Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon

被引:57
作者
Seidner, SR
Chen, YQ
Oprysko, PR
Mauray, F
Tse, MM
Lin, E
Koch, C
Clyman, RI
机构
[1] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Pharm, San Francisco, CA 94143 USA
[4] Univ Texas, Hlth Sci Ctr, Dept Pediat, San Antonio, TX 78284 USA
[5] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA
关键词
D O I
10.1203/00006450-200109000-00012
中图分类号
R72 [儿科学];
学科分类号
100202 ;
摘要
After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacin-induced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants.
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页码:365 / 373
页数:9
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