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1.
Front Physiol ; 13: 864010, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35733986

RESUMO

Neonatal pulmonary hypertension (NPHT) is produced by sustained pulmonary vasoconstriction and increased vascular remodeling. Soluble guanylyl cyclase (sGC) participates in signaling pathways that induce vascular vasodilation and reduce vascular remodeling. However, when sGC is oxidized and/or loses its heme group, it does not respond to nitric oxide (NO), losing its vasodilating effects. sGC protein expression and function is reduced in hypertensive neonatal lambs. Currently, NPHT is treated with NO inhalation therapy; however, new treatments are needed for improved outcomes. We used Cinaciguat (BAY-582667), which activates oxidized and/or without heme group sGC in pulmonary hypertensive lambs studied at 3,600 m. Our study included 6 Cinaciguat-treated (35 ug kg-1 day-1 x 7 days) and 6 Control neonates. We measured acute and chronic basal cardiovascular variables in pulmonary and systemic circulation, cardiovascular variables during a superimposed episode of acute hypoxia, remodeling of pulmonary arteries and changes in the right ventricle weight, vasoactive functions in small pulmonary arteries, and expression of NO-sGC-cGMP signaling pathway proteins involved in vasodilation. We observed a decrease in pulmonary arterial pressure and vascular resistance during the acute treatment. In contrast, the pulmonary pressure did not change in the chronic study due to increased cardiac output, resulting in lower pulmonary vascular resistance in the last 2 days of chronic study. The latter may have had a role in decreasing right ventricular hypertrophy, although the direct effect of Cinaciguat on the heart should also be considered. During acute hypoxia, the pulmonary vascular resistance remained low compared to the Control lambs. We observed a higher lung artery density, accompanied by reduced smooth muscle and adventitia layers in the pulmonary arteries. Additionally, vasodilator function was increased, and vasoconstrictor function was decreased, with modifications in the expression of proteins linked to pulmonary vasodilation, consistent with low pulmonary vascular resistance. In summary, Cinaciguat, an activator of sGC, induces cardiopulmonary modifications in chronically hypoxic and pulmonary hypertensive newborn lambs. Therefore, Cinaciguat is a potential therapeutic tool for reducing pulmonary vascular remodeling and/or right ventricular hypertrophy in pulmonary arterial hypertension syndrome.

2.
Vascul Pharmacol ; 144: 106971, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35150933

RESUMO

BACKGROUND: Fetal chronic hypoxia is associated with blood flow redistribution and oxidative damage in the brain, leading to increased perinatal morbimortality. Melatonin reduces oxidative stress, improves vascular function, and has neuroprotective effects. OBJECTIVES: This study aimed to determine the effects of an oral melatonin treatment to pregnant ewes at high-altitude, on the cerebrovascular function of their neonates. STUDY DESIGN: Ten high-altitude pregnant sheep received either vehicle or melatonin (10 mg/d) during the last third of gestation until delivery. Postnatal daily hemodynamic measurements were recorded from lambs until 12 days old. In addition, lambs were submitted to a graded oxygenation protocol to assess cerebrovascular responses. Subsequently, lambs were euthanized, and middle cerebral arteries (MCA) were collected for vascular function, protein levels, and morphostructural analyses. RESULTS: Antenatal treatment doubled plasma levels of melatonin in pregnant ewes. Melatonin increased carotid flow and decreased carotid vascular resistance in the lambs by the end of the first week. Furthermore, melatonin increased MCA's maximal vasoconstrictor and vasodilator responses, associated with nitric oxide-dependent and independent mechanisms. CONCLUSIONS: An oral treatment with melatonin during pregnancy promotes postnatal cerebral perfusion in chronically hypoxic neonates. Melatonin is a potential treatment for cerebrovascular dysfunction due to perinatal chronic hypoxia.


Assuntos
Melatonina , Animais , Antioxidantes/farmacologia , Feminino , Hipóxia/tratamento farmacológico , Pulmão , Melatonina/farmacologia , Estresse Oxidativo , Gravidez , Ovinos
3.
Antioxidants (Basel) ; 10(11)2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34829529

RESUMO

Pulmonary arterial hypertension of newborns (PAHN) constitutes a critical condition involving both severe cardiac remodeling and right ventricle dysfunction. One main cause of this condition is perinatal hypoxia and oxidative stress. Thus, it is a public health concern for populations living above 2500 m and in cases of intrauterine chronic hypoxia in lowlands. Still, pulmonary and cardiac impairments in PAHN lack effective treatments. Previously we have shown the beneficial effects of neonatal melatonin treatment on pulmonary circulation. However, the cardiac effects of this treatment are unknown. In this study, we assessed whether melatonin improves cardiac function and modulates right ventricle (RV) oxidative stress. Ten lambs were gestated, born, and raised at 3600 m. Lambs were divided in two groups. One received daily vehicle as control, and another received daily melatonin (1 mg·kg-1·d-1) for 21 days. Daily cardiovascular measurements were recorded and, at 29 days old, cardiac tissue was collected. Melatonin decreased pulmonary arterial pressure at the end of the experimental period. In addition, melatonin enhanced manganese superoxide dismutase and catalase (CAT) expression, while increasing CAT activity in RV. This was associated with a decrease in superoxide anion generation at the mitochondria and NADPH oxidases in RV. Finally, these effects were associated with a marked decrease of oxidative stress markers in RV. These findings support the cardioprotective effects of an oral administration of melatonin in newborns that suffer from developmental chronic hypoxia.

4.
Front Physiol ; 12: 697211, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421636

RESUMO

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 (R MAX) and potency (EC50) to potassium, noradrenaline (NA), and phenylephrine (PHE) were larger in HA-NBLL than LA-NBLL. R MAX 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.

5.
Vascul Pharmacol ; 138: 106853, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33766627

RESUMO

Pulmonary arterial hypertension of the newborn (PAHN) is a syndrome caused by chronic hypoxia, characterized by decreased vasodilator function, a marked vasoconstrictor activity, proliferation of smooth muscle cells (SMC) and thickening of the extracellular matrix in the pulmonary circulation, among other characteristics. Prostaglandins are derived from the arachidonic acid (AA) metabolism and are important regulators of pulmonary vascular tone. Since hypoxia induces oxidative stress and has been related to PAHN, a postnatal treatment with melatonin has been proposed due to its antioxidant properties. Here, we determined the effects of melatonin on pulmonary vascular homeostasis given by prostanoids. Ten PAHN newborn lambs were divided in two groups and treated either with vehicle or melatonin. After 1 week of treatment, we assessed pulmonary vascular prostanoids function and expression by wire myography, RT-PCR, Western Blot and immunohistochemistry. Melatonin improved in vivo and ex vivo pulmonary vasodilation. This was associated with an increased function and expression of vasodilator prostanoids at the expense of vasoconstrictor prostanoids. Our study demonstrates for the first time that melatonin may enhance the vasodilator prostanoid pathway in PAHN.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Melatonina/farmacologia , Prostaglandinas/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Animais Recém-Nascidos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Carneiro Doméstico , Transdução de Sinais
6.
Front Physiol ; 12: 765281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35082688

RESUMO

Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg-1] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.

7.
Front Bioeng Biotechnol ; 8: 590488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33244466

RESUMO

In this study, we assessed the effects of Atrial Natriuretic Peptide (ANP) and Cinaciguat, as experimental medicines to treat neonatal lambs exposed to chronic hypoxic conditions. To compare the different treatments, the mechanical responses of aorta, carotid, and femoral arterial walls were analyzed by means of axial pre-stretch and ring-opening tests, through a study with n = 6 animals for each group analyzed. The axial pre-stretch test measures the level of shortening in different zones of the arteries when extracted from lambs, while the ring-opening test is used to quantify the degree of residual circumferential deformation in a given zone of an artery. In addition, histological studies were carried out to measure elastin, collagen, and smooth muscle cell (SMC) nuclei densities, both in control and treated groups. The results show that mechanical response is related with histological results, specifically in the proximal abdominal aorta (PAA) and distal carotid zones (DCA), where the cell nuclei content is related to a decrease of residual deformations. The opening angle and the elastic fibers of the aorta artery were statistically correlated (p < 0.05). Specifically, in PAA zone, there are significant differences of opening angle and cell nuclei density values between control and treated groups (p-values to opening angle: Control-ANP = 2 ⋅ 10-2, Control-Cinaciguat = 1 ⋅ 10-2; p-values to cell nuclei density: Control-ANP = 5 ⋅ 10-4, Control-Cinaciguat = 2 ⋅ 10-2). Respect to distal carotid zone (DCA), significant differences between Control and Cinaciguat groups were observed to opening angle (p-value = 4 ⋅ 10-2), and cell nuclei density (p-value = 1 ⋅ 10-2). Our findings add evidence that medical treatments may have effects on the mechanical responses of arterial walls and should be taken into account when evaluating the complete medical outcome.

8.
J Dev Orig Health Dis ; 11(5): 452-463, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32705972

RESUMO

Chronic hypoxia during gestation induces greater occurrence of perinatal complications such as intrauterine growth restriction, fetal hypoxia, newborn asphyxia, and respiratory distress, among others. This condition may also cause a failure in the transition of the fetal to neonatal circulation, inducing pulmonary arterial hypertension of the neonate (PAHN), a syndrome that involves pulmonary vascular dysfunction, increased vasoconstrictor tone and pathological remodeling. As this syndrome has a relatively low prevalence in lowlands (~7 per 1000 live births) and very little is known about its prevalence and clinical evolution in highlands (above 2500 meters), our understanding is very limited. Therefore, studies on appropriate animal models have been crucial to comprehend the mechanisms underlying this pathology. Considering the strengths and weaknesses of any animal model of human disease is fundamental to achieve an effective and meaningful translation to clinical practice. The sheep model has been used to study the normal and abnormal cardiovascular development of the fetus and the neonate for almost a century. The aim of this review is to highlight the advances in our knowledge on the programming of cardiopulmonary function with the use of high-altitude newborn sheep as a translational model of PAHN.


Assuntos
Altitude , Desenvolvimento Fetal/fisiologia , Hipóxia Fetal/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Hipertensão Arterial Pulmonar/etiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hipóxia Fetal/fisiopatologia , Coração/embriologia , Coração/fisiopatologia , Humanos , Recém-Nascido , Pulmão/embriologia , Pulmão/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipertensão Arterial Pulmonar/prevenção & controle , Ovinos
9.
J Pineal Res ; 68(1): e12613, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31583753

RESUMO

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg-1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K+ , TX2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.


Assuntos
Pressão Arterial/efeitos dos fármacos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/metabolismo , Melatonina , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Melatonina/administração & dosagem , Melatonina/farmacocinética , Melatonina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ovinos , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologia
10.
Rev Med Chil ; 147(3): 281-288, 2019 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-31344164

RESUMO

BACKGROUND: Living above 2,500 meters in hypobaric conditions induces pulmonary arterial hypertension of the neonate (PAHN), a syndrome whose main features are: pathological remodeling of the pulmonary vessels, abnormal vascular reactivity and increased oxidative stress. Melatonin could have pulmonary antioxidant, anti-remodeling and vasodilating properties for this condition. AIM: To determine the effect of melatonin at the transcript level of prostanoid pathways in the lung of neonatal lambs gestated and born under hypobaric hypoxia. MATERIAL AND METHODS: Vehicle (1.4% of ethanol, n = 6) or melatonin (1 mg * kg1, n = 5) were administered from the postnatal day 4 to 21 to lambs gestated and born at 3,600 meters above sea level. After one week of treatment completion, lung tissue was obtained, the transcript and protein levels of prostanoid synthases and receptors were assessed by RT-PCR and Western Blot. RESULTS: Melatonin induced the expression of prostacyclin synthase transcript and increased protein expression of the prostacyclin receptor. In addition, the treatment decreased the expression of transcript and protein of cyclooxygenase-2, without changes in the expression of the prostanoid vasoconstrictor (thromboxane) pathway. CONCLUSIONS: Postnatal treatment with melatonin increases the expression of the prostacyclin-vasodilator pathway without changing the vasoconstrictor thromboxane pathway. Further, the decreased COX-2 induced by melatonin could be an index of lesser oxidative stress and inflammation in the lung.


Assuntos
Antioxidantes/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Melatonina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Prostaglandinas/metabolismo , Animais , Animais Recém-Nascidos , Hipertensão Pulmonar/metabolismo , Hipóxia , Artéria Pulmonar/efeitos dos fármacos , Ovinos
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