Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures

Herrera, Emílio; Farías, Jorge G.; Ebensperger, Germán; Reyes, Roberto V.; Llanos, Aníbal J.; Castillo, Rodrigo

doi:10.1016/j.phrs.2015.07.011

Cited by 22 publications

(30 citation statements)

References 112 publications

(125 reference statements)

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“…Therefore, a blunted vasoconstrictor response to acute hypoxia, shown in the present study, is reversing the high-altitude phenotype and balancing the vasoactive tone toward vasodilation when challenged. This could be explained by 2 facts: first, the antiremodelling and functional effects that decreases vasoconstriction and second, by the decreased oxidative stress that favors vasodilation due to decreased iCa +2 influx (Sylvester et al, 2012 ; Herrera et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Twelve newborn sheep ( Ovis aries ) were gestated, born and studied at high altitude (INCAS Research Station, Putre, 3,600 m), and randomly divided in two groups. These animals develop PHN due to their development under chronic hypoxia at high altitude (Herrera et al, 2007 , 2015 ; Torres et al, 2015 ). The control group received vehicle (CN, n = 6, 1.4% ethanol 0.5 mL kg −1 ) and the treated group received a dose of melatonin (MN, n = 6, Melatonin 1 mg kg −1 in 1.4% ethanol 0.5 mL kg −1 ) in a daily fashion during 10 days (3–12 days old).…”

Section: Methodsmentioning

confidence: 99%

“…Further, it has been shown that hypoxia and oxidative stress play an important role in the development of the structural alterations associated with PHN (Herrera et al, 2007 , 2015 ; Torres et al, 2015 ). In physiological conditions, reactive oxygen species (ROS) may act as modulators for a wide range of cellular mechanisms (Dröge, 2002 ; Konduri et al, 2007 ; Murphy et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

et al. 2018

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Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN), a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs.Methods: Twelve lambs (Ovis aries) gestated and born at highlands (3,600 m) were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle) and 6 were treated with melatonin (MN, 1 mg.kg−1.d−1) during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations.Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05). This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05) and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05). Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05). Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05).Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

et al. 2018

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“…Pulmonary arteries also mount a maladaptive response to chronic hypoxia, known as pathological pulmonary arterial remodeling, characterized by the hyperplasic and hypertrophic thickening of medial layer and later thickening of adventitia and intima, with increased extracellular matrix deposition. An example of the later is the exposure to chronic hypoxia during pregnancy, early birth or adult life, resulting in pulmonary hypertension, a condition characterized by elevated pulmonary arterial mPAP and PVR, pathological pulmonary artery remodeling, often complicated with right ventricular hypertrophy and cardiac failure ( Herrera et al, 2015 ; Suresh and Shimoda, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Revisiting the Role of TRP, Orai, and ASIC Channels in the Pulmonary Arterial Response to Hypoxia

et al. 2018

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The pulmonary arteries are exquisitely responsive to oxygen changes. They rapidly and proportionally contract as arterial PO2 decrease, and they relax as arterial PO2 is re-established. The hypoxic pulmonary vasoconstriction (HPV) is intrinsic since it does not require neural or endocrine factors, as evidenced in isolated vessels. On the other hand, pulmonary arteries also respond to sustained hypoxia with structural and functional remodeling, involving growth of smooth muscle medial layer and later recruitment of adventitial fibroblasts, secreted mitogens from endothelium and changes in the response to vasoconstrictor and vasodilator stimuli. Hypoxic pulmonary arterial vasoconstriction and remodeling are relevant biological responses both under physiological and pathological conditions, to explain matching between ventilation and perfusion, fetal to neonatal transition of pulmonary circulation and pulmonary artery over-constriction and thickening in pulmonary hypertension. Store operated channels (SOC) and receptor operated channels (ROC) are plasma membrane cationic channels that mediate calcium influx in response to depletion of internal calcium stores or receptor activation, respectively. They are involved in both HPV and pathological remodeling since their pharmacological blockade or genetic suppression of several of the Stim, Orai, TRP, or ASIC proteins in SOC or ROC complexes attenuate the calcium increase, the tension development, the pulmonary artery smooth muscle proliferation, and pulmonary arterial hypertension. In this Mini Review, we discussed the evidence obtained in in vivo animal models, at the level of isolated organ or cells of pulmonary arteries, and we identified and discussed the questions for future research needed to validate these signaling complexes as targets against pulmonary hypertension.

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“…Animals subjected to various paradigms of acute IH become more resistant to the lethal injury induced by subsequent exposures to severe hypoxic insults [ 5 , 6 , 7 ]. For instance, when compared to controls, mice treated with brief episodes of low frequency IH (8% O 2 × 10 min/21% O 2 × 10 min, six cycles) showed attenuated cellular and tissue injury to crucial organs, such as the lung and the brain, relative to extended hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Cardiovascular Protection Associated with Intermittent Hypobaric Hypoxia Exposure in a Rat Model: Role of Oxidative Stress

Aguilar

Gonzaléz‐Candia

Rodríguez

et al. 2018

IJMS

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More than 140 million people live and works (in a chronic or intermittent form) above 2500 m worldwide and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 55,000 persons work in high altitude shifts, where stays at lowlands and interspersed with working stays at highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders, due to an increase in free radical formation and a decrease in antioxidant capacity. However, in animal models, intermittent hypoxia (IH) induce preconditioning, like responses and cardioprotection. Here, we aimed to describe in a rat model the responses on cardiac and vascular function to 4 cycles of intermittent hypobaric hypoxia (IHH). Twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH, and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days hypoxia + 4 days normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the first and fourth cycle, cardiac structural, and functional variables were determined by echocardiography. Thereafter, ex vivo vascular function and biomechanical properties were determined in femoral arteries by wire myography. We further measured cardiac oxidative stress biomarkers (4-Hydroxy-nonenal, HNE; nytrotirosine, NT), reactive oxygen species (ROS) sources (NADPH and mitochondrial), and antioxidant enzymes activity (catalase, CAT; glutathione peroxidase, GPx, and superoxide dismutase, SOD). Our results show a higher ejection and shortening fraction of the left ventricle function by the end of the 4th cycle. Further, femoral vessels showed an improvement of vasodilator capacity and diminished stiffening. Cardiac tissue presented a higher expression of antioxidant enzymes and mitochondrial ROS formation in IHH, as compared with normobaric hypoxic controls. IHH exposure determines a preconditioning effect on the heart and femoral artery, both at structural and functional levels, associated with the induction of antioxidant defence mechanisms. However, mitochondrial ROS generation was increased in cardiac tissue. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.

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Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures

Cited by 22 publications

References 112 publications

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

Revisiting the Role of TRP, Orai, and ASIC Channels in the Pulmonary Arterial Response to Hypoxia

Mechanisms of Cardiovascular Protection Associated with Intermittent Hypobaric Hypoxia Exposure in a Rat Model: Role of Oxidative Stress

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