline infusion incidence of fetal breathing (FB) increased from 37.9 +/- 8.1% to 53.7 +/- 11.6% of total time (p0.002) and from 76.4 +/- 10.2% to 87.6 +/- 10.3% of REM sleep (p0.02). Diaphragmatic EMG/min increased from 6.9 +/- 4.0 to 17.3 +/- 13 arbitrary units (p0.02). By the second day of infusion, FB had returned to baseline value. Enprofylline and saline had no effect. 125 micrograms phenyl isopropyl adenosine (PIA) i.v. caused fetal apnea that was reduced from 143 +/- 45.5 min on the control day to 39.8 +/- 34.7 min (p0.001) during theophylline infusion. Enprofylline and saline had no effect, suggesting that the observed theophylline effect was due to its adenosine antagonism rather than to non-specific xanthine action. We conclude that endogenous adenosine suppresses FB, but since theophylline did not alter the basic relationship between FB and REM sleep it is not primarily responsible for apnea during NREM sleep.

The effect of sleep state on the respiratory response to hypercapnia was studied in 14 chronic fetal sheep, 125-140 days gestation. Fetal PaCO2 was raised by 11 to 34 Torr by gradually increasing the maternal FICO2 to 0.09. Fetal sleep state was monitored. Fetal breathing (FB) was analysed in terms of frequency (f), tracheal pressure (TP) and ventilation equivalent (VEq) = sigma TP /min. In 16 out of 17 experiments on apneic fetuses in NREM sleep, the fetuses switched to REM sleep and in 14 instances began to breathe within 2 1/2 min thereafter. The PaCO2 at which apneic fetuses started breathing was 54.8 +/- 8.4 Torr (mean +/- SD). In 4 out of 10 trials on breathing fetuses in REM sleep the fetuses switched to NREM sleep and stopped breathing before removal of the CO2 stimulus. During REM sleep hypercapnia stimulated FB by an increase in TP and by a reduction in the number and duration of apneic pauses. It is concluded that in the fetal lamb CO2 stimulates breathing only during REM sleep and that this stimulus is superimposed on the basic mechanism that stimulated spontaneous FB during this sleep state.

Although changes in systemic arterial mean pressure have been considered to contribute to the initiation of respiration of fetal sheep, the precise influence has not been satisfactorily elucidated. Respiratory efforts were monitored in 14 near term exteriorized fetal lambs using a liquid plethysmograph. Changes in mean systemic pressure ( BP ) in the absence of changes in blood gas tensions were produced on 15 occasions by rapid infusion or withdrawal of blood, infusion of norepinephrine or occlusion of one umbilical artery. Despite change of BP of as much as ± 50%, breathing was not initiated. On 18 occasions alterations in BP with concomitant hypercapnia and hypoxemia were produced by either occlusion of the umbilical vein, both umbilical arteries, entire cord or the maternal abdominal aorta. In all instances fetal gasping was evoked indicating that the initiation of breathing is independent of the site of interruption of fetal-plaeental gas exchange. By several methods of analysis there was no relationship between BP and the arterial PCO2 and PO2 at the time of gasp. Also, BP did not influence the latent period. It is concluded that changes in BP per se cannot initiate respiration. Furthermore, there is no interaction between hypercapnia-hypoxemia and BP in the initiation of breathing of fetal lambs.