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VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension

BACKGROUND: Pulmonary Arterial Hypertension (PAH) remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene caused the spontaneous expression of a PH phenotype that was...

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Autores principales: Hamidi, Sayyed A, Lin, Richard Z, Szema, Anthony M, Lyubsky, Sergey, Jiang, Ya Ping, Said, Sami I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210095/
https://www.ncbi.nlm.nih.gov/pubmed/22029879
http://dx.doi.org/10.1186/1465-9921-12-141
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author Hamidi, Sayyed A
Lin, Richard Z
Szema, Anthony M
Lyubsky, Sergey
Jiang, Ya Ping
Said, Sami I
author_facet Hamidi, Sayyed A
Lin, Richard Z
Szema, Anthony M
Lyubsky, Sergey
Jiang, Ya Ping
Said, Sami I
author_sort Hamidi, Sayyed A
collection PubMed
description BACKGROUND: Pulmonary Arterial Hypertension (PAH) remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene caused the spontaneous expression of a PH phenotype that was fully corrected by VIP. The objectives of this investigation were to answer the questions: 1) Can VIP protect against PH in other experimental models? and 2) Does combining VIP with an endothelin (ET) receptor antagonist bosentan enhance its efficacy? METHODS: Within 3 weeks of a single injection of monocrotaline (MCT, s.c.) in Sprague Dawley rats, PAH developed, manifested by pulmonary vascular remodeling, lung inflammation, RV hypertrophy, and death within the next 2 weeks. MCT-injected animals were either untreated, treated with bosentan (p.o.) alone, with VIP (i.p.) alone, or with both together. We selected this particular combination upon finding that VIP down-regulates endothelin receptor expression which is further suppressed by bosentan. Therapeutic outcomes were compared as to hemodynamics, pulmonary vascular pathology, and survival. RESULTS: Treatment with VIP, every other day for 3 weeks, begun on the same day as MCT, almost totally prevented PAH pathology, and eliminated mortality for 45 days. Begun 3 weeks after MCT, however, VIP only partially reversed PAH pathology, though more effectively than bosentan. Combined therapy with both drugs fully reversed the pathology, while preventing mortality for at least 45 days. CONCLUSIONS: 1) VIP completely prevented and significantly reversed MCT-induced PAH; 2) VIP was more effective than bosentan, probably because it targets a wider range of pro-remodeling pathways; and 3) combination therapy with VIP plus bosentan was more effective than either drug alone, probably because both drugs synergistically suppressed ET-ET receptor pathway.
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spelling pubmed-32100952011-11-08 VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension Hamidi, Sayyed A Lin, Richard Z Szema, Anthony M Lyubsky, Sergey Jiang, Ya Ping Said, Sami I Respir Res Research BACKGROUND: Pulmonary Arterial Hypertension (PAH) remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene caused the spontaneous expression of a PH phenotype that was fully corrected by VIP. The objectives of this investigation were to answer the questions: 1) Can VIP protect against PH in other experimental models? and 2) Does combining VIP with an endothelin (ET) receptor antagonist bosentan enhance its efficacy? METHODS: Within 3 weeks of a single injection of monocrotaline (MCT, s.c.) in Sprague Dawley rats, PAH developed, manifested by pulmonary vascular remodeling, lung inflammation, RV hypertrophy, and death within the next 2 weeks. MCT-injected animals were either untreated, treated with bosentan (p.o.) alone, with VIP (i.p.) alone, or with both together. We selected this particular combination upon finding that VIP down-regulates endothelin receptor expression which is further suppressed by bosentan. Therapeutic outcomes were compared as to hemodynamics, pulmonary vascular pathology, and survival. RESULTS: Treatment with VIP, every other day for 3 weeks, begun on the same day as MCT, almost totally prevented PAH pathology, and eliminated mortality for 45 days. Begun 3 weeks after MCT, however, VIP only partially reversed PAH pathology, though more effectively than bosentan. Combined therapy with both drugs fully reversed the pathology, while preventing mortality for at least 45 days. CONCLUSIONS: 1) VIP completely prevented and significantly reversed MCT-induced PAH; 2) VIP was more effective than bosentan, probably because it targets a wider range of pro-remodeling pathways; and 3) combination therapy with VIP plus bosentan was more effective than either drug alone, probably because both drugs synergistically suppressed ET-ET receptor pathway. BioMed Central 2011 2011-10-26 /pmc/articles/PMC3210095/ /pubmed/22029879 http://dx.doi.org/10.1186/1465-9921-12-141 Text en Copyright ©2011 Hamidi et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Hamidi, Sayyed A
Lin, Richard Z
Szema, Anthony M
Lyubsky, Sergey
Jiang, Ya Ping
Said, Sami I
VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension
title VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension
title_full VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension
title_fullStr VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension
title_full_unstemmed VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension
title_short VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension
title_sort vip and endothelin receptor antagonist: an effective combination against experimental pulmonary arterial hypertension
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210095/
https://www.ncbi.nlm.nih.gov/pubmed/22029879
http://dx.doi.org/10.1186/1465-9921-12-141
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