Submitted on April 15, 2006
Accepted on July 19, 2006
Inhibition of Cyclooxygenase Isoforms in Late- but not Mid-Gestation Decreases Contractility of the Ductus Arteriosus and Prevents Postnatal Closure in Mice
Jeff Reese1*, Judy D. Anderson2, Naoko Brown1, Christine Roman3, and Ronald I Clyman3
1 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
2 Department of Pediatrics, Vanderbilt University Medical Center, United States
3 Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States
* To whom correspondence should be addressed. E-mail: jeff.reese{at}vanderbilt.edu.
Use of cyclooxygenase (COX) inhibitors to delay preterm birth is complicated by in utero constriction of the ductus arteriosus, and delayed postnatal closure. Delayed postnatal closure has been attributed to loss of vasa vasorum flow and ductus wall ischemia resulting from constriction in utero. We used the murine ductus (which does not depend on vasa vasorum flow) to determine whether delayed postnatal closure may be due to mechanisms independent of in utero constriction. Acute inhibition of both COX isoforms constricted the fetal ductus on days 18 and 19 (term), but not earlier in gestation; COX-2 inhibition constricted the fetal ductus more than COX-1 inhibition. In contrast, mice exposed to prolonged inhibition of COX-1, COX-2, or both COX isoforms (starting on day 15, when the ductus does not respond to the inhibitors) had no contractile response to the inhibitors on days 18 or 19. Newborn mice closed their ductus within 4h of birth. Prolonged COX inhibition on days 11-14 of gestation had no effect on newborn ductal closure; however, prolonged COX inhibition on days 15-19 resulted in delayed ductus closure despite exposure to 80% oxygen after birth. Similarly, targeted deletion of COX-2 alone, or COX-1/COX-2 together, impaired postnatal ductus closure. Nitric oxide inhibition did not prevent the delay in ductus closure. These data show that impaired postnatal ductus closure is not due to in utero ductus constriction or upregulation of nitric oxide synthesis. They are consistent with a novel role for prostaglandins in ductus arteriosus contractile development.
