Differential Sensitivity to Angiotensin II and Norepinephrine in Human Uterine Arteries

Rosenfeld, Charles R.; DeSpain, Kevin; Word, R. Ann; Liu, Xiao Tie

doi:10.1210/jc.2011-1818

Cited by 18 publications

(15 citation statements)

References 37 publications

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“…If ATR expression by immunoblots reflects binding density, we provide further evidence that ATR expression is unchanged not only in third generation UVSM, but also precaruncular/placental VSM during ovine pregnancy. Similar findings have been observed in human UVSM (42).…”

Section: Discussionsupporting

confidence: 91%

“…The differences with small mammals may reflect species specificity (37). Importantly, similar findings occur in human UVSM (42).…”

Section: R65supporting

confidence: 53%

“…In contrast, the UVB is inherently sensitive to ␣-stimulation, which may contribute to maternal adaptation and survival during stress. Similar findings occur in human UVSM, raising important questions about the role of increased sympathetic outflow and altered UPBF in the pathogenesis of fetal growth restriction in women with preeclampsia and/or hypertension (23,42,50). These findings also suggest that ␣-agonists may not be appropriate pressor agents in treating hypotension in pregnancy.…”

Section: Perspectives and Significancementioning

confidence: 53%

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Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

Rosenfeld

DeSpain

Liu

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Rosenfeld CR, DeSpain K, Liu X-t. Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature. Am J Physiol Regul Integr Comp Physiol 302: R59-R67, 2012. First published October 26, 2011 doi:10.1152/ajpregu.00424.2011The intact ovine uterine vascular bed (UVB) is sensitive to ␣-agonists and refractory to angiotensin II (ANG II) during pregnancy; the converse occurs in the systemic circulation. The mechanism(s) responsible for these differences in uterine sensitivity are unclear and may reflect predominance of nonconstricting AT2 receptors (AT2R) in uterine vascular smooth muscle (UVSM). The contribution of the placental vasculature also is unclear. Third generation and precaruncular/placental arteries from nonpregnant (n ϭ 16) and term pregnant (n ϭ 23) sheep were used to study contraction responses to KCl, norepinephrine (NE), and ANG II (with/without ATR specific inhibitors) and determine UVSM ATR subtype expression and contractile protein content. KCl and NE increased third generation and precaruncular/ placental UVSM contractions in a dose-and pregnancy-dependent manner (P Յ 0.001). ANG II only elicited modest contractions in third generation pregnant UVSM (P ϭ 0.04) and none in precaruncular/placental UVSM. Moreover, compared with KCl and NE, ANG II contractions were diminished Ն 5-fold. Whereas KCl and ANG II contracted third generationϾϾprecaruncular/placental UVSM, NEinduced contractions were similar throughout the UVB. However, each agonist increased third generation contractions Ն 2-fold at term, paralleling increased actin/myosin and cellular protein content (P Յ 0.01). UVSM AT 1R and AT2R expression was similar throughout the UVB and unchanged during pregnancy (P Ͼ 0.1). AT 1R inhibition blocked ANG II-mediated contractions; AT 2R blockade, however, did not enhance contractions. AT 2R predominate throughout the UVB of nonpregnant and pregnant sheep, contributing to an inherent refractoriness to ANG II. In contrast, NE elicits enhanced contractility throughout the ovine UVB that exceeds ANG II and increases further at term pregnancy. placental artery; systemic artery; actin/myosin; angiotensin II receptors; ␣-agonists OVINE PREGNANCY IS ASSOCIATED with numerous cardiovascular changes (43, 48), including a Ͼ30-fold rise in uterine blood flow (UBF) and Ͼ40% increase in cardiac output. Additionally, there is development of refractoriness to the pressor effects of infused norepinephrine (NE) and angiotensin II (ANG II) in women and sheep (44,49,53). Although the ovine uterine vascular bed (UVB) also develops refractoriness to these agonists during pregnancy (32, 49), Naden and Rosenfeld (36) reported that the intact pregnant ovine UVB was more refractory to the vasoconstricting effects of ANG II than the systemic vasculature. Thus, blood pressure increased in the absence of significant decreases in uteroplacental blood flow (UPBF). In contrast, the UVB was quite sensitive to ␣-agonists, which decreased ovine UPBF at nonpressor doses, demonstrating differenc...

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Section: Discussionsupporting

confidence: 91%

“…The differences with small mammals may reflect species specificity (37). Importantly, similar findings occur in human UVSM (42).…”

Section: R65supporting

confidence: 53%

Section: Perspectives and Significancementioning

confidence: 53%

See 1 more Smart Citation

Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

Rosenfeld

DeSpain

Liu

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In contrast, recent studies in isolated umbilical arteries removed from pregnant and non-pregnant women showed that ANG II induced vascular contractions were not altered in the presence of AT2R inhibition. 47 This may implicate species differences in the role of AT2Rs in modulating haemodynamic effects of AT1Rs.…”

Section: Discussionmentioning

confidence: 99%

Do Angiotensin Type 2 Receptors Modulate Haemodynamic Effects of Type 1 Receptors in Conscious Newborn Lambs?

Vinturache

Smith

2014

J Renin Angiotensin Aldosterone Syst

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Introduction and hypothesis: It was hypothesized that in the immediate newborn period, when the renin-angiotensin system (RAS) is activated, angiotensin type 2 receptors (AT2Rs) buffer the haemodynamic effects of angiotensin type 1 receptors (AT1Rs), as occurs in adult animals when the RAS is activated. Materials and methods: Arterial (systolic, diastolic, and mean) pressures (SAP, DAP, MAP), mean venous pressures (MVP) and renal blood flows (RBF) were measured in conscious, chronically instrumented lambs aged ~1 (8±2 days, N=8) and 6 weeks (41±4 days, N=11). In each animal, measurements were made before and after administration of the selective AT1R antagonist ZD 7155 (experiment one) and the selective AT2R antagonist PD123319 (experiment two) as well as both antagonists, ZD 7155 and PD 123319 (experiment three). Results: Haemodynamic responses to combined inhibition of both AT1Rs and AT2Rs were similar to inhibition of AT1Rs alone: there was a significant decrease in SAP, DAP, and MAP and a significant increase in RBF within minutes of concomitant administration of ZD 7155 and PD 123319 in both age groups. These responses were similar to responses to ZD 7155 alone, whereas PD 123319 alone did not alter any of the measured variables. Conclusions: AT2Rs do not counterbalance the pressor and renal vasoconstrictor effects elicited by activation of AT1Rs in the immediate newborn period. During this time, AT1Rs appear to predominate in eliciting the haemodynamic effects of angiotensin II (ANG II), whereas the role of the upregulated AT2Rs remains elusive.

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“…Accumulating evidence suggests broad similarities in vascular function in pregnant women and sheep (6,14,36,37,42). Moreover, vasoactive agonists or antagonists can be infused intra-arterially into one uterine horn of pregnant ewes, limiting systemic effects and allowing the contralateral uterine horn to serve as a control (27,35,40).…”

mentioning

confidence: 99%

Prolonged uterine artery nitric oxide synthase inhibition modestly alters basal uteroplacental vasodilation in the last third of ovine pregnancy

Rosenfeld

Roy

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Rosenfeld CR, Roy T. Prolonged uterine artery nitric oxide synthase inhibition modestly alters basal uteroplacental vasodilation in the last third of ovine pregnancy. Am J Physiol Heart Circ Physiol 307: H1196 -H1203, 2014. First published August 15, 2014; doi:10.1152/ajpheart.00996.2013.-Mechanisms regulating uteroplacental blood flow (UPBF) in pregnancy remain unclear, but they likely involve several integrated signaling systems. Endotheliumderived nitric oxide (NO) is considered an important contributor, but the extent of its involvement is unclear. Bolus intra-arterial infusions of nitro-L-arginine methyl ester (L-NAME) modestly decrease ovine basal UPBF; however, the doses and duration of infusion may have been insufficient. We, therefore, examined prolonged uterine artery (UA) NO synthase inhibition with L-NAME throughout the last third of ovine pregnancy by performing either continuous 30-min UA infusion dose responses (n ϭ 4) or 72-h UA infusions (0.01 mg/ml) at 104 -108, 118 -125, and 131-137 days of gestation (n ϭ 7) while monitoring mean arterial pressure (MAP), heart rate (HR), and UPBF. Uteroplacental vascular resistance (UPVR) was calculated, and uterine cGMP synthesis was measured. Thirty-minute UA L-NAME infusions did not dose dependently decrease UPBF, increase UPVR, or decrease uterine cGMP synthesis (P Ͼ 0.1); however, MAP rose and HR fell modestly. Prolonged continuous 72-h UA L-NAME infusions decreased UPBF ϳ32%, increased UPVR ϳ68% (P Յ 0.001), and decreased uterine cGMP synthesis 70% at 54 -72 h (P Յ 0.004); the noninfused uterine horn was unaffected. These findings were associated with ϳ10% increases in MAP and decreases in HR that were greater at 104 -108 than 118 -125 and 131-137 days of gestation (P ϭ 0.006). Although uterine and UA NO and cGMP synthesis increase severalfold during ovine pregnancy, they contribute modestly to the maintenance and rise in UPBF in the last third of gestation. Thus, local UA NO may primarily modulate vasoconstrictor responses. Notably, the systemic vasculature appears more sensitive than the uterine vasculature to NO synthase inhibition. nitric oxide synthase inhibition; mean arterial pressure; cGMP synthesis; sheep; uteroplacental blood flow THE SUCCESS OF PREGNANCY is dependent on the processes associated with implantation, placentation with vasculogenesis, and the subsequent rise and maintenance of maternal and fetal placental blood flows. In most species, basal maternal uteroplacental blood flow (UPBF) increases severalfold in the last third of gestation, paralleling logarithmic increases in fetal weight (40,43). Although this is primarily due to progressive vasodilation and maintenance of low vascular resistance in the maternal uteroplacental circulation, there is also a modest contribution by vasculogenesis in sheep (12,39,47). In contrast, the rise in fetal placental blood flow is primarily due to increasing angiogenesis and branching morphogenesis in the last third of gestation, thereby substantially increasing the placental surface area and capac...

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Differential Sensitivity to Angiotensin II and Norepinephrine in Human Uterine Arteries

Cited by 18 publications

References 37 publications

Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

Do Angiotensin Type 2 Receptors Modulate Haemodynamic Effects of Type 1 Receptors in Conscious Newborn Lambs?

Prolonged uterine artery nitric oxide synthase inhibition modestly alters basal uteroplacental vasodilation in the last third of ovine pregnancy

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