Summary

While recombinant tissue plasminogen activator (rt-PA) issuccessfully used in human ischemic stroke, it may also causehemorrhagic complications. Animal experiments have shownthat hemorrhages are related to microvascular basal laminadamage.We investigated the effects of different doses of rt-PAon the brain microvasculature. Experimental cerebral ischemiain rats was induced for 3 h and followed by 24 h reperfusion(suture model). Each group of rats (n = 6) received either treatment(0.9, 9, or 18 mg rt-PA/kg body weight) or saline (controlgroup) at the end of ischemia. The loss of microvascular basallamina antigen collagen type IV was measured by Western blotof the ischemic and non-ischemic basal ganglia and cortex.Compared with the contralateral non-ischemic area, collagentype IV was significantly reduced in the ischemic area: (basal ganglia/cortex) 43% +/- 9% / 64% +/- 4 %. Low/moderate dosesof rt-PA had a protective effect: 0.9 mg 79% +/- 3% / 89% +/-6%, 9 mg 72% +/- 9%/ 81% +/- 12% (p < 0.05). Higher doses ofrt-PA (18 mg) had a similar effect as seen in untreated controls:57% +/- 11% / 59% +/- 9% (p < 0.05,Anova). MMP-9 and MMP-2, measured by gelatine zymography, steadily increased overhigher doses of rt-PA: MMP-9 (basal ganglia/cortex): control115% +/- 4% / 123% +/- 3% compared with 18 mg rt-PA 146%+/- 5%/ 162% +/- 6% (p < 0.05) and MMP-2: control 109% +/-4%/ 116% +/- 5% and 18 mg rt-PA 222% +/- 15%/ 252% +/- 2%(p < 0.05). Low to moderate doses of rt-PA protect themicrovascular basal lamina, whereas high doses of rt-PA havethe opposite effect, probably due to increased coactivation ofMMP-2 and MMP-9.