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Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching

INTRODUCTION: Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V’/Q’). Hypoxia is also a well-known modulator of the n...

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Autores principales: Chamorro, Virginia, Morales-Cano, Daniel, Milara, Javier, Barreira, Bianca, Moreno, Laura, Callejo, María, Mondejar-Parreño, Gema, Esquivel-Ruiz, Sergio, Cortijo, Julio, Cogolludo, Ángel, Barberá, Joan A., Perez-Vizcaino, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783366/
https://www.ncbi.nlm.nih.gov/pubmed/29364918
http://dx.doi.org/10.1371/journal.pone.0191239
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author Chamorro, Virginia
Morales-Cano, Daniel
Milara, Javier
Barreira, Bianca
Moreno, Laura
Callejo, María
Mondejar-Parreño, Gema
Esquivel-Ruiz, Sergio
Cortijo, Julio
Cogolludo, Ángel
Barberá, Joan A.
Perez-Vizcaino, Francisco
author_facet Chamorro, Virginia
Morales-Cano, Daniel
Milara, Javier
Barreira, Bianca
Moreno, Laura
Callejo, María
Mondejar-Parreño, Gema
Esquivel-Ruiz, Sergio
Cortijo, Julio
Cogolludo, Ángel
Barberá, Joan A.
Perez-Vizcaino, Francisco
author_sort Chamorro, Virginia
collection PubMed
description INTRODUCTION: Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V’/Q’). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized. MATERIALS AND METHODS: Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin. RESULTS: The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A(2) (TXA(2)) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V’/Q’ uncoupling and riociguat did not affect the V’/Q’ ratio. CONCLUSION: PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V’/Q’ coupling in a rat model of pulmonary fibrosis.
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spelling pubmed-57833662018-02-08 Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching Chamorro, Virginia Morales-Cano, Daniel Milara, Javier Barreira, Bianca Moreno, Laura Callejo, María Mondejar-Parreño, Gema Esquivel-Ruiz, Sergio Cortijo, Julio Cogolludo, Ángel Barberá, Joan A. Perez-Vizcaino, Francisco PLoS One Research Article INTRODUCTION: Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V’/Q’). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized. MATERIALS AND METHODS: Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin. RESULTS: The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A(2) (TXA(2)) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V’/Q’ uncoupling and riociguat did not affect the V’/Q’ ratio. CONCLUSION: PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V’/Q’ coupling in a rat model of pulmonary fibrosis. Public Library of Science 2018-01-24 /pmc/articles/PMC5783366/ /pubmed/29364918 http://dx.doi.org/10.1371/journal.pone.0191239 Text en © 2018 Chamorro et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chamorro, Virginia
Morales-Cano, Daniel
Milara, Javier
Barreira, Bianca
Moreno, Laura
Callejo, María
Mondejar-Parreño, Gema
Esquivel-Ruiz, Sergio
Cortijo, Julio
Cogolludo, Ángel
Barberá, Joan A.
Perez-Vizcaino, Francisco
Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
title Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
title_full Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
title_fullStr Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
title_full_unstemmed Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
title_short Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
title_sort riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783366/
https://www.ncbi.nlm.nih.gov/pubmed/29364918
http://dx.doi.org/10.1371/journal.pone.0191239
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