This Article Full Text Full Text (PDF) All Versions of this Article: 40/4/1482    most recent STROKEAHA.108.531509v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McCarthy, C. A. Articles by Widdop, R. E. Search for Related Content PubMed PubMed Citation Articles by McCarthy, C. A. Articles by Widdop, R. E. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Stroke Related Collections Cardiovascular Pharmacology ACE/Angiotension receptors Cerebrovascular disease/stroke Animal models of human disease Other Stroke Treatment - Medical

(Stroke. 2009;40:1482.)
© 2009 American Heart Association, Inc.

Original Contributions

Angiotensin AT₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

Claudia A. McCarthy, BBNS(Hons); Antony Vinh, PhD; Jennifer K. Callaway, PhD Robert E. Widdop, PhD

From the Department of Pharmacology (C.A.M., A.V., R.E.W.), Monash University, Clayton, Victoria, Australia; and the Department of Pharmacology (J.K.C.), University of Melbourne, Parkville, Victoria, Australia.

Correspondence to Robert E. Widdop, PhD, Department of Pharmacology, Monash University, Clayton Victoria 3800, Australia. E-mail robert.widdop{at}med.monash.edu.au

Background and Purpose— The angiotensin II type 2 receptor (AT₂R) is implicated to be neuroprotective in stroke, although this premise has not been directly tested. Therefore, we have examined the neuroprotective effect of AT₂R stimulation after intracerebroventricular administration of AT₂R agonist CGP42112 in a conscious rat model of stroke.

Methods— Spontaneously hypertensive rats were treated with either CGP42112 (0.1 to 10 ng/kg/min intracerebroventricularly) alone or in combination with the AT₂R antagonist PD123319 (36 ng/kg/min intracerebroventricularly) beginning 5 days before stroke induction. A focal reperfusion model of stroke was induced in conscious spontaneously hypertensive rats by administering endothelin-1 to the middle cerebral artery through a surgically implanted cannula. Behavioral tests were used to assess the severity of neurological deficit as a result of the ischemic event. Cortical and striatal infarct volumes were measured 72 hours poststroke.

Results— Blood pressure was unaffected by treatments. CGP42112 dose-dependently reduced cortical infarct volume poststroke, and PD123319 abolished the neuroprotective effect of CGP42112. PD123319 had no effect on infarct volume alone. These results were consistent with the behavioral findings, indicating that CGP42112 reduced motor deficit on the ledged beam test at 72 hours poststroke and immunohistochemical analyses showing that CGP42112 increased neuronal survival and minimized the loss of AT₂R expression in the infarcted region.

Conclusion— Based on infarct, behavioral, and immunohistochemical data, these results indicate that centrally administered CGP42112 exhibits a neuroprotective effect, which was independent of blood pressure. Thus, for the first time, we have shown that central AT₂R stimulation is neuroprotective in a conscious rat model of stroke.

Supplemental Materials and Methods

This article has been cited by other articles:

				K. Tsuda Angiotensin AT2 Receptor-Mediated Neuroprotection and Nitric Oxide-Bioavailability in Stroke Stroke, July 1, 2009; 40(7): e493 - e493. [Full Text] [PDF]

				C. A. McCarthy, A. Vinh, J. K. Callaway, and R. E. Widdop Response to Letter by Tsuda Stroke, July 1, 2009; 40(7): e494 - e494. [Full Text] [PDF]