Fineman J R, Takahashi Y, Roman C, Clyman R I
Department of Pediatrics, University of California, San Francisco, California 94143-0544, USA.
Am J Physiol. 1998 Nov;275(5):H1620-6. doi: 10.1152/ajpheart.1998.275.5.H1620.
Endothelin-1 (ET-1) is synthesized within the wall of the ductus arteriosus (DA) and is a potent constrictor of the DA in vitro. However, the role of endogenous ET-1 in closure of the DA at birth remains unclear. Therefore, we studied the effects of a selective ETA-receptor antagonist (PD-156707), or its vehicle, on DA closure in 13 late-gestation fetal lambs during the first 5 h after birth. We also studied the effects of ETA-receptor blockade on DA constriction induced by oxygen, indomethacin (a cyclooxygenase inhibitor), and LY-83583 (a soluble guanylate cyclase inhibitor) in vitro (n = 9 ductus arteriosus rings). In vehicle-treated lambs in vivo, the DA constricted during the 5-h study period after birth: DA resistance increased (from 0.007 +/- 0.01 to 3.406 +/- 4.15 mmHg. ml-1. min. kg-1; P < 0.05); the pressure gradient across the DA increased (from 1.4 +/- 2.1 to 25.2 +/- 9.4 mmHg; P < 0.05); and DA blood flow decreased (from 193.5 +/- 48.0 to 19.3 +/- 14.3 ml. kg-1. min-1; P < 0.05). In vitro, the DA was constricted by exposure to 30% oxygen (23 +/- 14% net active tension; P < 0.05), indomethacin (5 x 10(-6) M, 22 +/- 5% net active tension; P < 0.05), LY-83583 (10(-5) M, 24 +/- 10% net active tension; P < 0.05), and ET-1 (10(-7) M, 19 +/- 4% net active tension; P < 0.05). Although PD-156707 blocked both the in vivo and in vitro effects of exogenous ET-1, it had no effect on postnatal ductus constriction nor on in vitro ductus contractile responses to oxygen, indomethacin, or LY-83583. This study suggests that endogenous ET-1 does not play an important role in closure of the DA at birth.
内皮素 -1（ET -1）在动脉导管（DA）壁内合成，在体外是DA的强效收缩剂。然而，内源性ET -1在出生时DA闭合过程中的作用仍不清楚。因此，我们研究了选择性ETA受体拮抗剂（PD -156707）或其溶媒对13只妊娠晚期胎羊出生后最初5小时内DA闭合的影响。我们还研究了ETA受体阻断对体外DA由氧气、吲哚美辛（一种环氧化酶抑制剂）和LY -83583（一种可溶性鸟苷酸环化酶抑制剂）诱导的收缩的影响（n = 9个动脉导管环）。在体内接受溶媒处理的胎羊中，出生后长达5小时的研究期间DA发生收缩：DA阻力增加（从0.007±0.01增至3.406±4.15 mmHg·ml-1·min·kg-1；P<0.05）；DA两端的压力梯度增加（从1.4±2.1增至25.2±9.4 mmHg；P<0.05）；DA血流量减少（从193.5±48.0降至19.3±14.3 ml·kg-1·min-1；P<0.05）。在体外，DA因暴露于30%氧气（净活性张力23±14%；P<0.05）、吲哚美辛（5×10-6 M，净活性张力22±5%；P<0.05）、LY -83583（10-5 M，净活性张力24±10%；P<0.05）和ET -1（10-7 M，净活性张力19±4%；P<0.05）而收缩。尽管PD -156707阻断了外源性ET -1的体内和体外效应，但它对出生后导管收缩以及体外导管对氧气、吲哚美辛或LY -83583的收缩反应均无影响。本研究表明，内源性ET -1在出生时DA闭合过程中不起重要作用。
