Effect of probenecid on breathing movements and cerebral clearance of prostaglandin E2 in fetal sheep.

Abstract

1. Intravenous infusion of probenecid (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. 2. 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. 3. 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). 4. 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. 5. 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.