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Intravenous infusion of probencid (79-160 mg kg−1) into unanaesthetized fetal sheep (127-143 days gestation) in utero significantly decreased the incidence and amplitude of spontaneous breathing movements, but did not change the incidence of low voltage electrocortical (ECoG) activity, plasma prostaglandin E2 (PGE2) concentrations, blood gases or pH. In fetuses pretreated with paracetamol (350 mg kg−1) to inhibit PG synthase activity, infusion of probenecid did not change the mean incidence or amplitude of breathing movements, indicating that the inhibitory effect of probenecid on breathing movements required the presence of active PG synthesis. Probenecid infusion in four unanaesthetized fetuses significantly increased the PGE2 concentrations in cisternal cerebrospinal fluid (CSF) by 6.6 ± 1.5-fold (P < 0.05). In pentobarbitone-anaesthetized, exteriorized fetuses, probenecid infusion decreased the clearance of [3H]PGE2 from CSF during ventriculo-cisternal perfusion of artificial CSF containing [3H]PGE2. These results suggest that there is active transport of PGs from CSF to blood in fetal sheep from at least 127 days gestation. Inhibition of this transport results in the accumulation of PGs within interstitial fluid of the brain, one effect of which is to suppress the spontaneous activity of the respiratory centres. Prostaglandins (PGs) have neuromodulatory effects in the central and peripheral nervous systems and are known to influence catecholamine and cholinergic transmission (Hedqvist, 1977), and the release of several neuropeptides, especially those synthesized and released by the hypothalamus and pituitary gland. At physiological pH, PGs do not readily cross cell membranes (Bito & Baroody, 1975; Bito & Wallenstein, 1977) and therefore, it is likely that PGs do not enter the brain from the circulation in physiologically significant amounts. Rather, it has been shown in adult animals that PGs are cleared from the brain into the circulation by a saturable, energy-dependent transport mechanism (Bito, Davson & Hollingsworth, 1976). Whether such a mechanism is present in the fetal brain, and acts to limit the penetration of PGs from the circulation into the brain is not known. Cerebral tissue has little capacity to metabolize PGs (see Coceani, 1974), and the PGs found in cerebral extracellular fluid (ECF) and cisternal cerebrospinal fluid (CSF) probably reflects the endogenous synthesis of prostanoids by the brain. Koos (1985) found that inhibition of brain PG synthesis in fetal sheep by ventriculo-cisternal perfusion of meclofenamate resulted in a marked increase of breathing movements, suggesting that cerebral synthesis of PGs is important in regulating respiratory activity in utero. PG synthase has been localized immunocytochemically throughout the brain of adult sheep (Breder et al. 1992) and in the medulla of fetal sheep at 126 days gestation (Norton, Smith, Adamson, Bocking & Han, 1990). Attempts to selectively suppress the cerebral synthesis of PGs by infusion of indomethacin, a cyclo-oxygenase inhibitor, into the third ventricle of fetal sheep have only been partially successful, because plasma concentrations of PGE2 were also decreased by this treatment (Jones, Adamson, Bishai, Lees, Engelberts & Coceani, 1994), albeit to a lesser extent than that which occurred in the CSF. However, in these experiments, and those of Koos (1985), it is likely that the concentration gradient of PGs between the blood and brain was increased after the central inhibition of PG synthesis, even if some suppression of peripheral synthesis had also occurred. Thus, these studies suggest that PGs do not readily pass from the fetal circulation into the brain. The transport of a number of substances from the brain into blood occurs at both the cerebral endothelial interface (i.e. the ‘blood-brain barrier’) and the choroid plexus. The ability of probenecid to inhibit the transport of PGs by the isolated choroid plexus, and from CSF to blood in the intact blood-brain barrier has been well described (Bito, 1975; Bito, Davson & Hollingsworth, 1976). If intracerebral synthesis of PGE2 is important in the regulation of the activity of the respiratory centres in fetal sheep, it should be possible to show that probenecid treatment will lead to an increase of PGE2 concentration in CSF, and a partial or complete inhibition of spontaneous breathing movements. Unanaesthetized fetuses were thus treated in utero with probenecid either, while breathing movements were being recorded or, while cisternal CSF was being collected from a catheter chronically implanted in the cisterna magna. In addition, anaesthetized, exteriorized fetuses were studied to directly determine the clearance of [3H]PGE2 from the brain using a ventriculo-cisternal perfusion technique. The results indicate that PGE2 is normally transported out of the brain into the bloodstream in the fetus, as in the adult, and that intracerebral synthesis of PGE2 participates in the regulation of fetal respiratory activity. |
