Characterization of PGE<sub>2</sub>receptors in fetal and newborn lamb ductus arteriosus

Bouayad, Asmàa; Kajino, Hiroki; Waleh, Nahid; Fouron, Jean‐Claude; Andelfinger, Grégor; Varma, Daya R.; Skoll, Amanda; Vázquez, Alejandro; Gobeil, Fernand; Clyman, Ronald I.; Chemtob, Sylvain

doi:10.1152/ajpheart.2001.280.5.h2342

Cited by 81 publications

(90 citation statements)

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“…EP 1 is a constrictive receptor and EP 3 induces a decline in cAMP, inhibiting smooth muscle relaxation (Narumiya and FitzGerald 2001). The main receptor responsible for PGE 2 -induced DA relaxation varies among mammalian species and was reported as EP 4 in rabbits (Smith 1998;Smith et al 1994;Smith and McGrath 1995), mice (Nguyen et al 1997), rats , lambs (Waleh et al 2004), baboon (Waleh et al 2004), and humans (Leonhardt et al 2003), and as EP 2 in pigs (Bhattacharya et al 1999) and lambs (Bouayad et al 2001). The cAMP-inhibiting EP 3 receptor is also present in the rabbit and piglet DA, modulating the dilating eVect of PGE 2 (Bhattacharya et al 1999;Smith 1998;Smith et al 1994;Smith and McGrath 1995).…”

Section: Introductionmentioning

confidence: 99%

“…The cAMP-inhibiting EP 3 receptor is also present in the rabbit and piglet DA, modulating the dilating eVect of PGE 2 (Bhattacharya et al 1999;Smith 1998;Smith et al 1994;Smith and McGrath 1995). In contrast, stimulation of EP 3 receptor in the lamb DA produces not contraction but relaxation via a cAMP-independent pathway (Bouayad et al 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Another speculation might be that cAMP-mediated mechanisms are less involved in the relaxation evoked by PGE 2 in the aortic side. In fact, it has been demonstrated that PGE 2 dilates the late gestation fetal lamb DA through pathways that involve either cAMP (via EP 2 and EP 4 receptors) or ATP-dependent potassium channels (via EP3, Bouayad et al 2001). However, in the experiments that compared the pulmonary and the aortic side of the chicken DA, the vessels were contracted with a high potassium solution which precluded the relaxation induced by potassium channels activation.…”

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Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

et al. 2008

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Prostaglandin E 2 (PGE 2 ) is the major vasodilator prostanoid of the mammalian ductus arteriosus (DA). In the present study we analyzed the response of isolated DA rings from 15-, 19-and 21-day-old chicken embryos to PGE 2 and other vascular smooth muscle relaxing agents acting through the cyclic AMP signaling pathway. PGE 2 exhibited a relaxant response in the 15-day DA, but not in the 19-and 21-day DA. Moreover, high concentrations of PGE 2 (¸3 M in 15-day and ¸1 M in 19-day and 21-day DA) induced contraction of the chicken DA. The presence of the TP receptor antagonist SQ29,548, unmasked a relaxant eVect of PGE 2 in the 19-and 21-day DA and increased the relaxation induced by PGE 2 in the 15-day DA. The presence of the EP receptor antagonist AH6809 abolished PGE 2 -mediated relaxation. The relaxant responses induced by PGE 2 and the -adrenoceptor agonist isoproterenol, but not those elicited by the adenylate cyclase activator forskolin or the phosphodiesterase 3 inhibitor milrinone, decreased with maturation. High oxygen concentrations (95%) decreased the relaxation to PGE 2 . The relaxing potency and eYcacy of isoproterenol and milrinone were higher in the pulmonary than in the aortic side of the DA, whereas no regional diVerences were found in the response to PGE 2 . We conclude that, in contrast to the mammalian situation, PGE 2 is a weak relaxant agent of the chicken DA and, with advancing incubation, it even stimulates TP vasoconstrictive receptors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

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“…Theoretically, these agonists and antagonists can be clinically useful because they have fewer side-effects (11). The dilator receptor for PGE in the neonatal DA has been reported as being EP4 in rabbits, mice, and humans (11-13), and as EP2 in pigs and lambs (14,15). In this study, we report in vivo constriction of the fetal and neonatal ductus arteriosus in rats by an EP4 antagonist, AE3-208 (6).…”

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confidence: 64%

In Vivo Constriction of the Fetal and Neonatal Ductus Arteriosus by a Prostanoid EP4-Receptor Antagonist in Rats

et al. 2005

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Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33°C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 g/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 g/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants. Indomethacin has been used to constrict the PDA in premature babies (1,2) by inhibiting prostaglandin synthesis (3). However, it exhibits serious side-effects, such as suppression of renal function and gastrointestinal dysfunction (4). Recently, EP1, EP2, EP3, and EP4 were identified as receptors for PGE (5), and their specific distribution in tissues and organs has been studied (6 -10). More recently, agonists and antagonists for these receptors have been developed (10). Theoretically, these agonists and antagonists can be clinically useful because they have fewer side-effects (11). The dilator receptor for PGE in the neonatal DA has been reported as being EP4 in rabbits, mice, and humans (11-13), and as EP2 in pigs and lambs (14,15). In this study, we report in vivo constriction of the fetal and neonatal ductus arteriosus in rats by an EP4 antagonist, AE3-208 (6). METHODSDrugs. PGE1 (PGE 1 CD, M r 354) and AE3-208 (EP4 antagonist, M r 404) were supplied by Ono Pharmaceutical Co. (Osaka, Japan). PGE1 dissolved in saline and AE3-208 dissolved in 5% glucose were kept at -20°C until used. Indomethacin (M r 358, Sigma Chemical Co., St. Louis, MO) was purchased from Iwai Chemicals (Tokyo, Japan).Animals. Virgin Wistar rats (pregnancy period 21.5 d) were mated overnight from 1700 to 0900 h; the presence of sperm in vaginal smears fixed d 0 of pregnancy. The rats were housed in an environmentally controlled room, acclimatized to a 12-h light/12-h dark cycle, and maintained on co...

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“…Stimulation of PGE2 receptors activates adenylyl cyclases (Bouayad et al, 2001). The increased intracellular concentrations of cyclic AMP (cAMP) inhibit myosin light chain kinase, resulting in the DA relaxation (Smith, 1998).…”

Section: -2 Rapid Withdrawal Of the Vasodilator Effect Of Pge2mentioning

confidence: 99%

Regulation of vascular tone and remodeling of the ductus arteriosus

Yokoyama

Minamisawa

Ishikawa

2010

J. Smooth Muscle Res.

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The ductus arteriosus (DA), a fetal arterial connection between the main pulmonary artery and the descending aorta, normally closes immediately after birth. The DA is a normal and essential fetal structure. However, it becomes abnormal if it remains patent after birth. Closure of the DA occurs in two phases: functional closure of the lumen within the first hours after birth by smooth muscle constriction, and anatomic occlusion of the lumen over the next several days due to extensive neointimal thickening in human DA. There are several events that promote the DA constriction immediately after birth: (a) an increase in arterial oxygen tension, (b) a dramatic decline in circulating prostaglandinE2 (PGE2), (c) a decrease in blood pressure within the DA lumen, and (d) a decrease in the number of PGE2 receptors in the DA wall. Anatomical closure of the DA is associated with the formation of intimal thickening, which are characterized by (a) an area of subendothelial deposition of extracellular matrix, (b) the disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer, and (c) migration into the subendothelial space of undifferentiated medial smooth muscle cells. In addition to the well-known vasodilatory role of PGE2, our findings uncovered the role of PGE2 in anatomical closure of the DA. Chronic PGE2-EP4-cyclic AMP (cAMP)-protein kinase A (PKA) signaling during gestation induces vascular remodeling of the DA to promote hyaluronan-mediated intimal thickening and structural closure of the vascular lumen. A novel target of cAMP, Epac, has an acute promoting effect on smooth muscle cell migration without hyaluronan production and thus intimal thickening in the DA. Both EP4-cAMP downstream targets, Epac and PKA, regulate vascular remodeling in the DA.

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Characterization of PGE₂receptors in fetal and newborn lamb ductus arteriosus

Cited by 81 publications

References 38 publications

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

In Vivo Constriction of the Fetal and Neonatal Ductus Arteriosus by a Prostanoid EP4-Receptor Antagonist in Rats

Regulation of vascular tone and remodeling of the ductus arteriosus

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Characterization of PGE2receptors in fetal and newborn lamb ductus arteriosus

Cited by 81 publications

References 38 publications

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

In Vivo Constriction of the Fetal and Neonatal Ductus Arteriosus by a Prostanoid EP4-Receptor Antagonist in Rats

Regulation of vascular tone and remodeling of the ductus arteriosus

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Characterization of PGE₂receptors in fetal and newborn lamb ductus arteriosus