Role of the α-adrenergic system in femoral vascular reactivity in neonatal llamas and sheep: a comparative study between highland and lowland species

Moraga, Fernando A.; Reyes, Roberto V.; Herrera, Emílio; Riquelme, Raquel; Ebensperger, Germán; Pulgar, Víctor M.; Parer, Julian T.; Giussani, Dino A.; Llanos, Aníbal J.

doi:10.1152/ajpregu.00124.2010

Cited by 12 publications

(26 citation statements)

References 39 publications

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“…Specific primers used for sequence detection were ROCKI (forward 5=-CCACCAGGAAGGTGTACGCTATGA-3=, reverse 5=-AATCGGGCCCATTTTTCA GGCACG-3=), ROCKII (forward 5=-GCCCGGTTAAGGAAAACACAGGCA-3=, reverse 5=-TC-CATGGGTTCGGTCCCTCCT-3=), RhoA (forward 5=-ACGAC-GAGCACACAAGGCGG-3=, reverse 5=-ACGTCTGGCTTGCA-GAGCAGC-3=) all designed using Primer3 software. PKG and 18S primers have been previously described (16,33). Expected size products were ROCKI 241 bp, ROCKII 177 bp, RhoA 182 bp, PKG 253 bp, and 18S-rRNA 152 bp.…”

Section: Methodsmentioning

confidence: 99%

Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

López

Ebensperger

Herrera

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Exposure to high-altitude chronic hypoxia during pregnancy may cause pulmonary hypertension in neonates, as a result of vasoconstriction and vascular remodeling. We hypothesized that susceptibility to pulmonary hypertension, due to an augmented expression and activity of the RhoA/Rho-kinase (ROCK) pathway in these neonates, can be reduced by daily administration of fasudil, a ROCK inhibitor. We studied 10 highland newborn lambs with conception, gestation, and birth at 3,600 m in Putre, Chile. Five highland controls (HLC) were compared with 5 highland lambs treated with fasudil (HL-FAS; 3 mg·kg(-1)·day(-1) iv for 10 days). Ten lowland controls were studied in Lluta (50 m; LLC). During the 10 days of fasudil daily administration, the drug decreased pulmonary arterial pressure (PAP) and resistance (PVR), basally and during a superimposed episode of acute hypoxia. HL-FAS small pulmonary arteries showed diminished muscular area and a reduced contractile response to the thromboxane analog U46619 compared with HLC. Hypoxia, but not fasudil, changed the protein expression pattern of the RhoA/ROCKII pathway. Moreover, HL-FAS lungs expressed less pMYPT1(T850) and pMYPT1T(696) than HLC, with a potential increase of the myosin light chain phosphatase activity. Finally, hypoxia induced RhoA, ROCKII, and PKG mRNA expression in PASMCs of HLC, but fasudil reduced them (HL-FAS) similarly to LLC. We conclude that fasudil decreases the function of the RhoA/ROCK pathway, reducing the PAP and PVR in chronically hypoxic highland neonatal lambs. The inhibition of ROCKs by fasudil may offer a possible therapeutic tool for the pulmonary hypertension of the neonates.

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Section: Methodsmentioning

confidence: 99%

Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

López

Ebensperger

Herrera

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…One such species is the llama ( Lama glama ), which developed efficient protective mechanisms to avoid maladaptation resulting from chronic hypoxia, such as a decreased hormonal vasoconstrictor response, an increased blood hemoglobin concentration, decreased cerebral O 2 consumption, and increased Lactate Dehydrogenase activity (Llanos et al, 2003 ; Ebensperger et al, 2005 ). The llama possesses an attenuated cardiovascular response to hypoxia, which prevents the development of pulmonary hypertension and arteriolar muscle remodeling (Harris et al, 1982 ; Moraga et al, 2011 ). Contrary to llamas, newborn sheep gestated and born at high altitude have marked pulmonary hypertension compared to their counterparts (Llanos et al, 2011a ).…”

Section: Introductionmentioning

confidence: 99%

Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia

et al. 2018

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There are animal species that have adapted to life at high altitude and hypobaric hypoxia conditions in the Andean highlands. One such species is the llama (Lama glama), which seem to have developed efficient protective mechanisms to avoid maladaptation resulting from chronic hypoxia, such as a resistance to the development of hypoxia -induced pulmonary hypertension. On the other hand, it is widely known that different models of hypertension can arise as a result of changes in endothelial function. The respect, one of the common causes of deregulation in endothelial vasodilator function have been associated with down-regulation of the NO synthesis and an increase in plasma levels of asymmetric dimethylarginine (ADMA) and homocysteine. Additionally, it is also known that NO production can be regulated by plasma levels of L-arginine as a result of the competition between nitric oxide synthase (NOS) and arginase. The objective of this study, was to determine the baseline concentrations of ADMA and homocysteine in llama, and to evaluate their effect on the arginase pathway and their involvement in the resistance to the development of altitude-induced pulmonary hypertension. METHOD: Lowland and highland newborn sheep and llama were investigated near sea level and at high altitude. Blood determinations of arterial blood gases, ADMA and homocysteíne are made and the effect of these on the arginase activity was evaluated. RESULTS: The basal concentrations of ADMA and homocysteine were determined in llama, and they were found to be significantly lower than those found in other species and in addition, the exposure to hypoxia is unable to increase its concentration. On the other hand, it was observed that the llama exhibited 10 times less arginase II activity as compared to sheep, and the expression was not induced by hypoxia. Finally, ADMA y Hcy, has no effect on the type II arginase pathway. CONCLUSION: Based on our results, we propose that low concentrations of ADMA and homocysteine found in llamas, the low expression of arginase type II, DDAH-2 and CBS, as well as its insensitivity to activation by homocysteine could constitute an adaptation mechanism of these animals to the hypoxia.

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“…The proposed mechanism suggests that PHE promotes α 1 -adrenoceptor activation in endothelium, increasing NO production that opposes vasoconstriction (Tuttle and Falcone, 2001;Raj and Subramani, 2016;Marconi et al, 2020). This result suggests different subtypes of α 1 -adrenoceptor with a specific location in the small femoral artery, one type of α 1 -adrenoceptor present in the endothelium, and other α 1 -adrenoceptors present in smooth muscle cells, as proposed by Moraga et al (2011).…”

Section: Potency To Potassium (Ec 50 )mentioning

confidence: 69%

“…The enhanced α-adrenergic vascular reactivity found in the HA NBLL is also observed in the fetal and neonatal llama at sea level (Giussani et al, 1999;Moraga et al, 2011;Reyes et al, 2020). The importance of the α-adrenergic signaling during acute hypoxia in the fetus is vital since its blockade causes cardiovascular collapse and death (Giussani et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Vasoconstriction Mediated by α1-Adrenergic Mechanisms in Small Femoral Arteries in Newborn Llama and Sheep Gestated at Low and High Altitudes

et al. 2021

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The authors previously demonstrated that newborn llama (NBLL) express high levels of α1 adrenergic receptors, which provide a potent vasoconstriction response when compared with newborn sheep (NBSH) gestated at sea level. However, data regarding the impact of chronic gestational hypobaric hypoxia on α-adrenergic vasoconstriction in the neonatal life has not been studied. We evaluated if gestation under chronic hypobaric hypoxia modifies α1-adrenergic vasoconstrictor function in NBLL and NBSH. We compared the vasoconstrictor response induced by potassium and α-adrenergic stimuli in isolated small femoral arteries of NBLL and NBSH gestated at high altitude (HA; 3,600 m) or low altitude (LA; 580 m). The maximal contraction (RMAX) and potency (EC50) to potassium, noradrenaline (NA), and phenylephrine (PHE) were larger in HA-NBLL than LA-NBLL. RMAX to potassium, NA, and PHE were lower in HA-NBSH when compared with LA-NBSH and potency results were similar. Competitive blockade with prazosin showed that RNLL LA/HA have a similar pA2. In contrast, NBSH had increased pA2 values in HA when compared with LA. Finally, small femoral arteries denudated or treated with LNAME in LA and HA lacked NO or endothelium participation in response to PHE stimulation. In contrast, NBSH displayed that denudation or blockade with LNAME support NO or endothelium participation in response to PHE activation. In conclusion, HA chronic hypoxia enhances α1 adrenergic receptor activity in small femoral arteries in NBLL to a higher degree than NBSH, implying a higher vasoconstriction function.

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Role of the α-adrenergic system in femoral vascular reactivity in neonatal llamas and sheep: a comparative study between highland and lowland species

Cited by 12 publications

References 39 publications

Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia

Enhanced Vasoconstriction Mediated by α1-Adrenergic Mechanisms in Small Femoral Arteries in Newborn Llama and Sheep Gestated at Low and High Altitudes

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