Abstract TP104: Candesartan Increases Matrix Metalloproteinase Activation but Still Provides Benefit When in Combination with Tissue Plasminogen Activator in Experimental Embolic Stroke
Background & Objective: Recently, combination therapy with tissue plasminogen activator (tPA) has been shown to worsen stroke outcome in experimental and clinical studies (Erythropoietin). Candesartan increases matrix metalloproteinase (MMP) activation and exhibits vascular protection in experimental stroke. It is imperative to test for interactions with tPA. The present study evaluated the effect of candesartan in combination with tPA in a rat model of embolic stroke.
Methods: Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) and treated with either candesartan (1mg/kg) alone early at 3h, tPA (10mg/kg) alone at 6h, the combination of candesartan (early 3h and delayed 24h) and tPA (6h), or saline control. A battery of functional outcome test was performed before sacrifice at 24 and 48h after eMCAO and infarct sizes, hemoglobin content (Hb) and tissue MMP activity analyzed.
Results: The combination therapy of candesartan (3h) and tPA (6h) after MCAO reduced the brain hemorrhage in terms of Hb content and improved functional outcome compared with rats treated with tPA alone. However, when the candesartan therapy was delayed to 24 h (tPA at 6h) after MCAO, the benefit was lost. Furthermore, candesartan (3h) alone and also in combination with tPA increased MMP activation compared with respective controls.
Conclusions: Acute administration of candesartan, despite increasing MMP activation, reduces bleeding associated with tPA use in the rat embolic model. MMP activation alone is insufficient to cause increased hemorrhagic transformation. Table 1. Summary of experimental stroke data. SE are shown in parentheses. P<0.05 was considered significant.
- © 2012 by American Heart Association, Inc.