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Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition
Chronic intermittent hypoxia (CIH), the main attribute of obstructive sleep apnea (OSA), produces oxidative stress, endothelial dysfunction, and hypertension. Nitric oxide (NO) plays a critical role in controlling the vasomotor tone. The NO level depends on the L-arginine level, which can be reduced...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066978/ https://www.ncbi.nlm.nih.gov/pubmed/30087615 http://dx.doi.org/10.3389/fphys.2018.00901 |
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author | Krause, Bernardo J. Casanello, Paola Dias, Ana C. Arias, Paulina Velarde, Victoria Arenas, German A. Preite, Marcelo D. Iturriaga, Rodrigo |
author_facet | Krause, Bernardo J. Casanello, Paola Dias, Ana C. Arias, Paulina Velarde, Victoria Arenas, German A. Preite, Marcelo D. Iturriaga, Rodrigo |
author_sort | Krause, Bernardo J. |
collection | PubMed |
description | Chronic intermittent hypoxia (CIH), the main attribute of obstructive sleep apnea (OSA), produces oxidative stress, endothelial dysfunction, and hypertension. Nitric oxide (NO) plays a critical role in controlling the vasomotor tone. The NO level depends on the L-arginine level, which can be reduced by arginase enzymatic activity, and its reaction with the superoxide radical to produce peroxynitrite. Accordingly, we hypothesized whether a combination of an arginase inhibitor and an antioxidant may restore the endothelial function and reduced arterial blood pressure (BP) in CIH-induced hypertensive rats. Male Sprague-Dawley rats 200 g were exposed either to CIH (5% O(2), 12 times/h 8 h/day) or sham condition for 35 days. BP was continuously measured by radio-telemetry in conscious animals. After 14 days, rats were treated with 2(S)-amino-6-boronohexanoic acid (ABH 400 μg/kg day, osmotic pump), N-acetylcysteine (NAC 100 mg/kg day, drinking water), or the combination of both drugs until day 35. At the end of the experiments, external carotid and femoral arteries were isolated to determine vasoactive contractile responses induced by KCL and acetylcholine (ACh) with wire-myography. CIH-induced hypertension (~8 mmHg) was reverted by ABH, NAC, and ABH/NAC administration. Carotid arteries from CIH-treated rats showed higher contraction induced by KCl (3.4 ± 0.4 vs. 2.4 ± 0.2 N/m(2)) and diminished vasorelaxation elicits by ACh compared to sham rats (12.8 ± 1.5 vs. 30.5 ± 4.6%). ABH reverted the increased contraction (2.5 ± 0.2 N/m(2)) and the reduced vasorelaxation induced by ACh in carotid arteries from CIH-rats (38.1 ± 4.9%). However, NAC failed to revert the enhanced vasocontraction (3.9 ± 0.6 N/m(2)) induced by KCl and the diminished ACh-induced vasorelaxation in carotid arteries (10.7 ± 0.8%). Femoral arteries from CIH rats showed an increased contractile response, an effect partially reverted by ABH, but completely reverted by NAC and ABH/NAC. The impaired endothelial-dependent relaxation in femoral arteries from CIH rats was reverted by ABH and ABH/NAC. In addition, ABH/NAC at high doses had no effect on liver and kidney gross morphology and biochemical parameters. Thus, although ABH, and NAC alone and the combination of ABH/NAC were able to normalize the elevated BP, only the combined treatment of ABH/NAC normalized the vascular reactivity and the systemic oxidative stress in CIH-treated rats. |
format | Online Article Text |
id | pubmed-6066978 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60669782018-08-07 Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition Krause, Bernardo J. Casanello, Paola Dias, Ana C. Arias, Paulina Velarde, Victoria Arenas, German A. Preite, Marcelo D. Iturriaga, Rodrigo Front Physiol Physiology Chronic intermittent hypoxia (CIH), the main attribute of obstructive sleep apnea (OSA), produces oxidative stress, endothelial dysfunction, and hypertension. Nitric oxide (NO) plays a critical role in controlling the vasomotor tone. The NO level depends on the L-arginine level, which can be reduced by arginase enzymatic activity, and its reaction with the superoxide radical to produce peroxynitrite. Accordingly, we hypothesized whether a combination of an arginase inhibitor and an antioxidant may restore the endothelial function and reduced arterial blood pressure (BP) in CIH-induced hypertensive rats. Male Sprague-Dawley rats 200 g were exposed either to CIH (5% O(2), 12 times/h 8 h/day) or sham condition for 35 days. BP was continuously measured by radio-telemetry in conscious animals. After 14 days, rats were treated with 2(S)-amino-6-boronohexanoic acid (ABH 400 μg/kg day, osmotic pump), N-acetylcysteine (NAC 100 mg/kg day, drinking water), or the combination of both drugs until day 35. At the end of the experiments, external carotid and femoral arteries were isolated to determine vasoactive contractile responses induced by KCL and acetylcholine (ACh) with wire-myography. CIH-induced hypertension (~8 mmHg) was reverted by ABH, NAC, and ABH/NAC administration. Carotid arteries from CIH-treated rats showed higher contraction induced by KCl (3.4 ± 0.4 vs. 2.4 ± 0.2 N/m(2)) and diminished vasorelaxation elicits by ACh compared to sham rats (12.8 ± 1.5 vs. 30.5 ± 4.6%). ABH reverted the increased contraction (2.5 ± 0.2 N/m(2)) and the reduced vasorelaxation induced by ACh in carotid arteries from CIH-rats (38.1 ± 4.9%). However, NAC failed to revert the enhanced vasocontraction (3.9 ± 0.6 N/m(2)) induced by KCl and the diminished ACh-induced vasorelaxation in carotid arteries (10.7 ± 0.8%). Femoral arteries from CIH rats showed an increased contractile response, an effect partially reverted by ABH, but completely reverted by NAC and ABH/NAC. The impaired endothelial-dependent relaxation in femoral arteries from CIH rats was reverted by ABH and ABH/NAC. In addition, ABH/NAC at high doses had no effect on liver and kidney gross morphology and biochemical parameters. Thus, although ABH, and NAC alone and the combination of ABH/NAC were able to normalize the elevated BP, only the combined treatment of ABH/NAC normalized the vascular reactivity and the systemic oxidative stress in CIH-treated rats. Frontiers Media S.A. 2018-07-24 /pmc/articles/PMC6066978/ /pubmed/30087615 http://dx.doi.org/10.3389/fphys.2018.00901 Text en Copyright © 2018 Krause, Casanello, Dias, Arias, Velarde, Arenas, Preite and Iturriaga. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Krause, Bernardo J. Casanello, Paola Dias, Ana C. Arias, Paulina Velarde, Victoria Arenas, German A. Preite, Marcelo D. Iturriaga, Rodrigo Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition |
title | Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition |
title_full | Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition |
title_fullStr | Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition |
title_full_unstemmed | Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition |
title_short | Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition |
title_sort | chronic intermittent hypoxia-induced vascular dysfunction in rats is reverted by n-acetylcysteine supplementation and arginase inhibition |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066978/ https://www.ncbi.nlm.nih.gov/pubmed/30087615 http://dx.doi.org/10.3389/fphys.2018.00901 |
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