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1 Department of Pediatrics and 2 Cardiovascular Research Institute, University of California, San Francisco, California 94143-0544
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 · kg1;
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 · kg1 · min1;
P < 0.05). In vitro, the DA was
constricted by exposure to 30% oxygen (23 ± 14% net active
tension; P < 0.05), indomethacin (5 × 106 M, 22 ± 5%
net active tension; P < 0.05),
LY-83583 (105 M, 24 ± 10% net active tension; P < 0.05),
and ET-1 (107 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.
endothelin receptors; oxygen; prostaglandins
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