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Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension

Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 bl...

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Autores principales: Alhusban, Ahmed, Kozak, Anna, Pillai, Bindu, Ahmed, Heba, Sayed, Mohammed A., Johnson, Maribeth H., Ishrat, Tauheed, Ergul, Adviye, Fagan, Susan C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480858/
https://www.ncbi.nlm.nih.gov/pubmed/28640888
http://dx.doi.org/10.1371/journal.pone.0178867
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author Alhusban, Ahmed
Kozak, Anna
Pillai, Bindu
Ahmed, Heba
Sayed, Mohammed A.
Johnson, Maribeth H.
Ishrat, Tauheed
Ergul, Adviye
Fagan, Susan C.
author_facet Alhusban, Ahmed
Kozak, Anna
Pillai, Bindu
Ahmed, Heba
Sayed, Mohammed A.
Johnson, Maribeth H.
Ishrat, Tauheed
Ergul, Adviye
Fagan, Susan C.
author_sort Alhusban, Ahmed
collection PubMed
description Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 blocker-mediated protective and pro-recovery effects in animals with hypertension. We also evaluated the effect of acute eNOS inhibition in hypertensive animals. To achieve these goals, spontaneously hypertensive rats (SHR) were implanted with blood pressure transmitters, and randomized to receive either an eNOS inhibitor (L-NIO) or saline one hour before cerebral ischemia induction. After 3 hours of ischemia, animals were further randomized to receive either candesartan or saline at the time of reperfusion and sacrificed either 24 hours or 7 days later. Candesartan induced an early protective effect that was independent of eNOS inhibition (50% improvement in motor function). However, the protective effect of candesartan was associated with about five fold up regulation of BDNF expression and about three fold reduction in ER stress markers, in an eNOS dependent manner. The early benefit of a single dose of candesartan, present at 24 hours after stroke, was diminished at 7 days, perhaps due to a failure to induce an angiogenic response in these hypertensive animals. In conclusion, our findings demonstrate an early prorecovery effect of candesartan at both functional and molecular levels. Candesartan induced prorecovery signaling was mediated through eNOS. This effect was not maintained at 7 days after experimental ischemia.
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spelling pubmed-54808582017-07-05 Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension Alhusban, Ahmed Kozak, Anna Pillai, Bindu Ahmed, Heba Sayed, Mohammed A. Johnson, Maribeth H. Ishrat, Tauheed Ergul, Adviye Fagan, Susan C. PLoS One Research Article Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 blocker-mediated protective and pro-recovery effects in animals with hypertension. We also evaluated the effect of acute eNOS inhibition in hypertensive animals. To achieve these goals, spontaneously hypertensive rats (SHR) were implanted with blood pressure transmitters, and randomized to receive either an eNOS inhibitor (L-NIO) or saline one hour before cerebral ischemia induction. After 3 hours of ischemia, animals were further randomized to receive either candesartan or saline at the time of reperfusion and sacrificed either 24 hours or 7 days later. Candesartan induced an early protective effect that was independent of eNOS inhibition (50% improvement in motor function). However, the protective effect of candesartan was associated with about five fold up regulation of BDNF expression and about three fold reduction in ER stress markers, in an eNOS dependent manner. The early benefit of a single dose of candesartan, present at 24 hours after stroke, was diminished at 7 days, perhaps due to a failure to induce an angiogenic response in these hypertensive animals. In conclusion, our findings demonstrate an early prorecovery effect of candesartan at both functional and molecular levels. Candesartan induced prorecovery signaling was mediated through eNOS. This effect was not maintained at 7 days after experimental ischemia. Public Library of Science 2017-06-22 /pmc/articles/PMC5480858/ /pubmed/28640888 http://dx.doi.org/10.1371/journal.pone.0178867 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Alhusban, Ahmed
Kozak, Anna
Pillai, Bindu
Ahmed, Heba
Sayed, Mohammed A.
Johnson, Maribeth H.
Ishrat, Tauheed
Ergul, Adviye
Fagan, Susan C.
Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension
title Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension
title_full Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension
title_fullStr Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension
title_full_unstemmed Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension
title_short Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension
title_sort mechanisms of acute neurovascular protection with at1 blockade after stroke: effect of prestroke hypertension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480858/
https://www.ncbi.nlm.nih.gov/pubmed/28640888
http://dx.doi.org/10.1371/journal.pone.0178867
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