Characterisation of the effect of oxygen tension on response of fetal rabbit ductus arteriosus to vasodilators

Abstract

Objective: The aims of the study were (1) to elucidate the effects of raised oxygen tension on the response of the ductus arteriosus to a range of vasodilators; and (2) to establish the effect, if any, of cyclo-oxygenase inhibition on the interaction between oxygen and prostaglandin (PG)E2.

Methods: Rings of ductus arteriosus were isolated from fetal New Zealand White rabbits at 28 d gestation (term = 31) and precontracted with 10 microM noradrenaline in the presence of the cyclo-oxygenase inhibitor indomethacin (1 microM). Cumulative relaxation response curves were obtained from a range of vasodilators and their pEC50 (-log10 of the interpolated molar concentration causing 50% of the maximum response) and maximum relaxant response (MRR) were determined in 15% oxygen (neonatal oxygen tension, 13-14.3 kPa) and 2% oxygen (fetal oxygen tension, 2.5-3.0 kPa). In addition, the effects of (1) omitting indomethacin and (2) its substitution by 1 microM flubriprofen were studied on the interaction between oxygen and PGE2.

Results: In 1 microM indomethacin, nifedipine and atrial natriuretic peptide had no effect on ductal tone in either oxygen tension. In 15% oxygen, the rank order of MRR was forskolin > cicaprost > PGE2 >> cromakalim >> sodium nitroprusside approximately adenosine approximately 0. The MRR of all agonists was increased in 2% oxygen except forskolin which caused complete relaxation in 15% oxygen. In 15% oxygen, the rank order of pEC50 was PGE2 >> cicaprost approximately cromakalim approximately forskolin. PGE2 was 70.8 times more potent than cicaprost. The pEC50 of all four agonists was increased in 2% oxygen. The increase in pEC50 could not be explained by a decreased extent of precontraction. The MRR to PGE2 in 15% oxygen and the magnitude of the increase in pEC50 to PGE2 going from 15% to 2% oxygen were the same in 1 microM flubriprofen, 1 microM indomethacin, or in the absence of these drugs. However, in 2% oxygen, the MRR to PGE2 was increased in 1 microM indomethacin or 1 microM flubriprofen compared with control.

Conclusions: (1) Increasing oxygen tension from fetal to neonatal levels desensitises the ductus arteriosus to a range of vasodilators. (2) There is evidence that prostacyclin has a physiological role in the control of the rabbit ductus arteriosus. (3) The effect of oxygen on the potency of PGE2 is independent of cyclo-oxygenase products, whereas its effect on the efficacy of PGE2 is modulated by an endogenous cyclo-oxygenase product.