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Objectives: Focal cerebral ischemia is responsible for alterations of vascular permeability, and the loss of microvascular integrity is a primary source of subsequent hemorrhages. We evaluated the influence of different durations of ischemia and reperfusion on infarction size and microvascular damage after focal cerebral ischemia in the mouse. Methods: C57BL/6 mice (n = 39) were subjected to focal cerebral ischemia (I) and reperfusion (R). Consecutive brain sections were analysed for infarction volumes (Nissl-staining) and for collagen type IV (immunohistochemistry and western blot). Results: Infarction size (percentage of the infarction volume versus ipsilateral hemisphere) increased with total time of ischemia and reperfusion: 19 ± 2% (I3R0), 30 ± 2% (I3R3), 36 ± 4% (I3R12), 41 ± 4% (I1R24), 45 ± 6% (I2R24) and 58 ± 2% (I3R24). The ischemic hemispheres showed a significant progressive reduction of collagen type IV positive vessels (ischemic versus non-ischemic contralateral area): 90 ± 3% (I3R0), 88 ± 1% (I3R3), 82 ± 3% (I3R12), 85 ± 3% (I1R24), 79 ± 3% (I2R24), 72 ± 2% (I3R24). Conclusions: Both prolonged ischemia and reperfusion lead to an increased infarction volume, as well as progressive microvascular damage. [ABSTRACT FROM AUTHOR]

Abstract: The spontaneously hypertensive stroke-prone rat (SHR-SP) is an experimental model of malignant hypertension which lead to secondary alterations of the extracellular matrix. Our aim was to determine ACE-inhibitor related changes of proteases involved in the reconstruction of the extracellular matrix in the brain. Twelve SHR-SP rats were randomized into two groups. Each group was treated with either an antihypertensive dose of ramipril or placebo for 6 months. Brain tissue plasminogen activator (t-PA) and urokinase (u-PA) were quantified by using casein-dependent plasminogen zymography, matrix metalloproteinase (MMP)-2 and MMP-9, by MMP-zymography, and tissue inhibitor of MMP (TIMP)-1 and -2, by reverse zymography. The amounts of u-PA, t-PA, and MMPs were significantly reduced in animals treated with ACE inhibitor. Plasminogen zymography showed a 39% reduction of u-PA in the basal ganglia (p <0.0001); t-PA expression was reduced by 26% in the cortex and by 33% in the basal ganglia (p <0.0001). MMP-2 expression was reduced by 15% in the cortex (p <0.05) and by 10% in the basal ganglia (p <0.05); MMP-9 expression significantly decreased by 37% in the cortex and by 25% in the basal ganglia (p <0.0001 each). No differences were observed in the amount of TIMP-1 or TIMP-2. These findings provide new insights into the biochemical mechanisms underlying extracellular matrix proliferation and its modulation by ACE inhibitors. Therapeutic alterations that influence the proteolytic systems might prove important in the prevention of extracellular matrix accumulation and secondary microvascular vessel wall changes. [Copyright &y& Elsevier]