Date of Award

2-11-2003

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

George Lister

Abstract

Exposure of the fetus to indomethacin produces constriction of the fetal ductus arteriosus (DA) and hypoxia in the avascular muscle media of the vessel wall. Hypoxia induces cell death, which increases the incidence of patent DA in the newborn period. We used a fetal sheep model to determine the factors that were responsible for indomethacin-induced hypoxia at various degrees of DA constriction. Indomethacin produced DA constriction in all fetuses studied in vivo. Cell death in the DA wall was directly related to the degree of indomethacin-induced DA constriction and was present at both moderate (pressure gradient across DA <16 >mmHg) and marked (≥16 mmHg) degrees of constriction. Indomethacin did not alter oxygen consumption in DA rings studied in vitro, indicating that oxygen demand in the constricting tissue is not significantly increased by indomethacin. Both moderate and marked degrees of DA constriction reduced vasa vasorum flow to the ductus (moderate = 69±25%; marked = 30±16% of pre-indomethacin exposure values) and increased the thickness of the ductus wall. In contrast, DA luminal blood flow was not affected by moderate degrees of constriction and was reduced only after marked constriction. Our findings suggest that changes in vasa vasorum blood flow and muscle media thickness are the primary contributors to hypoxia-induced cell death at moderate degrees of indomethacin-induced constriction. Diminished luminal blood flow only appears to contribute to the induction of cell death following the development of marked degrees of constriction. These findings help to explain why in utero exposure to indomethacin in late gestation fetuses, which depend on vasa vasorum to supply O2 to the DA muscle media, leads to hypoxia-induced remodeling and and increased incidence of postnatal patent DA. Note: Figures and Diagrams created with Cricket Graph for Macintosh may not open or be legible without the possession of that application.

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This is an Open Access Thesis.

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