Effects of recombinant tissue plasminogen activator after intraluminal thread occlusion in mice - Role of hemodynamic alterations

Background and Purpose-It has been suggested that recombinant tissue plasmi nogen activator (rtPA) may cause an aggravation of injury after transient f ocal ischemia via excitotoxic side effects. Such rtPA toxicity would be of major clinical significance since rtPA is increasingly used in stroke treat ment. This study was conducted to evaluate the effects of dose, application time, and hemodynamic changes after intravenous rtPA treatment in focal is chemia. Methods-Mice were subjected to a 90-minute episode of middle cerebral arter y thread occlusion, and rtPA effects were assessed by laser-Doppler flowmet ry, [C-14]iodoantipyrine autoradiography, and triphenyltetrazolium chloride staining. Results and Conclusions-We provide evidence that rtPA provokes complex hemo dynamic alterations in the ischemic brain tissue, which include an initial hyperperfusion and a more delayed hypoperfusion response. Changes are most pronounced in the periphery of the ischemic infarct, where regional blood f low drops below critical thresholds of tissue viability. Our observations s uggest that changes of perfusion may at least partly explain the rtPA-induc ed increase of infarct size, which has previously been reported and which w e also confirmed in the present experiments. Notably, both the secondary hy poperfusion and increase of infarct volume were abolished when rtPA-treated animals received additional heparin infusions. This finding suggests that a secondary hypercoagulability may compromise brain perfusion after rtPA de livery. Accordingly, early treatment with heparin might help to prevent the rtPA-induced changes.