Low dose indomethacin via fetal vein or cerebral ventricle stimulates breathing movements in fetal sheep

Abstract

Indomethacin, a prostaglandin synthesis inhibitor, transforms normally intermittent fetal breathing into nearly continuous breathing. If indomethacin acts in brain, we hypothesized that indomethacin would stimulate breathing at a lower dose when given via the lateral cerebral ventricle (i.c.v) than via the fetal jugular vein (i.v.). Chronically catheterized fetal sheep were studied at 0.88 of gestation (128 days). A 2-h control period was followed by an indomethacin infusion at 7 micrograms.kg-1 fetal body weight over the first 10 min of each hour for 3 h then at 28 micrograms.kg-1 over the first 10 min of each hour for the next 3 h, either i.c.v. (n = 7) or i.v. (n = 6). Plasma prostaglandin E2 concentrations decreased similarly by both routes, although the decrease was only significant for the i.c.v. route. Indomethacin at 7 micrograms.kg-1.h-1 did not change fetal breathing activity by either route within 3 h. During the 2nd and 3rd h at 28 micrograms.kg-1.h-1, breathing incidence increased (from approximately 35 to approximately 80% time), breath amplitude and rate increased, and arterial O2 content decreased slightly (all changes significant). ANOVA revealed no significant differences in responses evoked by the two routes. Fetal arterial pressure, heart rate, Pco2, and pH were unchanged (both doses, both routes). The indomethacin dose (105 micrograms.kg-1 over 6 h) was > or = 10-fold lower than that used in previous studies on breathing in fetal sheep but similar to that used clinically to treat patent ductus arteriosus. We conclude that site(s) mediating effects of indomethacin on breathing respond to a low dose and are equally accessible by i.c.v. and i.v. routes.