Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening

Regulation of ductus arteriosus (DA) tension depends on a balance between o xygen-induced constriction and PG and nitric oxide (NO)-mediated relaxation . After birth, increasing Pa-O2 produces DA constriction. However, as the f ull-term ductus constricts, it develops severe tissue hypoxia in its inner vessel wall (oxygen concentration <0.2%). We used isolated rings of fetal l amb DA to determine why the constricted ductus does not relax and reopen as it becomes hypoxic. We used a modification of the 2-(2-nitro-1H-imidazol-1 -yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF5) technique (Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Lord EM, Weiss H, Wale N, Ev an SM, and Koch CJ. Pediatr Res 45: 19-29, 1999) to determine mean tissue o xygen concentration. A decrease in the ductus' mean tissue oxygen concentra tion from 1.4 to 0.1% lowers the isometric tone of the ductus by 15 +/- 10% of its maximal active tension (the maximal tension that can be produced by the ductus). Although decreases in oxygen concentration diminish ductus te nsion, most of the vasoconstrictor tone in the ductus is independent of amb ient oxygen concentration. This oxygen-independent tone is equivalent to 64 +/- 10% of the maximal active tension. At mean tissue oxygen concentration s <0.2%, endogenous PGs and NO inhibit more than 40% of the active tension developed by the ductus. However, when tissue oxygen concentrations drop be low 0.2%, the constitutive relaxation of the ductus by endogenous PGs and N O is lost. In the absence of PG and NO production, tension increases to a l evel normally observed only after treatment of the ductus with indomethacin and nitro-L-arginine methyl ester (inhibitors of PG and NO production). Th erefore, under conditions of severe hypoxia (tissue oxygen concentration,0. 2% oxygen), the loss of PG- and NO-mediated relaxation more than compensate s for the loss of oxygen-induced tension. We hypothesize that this increase d ductus tone enables the vessel to remain closed as it undergoes tissue re modeling.