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Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice

Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechan...

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Autores principales: Beck, Lilliana, Pinilla, Estéfano, Arcanjo, Daniel Dias Rufino, Hernanz, Raquel, Prat-Duran, Judit, Petersen, Asbjørn Graver, Köhler, Ralf, Sheykhzade, Majid, Comerma-Steffensen, Simon, Simonsen, Ulf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906977/
https://www.ncbi.nlm.nih.gov/pubmed/33643042
http://dx.doi.org/10.3389/fphar.2020.619152
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author Beck, Lilliana
Pinilla, Estéfano
Arcanjo, Daniel Dias Rufino
Hernanz, Raquel
Prat-Duran, Judit
Petersen, Asbjørn Graver
Köhler, Ralf
Sheykhzade, Majid
Comerma-Steffensen, Simon
Simonsen, Ulf
author_facet Beck, Lilliana
Pinilla, Estéfano
Arcanjo, Daniel Dias Rufino
Hernanz, Raquel
Prat-Duran, Judit
Petersen, Asbjørn Graver
Köhler, Ralf
Sheykhzade, Majid
Comerma-Steffensen, Simon
Simonsen, Ulf
author_sort Beck, Lilliana
collection PubMed
description Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechanisms involved in the relaxant effect of pirfenidone in rat intrapulmonary arteries and coronary arteries from normal mice. Then in a second study, we investigated whether pirfenidone restores endothelial function in the aorta and mesenteric arteries from diabetic animals. From 16–18-week old normal male C57BL/6 mice and normoglycemic (db/db+), and type 2 diabetic (db/db) male and female mice, arteries were mounted in microvascular isometric myographs for functional studies, and immunoblotting was performed. In rat pulmonary arteries and mouse coronary arteries, pirfenidone induced relaxations, which were inhibited in preparations without endothelium. In mouse coronary arteries, pirfenidone relaxation was inhibited in the presence of a nitric oxide (NO) synthase inhibitor, N(G)-nitro-l-arginine (L-NOARG), a blocker of large-conductance calcium-activated potassium channels (BK(Ca)), iberiotoxin, and a blocker of K(V)7 channels, XE991. Patch clamp studies in vascular smooth muscle revealed pirfenidone increased iberiotoxin-sensitive current. In the aorta and mesenteric small arteries from diabetic db/db mice relaxations induced by the endothelium-dependent vasodilator, acetylcholine, were markedly reduced compared to db/db + mice. Pirfenidone enhanced the relaxations induced by acetylcholine in the aorta from diabetic male and female db/db mice. An opener of K(V)7 channels, flupirtine, had the same effect as pirfenidone. XE991 reduced the effect of pirfenidone and flupirtine and further reduced acetylcholine relaxations in the aorta. In the presence of iberiotoxin, pirfenidone still increased acetylcholine relaxation in aorta from db/db mice. Immunoblotting for K(V)7.4, K(V)7.5, and BK(Ca) channel subunits were unaltered in aorta from db/db mice. Pirfenidone failed to improve acetylcholine relaxation in mesenteric arteries, and neither changed acetylcholine-induced transient decreases in blood pressure in db/db+ and db/db mice. In conclusion, pirfenidone vasodilates pulmonary and coronary arteries. In coronary arteries from normal mice, pirfenidone induces NO-dependent vasodilatation involving BK(Ca) and K(V)7 channels. Pirfenidone improves endothelium-dependent vasodilatation in aorta from diabetic animals by a mechanism involving voltage-gated K(V)7 channels, a mechanism that may contribute to the antifibrotic effect of pirfenidone.
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spelling pubmed-79069772021-02-27 Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice Beck, Lilliana Pinilla, Estéfano Arcanjo, Daniel Dias Rufino Hernanz, Raquel Prat-Duran, Judit Petersen, Asbjørn Graver Köhler, Ralf Sheykhzade, Majid Comerma-Steffensen, Simon Simonsen, Ulf Front Pharmacol Pharmacology Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechanisms involved in the relaxant effect of pirfenidone in rat intrapulmonary arteries and coronary arteries from normal mice. Then in a second study, we investigated whether pirfenidone restores endothelial function in the aorta and mesenteric arteries from diabetic animals. From 16–18-week old normal male C57BL/6 mice and normoglycemic (db/db+), and type 2 diabetic (db/db) male and female mice, arteries were mounted in microvascular isometric myographs for functional studies, and immunoblotting was performed. In rat pulmonary arteries and mouse coronary arteries, pirfenidone induced relaxations, which were inhibited in preparations without endothelium. In mouse coronary arteries, pirfenidone relaxation was inhibited in the presence of a nitric oxide (NO) synthase inhibitor, N(G)-nitro-l-arginine (L-NOARG), a blocker of large-conductance calcium-activated potassium channels (BK(Ca)), iberiotoxin, and a blocker of K(V)7 channels, XE991. Patch clamp studies in vascular smooth muscle revealed pirfenidone increased iberiotoxin-sensitive current. In the aorta and mesenteric small arteries from diabetic db/db mice relaxations induced by the endothelium-dependent vasodilator, acetylcholine, were markedly reduced compared to db/db + mice. Pirfenidone enhanced the relaxations induced by acetylcholine in the aorta from diabetic male and female db/db mice. An opener of K(V)7 channels, flupirtine, had the same effect as pirfenidone. XE991 reduced the effect of pirfenidone and flupirtine and further reduced acetylcholine relaxations in the aorta. In the presence of iberiotoxin, pirfenidone still increased acetylcholine relaxation in aorta from db/db mice. Immunoblotting for K(V)7.4, K(V)7.5, and BK(Ca) channel subunits were unaltered in aorta from db/db mice. Pirfenidone failed to improve acetylcholine relaxation in mesenteric arteries, and neither changed acetylcholine-induced transient decreases in blood pressure in db/db+ and db/db mice. In conclusion, pirfenidone vasodilates pulmonary and coronary arteries. In coronary arteries from normal mice, pirfenidone induces NO-dependent vasodilatation involving BK(Ca) and K(V)7 channels. Pirfenidone improves endothelium-dependent vasodilatation in aorta from diabetic animals by a mechanism involving voltage-gated K(V)7 channels, a mechanism that may contribute to the antifibrotic effect of pirfenidone. Frontiers Media S.A. 2021-01-12 /pmc/articles/PMC7906977/ /pubmed/33643042 http://dx.doi.org/10.3389/fphar.2020.619152 Text en Copyright © 2021 Beck, Pinilla, Arcanjo, Hernanz, Prat-Duran, Petersen, Köhler, Sheykhzade, Comerma-Steffensen and Simonsen. 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 Pharmacology
Beck, Lilliana
Pinilla, Estéfano
Arcanjo, Daniel Dias Rufino
Hernanz, Raquel
Prat-Duran, Judit
Petersen, Asbjørn Graver
Köhler, Ralf
Sheykhzade, Majid
Comerma-Steffensen, Simon
Simonsen, Ulf
Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
title Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
title_full Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
title_fullStr Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
title_full_unstemmed Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
title_short Pirfenidone Is a Vasodilator: Involvement of K(V)7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
title_sort pirfenidone is a vasodilator: involvement of k(v)7 channels in the effect on endothelium-dependent vasodilatation in type-2 diabetic mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906977/
https://www.ncbi.nlm.nih.gov/pubmed/33643042
http://dx.doi.org/10.3389/fphar.2020.619152
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