LOW-DOSE INDOMETHACIN VIA FETAL VEIN OR CEREBRAL VENTRICLE STIMULATESBREATHING MOVEMENTS IN FETAL SHEEP

Indomethacin, a prostaglandin synthesis inhibitor, transforms normally intermittent fetal breathing into nearly continuous breathing. If ind omethacin acts in brain, we hypothesized that indomethacin would stimu late breathing at a lower dose when given via the lateral cerebral ven tricle (i.c.v.) than via the fetal jugular vein (i.v.). Chronically ca theterized fetal sheep were studied at 0.88 of gestation (128 days). A 2-h control period was followed by an indomethacin infusion at 7 mu g .kg(-1) fetal body weight over the first 10 min of each hour for 3 h t hen at 28 mu g.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 E-2 c oncentrations decreased similarly by both routes, although the decreas e was only significant for the i.c.v. route. Indomethacin at 7 mu g.kg (-1).h(-1) did not change fetal breathing activity by either route wit hin 3 h. During the 2nd and 3rd h at 28 mu g.kg(-1).h(-1), breathing i ncidence increased (from approximate to 35 to approximate to 80% time) , breath amplitude and rate increased, and arterial O-2 content decrea sed slightly (all changes significant). ANOVA revealed no significant differences in responses evoked by the two routes. Fetal arterial pres sure, heart rate, PCO2, and pH were unchanged (both doses, both routes ). The indomethacin dose (105 mu g.kg(-1) over 6 h) was greater than o r equal to 10-fold lower than that used in previous studies on breathi ng in fetal sheep but similar to that used clinically to treat patent ductus arteriosus. We conclude that site(s) mediating effects of indom ethacin on breathing respond to a low dose and are equally accessible by i.c.v. and i.v. routes.