Effects of TAK-044, a Nonselective Endothelin Receptor Antagonist, on the Spontaneous and Indomethacin- or Methylene Blue-Induced Constriction of the Ductus Arteriosus in Rats.

Abstract

ABSTRACT. We studied the effects of TAK-044, a nonselective endothelin (ET) receptor antagonist, on the indomethacin-or methylene blue-induced constriction of the ductus arteriosus (DA) in rats and compared them with the effects on spontaneous DA constriction. Injection of TAK-044 into 21-day-old fetuses in utero was performed through the uterine wall of laparotomized mother rats under light ether anesthesia. The fetuses were autopsied 3 hr after treatment with TAK-044 (10 mg/kg) in utero and simultaneous administration to the laparotomized mother rats of indomethacin (3 mg/kg, po) or methylene blue (100 mg/kg, ip). In the second experiment, pregnant rats were decapitated on day 21 of gestation to obtain newborn rats by cesarean delivery. Newborn rats which were given TAK-044 (2, 10 mg/kg) immediately after or 1 hr before cesarean delivery were autopsied at various times after birth. In both experiments, pups were rapidly frozen in an acetone-dry ice mixture at autopsy to evaluate the DA constriction by the whole-body freezing and shaving method. TAK-044 injection into the fetus 3 hr before autopsy completely inhibited the DA constriction induced by maternal treatment with indomethacin or methylene blue. TAK-044 caused dose-dependent inhibition of the spontaneous closure of the DA after birth. The inhibitory effect was more pronounced in pups which were given TAK-044 in utero 1 hr before birth; however, the inhibitory effect was incomplete in newborn pups. These results, together with the previous finding that BQ-123, an ET A -specific receptor antagonist, inhibits the ductal constriction induced by oxygen in vitro [Coceani et al., 1992], indicate that the ET A receptor plays a significant role in the indomethacin-or methylene blue-induced DA constriction as well as in the spontaneous DA constriction after birth, and also indicate that the inhibition of ET A receptor by TAK-044 was more easily achieved in fetuses than in neonates.-KEY WORDS: ductus arteriosus, endothelin receptor, indomethacin, methylene blue, TAK-044.The ductus arteriosus (DA) connects the main pulmonary artery and the descending aorta during the fetal period, allowing blood to flow from the right ventricle to bypass the lungs. Ductal patency in utero is an active state principally maintained by the potent dilator effect of prostaglandins, particularly PGE 2 [9], and the nitric oxidecGMP system [15,30]. Closure at birth occurs because of contraction of the smooth muscle of the DA. The major factor actively stimulating contraction is probably the effect of increasing oxygen tension. After birth, the ductus is exposed to arterial blood because of the reversal of the direction of flow [14], and arterial oxygen tension rises rapidly after delivery [17].There is a large body of evidence obtained from studies on the lamb ductus arteriosus which supports the cytochrome P 450 /endothelin (ET)-1 hypothesis [8]. In this hypothesis, cytochrome P 450 is the oxygen sensor, and its activation promotes contraction. The effect of oxygen on the enzyme is propos...

Intrauterine ductus arteriosus constriction: analysis of a historic cohort of 20 cases

“…Prostaglandin use in human fetuses for this purpose was not described. Experimental studies 35 demonstrate positive effects with the use of endothelin antagonists, decreasing the consequences of ductal constriction. The possible role of nitric oxide in dilating the fetal ductus arteriosus has already been suggested 23 .…”

Current Perspectives on Pathobiology of the Ductus Arteriosus

“…Instead, Coceani and colleagues have long proposed that oxygen-induced DA constriction occurs by a multistep process [79] that is mediated via separate mechanisms for oxygen sensing (by CYP enzymes) and effectors of the oxygen response. Endothelin-1 (ET-1) is proposed as the effector, based on its potent vasocontrictive effects, the local oxygen-stimulated production of ET-1 in the DA wall, and inhibition of its actions on the DA by receptor blockade (by BQ123 or others) or by inhibition of ET-1 synthesis (by phosphoramidon) [79,83,84]. In mice, deletion of the ET A receptor for ET-1 results in decreased oxygen-induced DA constriction [85], further supporting its role as an effector.…”

The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

“…Haleen and K. M. Welch, unpublished data). A final, possible complication, also originating from experimental data (Coceani et al, 1999;Takizawa et al, 2000) is that the ET A R antagonist could reopen the ductus arteriosus in the young infant. Such an event, however, seems remote since closure of the vessel becomes irreversible beyond the immediate neonatal period.…”