The Renin-Angiotensin System in Conscious Newborn Sheep: Metabolic Clearance Rate and Activity

Velaphi, Sithembiso; DeSpain, Kevin; Roy, Timothy A.; Rosenfeld, Charles R.

doi:10.1203/pdr.0b013e3180534252

Cited by 11 publications

(15 citation statements)

References 45 publications

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“…Although speculative, increases in bronchial and vascular smooth muscle AT 1 R and tissue angiotensinogen, resulting in increased ANG II after meconium exposure, could enhance local RAS activity and contribute to the increases in airway and/or vascular resistance that complicate MAS (5). Further, the increases in circulating ANG II after birth (30,31) could facilitate pulmonary hypertension in the presence of increased pulmonary smooth muscle AT 1 R in MAS. This has not been examined and warrants study.…”

Section: Discussionmentioning

confidence: 99%

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

et al. 2008

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ABSTRACT:The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT 1 R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT 1 R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT 1 R protein approximately 3-fold (p ϭ 0.006), mRNA 29% (p ϭ 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT 1 R expression Ͼ3-fold in cultured type II pneumocytes and caused concentrationdependent cell death inhibited by losartan. Meconium increases AT 1 R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT 1 R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression. T he fetal excretion of meconium into the amniotic fluid occurs in 18 -20% of near-term and term pregnancies and is associated with intra-uterine stress (1-5). When episodes are severe, fetal respiratory efforts are altered and meconium contaminated amniotic fluid may be inhaled before, at the time of, or soon after birth in approximately 5% of neonates. These neonates may develop pneumonitis and lung injury secondary to meconium aspiration syndrome (MAS) (2,3,5,6). Thirty percent of neonates with MAS require mechanical ventilation, and many develop respiratory failure requiring inhaled nitric oxide, high-frequency ventilation, or extracorporal membrane oxygenation. It is unclear, however, what contributes to the pathogenesis and severity of MAS.The clinical manifestations of MAS reflect airway obstruction due to inhaled particulate matter and development of chemical pneumonitis and inflammation, which contribute to the severity of MAS (5). Inflammatory cytokines are elevated in the blood of newborn piglets and the tracheal lavage and lungs of animals after pulmonary instillation of meconium (5,7-10). In most animal studies, homogenized meconium containing particulate matter was instilled into the lungs, making it difficult to separate the obstructive and inflammatory components. We (7) removed the obstructive effects of the particulate matter by using a sterile filtrated supernatant from homogenized term human meconium (MS). In newborn rabbits, MS caused pulmonary inflammation, neutrophil migration, epithelial cell apoptosis, and activation of the pulmonary renin-angiotensin system (RAS) ...

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Section: Discussionmentioning

confidence: 99%

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

et al. 2008

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“…Five chronically instrumented newborn singleton sheep were studied at 9 -38 days after birth. The animal preparation has been described previously (32)(33)(34). Briefly, pregnant ewes were brought to the University of Texas Southwestern Medical Center at Dallas at ϳ145 days of gestation (full term ϭ 150 days) and allowed to deliver, and surgery was performed at 3-5 days after birth.…”

Section: Methodsmentioning

confidence: 99%

“…Animals were not studied until 3-4 days postoperatively to allow for recovery, which was judged by consistent weight gain, normal arterial blood gases, and stable hemodynamic parameters (32)(33)(34). At the time of each study, animals were removed from the mother and placed in a sling, and hemodynamic parameters were allowed to stabilize for 30 -40 min.…”

Section: Methodsmentioning

confidence: 99%

“…However, the mechanisms that contribute to these processes and the subsequent rise in BP are poorly understood. They may include changes in circulating pressors, e.g., ANG II, arginine vasopressin (AVP), or catecholamines (7), decreases in vasodilators, alterations in vascular responsiveness due to changes in vascular smooth muscle (VSM) maturation (13) or receptor expression (5), or alterations in the metabolism of endogenous constrictors (25,32). For example, the angiotensin type 2 (AT 2 ) receptor is the predominant ANG II receptor subtype in newborn sheep until after 1 mo of age (4,5), resulting in attenuated peripheral ANG II-mediated vasoconstrictor responses in fetal and newborn sheep (16,33).…”

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confidence: 99%

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Metabolism and synthesis of arginine vasopressin in conscious newborn sheep

Miao¹,

Velaphi²,

Roy³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Arginine vasopressin (AVP) is an important regulator of cardiovascular homeostasis in the fetus, but its role after birth is unclear. Although infused AVP increases mean arterial pressure (MAP) during the 1st mo after birth, pressor responses are unchanged, suggesting that vascular responsiveness is also unchanged. Alternatively, this could reflect increases in AVP metabolic clearance rate (MCR(AVP)). However, newborn AVP metabolism and synthesis are poorly studied. Therefore, we examined the pressor responses to infused AVP and the pattern of circulating AVP, AVP production rate (PR(AVP)), and MCR(AVP) in conscious newborn sheep (n = 5) at 9-38 days after birth. Basal MAP rose and heart rate (HR) fell during the study period (P < or = 0.02), while circulating AVP was unchanged (P > 0.1), averaging 3.01 +/- 0.86 pg/ml. Infused AVP elicited steady-state responses at 10-40 min, increasing plasma AVP and MAP and decreasing HR (P < 0.001). Although pressor responses were unchanged between 9 and 38 days, the rise in MAP correlated with increases in plasma AVP (R = 0.47, P = 0.02, n = 24). MCR(AVP) was unchanged throughout the 1st mo (P > 0.2), averaging 205 +/- 17 ml.kg(-1).min(-1), and was associated with an elevated PR(AVP), 973 +/- 267 pg.kg(-1).min(-1), which also was unchanged (P > 0.1). After birth, MCR(AVP) and PR(AVP) are elevated, probably accounting for the stable plasma AVP levels. The former is also likely to account for the stable pressor responses to infused AVP during the 1st mo. The reason for the elevated PR(AVP) is unclear but may relate to increases in vascular volume associated with postnatal growth.

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“…For example, there are increased plasma levels of renin, angiotensin converting enzyme (ACE), and ANG II at birth and a decline as postnatal maturation proceeds. [10][11][12][13][14][15][16][17] The expression of AT1Rs and AT2Rs is also developmentally regulated, with AT2Rs predominating in the brain, adrenal gland and kidney of fetal and newborn rats, fowl, rabbits, sheep and humans. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] In near-term fetal sheep and newborn lambs, AT2Rs are primarily expressed in systemic artery vascular smooth muscle cells.…”

Section: Introductionmentioning

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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The Renin-Angiotensin System in Conscious Newborn Sheep: Metabolic Clearance Rate and Activity

Cited by 11 publications

References 45 publications

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

Metabolism and synthesis of arginine vasopressin in conscious newborn sheep

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

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