Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats.

To find a better treatment for patient ductus arteriosus of preterm infants, we studied the combined effect of indomethacin and betamethasone on the fetal ductus in rats. We used a rapid whole-body freezing technique, and the ratio of the inner diameter of the ductus to the main pulmonary artery, which was 1.0 in controls, was used as an index of constriction. Indices of ductal constriction 4 h after administration of indomethacin (1 mg/kg) alone, betamethasone (1 mg/kg) alone or in combination in near-term rats were 0.56 +/- 0.05 (mean +/- SEM), 0.76 +/- 0.06, and 0.17 +/- 0.03, respectively. In preterm rats too, a marked increase in fetal ductus constriction was observed with the combined administration of these two drugs. Study of the dose effect of betamethasone revealed that maximal effects were obtained with 1 mg/kg of betamethasone combined with indomethacin in both preterm and near-term fetal rats. Increased constriction of the fetal ductus with combination treatment persisted from 1 to 8 h after administration. Administration of betamethasone 24 h before the rat was killed did not augment constriction of the fetal ductus by indomethacin administered 4 h before they were killed. Fetal ductus constriction by sulindac, another nonsteroidal antiinflammatory drug with little inhibitory effect on renal function, also was augmented by combined use with betamethasone (1 mg/kg). In conclusion, ductal constriction was markedly increased by combined administration of indomethacin and betamethasone in near-term and preterm fetal rats.