In vitro pharmacological characterization of the prostanoid receptor population in the non-pregnant porcine myometrium

Cao, Jinshan; Shayibuzhati, Mikeremu; Tajima, Tsuyoshi; Kitazawa, Takio; Taneike, Tetsuro

doi:10.1016/s0014-2999(02)01489-9

Cited by 52 publications

(31 citation statements)

References 26 publications

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“…Moreover, as shown in Table 1, ONO-4819 did not induce any increase in uterine activity, even at a high dose (3 g/kg/h). These findings are consistent with the observation that EP4 agonists did not induce any contraction of porcine uterine strips in vitro (22).…”

Section: Da Contraction In Vitro and The Effect Of Ep4 Agonistsupporting

confidence: 93%

An EP4 Receptor Agonist Prevents Indomethacin-Induced Closure of Rat Ductus Arteriosus In Vivo

et al. 2004

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Indomethacin exerts a strong tocolytic effect by suppressing uterine contractions mediated by prostaglandins. However, indomethacin also induces in utero closure of fetal ductus arteriosus (DA), leading to serious neonatal consequences. Using rats, we tested the effect of an agonist for a subtype of prostaglandin E2 receptor (EP4), ONO-AE1-437 and its prodrug ONO-4819, as a DA dilator during indomethacin treatment. In vitro, ONO-AE1-437 exhibited a potent dilatory effect on DA against O 2 -and indomethacin-induced contractions in a concentration-dependent manner. In vivo, rat dams were given indomethacin (10 mg/kg, p.o.) alone or with ONO-4819 (0.3 g/kg/h, s.c.) on d 21 of gestation and pups were delivered 4 h later through cesarean section to evaluate the ratio of diameter of DA to that of pulmonary artery. Pups from dams with no drug had DA/PA ratio of 0.9 Ϯ 0.05, whereas those from dams with indomethacin alone had a decreased ratio of 0.2 Ϯ 0.03. When ONO-4819 was co-administered to the dams, the ratio recovered significantly to 0.7 Ϯ 0.06. The administration of ONO-4819 to the dams did not induce any increase in the uterine activity. These results suggest that administration of an EP4 agonist in addition to indomethacin might prevent adverse reactions of indomethacin on fetal DA without restricting its tocolytic effects. In the late gestational period, PG play key roles in the physiologic processes leading to labor. In the mother, PG are key players in the initiation and progression of parturition (1,2), whereas in the fetus they participate in the regulation of circulatory change at birth. In this regulation, the closure of the DA is a critical event (3). DA functions in utero as a shunt vessel that connects the PA and the systemic circulation, bypassing the unexpanded fetal lungs. After birth, the DA closes rapidly as pulmonary circulation is established. The fetal DA is normally maintained patent by dilators, of which PGE 2 is a major mediator that is supplied mainly by the placenta (3). At birth, the increase in oxygen tension along with the drop in PGE 2 level in neonatal circulation, which follow initiation of pulmonary respiration and placental segregation, respectively, result in postnatal closure of DA (3). Four subtypes of PGE 2 receptor have been identified, designated EP1, EP2, EP3, and EP4 (4). Although the distribution of PG receptors shows variation among species, EP4 has been shown to be a primary receptor subtype of PGE 2 at fetal DA in several mammals (5-7). In the case of humans, data are available only at neonatal DA in which EP4 is also a major receptor subtype of PGE 2 (8). Mice lacking EP4 gene died of patent DA soon after birth (9,10), implying an additional function of EP4 as a sensor of circulating PGE 2 to prepare DA closure after birth.Indomethacin is an NSAID that suppresses prostanoid synthesis by inhibiting COX. In the context of preterm labor, there is some controversy as to whether NSAID are a useful therapeutic choice, despite their tocolytic effect, because morbid neonatal ...

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Section: Da Contraction In Vitro and The Effect Of Ep4 Agonistsupporting

confidence: 93%

An EP4 Receptor Agonist Prevents Indomethacin-Induced Closure of Rat Ductus Arteriosus In Vivo

et al. 2004

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“…Layer-specific differences in pharmacological responses of uterine or cervical muscles have already been reported (Cao et al, 2002). Previously, we found that 10 μM prostaglandin E 1 reduced the spontaneous contractions of the circular layer in sheep cervix, but had no significant effect on the longitudinal layer in concentrations varying of 0.1-10 μM (Pereira et al, 2007).…”

Section: Resultssupporting

confidence: 56%

“…In the same study, prostaglandin F 2α (0.5-30.0 μM) produced a maximum inhibitory effect of 100% on spontaneous contractions of longitudinal segments and only 30% in the circular layers. The variations in responsiveness could be due to different factors, such as distribution and/or concentration of receptors and type of prostaglandin tested (Cao et al, 2002). Both EOCN and prostaglandins presented inhibition spontaneous contractile activity in ovine cervical circular muscles.…”

Section: Resultsmentioning

confidence: 95%

Relaxant effect of the essential oil of Croton nepetifolius on ovine cervix

Pereira¹,

Melo²,

Morais³

et al. 2012

Rev. bras. farmacogn.

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Abstract:We investigated the in vitro effect of the essential oil of Croton nepetifolius Baill., Euphorbiaceae (EOCN), on spontaneous or induced contractions of circular and longitudinal muscles from the ovine cervix during the luteal phase of the estrous cycle. The relaxant effect of EOCN was expressed as a percentage of the contraction recorded before the addition of the oil and calculated relative to the preparations exposed only to the vehicle. The IC50 (concentration of oil required to produce a 50% maximal reduction in muscle contraction) for relaxation of spontaneous contractions in circular and longitudinal muscles was signifi cantly lower than the IC50 for blockade of K + -induced contraction (27.19 µg mL -1 versus 262.72 µg mL -1 and 40.92 µg mL -1 versus 222.47 µg mL -1 , respectively). Interestingly, there was a high degree of selectivity in the action of EOCN on cervix layers concerning the inhibition of acetylcholine-induced contraction in circular (IC50 277.10 µg mL -1 ) and longitudinal (IC50 52.56 µg mL -1 ) muscles. In conclusion, EOCN is able to relax ovine cervix during the luteal phase. This work opens the perspective of applying EOCN in ovine embryo transfer.

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“…It is known that PGE 2 may both stimulate or inhibit the contractile activity of the uterus depending on its concentration and the physiological stage of the uterus (Crankshaw and Gaspar 1995;Popat and Crankshaw 2001;Cao et al 2002). PGE 2 is also considered a potent vasodilator and relaxant acting on MYO and thus an important mediator of inflammation, and a factor contributing to the development of pathological process and its maintenance (Slama et al 1991;Slama et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Participation of Prostaglandin E2 in Contractile Activity of Inflamed Porcine Uterus

et al. 2010

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The aim of our study was to estimate the participation of prostaglandin E 2 (PGE 2 ) in the contractile activity of inflamed porcine uterus. On day 3 of the oestrous cycle, 50 ml of saline or 50 ml of Escherichia coli suspension, containing 10 9 colony-forming units/ml, was injected into each uterine horn in the control or experimental group, respectively. Seven days later the uteri were collected. Endometritis developed in all bacteria-inoculated gilts. Endometrium/myometrium and myometrium strips were incubated with PGE 2 alone or together with PGE 2 receptor (EP) subtypes (EP 2 , EP 4 , EP 1 and EP 3 ) blockers: AH 6809 (BEP 2 ), ONO-AE 2 (BEP 4 ), ONO-AE 3 -240 (BEP 1 ) and SC19220 (BEP 3 ), respectively. In the control group, PGE 2 (10 -8 and 10 -7 M) increased the intensity of contractions in endometrium/myometrium, and at the higher dose in myometrium. PGE 2 (10 -8 M) decreased the contraction intensity of the strips from inflamed uteri. After the use of BEP 2 , PGE 2 (10 -7 M) increased the values of this indicator in endometrium/myometrium and myometrium from the control gilts. In these animals, PGE 2 (10 -8 M) in the presence of BEP 4 reduced the contraction intensity in endometrium/myometrium. In the bacterial group, PGE 2 (10 -8 M) in the presence of BEP 2 and BEP 4 enhanced the intensity of contractions in myometrium. Similar reaction was evoked by PGE 2 (10 -7 M) in endometrium/myometrium of the inflamed uteri in the presence of BEP 4 . The intensity of contractions in myometrium from the inflamed uteri significantly decreased after the use of BEP 1 and PGE 2 (10 -7 M). PGE 2 (10 -7 M) administered after BEP 3 , significantly decreased the intensity of contractions in myometrium of the control gilts. These results show that PGE 2 decreases the contraction intensity of inflamed porcine uteri. Further studies are needed to closely determine the role of PGE 2 and other prostanoids in the contractile activity of inflamed uterine tissue.

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In vitro pharmacological characterization of the prostanoid receptor population in the non-pregnant porcine myometrium

Cited by 52 publications

References 26 publications

An EP4 Receptor Agonist Prevents Indomethacin-Induced Closure of Rat Ductus Arteriosus In Vivo

An EP4 Receptor Agonist Prevents Indomethacin-Induced Closure of Rat Ductus Arteriosus In Vivo

Relaxant effect of the essential oil of Croton nepetifolius on ovine cervix

Participation of Prostaglandin E2 in Contractile Activity of Inflamed Porcine Uterus

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