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

PLoS One. 2017 Jun 22;12(6):e0178867. doi: 10.1371/journal.pone.0178867. eCollection 2017.


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.

MeSH terms

  • Acute Disease
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Benzimidazoles / pharmacology*
  • Biphenyl Compounds
  • Blood Vessels / drug effects*
  • Blood Vessels / metabolism
  • Blood Vessels / pathology
  • Blood Vessels / physiopathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Gene Expression Regulation / drug effects
  • Hypertension / complications*
  • Male
  • Nerve Growth Factors / metabolism
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Nogo Proteins / metabolism
  • Oxidative Stress / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Rats, Inbred SHR
  • Reactive Nitrogen Species / metabolism
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptor, trkB
  • Signal Transduction / drug effects
  • Stroke / metabolism
  • Stroke / pathology
  • Stroke / physiopathology
  • Stroke / prevention & control*
  • Tetrazoles / pharmacology*
  • Unfolded Protein Response / drug effects


  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Biphenyl Compounds
  • Brain-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Nogo Proteins
  • Reactive Nitrogen Species
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type III
  • Ntrk2 protein, rat
  • Protein-Tyrosine Kinases
  • Receptor, trkB
  • candesartan