Contractile effect of endothelin in human placental veins: Role of endothelium prostaglandins and thromboxane

doi:10.1016/0002-9378(93)90027-G

American Journal of Obstetrics and Gynecology

Volume 169, Issue 4, October 1993, Pages 919-924

https://doi.org/10.1016/0002-9378(93)90027-G Get rights and content

Objective: The aim was to study the effects of endothelin-1 on human placental veins and the role of cyclooxygenase products as mediators of these effects.

Study Design: Rings of placental veins with and without endothelium were suspended in organ chambers filled with physiologic salt solution. After a period of stabilization at optimal basal tension, isometric tensions in the control group were recorded at increasing concentrations of endothelin-1 (10⁻¹⁰ to 10⁻⁷ mol/L). Rings in the experimental groups were treated with either indomethacin (cyclooxygenase inhibitor, 10⁻⁵ mol/L), dazoxiben (thromboxane synthetase inhibitor, 10⁻⁴ mol/L), or SQ29548 (thromboxane receptor antagonist, 10⁻⁶ mol/L) before addition of endothelin-1. To demonstrate the presence of functional thromboxane receptors in the rings, contractile responses to U-46619 (10⁻⁹ to 10⁻⁶ mol/L), a thromboxane A₂ analog were measured. The effectiveness of SQ29548 blockade was tested in rings treated with SQ29548 (10⁻⁶ mol/L) before addition of U-46619. The concentration-response curves of the treated and control groups were compared with the Student paired t test.

Results: Endothelin-1 in doses of 10⁻¹⁰ to 10⁻⁷ mol/L caused concentration-dependent contraction of placental veins. Indomethacin significantly reduced the response of veins with endothelium to low endothelin-1 concentrations (10^−9.5 to 10⁻⁹ mol/L), (p < 0.05). However, it had no effect at higher endothelin-1 concentrations or in vessels without endothelium. The presence of functional thromboxane A₂ receptors was confirmed by the vasoconstrictor effect of U-46619 and its blockade by treatment with SQ29548. Neither SQ29548 nor the thromboxane A₂ synthesis inhibitor dazoxiben significantly influenced the response to endothelin-1.

Conclusions: These results demonstrated that endothelin-1 is a potent vasoconstrictor in the human placental vein. Although functional thromboxane A₂ receptors exist in this vessel, endothelin-1's action is independent of thromboxane A₂. Prostaglandins may mediate part of the endothelin-1-induced placental vasoconstriction. However, endothelin-1 acts primarily by a direct effect on vascular smooth muscle cells.

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Endothelium-Dependent Contractions: Prostacyclin and Endothelin-1, Partners in Crime?
2016, Advances in Pharmacology
Citation Excerpt :
Prostacyclin, however, attenuates the vasoconstrictor responses to ET-1 in human veins in vivo (Haynes & Webb, 1993) and inhibits its production and secretion from endothelial cells (Prins et al., 1994). By contrast, contractions to ET-1 are partially mediated by prostanoids distinct from thromboxane A2 in isolated human placental veins with endothelium (Le, Wasserstrum, Mombouli & Vanhoutte, 1993). Indeed, endoperoxides (the precursors of prostanoids, including prostacyclin) contribute to the vasoconstriction induced by ET-1 in porcine coronary arteries with regenerated endothelium (Park et al., 1999), while prostacyclin attenuates ET-1-induced vascular tone in this preparation from healthy young animals (Suzuki, Kajikuri, Suzuki, & Itoh, 1991).
Both the lipid prostacyclin and the peptide endothelin-1 are endothelium-derived substances. Endothelin-1 is one of the most powerful endogenous vasoconstrictors, while prostacyclin is a potent antiaggregatory and vasodilator mediator upon activation of prostaglandin I₂ (IP) receptors. During endothelium-dependent, prostanoid-mediated contractions/constrictions, however, prostacyclin appears to be a major endothelium-derived contracting factor (EDCF). Such cyclooxygenase-dependent responses, whether measured ex vivo or in vivo, are exacerbated by aging, obesity, diabetes, or hypertension. On the background of such cardiovascular risk factors, endothelin-1 may potentiate these contractions by promoting prostacyclin production. The latter is reduced by endothelin-A (ET_A) receptor antagonists. This receptor subtype is recognized for mediating contractions of smooth muscle cells to endothelin-1. However, it is present also on endothelial cells, where its activation increases intracellular calcium concentration with subsequent initiation of phospholipase A₂ that provides arachidonic acid for metabolism by cyclooxygenases. Thus, endothelin-1 favors cyclooxygenase-dependent vasoconstrictor prostanoid formation, including prostacyclin. Activation of endothelial endothelin-B (ET_B) receptors promotes the release of nitric oxide, which opposes both EDCF and endothelin-1. This is less pronounced in disease promoting ET_A- and smooth muscle ET_B receptor-dependent as well as prostanoid-mediated contractions. In addition, the thromboxane prostanoid (TP) receptors on vascular smooth muscle cells become hyperresponsive to EDCF under pathophysiological conditions, while IP receptor responsiveness diminishes. A better understanding of the interaction between prostacyclin and endothelin-1 and the determination of the roles of the TP and IP receptors involved in prostanoid-mediated contractions in health and during disease will help to define advanced pharmacological strategies for the therapy of cardiovascular disorders.
Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells
2008, Placenta
Citation Excerpt :
Because placental vessels lack autonomic innervations, locally hormonal effects of the placenta must play a dominate role in the regulation of fetal-placental vascular contractility. Placental tissues are not only able to produce various vasoactive agents, like angiotensin II (Ang II) [1–3], thromboxane (TX) [4–6], and endothelin (ET) [7,8], but also possess receptors for each of these vasoactivators, which ensure that the placental vasomotor activity is controlled in both the autocrine and/or the paracrine fashions. Using an organ bath perfusion model, we recently demonstrated that vasoconstrictors produced by preeclamptic placentas could induce constriction of chorionic plate arteries [9].
Our previously published work has shown that non-ACE angiotensin II (Ang II) generating system is dominate in the placenta and may play a critical role in regulation of placental vascular contractile function. In the present study, using a collagen gel contraction assay we further studied contractility of placental vascular smooth muscle cells (VSMCs) in response to factors produced by preeclamptic (PE) placentas. Placental VSMCs/type-1 collagen gels were incubated with PE placental conditioned medium in the presence or absence of inhibitors or receptor blockers. Captopril (an ACE inhibitor), chymostatin (a non-ACE chymase inhibitor), losartan (an AT1 receptor blocker) and PD123,319 (an AT2 receptor blocker) were used to study the specific ACE vs. non-ACE and AT1 vs. AT2 effects on placental VSMC contractility, respectively. Our results showed that chymostatin, but not captopril, and PD123,319, but not losartan, significantly attenuated placental VSMC/collagen gel contraction, p < 0.01, respectively. The inhibitory effects of chymostatin and PD123,319 were dose-dependent. Our results suggest that chymase, a non-ACE Ang II generating enzyme, may contribute significantly to Ang II generated in the placenta vascular tissue and that the AT2 receptor may play an important role in the regulation of Ang II induced contractility of placental VSMCs. These results provide new insights into Ang II generation and Ang II receptor regulation of vessel contractile function in the placental vasculature. These results also suggest the potential role of increased chymase activity and altered AT2 receptor function in placental related pregnancy disorders such as preeclampsia and IUGR.
Vasoreactivity of Chorionic Plate Arteries in Response to Vasoconstrictors Produced by Preeclamptic Placentas
2007, Placenta
Citation Excerpt :
Therefore, vasoconstrictors produced by placental trophoblast cells may play a critical role in regulating vasomotor tone in the placental vasculature. Past studies have described that placental tissues produce ANG II [12–16], TX [17,18] and ET [19–21] and they are major contributors to the vasoconstriction in PE. Receptors for ANG II [2,6,22–25], TX [26,27], and ET [28] are present in placental trophoblasts and vasculature.
Inadequate blood flow and increased vasoconstriction of the placenta contribute to pregnancy associated disorders such as preeclampsia (PE). Because placental vessels lack autonomic innervation, humoral effects of the placenta must play critical roles in regulation of fetal-placental vascular contractility. In this study, we examined the nature of humoral factors produced by PE trophoblasts on placental vessel contractility using an organ bath perfusion model. Vasomotor responses were studied in vitro using placental chorionic plate arteries. Vessel rings from third branch chorionic plate arteries were dissected from human placentas following normal or PE delivery. The arterial rings were equilibrated in Krebs Henseleit buffer and exposed to placental conditioned medium, which was prepared by culture of villous tissue from PE placentas. Receptor antagonists for angiotensin II (ANG II), thromboxane (TX), and endothelin (ET) were used to determine which humoral factor produced by placental tissue (trophoblasts) was more effective in promoting vasoconstriction. The role of angiotensin converting enzyme (ACE) and non-ACE ANG II generating enzymes in regulation of placental vasomotor tone were also investigated. A total of 80 arterial rings from 48 placentas were studied. Our results showed: 1) enhanced vasomotor tone in arteries from PE placentas compared to those from normal placentas; 2) PE-CM induced vaso-constrictive activity could be partially attenuated by receptor antagonists for TX, ANG II and ET, respectively; and 3) chymostatin (a chymase inhibitor) produced a stronger inhibitory effect than captopril (ACE inhibitor) on PE conditioned medium induced vasoconstriction. Our data demonstrate increased vasocontractility in PE placentas and suggest that the non-ACE pathway is probably a major source of ANG II produced in the human placenta.
Oxygen tension and normalisation pressure modulate nifedipine-sensitive relaxation of human placental chorionic plate arteries
2006, Placenta
Fetoplacental blood vessel constriction in response to reduced oxygenation has been demonstrated in placenta perfused in vitro. In pulmonary vessels, hypoxic vasoconstriction involves Ca²⁺ influx into smooth muscle through membrane ion channels including voltage-gated Ca²⁺ channels (VGCCs). We hypothesised that VGCCs are involved in agonist-induced constriction of fetoplacental resistance vessels and that their contribution is modulated by oxygen. Chorionic plate small arteries were studied using wire myography. Arteries were normalised at high (0.9 of L_13.3 kPa) or low (0.9 of L_5.1 kPa) stretch and experiments performed at 156, 38 or 15 mmHg oxygen. At low stretch, U46619 (thromboxane-mimetic) or KCl (smooth muscle depolarisation) constriction was greater at 38 than 156 or 15 mmHg oxygen. An L-type VGCC blocker nifedipine, inhibited KCl constriction by >85% but was less effective in U46619 constrictions (43–67%). At high stretch, nifedipine inhibition of KCl- and U46619-induced constriction was less at 15 than 38 or 156 mmHg oxygen. Oxygen did not affect constriction to U46619 or nifedipine-induced relaxation when vessels were normalised at high stretch. In conclusion, oxygen modulates chorionic plate arterial constriction at low stretch but regulation is lost at high stretch. U46619 constriction is underlain by VGCCs and nifedipine-insensitive processes; their relative contribution is influenced by oxygen.
Influence of magnesium sulphate and isradipine on human placental cotyledon fetal vessels in vitro
2001, European Journal of Obstetrics and Gynecology and Reproductive Biology
Increased systemic vascular resistance and blood pressure during pregnancy may be due to impaired prostacycline PGI₂-thromboxan (TX) A₂ balance. The aim of the study was to compare the influence of magnesium sulphate and isradipine on the placental vascular resistance induced by stable thromboxan A₂ analogue U 46619 in experimental bilateral perfusion of the human placental cotyledon. The research used the experimental model described by Schneider et al. [Am. J. Obstet. Gynecol. 114 (1972) 822]. The control group consisted of six placental lobule perfusions lasting 120 min each. Constant increase in perfusion pressure of mean value 185% of the initial pressure was obtained from about the 60th min of the experiment and maintained till the end. Having obtained constant increase in perfusion pressure from the 60th min of the experiment, magnesium sulphate and isradipine were administered along with thromboxan A₂ analogue U 46619 into the fetal circulation. Both drugs lowered perfusion pressure, experimentally increased by thromboxan A₂ analogue U 46619. The onset of magnesium sulphate activity was quicker than isradipine. According to the results of our in vitro study, magnesium sulphate and isradipine may have a beneficial effect on vascular resistance of cotyledon vessels in PIH in vivo, too.
Isolated human chorionic vascular reactivity: Technical considerations for fresh preparations
1998, General Pharmacology
- 1.
  1. Sixty chorionic vascular rings from normal term placentas were immersed in an organ bath for isometric tension recording to study (A) the contractile response to 120 mM of potassium chloride (KCI) after adjustment and equilibration to 1–5 g of passive tension; and (B) the concentration-response curve to KCI after adjustment and equilibration to the optimal passive tension.
- 2.
  2. Adjustment to 4 g of passive tension elicited the maximal (P<0.007) and the latest (P<0.006) KCl-induced contraction among arterial rings. Venous rings showed the greatest contraction when adjusted to 3 g, but the differences were not significant except when compared to 1 g of passive tension (P<0.03).
- 3.
  3. The EC₅₀ for chorionic arteries and veins was 14.2 and 25.7 mM, respectively (P<0.003). The maximal contraction was already obtained with 40 mM of KCl.
- 4.
  4. Our results suggest that (A) the optimal passive tension for fresh human chorionic arteries is 4 g; (B) chorionic venous reactivity is less influenced by the initial tension; and (C) the optimal concentration of KCl to be used as a contracting agent of these tissues is 40 mM.

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¹: Supported in part by grant HL-35614 from the National Institutes of Health.

²: Presented at the Thirteenth Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, February 8–13, 1993.

^*: From the Departments of Obstetrics/Gynecology and Medicine and the Center for Experimental Therapeutics, Baylor College of Medicine.

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Contractile effect of endothelin in human placental veins: Role of endothelium prostaglandins and thromboxane1,2

Placenta

Prostaglandins

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Production of endothelin-1 by human trophoblasts

Am J Obstet Gynecol

Human cultured endothelial cells do secrete endothelin-1

J Cardiovasc Pharmacol

Endothelin in maternal and umbilical cord blood in spontaneous labor and at elective cesarean delivery

Obstet Gynecol

Endothelin: release by and potent constrictor effect on the fetal vessels of human perfused placental lobules

Reprod Fertil Dev

Endothelin-1,2 levels in umbilical vein serum of second-trimester fetuses and growth-retarded third-trimester fetuses at time of cordocentesis

Am J Obstet Gynecol

Preeclampsia: an imbalance in placental prostacyclin and thromboxane production

Am J Obstet Gynecol

Role of thromboxane A2/prosta-glandin H2 receptor in the vasoconstrictor response of rat aorta to endothelin

J Pharmacol Exp Ther

Role of endothelium in endothelin-evoked contractions in the rat aorta

Hypertension

Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells

Circulation

Increased maternal plasma concentration of endothelin-1 during labor pain or on delivery and the existence of a large amount of endothelin-1 in amniotic fluid

Gynecol Endocrinol

Role of thromboxane A₂/prosta-glandin H₂ receptor in the vasoconstrictor response of rat aorta to endothelin