LABORATORY INVESTIGATION CONGENITAL HEART DISEASE Decreased contractility of the ductus arteriosus in experimental pulmonic stenosis

Delayed closure of the ductus arteriosus after birth has been observed in newborn infants with critical pulmonic stenosis and in newborn lambs with experimental pulmonic stenosis. This delayed ductal closure may be caused by a decreased ability of the muscle to contract when exposed to oxygen or to an increased production of or sensitivity to prostaglandin (PG) E2, the endogenous ductus arteriosus vasodilator. To determine whether the abnormal hemodynamic pattern during fetal life associated with pulmonic stenosis alters the responsiveness of the ductus arteriosus, we operated on 10 fetal lambs of gestational ages 70 to 77 days (term is 148 days) and placed a band around the pulmonary artery. Catheterization at 137 to 142 days showed severe pulmonic stenosis. We then studied isolated rings of ductus arteriosus from these lambs. The oxygen-induced increase in tension in rings of ductus arteriosus from lambs with pulmonic stenosis was significantly decreased (2.55 0.38; n = 10) compared with rings from control lambs (4.03 ± 0.51; n = 6, p < .03). There was no difference between the two groups in either the amount of PGE2 released by the rings or in the sensitivity (expressed as median effective dose) of the rings to PGE2. There was also no difference in the increase in tension when endogenous PGE2 was inhibited by indomethacin. We conclude that delayed closure of the ductus arteriosus in lambs with experimental pulmonic stenosis is not caused by increased sensitivity to or production of PGE2 in the ductus arteriosus (as it is in premature lambs) but rather is the result of a diminished ability of the ductus arteriosus to contract when exposed to oxygen. Circulation 70, No. 4, 695-699, 1984. IN NORMAL, full-term infants, functional closure of the ductus arteriosus usually occurs within the first 24 hr of life.' Delayed closure of the ductus arteriosus after birth has been observed in newborn infants with critical pulmonic stenosis2 and in lambs with experimental pulmonic stenosis.3 The tone of the ductus arteriosus in vivo represents a balance between constricting and relaxing influences. Many studies have demonstrated that oxygen causes contraction of the ductus arteriosus; there is increasing evidence that prostaglandins maintain the patency of the ductus in the fetus and preterm neonate by inhibiting the contractile effects of oxygen on the ductus. Inhibitors of prostaglandin synthesis (such as indomethacin) constrict the ductus in several species (for review see ref. 4). Although prostaglandin E2 (PGE2) is a minor product of prostaglandin production in the lamb ductus arterioFrom the Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, and the Department of Pediatrics, Mt. Zion Hospital and Medical Center, San Francisco. Supported by grants from the USPHS, Program Project HL24056 and SCOR HL27356. Address for correspondence: Ronald I. Clyman, M.D., HSE-1403, University of California, San Francisco, CA 94143. Received March 29, 1984; revision accepted July 5, 1984. *Present address: Department of Pediatrics, Indiana University, 702 Barnhill Ave., Indianapolis, IN 46223. Vol. 70, No. 4, October 1984 sus, the marked sensitivity of the ductus to PGE2 makes it likely that this may be the most important endogenous prostaglandin to regulate ductus patency.4 It is possible that the delayed closure of the ductus arteriosus in lambs and humans with pulmonic stenosis may be the result of a decreased ability of the ductus to contract when exposed to oxygen and/or to an increased production of or sensitivity to PGE2. In this study we used fetal lambs with experimentally induced pulmonic stenosis to determine whether the abnormal hemodynamic pattern associated with pulmonic stenosis during fetal development alters the responsiveness of the ductus arteriosus to these constricting or relaxing influences.