Effect of AR-R 17477, a potent neuronal nitric oxide synthase inhibitor, on infarction volume resulting from permanent focal ischemia in rats

Izumi Harukuni, Richard J. Traystman, Jeffrey Kirsch

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: We tested whether AR-R 17477, a selective inhibitor of neuronal nitric oxide synthase, reduces brain injury in rats subjected to permanent focal ischemia. Design: Randomized within cohort; nonblinded study. Setting: University basic science laboratory. Subjects: Halothane- anesthetized male Wistar rats (n = 53). Interventions: Rats were treated with either intravenous saline (diluent) or AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of permanent focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of ischemia. Measurements and Main Results: Pretreatment with 1 mg/kg AR-R 17477 was associated with a decreased infarct volume (2,3,5-triphenyltetrazolium chloride staining) in the striatum (saline, 81 ± 7 mm3; AR-R 17477, 55 ± 3 mm3) but not in the cortex at 18 hrs of occlusion (saline, 302 ± 29 mm3; AR-R 17477, 237 ± 36 mm3). However, this therapeutic effect of AR-R 17477 was no longer evident if the rats were allowed to survive for 48 hrs before analysis of infarction volume. In fact, in this separate cohort of animals, three of eight AR-R 17477-treated and five of eight saline-treated rats died before completing 48 hrs of ischemia. Efficacy of AR-R 17477 was completely absent (even at 18 hrs of ischemia) when drug treatment was delayed until 1 hr after the onset of ischemia. Infarction volume at 18 hrs of ischemia was similar between rats treated with saline, 1 mg/kg (cortex, 229 ± 43 mm3; striatum, 67 ± 8 mm3) or 3 mg/kg AR-R 17477 (cortex, 284 ± 34 mm3; striatum, 75 ± 5 mm3). In addition, only one of eight rats treated with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of occlusion, compared with three of eight rats treated with saline. Conclusions: Neuronally generated nitric oxide is a mediator of brain injury during permanent focal ischemia in rats. However, severity of the ischemic insult appears to limit the therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR-R 17477.

Original languageEnglish (US)
Pages (from-to)2508-2511
Number of pages4
JournalCritical Care Medicine
Volume27
Issue number11
StatePublished - 1999
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type I
Infarction
Ischemia
Brain Injuries
Therapeutic Uses
Halothane
Brain Ischemia
Wistar Rats
Nitric Oxide
Staining and Labeling

Keywords

  • Blood pressure
  • Blood-brain barrier penetration
  • Brain injury
  • Cerebral infarction
  • Injury progression
  • Intravascular occlusion
  • Middle cerebral artery occlusion
  • Nitric oxide synthase inhibitor
  • Rodent
  • Stroke

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

@article{6677cda514834ee697115fe3324ff20c,
title = "Effect of AR-R 17477, a potent neuronal nitric oxide synthase inhibitor, on infarction volume resulting from permanent focal ischemia in rats",
abstract = "Objective: We tested whether AR-R 17477, a selective inhibitor of neuronal nitric oxide synthase, reduces brain injury in rats subjected to permanent focal ischemia. Design: Randomized within cohort; nonblinded study. Setting: University basic science laboratory. Subjects: Halothane- anesthetized male Wistar rats (n = 53). Interventions: Rats were treated with either intravenous saline (diluent) or AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of permanent focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of ischemia. Measurements and Main Results: Pretreatment with 1 mg/kg AR-R 17477 was associated with a decreased infarct volume (2,3,5-triphenyltetrazolium chloride staining) in the striatum (saline, 81 ± 7 mm3; AR-R 17477, 55 ± 3 mm3) but not in the cortex at 18 hrs of occlusion (saline, 302 ± 29 mm3; AR-R 17477, 237 ± 36 mm3). However, this therapeutic effect of AR-R 17477 was no longer evident if the rats were allowed to survive for 48 hrs before analysis of infarction volume. In fact, in this separate cohort of animals, three of eight AR-R 17477-treated and five of eight saline-treated rats died before completing 48 hrs of ischemia. Efficacy of AR-R 17477 was completely absent (even at 18 hrs of ischemia) when drug treatment was delayed until 1 hr after the onset of ischemia. Infarction volume at 18 hrs of ischemia was similar between rats treated with saline, 1 mg/kg (cortex, 229 ± 43 mm3; striatum, 67 ± 8 mm3) or 3 mg/kg AR-R 17477 (cortex, 284 ± 34 mm3; striatum, 75 ± 5 mm3). In addition, only one of eight rats treated with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of occlusion, compared with three of eight rats treated with saline. Conclusions: Neuronally generated nitric oxide is a mediator of brain injury during permanent focal ischemia in rats. However, severity of the ischemic insult appears to limit the therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR-R 17477.",
keywords = "Blood pressure, Blood-brain barrier penetration, Brain injury, Cerebral infarction, Injury progression, Intravascular occlusion, Middle cerebral artery occlusion, Nitric oxide synthase inhibitor, Rodent, Stroke",
author = "Izumi Harukuni and Traystman, {Richard J.} and Jeffrey Kirsch",
year = "1999",
language = "English (US)",
volume = "27",
pages = "2508--2511",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
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TY - JOUR

T1 - Effect of AR-R 17477, a potent neuronal nitric oxide synthase inhibitor, on infarction volume resulting from permanent focal ischemia in rats

AU - Harukuni, Izumi

AU - Traystman, Richard J.

AU - Kirsch, Jeffrey

PY - 1999

Y1 - 1999

N2 - Objective: We tested whether AR-R 17477, a selective inhibitor of neuronal nitric oxide synthase, reduces brain injury in rats subjected to permanent focal ischemia. Design: Randomized within cohort; nonblinded study. Setting: University basic science laboratory. Subjects: Halothane- anesthetized male Wistar rats (n = 53). Interventions: Rats were treated with either intravenous saline (diluent) or AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of permanent focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of ischemia. Measurements and Main Results: Pretreatment with 1 mg/kg AR-R 17477 was associated with a decreased infarct volume (2,3,5-triphenyltetrazolium chloride staining) in the striatum (saline, 81 ± 7 mm3; AR-R 17477, 55 ± 3 mm3) but not in the cortex at 18 hrs of occlusion (saline, 302 ± 29 mm3; AR-R 17477, 237 ± 36 mm3). However, this therapeutic effect of AR-R 17477 was no longer evident if the rats were allowed to survive for 48 hrs before analysis of infarction volume. In fact, in this separate cohort of animals, three of eight AR-R 17477-treated and five of eight saline-treated rats died before completing 48 hrs of ischemia. Efficacy of AR-R 17477 was completely absent (even at 18 hrs of ischemia) when drug treatment was delayed until 1 hr after the onset of ischemia. Infarction volume at 18 hrs of ischemia was similar between rats treated with saline, 1 mg/kg (cortex, 229 ± 43 mm3; striatum, 67 ± 8 mm3) or 3 mg/kg AR-R 17477 (cortex, 284 ± 34 mm3; striatum, 75 ± 5 mm3). In addition, only one of eight rats treated with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of occlusion, compared with three of eight rats treated with saline. Conclusions: Neuronally generated nitric oxide is a mediator of brain injury during permanent focal ischemia in rats. However, severity of the ischemic insult appears to limit the therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR-R 17477.

AB - Objective: We tested whether AR-R 17477, a selective inhibitor of neuronal nitric oxide synthase, reduces brain injury in rats subjected to permanent focal ischemia. Design: Randomized within cohort; nonblinded study. Setting: University basic science laboratory. Subjects: Halothane- anesthetized male Wistar rats (n = 53). Interventions: Rats were treated with either intravenous saline (diluent) or AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of permanent focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of ischemia. Measurements and Main Results: Pretreatment with 1 mg/kg AR-R 17477 was associated with a decreased infarct volume (2,3,5-triphenyltetrazolium chloride staining) in the striatum (saline, 81 ± 7 mm3; AR-R 17477, 55 ± 3 mm3) but not in the cortex at 18 hrs of occlusion (saline, 302 ± 29 mm3; AR-R 17477, 237 ± 36 mm3). However, this therapeutic effect of AR-R 17477 was no longer evident if the rats were allowed to survive for 48 hrs before analysis of infarction volume. In fact, in this separate cohort of animals, three of eight AR-R 17477-treated and five of eight saline-treated rats died before completing 48 hrs of ischemia. Efficacy of AR-R 17477 was completely absent (even at 18 hrs of ischemia) when drug treatment was delayed until 1 hr after the onset of ischemia. Infarction volume at 18 hrs of ischemia was similar between rats treated with saline, 1 mg/kg (cortex, 229 ± 43 mm3; striatum, 67 ± 8 mm3) or 3 mg/kg AR-R 17477 (cortex, 284 ± 34 mm3; striatum, 75 ± 5 mm3). In addition, only one of eight rats treated with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of occlusion, compared with three of eight rats treated with saline. Conclusions: Neuronally generated nitric oxide is a mediator of brain injury during permanent focal ischemia in rats. However, severity of the ischemic insult appears to limit the therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR-R 17477.

KW - Blood pressure

KW - Blood-brain barrier penetration

KW - Brain injury

KW - Cerebral infarction

KW - Injury progression

KW - Intravascular occlusion

KW - Middle cerebral artery occlusion

KW - Nitric oxide synthase inhibitor

KW - Rodent

KW - Stroke

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M3 - Article

VL - 27

SP - 2508

EP - 2511

JO - Critical Care Medicine

JF - Critical Care Medicine

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