scholarly journals Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Jesus Prieto-Lloret ◽  
Elena Olea ◽  
Ana Gordillo-Cano ◽  
Inmaculada Docio ◽  
Ana Obeso ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Carotid Body ◽  
Pulmonary Circulation ◽  
Intermittent Hypoxia ◽  
Pulmonary Arteries ◽  
Systemic Circulation ◽  
Systemic Hypertension ◽  
Chronic Intermittent Hypoxia ◽  
Respiratory Disorder ◽  
Obstructive Sleep

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

scholarly journals Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Esteban A. Moya ◽  
Paulina Arias ◽  
Carlos Varela ◽  
María P. Oyarce ◽  
Rodrigo Del Rio ◽  
...  
Keyword(s):  
Carotid Body ◽  
Reactive Nitrogen Species ◽  
Intermittent Hypoxia ◽  
Acute Hypoxia ◽  
Systemic Hypertension ◽  
Chronic Intermittent Hypoxia ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Obstructive Sleep

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO−scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2(266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO−formation.

scholarly journals Cardiac Response to Chronic Intermittent Hypoxia with a Transition from Adaptation to Maladaptation:The Role of Hydrogen Peroxide

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Xia Yin ◽  
Yang Zheng ◽  
Quan Liu ◽  
Jun Cai ◽  
Lu Cai
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Intermittent Hypoxia ◽  
Cardiac Response ◽  
Chronic Intermittent Hypoxia ◽  
Critical Element ◽  
Respiratory Disorder ◽  
Obstructive Sleep ◽  
Antioxidative Therapy

Obstructive sleep apnea (OSA) is a highly prevalent respiratory disorder of sleep, and associated with chronic intermittent hypoxia (CIH). Experimental evidence indicates that CIH is a unique physiological state with potentially “adaptive” and “maladaptive” consequences for cardio-respiratory homeostasis. CIH is also a critical element accounting for most of cardiovascular complications of OSA. Cardiac response to CIH is time-dependent, showing a transition from cardiac compensative (such as hypertrophy) to decompensating changes (such as failure). CIH-provoked mild and transient oxidative stress can induce adaptation, but severe and persistent oxidative stress may provoke maladaptation. Hydrogen peroxide as one of major reactive oxygen species plays an important role in the transition of adaptive to maladaptive response to OSA-associated CIH. This may account for the fact that although oxidative stress has been recognized as a driver of cardiac disease progression, clinical interventions with antioxidants have had little or no impact on heart disease and progression. Here we focus on the role of hydrogen peroxide in CIH and OSA, trying to outline the potential of antioxidative therapy in preventing CIH-induced cardiac damage.

scholarly journals Nitration of MnSOD in the Carotid Body and Adrenal Gland Induced by Chronic Intermittent Hypoxia

2018 ◽  
Vol 66 (10) ◽  
pp. 753-765
Author(s):  
Esteban A. Moya ◽  
Paulina Arias ◽  
Rodrigo Iturriaga
Keyword(s):  
Oxidative Stress ◽  
Adrenal Gland ◽  
Enzymatic Activity ◽  
Adrenal Medulla ◽  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Sprague Dawley ◽  
Obstructive Sleep ◽  
Key Enzyme

Chronic intermittent hypoxia (CIH), main feature of obstructive sleep apnea, produces nitro-oxidative stress, which contributes to potentiate carotid body (CB) chemosensory discharges and sympathetic-adrenal-axis activity, leading to hypertension. The MnSOD enzymatic activity, a key enzyme on oxidative stress control, is reduced by superoxide-induced nitration. However, the effects of CIH-induced nitration on MnSOD enzymatic activity in the CB and adrenal gland are not known. We studied the effects of CIH on MnSOD protein and immunoreactive (MnSOD-ir) levels in the CB, adrenal gland and superior cervical ganglion (SCG), and on 3-nitrotyrosine (3-NT-ir), CuZnSOD (CuZnSOD-ir), MnSOD nitration, and its enzymatic activity in the CB and adrenal gland from male Sprague-Dawley rats exposed to CIH for 7 days. CIH increased 3-NT-ir in CB and adrenal gland, whereas MnSOD-ir increased in the CB and in adrenal cortex, but not in the whole adrenal medulla or SCG. CIH nitrated MnSOD in the CB and adrenal medulla, but its activity decreased in the adrenal gland. CuZnSOD-ir remained unchanged in both tissues. All changes observed were prevented by ascorbic acid treatment. Present results show that CIH for 7 days produced MnSOD nitration, but failed to reduce its activity in the CB, because of the increased protein level.

Effect of TNF-α Blockage on Pulmonary Vasculature in Chronic Intermittent Hypoxia-Induced Pulmonary Hypertension: An Animal Model of Obstructive Sleep Apnea

CHEST Journal ◽  
2014 ◽  
Vol 146 (4) ◽  
pp. 856A
Author(s):  
Niwan Klinngam ◽  
Akeruetai Suwannakin ◽  
Sompol Sanguanrungsirikul ◽  
Poonchavist Chantranuwatana ◽  
Kittipong Maneechotesuwan ◽  
...  
Keyword(s):  
Animal Model ◽  
Obstructive Sleep Apnea ◽  
Pulmonary Hypertension ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Pulmonary Vasculature ◽  
Chronic Intermittent Hypoxia ◽  
Obstructive Sleep ◽  
Tnf Α

scholarly journals Effects of allergic airway inflammation and chronic intermittent hypoxia on systemic blood pressure

2020 ◽  
Vol 319 (5) ◽  
pp. R566-R574
Author(s):  
Ashish Chaddha ◽  
Oleg Broytman ◽  
Mihaela Teodorescu
Keyword(s):  
Blood Pressure ◽  
Pulmonary Function ◽  
Airway Inflammation ◽  
Intermittent Hypoxia ◽  
Systemic Blood Pressure ◽  
Brown Norway ◽  
Systemic Hypertension ◽  
Chronic Intermittent Hypoxia ◽  
Systemic Blood ◽  
Obstructive Sleep

Asthma and obstructive sleep apnea (OSA) are highly prevalent chronic conditions, and both are associated with systemic hypertension. Additionally, asthma and OSA reciprocally interact, mutually exacerbating each other. In this study, we tested the effect of allergen-induced lower airway inflammation and concurrent chronic intermittent hypoxia (CIH) on systemic blood pressure (BP), pulmonary function, and proinflammatory cytokines, in a rat model. Brown Norway rats were exposed to 43 days of normoxia (NORM) or CIH, concurrent with weekly house dust mite (HDM) challenges. BP was measured 1 day after the last HDM challenge. On day 44, pulmonary function was tested, and blood for Th-2 and Th-1 cytokine levels was collected. HDM significantly increased mean ( P = 0.002), systolic ( P = 0.003), and diastolic ( P = 0.004) BP compared with saline-challenged controls. Higher mean BP significantly correlated to increased total respiratory system resistance ( R2 = 0.266, P = 0.002), driven by an association with parenchymal tissue dampening ( R2 = 0.166, P = 0.016). HDM relative to saline-challenged controls increased the expression of serum IL-6 ( P = 0.008), but no relationships of systemic BP with IL-6 or any other cytokines were found. CIH did not alter the allergen-induced responses on BP, although it tended to increase the expression of serum IL-6 ( P = 0.06) and monocyte chemoattractant protein-1 (MCP-1, P = 0.09), regardless of HDM challenge. Chronic allergen-induced airway inflammation results in systemic hypertension that is correlated to the degree of distal airway obstruction induced by the allergen. These effects do not appear to be explained by the associated systemic inflammation.

scholarly journals Stim-activated TRPC-ORAI channels in pulmonary hypertension induced by chronic intermittent hypoxia

2020 ◽  
Vol 10 (1_suppl) ◽  
pp. 13-22
Author(s):  
Sebastian Castillo-Galán ◽  
German A. Arenas ◽  
Roberto V. Reyes ◽  
Bernardo J. Krause ◽  
Rodrigo Iturriaga
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Intermittent Hypoxia ◽  
Systolic Pressure ◽  
Transient Receptor Potential Channels ◽  
Chronic Intermittent Hypoxia ◽  
Ventricular Ejection Fraction ◽  
Pulmonary Vascular Remodeling ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA), a breathing disorder featured by chronic intermittent hypoxia (CIH) is associated with pulmonary hypertension (PH). Rodents exposed to CIH develop pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. Overexpression of Stim-activated Transient Receptor Potential Channels (TRPC) and Calcium Release-Activated Calcium Channel Protein (ORAI) TRPC-ORAI Ca2+ channels (STOC) has been involved in pulmonary vascular remodeling and PH in sustained hypoxia. However, it is not known if CIH may change STOC levels. Accordingly, we studied the effects of CIH on the expression of STOC subunits in the lung and if these changes paralleled the progression of the vascular pulmonary remodeling and PH in a preclinical model of OSA. Male Sprague-Dawley rats (∼200 g) were exposed to CIH (5%O2, 12 times/h for 8 h) for 14, 21, and 28 days. We measured right ventricular systolic pressure (RVSP), cardiac morphometry with MRI, pulmonary vascular remodeling, and wire-myographic arterial responses to KCl and endothelin-1 (ET-1). Pulmonary RNA and protein STOC levels of TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2, and STIM1 subunits were measured by qPCR and western blot, and results were compared with age-matched controls. CIH elicited a progressive increase of RVSP and vascular contractile responses to KCl and ET-1, leading to vascular remodeling and augmented right ventricular ejection fraction, which was significant at 28 days of CIH. The levels of TRPC1, TRPC4, TRPC 6, ORAI 1, and STIM 1 channels increased following CIH, and some of them paralleled morphologic and functional changes. Our findings show that CIH increased pulmonary STOC expression, paralleling vascular remodeling and PH.

scholarly journals Effects of Intermittent Hypoxia on Pulmonary Vascular and Systemic Diseases

2019 ◽  
Vol 16 (17) ◽  
pp. 3101 ◽  
Author(s):  
Hiroshi Kimura ◽  
Hiroyo Ota ◽  
Yuya Kimura ◽  
Shin Takasawa
Keyword(s):  
Insulin Resistance ◽  
Pulmonary Hypertension ◽  
Insulin Secretion ◽  
Sleep Apnea ◽  
Pulmonary Circulation ◽  
Intermittent Hypoxia ◽  
Pathophysiological Mechanism ◽  
Cellular Mechanisms ◽  
Obstructive Sleep ◽  
Lifestyle Related Diseases

Obstructive sleep apnea (OSA) causes many systemic disorders via mechanisms related to sympathetic nerve activation, systemic inflammation, and oxidative stress. OSA typically shows repeated sleep apnea followed by hyperventilation, which results in intermittent hypoxia (IH). IH is associated with an increase in sympathetic activity, which is a well-known pathophysiological mechanism in hypertension and insulin resistance. In this review, we show the basic and clinical significance of IH from the viewpoint of not only systemic regulatory mechanisms focusing on pulmonary circulation, but also cellular mechanisms causing lifestyle-related diseases. First, we demonstrate how IH influences pulmonary circulation to cause pulmonary hypertension during sleep in association with sleep state-specific change in OSA. We also clarify how nocturnal IH activates circulating monocytes to accelerate the infiltration ability to vascular wall in OSA. Finally, the effects of IH on insulin secretion and insulin resistance are elucidated by using an in vitro chamber system that can mimic and manipulate IH. The obtained data implies that glucose-induced insulin secretion (GIS) in pancreatic β cells is significantly attenuated by IH, and that IH increases selenoprotein P, which is one of the hepatokines, as well as TNF-α, CCL-2, and resistin, members of adipokines, to induce insulin resistance via direct cellular mechanisms. Clinical and experimental findings concerning IH give us productive new knowledge of how lifestyle-related diseases and pulmonary hypertension develop during sleep.

scholarly journals Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia

2014 ◽  
Vol 117 (7) ◽  
pp. 765-776 ◽  
Author(s):  
Mi-Kyung Shin ◽  
Qiaoling Yao ◽  
Jonathan C. Jun ◽  
Shannon Bevans-Fonti ◽  
Doo-Young Yoo ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Fasting Blood Glucose ◽  
Whole Body ◽  
Chronic Intermittent Hypoxia ◽  
Glucose Flux ◽  
Obstructive Sleep ◽  
Glucose Output ◽  
Carotid Body Denervation

Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH. Male C57BL/6J mice underwent carotid sinus nerve dissection (CSND) or sham surgery and then were exposed to IH or intermittent air (IA) for 4 or 6 wk. Hypoxia was administered by decreasing a fraction of inspired oxygen from 20.9% to 6.5% once per minute, during the 12-h light phase (9 a.m.–9 p.m.). As expected, denervated mice exhibited blunted hypoxic ventilatory responses. In sham-operated mice, IH increased fasting blood glucose, baseline hepatic glucose output (HGO), and expression of a rate-liming hepatic enzyme of gluconeogenesis phospho enolpyruvate carboxykinase (PEPCK), whereas the whole body glucose flux during hyperinsulinemic euglycemic clamp was not changed. IH did not affect glucose tolerance after adjustment for fasting hyperglycemia in the intraperitoneal glucose tolerance test. CSND prevented IH-induced fasting hyperglycemia and increases in baseline HGO and liver PEPCK expression. CSND trended to augment the insulin-stimulated glucose flux and enhanced liver Akt phosphorylation at both hypoxic and normoxic conditions. IH increased serum epinephrine levels and liver sympathetic innervation, and both increases were abolished by CSND. We conclude that chronic IH induces fasting hyperglycemia increasing baseline HGO via the CSN sympathetic output from carotid body chemoreceptors, but does not significantly impair whole body insulin sensitivity.

scholarly journals Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 155
Author(s):  
Daniel Morales-Cano ◽  
Bianca Barreira ◽  
Beatriz De Olaiz Navarro ◽  
María Callejo ◽  
Gema Mondejar-Parreño ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Gas Exchange ◽  
Pulmonary Circulation ◽  
Pulmonary Arteries ◽  
Blood Perfusion ◽  
Mesenteric Arteries ◽  
Oxygen Sensitivity ◽  
Low Oxygen ◽  
Oxygen Selectivity

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

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