Increased Constriction of the Ductus Arteriosus with Combined Administration of Indomethacin and Betamethasone in Fetal Rats

Abstract

ABSTRACT. To find a better treatment for patent 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 f 0.05 (mean f SEM), 0.76 f 0.06, and 0.17 f 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. (Pediatr Res 25:169-75, 1989) Abbreviations DA, ductus arteriosus PA, pulmonary artery Since the first reports (1, 2) on pharmacologic closure of the patent DA of preterm infants in 1976, indomethacin has been widely used to constrict the DA of the preterm infant. However, success rates of DA closure by indomethacin treatment in preterm infants were variable, indicating that therapy with indomethacin is less than perfect (3, 4). Our earlier study showed fetal ductal constriction by glucocorticoid hormones, including betamethasone (5). A subsequent study revealed that combined Received May 23, 1988; accepted September 13, 1988. Correspondence and reprint requests Kazuo Momma, The Heart Institute of Japan, Tokyo Women's Medical College, Kawadacho 8-1, Shinjukuku, Tokyo 162, Japan.Supported by grants from the Ministry of Education, Science, and Culture of Japan, the Welfare Ministry of Japan, the Japan Promotion Society for Cardiovascular Diseases and Japan Cardiovascular Research Foundation. 6administration of betamethasone and indomethacin markedly augments constriction of the fetal DA in both preterm and nearterm rats. MATERIALS AND METHODSVirgin Wistar rats (pregnancy period, 21.5 days) were mated overnight from 1700 to 900 h, and the presence of sperm on vaginal smears dated the 0 day of pregnancy. These rats were fed commercial solid food and water. Indomethacin (Sumitomo Chemical Co., Osaka, Japan) or sulindac (Merck-Banyu, Tokyo, Japan) was administered through an orogastric ...

Neonatal Necrotizing Enterocolitis With Intestinal Perforation in Extremely Premature Infants Receiving Early Indomethacin Treatment for Patent Ductus Arteriosus

“…Increased periductal smooth muscle contraction with a combination of indomethacin and steroids have been demonstrated in a rat model of PDA. 22 Whereas our data suggest that early treatment with indomethacin may have reduced the need for surgical PDA ligation, the rate of NEC with intestinal perforation overshadows this potential beneficial effect. It may be that those factors responsible for a more forceful ductal constriction were also responsible for NEC with intestinal perforation.…”

Indomethacin and Corticosteroids: An Additive Constrictive Effect on the Ductus Arteriosus

“…These results concur with studies performed in preterm rat fetuses that shows increased frequency of ductal constriction by combined administration of indomethacin and betamethasone. 9 In another animal model, pretreatment of lamb fetuses with hydrocortisone caused a decrease in the sensitivity of the fetal duc-…”

Cardiovascular and Pulmonary Effects of Betamethasone during Midtrimester on Fetal Rats

“…However, some researchers [16] have pre sented evidence that exposure of the fetus to corticosteroids has varied effects on fetal sub strate availability, causes reduction in the bio synthesis of DNA and RNA, and prolonged inhibition of mitosis and cellular synthetic activity. These effects in turn lead to impair ment of growth, particularly in the brain, lung, heart, kidney, adrenal gland, and skele tal muscles [16,17], The hypoplastic thymus and lung and decreased heart mass in this study were considered to be primarily the result of these adverse effects of corticoste roids.…”