Pharmacological knockout of endothelin ET(A) receptors.

We employed newly developed antagonists, which are specific for endothelin ET(A) receptors, to test whether this drug could mimic the phenotype of the mouse with corresponding gene knock out. Newborn rats, whose dams were given the ET(A) antagonist from day 7 of gestation, exhibited the typical ET(A)-lacking phenotypes like craniofacial abnormalities and major vessel anomalies. Interestingly, craniofacial abnormality was seen in the pups that were exposed to the drug in the mid-gestational period, while another phenotype, patent ductus arteriosus (DA), was seen in the pups that were exposed to the drug in the late gestation. We have focused on the function of the ET system in DA closure after birth because the animals with a genetic defect of ET(A) would die of suffocation shortly after birth. Rat pups were delivered by Caesarean section and were given the antagonist intraperitoneally. The antagonists caused an inhibition of DA closure in vivo at 3 h after birth when DA closure was completed in the control pups. Next, we tested the potential utilities of the ET(A) specific antagonists in tocolysis with NSAIDs which sometimes leads to a closure of fetal DA in utero. Indomethacin administration to rat dams resulted in the constriction of DA in utero which was cancelled by the co-administration of the antagonists. These results suggested that ET(A) plays a physiological role in the postnatal closure of the rat DA in vivo and that ET(A) specific antagonists may be able to leave fetal DA intact during tocolysis with NSAIDs.