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Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis

Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffec...

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Autores principales: van Duin, Richard W. B., Stam, Kelly, Uitterdijk, André, Bartelds, Beatrijs, Danser, A. H. Jan, Reiss, Irwin K. M., Duncker, Dirk J., Merkus, Daphne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723751/
https://www.ncbi.nlm.nih.gov/pubmed/31409013
http://dx.doi.org/10.3390/jcm8081204
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author van Duin, Richard W. B.
Stam, Kelly
Uitterdijk, André
Bartelds, Beatrijs
Danser, A. H. Jan
Reiss, Irwin K. M.
Duncker, Dirk J.
Merkus, Daphne
author_facet van Duin, Richard W. B.
Stam, Kelly
Uitterdijk, André
Bartelds, Beatrijs
Danser, A. H. Jan
Reiss, Irwin K. M.
Duncker, Dirk J.
Merkus, Daphne
author_sort van Duin, Richard W. B.
collection PubMed
description Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP/HF vs. HP/LF territories. Swine underwent pulmonary vein banding (PVB; n = 7) or sham surgery (n = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP/LF and HP/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP/LF and HP/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP/HF and sensitivity to bradykinin was lower in PVB HP/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP/HF vs. HP/LF vasculature.
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spelling pubmed-67237512019-09-10 Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis van Duin, Richard W. B. Stam, Kelly Uitterdijk, André Bartelds, Beatrijs Danser, A. H. Jan Reiss, Irwin K. M. Duncker, Dirk J. Merkus, Daphne J Clin Med Article Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP/HF vs. HP/LF territories. Swine underwent pulmonary vein banding (PVB; n = 7) or sham surgery (n = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP/LF and HP/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP/LF and HP/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP/HF and sensitivity to bradykinin was lower in PVB HP/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP/HF vs. HP/LF vasculature. MDPI 2019-08-12 /pmc/articles/PMC6723751/ /pubmed/31409013 http://dx.doi.org/10.3390/jcm8081204 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
van Duin, Richard W. B.
Stam, Kelly
Uitterdijk, André
Bartelds, Beatrijs
Danser, A. H. Jan
Reiss, Irwin K. M.
Duncker, Dirk J.
Merkus, Daphne
Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis
title Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis
title_full Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis
title_fullStr Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis
title_full_unstemmed Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis
title_short Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis
title_sort intervening with the nitric oxide pathway to alleviate pulmonary hypertension in pulmonary vein stenosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723751/
https://www.ncbi.nlm.nih.gov/pubmed/31409013
http://dx.doi.org/10.3390/jcm8081204
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