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Stroke Research and Treatment
Volume 2014 (2014), Article ID 560491, 9 pages
http://dx.doi.org/10.1155/2014/560491
Research Article

Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism

1Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
2Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, HM 1212, 1120 15th Street, Augusta, GA 30912, USA
3Department of Biostatistics, Georgia Regents University, Augusta, GA 30912, USA
4Vision Discovery Institute, Georgia Regents University, Augusta, GA 30912, USA
5Department of Physiology, Georgia Regents University, Augusta, GA 30912, USA
6Department of Neurology, Georgia Regents University, Augusta, GA 30912, USA

Received 19 March 2014; Revised 23 June 2014; Accepted 7 July 2014; Published 24 July 2014

Academic Editor: Mohammad Moshahid Khan

Copyright © 2014 Tauheed Ishrat et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n = 9–14/group; a total of 99) were treated in a factorial design with candesartan 1 mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30 mg/kg IP or GM6001 50 mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3 h of middle cerebral artery occlusion (MCAO) and 21 h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone ( ) and in combination with FeTPPs ( ). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT ( ) and worsened neurologic score ( ). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism.