Inhibition of the contraction of the ductus arteriosus to oxygen by 1-aminobenzotriazole, a mechanism-based inactivator of cytochrome P450

1 We have proposed that contractile tension of the ductus arteriosus is sustained by a cytochrome P450-linked mechanism acting as a limiting step in the synthesis of endothelin-1 (ET-1). In the present study, we have used the isolated ductus from near-term foetal lambs and guinea-pigs to investigate the effect on both muscle tone and ET-1 formation of 1-aminobenzotriazole (ABT), a suicide substrate for mono-oxygenase reactions. 2 ABT relaxed the lamb ductus at rest (2.5% O-2) and during the oxygen contraction (ii to 95% O-2) The effect was seen at 40 mu M, and at 0.8 mM active tone was almost completely abolished. ABT (1 mM) also reversed the oxygen contraction in the guinea-pig ductus. 3 In the lamb ductus, the ABT response was not affected by removal of the endothelium or by treatment with 2.8 mu M indomethacin (al 2.5% O-2) and the ensuing contraction. 4 At both low and high concentration, ABT relaxed marginally, or not at all, the potassium-contracted (55 mM) ductus from either species. 5 ET-1 release from either the intact or endothelium-denuded lamb ductus tended to decrease in the presence of ABT (1 mM), whilst during the same treatment cyclic GMP content of the tissue remained unchanged. 6 We conclude that ABT relaxation is due to suppression of a contractile mechanism and not to activation of prostaglandin- and NO-mediated relaxing mechanisms. This contractile mechanism has a cytochrome P450-based mono-oxygenase reaction as a key component.