Maternal Plasma Endothelin Levels and Fetal Status in Normal and Preeclamptic Pregnancies

Furuhashi, N; Kimura, H.; Nagae, H.; Yajima, Akira

doi:10.1159/000292386

Cited by 21 publications

(6 citation statements)

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“…ET‐1 has been suggested to play a role in pre‐eclampsia (Maynard et al ., ). ET‐1 levels are increased in pre‐eclampsia, particularly when accompanied with intrauterine growth restriction (McQeen et al ., ; Furuhashi et al ., ), and modulation of the ET‐1 system may be an important target in the management of pre‐eclampsia. Studies have shown that infusion of ET A R antagonist reduces BP in the L‐NAME‐infused reduced uterine perfusion pressure and sFlt‐1‐infused rat models of hypertension in pregnancy (Olson et al ., ; Alexander et al ., ; Murphy et al ., 2010; 2012; Tam Tam et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Mazzuca

Dang

Khalil

2013

British J Pharmacology

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BACKGROUND AND PURPOSENormal pregnancy is associated with decreased vascular resistance and increased release of vasodilators. Endothelin-1 (ET-1) causes vasoconstriction via endothelin receptor type A (ETAR), but could activate ETBR in the endothelium and release vasodilator substances. However, the roles of ETBR in the regulation of vascular function during pregnancy and the vascular mediators involved are unclear. EXPERIMENTAL APPROACHPressurized mesenteric microvessels from pregnant and virgin Sprague-Dawley rats were loaded with fura-2/AM for simultaneous measurement of diameter and [Ca 2+ ]i. KEY RESULTSHigh KCl (51 mM) and phenylephrine (PHE) caused increases in vasoconstriction and [Ca 2+ ]i that were similar in pregnant and virgin rats. ET-1 caused vasoconstriction that was less in pregnant than virgin rats, with small increases in [Ca 2+ ]i. Pretreatment with the ETBR antagonist BQ-788 caused greater enhancement of ET-1-induced vasoconstriction in pregnant rats. ACh caused endothelium-dependent relaxation and decreased [Ca 2+ ]i, and was more potent in pregnant than in virgin rats. ET-1 + ETAR antagonist BQ-123, and the ETBR agonists sarafotoxin 6c (S6c) and IRL-1620 caused greater vasodilation in pregnant than in virgin rats with no changes in [Ca 2+ ]i, suggesting up-regulated ETBR-mediated relaxation pathways. ACh-, S6c-and IRL-1620-induced relaxation was reduced by the NO synthase inhibitor Nω-nitro-L-arginine methyl ester, and abolished by tetraethylammonium or endothelium removal. Western blots revealed greater amount of ETBR in intact microvessels of pregnant than virgin rats, but reduced levels in endothelium-denuded microvessels, supporting a role of endothelial ETBR. CONCLUSIONS AND IMPLICATIONSThe enhanced ETBR-mediated microvascular relaxation may contribute to the decreased vasoconstriction and vascular resistance during pregnancy. ]i, intracellular free Ca 2+ concentration; EDHF, endothelium-derived hyperpolarizing factor; eNOS, endothelial NOS; ET-1, endothelin-1; ETAR, endothelin receptor type A; ETBR, endothelin receptor type B; INDO, indomethacin; IRL-1620, Suc-Asp-Glu-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-AspIle-Ile-Trp; L-NAME, Nω-nitro-L-arginine methyl ester; pD2 (−log EC50), concentration of drug required to evoke a half-maximal response; PGI2, prostacyclin; PHE, phenylephrine; S6c, sarafotoxin 6c; SNP, sodium nitroprusside; TEA, tetraethylammonium chloride; VSM, vascular smooth muscle BJP British Journal of Pharmacology

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Section: Discussionmentioning

confidence: 99%

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Mazzuca

Dang

Khalil

2013

British J Pharmacology

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“…We chose to measure circulating levels of ET-1, NO x , sFlt-1, and PlGF given previous studies showing their importance in relation to the occurrence of fetal growth restriction and preeclampsia (1,7,8,17,18,25). For example, ET-1 is a potent vasoconstrictor that is known to be elevated in pregnancies complicated by preeclampsia or SGA (7,8), and when its vasoconstrictor actions are inhibited with the use of ET-1 antagonists, hypoxia-associated reductions in uteroplacental blood flow and fetal growth in rat models are completely abolished (27). In this study, ET-1 levels were not elevated at high relative to low altitude during pregnancy or in the nonpregnant state.…”

Section: Discussionmentioning

confidence: 99%

Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude

Julian

Galan²,

Wilson³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

104

107

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Moore LG. Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude. Am J Physiol Regul Integr Comp Physiol 295: R906 -R915, 2008. First published June 25, 2008 doi:10.1152/ajpregu.00164.2008.-Reduced uteroplacental blood flow is hypothesized to play a key role in altitude-associated fetal growth restriction. It is unknown whether reduced blood flow is a cause or consequence of reduced fetal size. We asked whether determinants of uteroplacental blood flow were altered prior to reduced fetal growth and whether vasoactive and/or angiogenic factors were involved. Women residing at low (LA; 1600 m, n ϭ 18) or high altitude (HA; 3100 m, n ϭ 25) were studied during pregnancy (20, 30, and 36 wk) and 4 mo postpartum (PP) using Doppler ultrasound. In each study, endothelin (ET-1), nitric oxide metabolites (NO x), soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF) levels were quantified. At HA, birth weights were lower (P Ͻ 0.01) and small-for-gestational age was more common (P Ͻ 0.05) compared with LA. HA was associated with lower uterine artery (UA) diameter (P Ͻ 0.01) and blood flow (P Ͻ 0.05). Altitude did not affect ET-1, sFlt-1 or PlGF; however, ET-1/NO x was greater and NOx lower during pregnancy and PP at HA vs. LA. ET-1/NO x was negatively associated with birth weight (20 wk, P Ͻ 0.01; 36 wk, P ϭ 0.05) at LA and HA combined. At HA, UA blood flow (30 wk) was positively associated with birth weight ( †). UA blood flow and ET-1/NO x levels accounted for 45% (20 wk) and 32% (30 wk) of birth weight variation at LA and HA combined, primarily attributed to effects at HA. We concluded that elevated ET-1/NO x and altered determinants of uteroplacental blood flow occur prior to altitude-associated reductions in fetal growth, and therefore, they are likely a cause rather than a consequence of smaller fetal size. fetal growth restriction; hypoxia; small-for-gestational age; uteroplacental oxygen delivery; pregnancy SMALL-FOR-GESTATIONAL AGE (SGA) is a common complication of pregnancy that raises the risk of morbidity and mortality during the perinatal period, as well as in later life (2, 11). Among the many determinants of SGA is the chronic hypoxia of residence at high altitude (Ն2,500 m; 8,200 ft). Birth weight declines progressively, and potently, with increasing altitude such that infants born to women permanently residing at elevations Ն2,500 m are at a greater risk of low birth weight than infants born at lower altitudes (13-15, 34). Altitudinal differences in gestational age, socioeconomic status, parity, maternal height, or the frequency of hypertensive complications do not explain the degree to which birth weight decreases with altitude, indicating that it is likely chronic hypoxia per se that is decreasing fetal growth (12,13,15). Despite the pervasive effect of high altitude on birth weight, the mechanisms by which hypoxia acts to reduce fetal growth are not well understood.A considera...

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“…ET-1, a well known potent vasoconstrictor, may be involved in the pathogenesis of hypertension in pregnancy [14,15]. The relationship between insulin and ET-1 is not clear.…”

Section: Discussionmentioning

confidence: 99%

Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine

et al. 2001

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Recent studies have shown that maternal hyperinsulinaemia is a risk factor for the development of hypertension in pregnancy. Experimentally, pregnant rats with chronic exogenously induced hyperinsulinaemia (P-INS rats) have increased blood pressure at the end of gestation. This is associated with a blunted elevation of the excretion of the urinary metabolites of nitrate (UNO(x)). In the present study, we aimed to evaluate the mechanism(s) of the increase in blood pressure in this model. Four groups were studied: normal pregnant rats (P rats), P-INS rats, P-INS rats treated with L-arginine (2 g/l in the drinking water) (L-ARG rats) and hyperinsulinaemic virgin rats (V-INS rats). Systolic blood pressure (SBP), UNO(x) excretion (on ingestion of a controlled low-nitrate diet), urine noradrenaline (norepinephrine) and plasma endothelin levels were evaluated. Rats were killed on day 22 of pregnancy. Five P-INS rats were not killed at this time, in order to measure SBP 30 and 60 days after delivery. Fetal number and fetal body weight were evaluated. At the end of pregnancy, a 10+/-3% increase in SBP was found in P-INS rats, contrasting with a fall of -15+/-4% in P rats (P<0.01). In the L-ARG group at the end of pregnancy, SBP values had fallen by -14+/-2%, to values comparable with those of P rats. The increase in UNO(x) excretion was 175+/-38% in P rats, 106+/-12% in L-ARG rats and 41+/-8% in P-INS rats (P<0.01 compared with P and L-ARG groups). No differences were found in the urinary excretion of noradrenaline or in the plasma levels of endothelin-1 between the pregnant groups. Fetal number was similar in all groups, but fetal body weight was lower for P-INS rats compared with P and L-ARG rats. Thus the blood pressure response to L-arginine strongly suggests that a decrease in NO availability may be the main pathogenic mechanism involved in the development of hypertension in this model.

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Maternal Plasma Endothelin Levels and Fetal Status in Normal and Preeclamptic Pregnancies

Cited by 21 publications

References 9 publications

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude

Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine

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Maternal Plasma Endothelin Levels and Fetal Status in Normal and Preeclamptic Pregnancies

Cited by 21 publications

References 9 publications

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca2+]i in mesenteric microvessels of pregnant rats

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca2+]i in mesenteric microvessels of pregnant rats

Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude

Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine

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Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats