Abstract W P245: Impaired Response to Post-Stroke Candesartan Treatment in a Model of Type 2 Diabetes: Relationship to Angiotensin Receptors Expression

Abstract

Introduction: Angiotensin type 1 receptor (AT1) blockers (ARBs) provide beneficial effects in preclinical stroke research, that are mediated through the indirect aniogtensin type 2 receptor (AT2) stimulation. However, most of the studies have been conducted in normoglycemic animals. This study is the first to test the effect of post-stroke treatment with the ARB, candesartan, in the presence of pre-existing diabetes. Methods: Type II diabetic Goto-Kakizaki (GK) rats (n=14, blood glucose = 162.6±15.9 mg/dL), were subjected to 3 h MCA suture occlusion, and randomized to either IV saline or candesartan (1 mg/kg) at reperfusion. Blood pressure (BP), behavioral outcome, vascular integrity and molecular analysis were assessed at 24 h. AT1 and AT2 expression was examined at 24 h and compared to sham GKs and normoglycemic Wistar rats subjected to same experimental conditions. Results (Table): In GKs, candesartan reduced the stroke-induced elevation in BP only modestly. In contrast to previous studies in normoglycemic Wistars, candesartan failed to improve neurobehavioral outcome, preserve vascular integrity or reduce oxidative/nitrative stress or apoptotic markers after stroke in GK rats. Interestingly, stroke reduced the expression of AT2 in both hemispheres of GKs. Such an effect was not ameliorated by candesartan treatment. Conversely, stroke upregulated AT2 expression in the contralesional hemispheres of Wistars, an effect that was augmented by candesartan. Conclusion: GK rats have reduced sensitivity to post-stroke candesartan treatment. AT2 downregulation after stroke and failure of candesartan to rescue its expression could be the reason. This study highlights the importance of studying stroke therapeutics in animal models with co-morbid conditions that better reflects the stroke patient population.