Nitric Oxide Inhibits Closure of the Ductus Arteriosus following Antenatal Exposure to Indomethacin † 982

Indomethacin (Indo) is often used as a tocolytic agent for preterm labor. Four controlled studies have found that if preterm infants fail tocolysis and deliver within 2-3 d of antenatal Indo exposure, there is an increased incidence of patent ductus arteriosus that is refractory to post natal Indo (p<0.01). This results in an increased need for surgical ligation (p. < 0.01). We gave a 45-h infusion of Indo (0.18 mg/kg/h, plasma concentration 468 ng/ml) or vehicle into 21 125-d gestation fetal lambs (145 d, term) to test the following hypothesis: antenatal exposure to Indo increases production of nitric oxide (NO) by the ductus; and the increased NO production inhibits the postnatal O₂-induced closure of the ductus. In 5 fetuses that were examined after 45 h of Indo infusion, the ductus was markedly constricted. The infusions were stopped after 45 h in the remaining 16 fetuses, and they were allowed to recover for 22 h before their ductus were studied in vitro. The in vivo ductus diameter of the Indo-infused and control fetuses were similar 22 h after stopping the infusion. The ductus from both groups developed the same maximal tension to K⁺ stimulation(Indo = 22.5 ± 2.5 g; control = 22 ± 2.5 g). However, the contractile response to 30% O₂ was less in the Indo-infused (2.7± 0.6 g) than in the control (4.4± 1.3 g, p < 0.01) group. In vitro prostaglandin (PG) E₂ production by the ductus was similar in both groups; similarly, the in vitro contractile response to Indo (5.6 × 10^-6 M) was only slightly less in the Indo-infused (8.2 ± 1.5 g) than in the control (9.9 ± 2.7 g, p>0.05) group. Both groups were equally sensitive to the dilating effects of exogenous PGE₂ and sodium nitroprusside. However, inhibition of NO production by L-NAME (10^-4 M) caused a significantly greater constriction in the Indo-infused (6.1 ± 1.3 g) than in the control (3.5 ± 1.4 g, p<0.01) group. As a result, when both prostaglandin production and NO production were limited, the combined (O₂ + Indo + L-NAME)-induced tension was the same in both groups (Indo-infused = 17 ± 2.3 g; control = 17.9 ± 1.4 g).Conclusion: Antenatal exposure to Indo increases NO production in the ductus; this may account for the increased incidence of patent ductus arteriosus after antenatal Indo, and for its refractoriness to postnatal Indo treatment.