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

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.