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

Ahmed Alhusban, Anna Kozak, Bindu Pillai, Heba Ahmed, Mohammed A. Sayed, Maribeth H. Johnson, Tauheed Ishrat, Adviye Ergul, Susan C. Fagan

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0178867
JournalPloS one
Volume12
Issue number6
DOIs
StatePublished - Jun 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Alhusban, A., Kozak, A., Pillai, B., Ahmed, H., Sayed, M. A., Johnson, M. H., Ishrat, T., Ergul, A., & Fagan, S. C. (2017). Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension. PloS one, 12(6), [e0178867]. https://doi.org/10.1371/journal.pone.0178867