Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

Camelo, Jr Js; Martins, AR; Rosa, Eloi Francisco; Ramos, Simone G.; Hehre, Dorothy; Bancalari, Eduardo; Suguihara, Cleide

doi:10.1590/s0100-879x2012007500014

Cited by 6 publications

(7 citation statements)

References 39 publications

(46 reference statements)

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“…Several animal models of neonatal PVD and PH, including a neonatal swine model with hypoxia-induced PH, have been previously established (4,9,10,18,20,45,46,53). In the present study, resting PAP decreased over time after reexposure to normoxia in hypoxia-exposed animals, and overt PH (defined as mean PAP Ն 25 mmHg) was no longer consistently present 2 wk after reexposure to normoxia.…”

Section: Characterization Of the Neonatal Swine Model For Neonatal Pvdmentioning

confidence: 46%

“…Furthermore, chronic instrumentation of such young piglets is challenging as the surgical area and anatomic structures are smaller, and it is more difficult to wean the piglets off the ventilator during recovery from surgery. Finally, in the present study, we chose not to acquire hemodynamic data during the neonatal period, as this has previously been studied by Camelo et al (10) and would preclude prolonged followup because of the large weight gain of the piglets in the first weeks of life, which would result in catheter failure.…”

Section: Methodological Considerationsmentioning

confidence: 99%

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Structural and functional changes of the pulmonary vasculature after hypoxia exposure in the neonatal period - a new swine model of pulmonary vascular disease

Wijs-Meijler¹,

Duin²,

Duncker

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Pulmonary vascular disease (PVD) represents an underestimated and increasing clinical burden not only in the neonatal period but also later in life, when exercise tolerance is decreased. Animal models performing long-term followup after a perinatal insult are lacking. This study aimed to develop and characterize a neonatal swine model with hypoxia-induced PVD during long-term followup after reexposure to normoxia and to investigate the exercise response in this model. Piglets were exposed to a normoxic ( n = 10) or hypoxic environment ( n = 9) for 4 wk. Neonatal hypoxia exposure resulted in pulmonary hypertension. Mean pulmonary artery pressure was elevated 1 day after reexposure to normoxia (30.2 ± 3.3 vs. 14.3 ± 0.9 mmHg) and remained significantly higher in the second week (32.8 ± 3.8 vs. 21.4 ± 1.2 mmHg), accompanied by decreased exercise tolerance. Exercise resulted in a trend toward an exaggerated increase of pulmonary artery pressure in hypoxia-exposed animals ( week 6, P = 0.086). Although pulmonary hypertension was transient, thickening of pulmonary arterioles was found at the end of followup. Furthermore, right ventricular dilation, lower right ventricular fractional area change ( week 8, 40.0 ± 2.7% vs. 29.5 ± 4.7%), and tricuspid annular plane systolic excursion ( week 8, 27.0 ± 2.5 vs. 22.9 ± 2.1 mm) persisted during followup. Male animals showed more severe PVD than female animals. In conclusion, we developed a neonatal swine model that allows examination of the long-term sequelae of damage to the developing neonatal lung, the course of the disease and the effect of therapy on long-term outcome. NEW & NOTEWORTHY The swine model of neonatal pulmonary vascular disease developed in the present study is the first that allows exercise testing and examination of long-term sequelae of a perinatal hypoxic insult, the course of the disease, and the effect of therapy on long-term outcome.

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Section: Characterization Of the Neonatal Swine Model For Neonatal Pvdmentioning

confidence: 46%

Section: Methodological Considerationsmentioning

confidence: 99%

Structural and functional changes of the pulmonary vasculature after hypoxia exposure in the neonatal period - a new swine model of pulmonary vascular disease

Wijs-Meijler¹,

Duin²,

Duncker

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…Two of the candidate PSGs, AGTRAP and UBE2D1 , are both involved in the response to hypoxia, corresponding to the first functional group of GO categories. AGTRAP encodes proteins that interact with the angiotensin II type I receptor to negatively regulate angiotensin II signaling [ 41 ], which may partially attenuate hypoxia-induced pulmonary hypertension [ 42 ]. UBE2D1 enables the ubiquitination of the hypoxia-inducible transcription factor HIF-1α by interacting with the E1 ubiquitin-activating enzyme and the E3 ubiquitin-protein ligases [ 43 , 44 ].…”

Section: Resultsmentioning

confidence: 99%

Comparative transcriptomic analysis revealed adaptation mechanism of Phrynocephalus erythrurus, the highest altitude Lizard living in the Qinghai-Tibet Plateau

et al. 2015

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BackgroundOrganisms living at high altitudes must overcome three major environmental challenges: hypoxia, cold, and intense UV radiation. The molecular mechanisms that enable these challenges to be overcome have mainly been studied in endothermic organisms; relatively little attention has been paid to poikilothermic species. Here, we present deep transcriptome sequencing in two closely related lizards, the high altitude-dwelling Phrynocephalus erythrurus and the lowland-dwelling P. putjatia, to identify candidate genes under positive selection and to explore the convergent evolutionary adaptation of poikilothermic animals to high altitude life.ResultsMore than 70 million sequence reads were generated for each species via Illumina sequencing. De novo assembly produced 56,845 and 63,140 transcripts for P. erythrurus and P. putjatia, respectively. P. erythrurus had higher Ka/Ks ratios than P. putjatia, implying an accelerated evolutionary rate in the high altitude lizard lineage. 206 gene ontology (GO) categories with accelerated evolutionary rates and 43 candidate positively selected genes were detected along the P. erythrurus lineage. Some of these GO categories have functions associated with responses to hypoxia, energy metabolism and responses to UV damage. We also found that the high-altitude ranid frog R. kukunoris had higher Ka/Ks ratios than the closely related low-altitude frog R. chensinensis, and that the functional categories with accelerated evolutionary rates in R. kukunoris overlapped extensively with those detected along the P. erythrurus lineage.ConclusionsThe mechanisms of high altitude adaptation in P. erythrurus were tentatively inferred. By comparing two pairs of low- and high-altitude poikilothermic species, we found that similar functional categories had undergone positive selection in high altitude-dwelling Phrynocephalus and Rana lineages, indicating that similar mechanisms of adaptation to high altitude might have evolved in both genera. Our findings provide important guidance for future functional studies on high altitude adaptation in poikilothermic animals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-015-0371-8) contains supplementary material, which is available to authorized users.

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“…; Camelo et al. ). Swine lungs share many anatomical, histological, biochemical, and physiological features with human lungs (Rogers et al.…”

Section: Discussionmentioning

confidence: 98%

“…Unfortunately, these patients often have a poor responsiveness to inhaled NO and alternative effective treatments for chronic PH in these patients remain largely limited. To better understand the pathophysiological mechanisms and to develop new therapies, several animal models for neonatal PVD and pulmonary hypertension, including a neonatal swine model with hypoxia-induced pulmonary hypertension, have already been established (Plunkett et al 1996;Scarborough et al 1998;Perreault et al 2001;Binns-Loveman et al 2005;Fike et al 2005Fike et al , 2015Ananthakrishnan et al 2009;Camelo et al 2012). Swine lungs share many anatomical, histological, biochemical, and physiological features with human lungs (Rogers et al 2008) and the relevance of the developing pulmonary circulation of neonatal piglets to human infants has been established already in the early '80s Hislop 1981, 1982).…”

Section: Animal Modelmentioning

confidence: 99%

Changes in the nitric oxide pathway of the pulmonary vasculature after exposure to hypoxia in swine model of neonatal pulmonary vascular disease

et al. 2018

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Neonatal pulmonary vascular disease (PVD) is increasingly recognized as a disease that complicates the cardiopulmonary adaptations after birth and predisposes to long‐term cardiopulmonary disease. There is growing evidence that PVD is associated with disruptions in the nitric oxide (NO)‐cGMP‐phosphodiesterase 5 (PDE5) pathway. Examination of the functionality of different parts of this pathway is required for better understanding of the pathogenesis of neonatal PVD. For this purpose, the role of the NO‐cGMP‐PDE5 pathway in regulation of pulmonary vascular function was investigated in vivo, both at rest and during exercise, and in isolated pulmonary small arteries in vitro, in a neonatal swine model with hypoxia‐induced PVD. Endothelium‐dependent vasodilatation was impaired in piglets with hypoxia‐induced PVD both in vivo at rest and in vitro. Moreover, the responsiveness to the NO‐donor SNP was reduced in hypoxia‐exposed piglets in vivo, while the relaxation to SNP and 8‐bromo‐cyclicGMP in vitro were unaltered. Finally, PDE5 inhibition‐induced pulmonary vasodilatation was impaired in hypoxia‐exposed piglets both in vitro and in vivo at rest. During exercise, however, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in hypoxia‐exposed as compared to normoxia‐exposed piglets. In conclusion, the impaired endothelium‐dependent vasodilatation in piglets with hypoxia‐induced PVD was accompanied by reduced responsiveness to NO, potentially caused by altered sensitivity and/or activity of soluble guanylyl cyclase (sGC), resulting in an impaired cGMP production. Our findings in a newborn animal model for neonatal PVD suggests that sGC stimulators/activators may be a novel treatment strategy to alleviate neonatal PVD.

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Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

Cited by 6 publications

References 39 publications

Structural and functional changes of the pulmonary vasculature after hypoxia exposure in the neonatal period - a new swine model of pulmonary vascular disease

Structural and functional changes of the pulmonary vasculature after hypoxia exposure in the neonatal period - a new swine model of pulmonary vascular disease

Comparative transcriptomic analysis revealed adaptation mechanism of Phrynocephalus erythrurus, the highest altitude Lizard living in the Qinghai-Tibet Plateau

Changes in the nitric oxide pathway of the pulmonary vasculature after exposure to hypoxia in swine model of neonatal pulmonary vascular disease

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