Hyperglycemia generally enhances cerebral ischemic injury. Most research has focused on the adverse effect of increased lactate production (acidosis) leading to neuronal injury. The effects of hyperglycemia on another possible primary target, the cerebral microvasculature, is examined in this study. Focal cerebral ischemia was achieved by thread occlusion of the middle cerebral artery (MCA). Preischemic hyperglycemia was induced by intra peritoneal administration of 50% of D-glucose solution. In contrast to normoglycemic controls, glucose-injected rats showed a well demarcated pale infarct after 2 or 4 hours of ischemia reflecting a reduction in cerebral plasma volume (CPV) to 73 +/- 9 and 55 +/- 6% of the contralateral hemisphere by 2 and 4 hours respectively. Cerebral blood flow (CBF) measured by laser Doppler flowmetry indicated that after the initial decline in CBF with MCA occlusion, hyperglycemia led to a further progressive reduction during ischemia. On reperfusion, hyperglycemia resulted in poor restoration of CBF, increased occurrence of hemorrhagic infarction (12 of 12) and a large infarct volume. Hyperglycemia induces progressive cerebrovascular changes during ischemia and affects hemodynamic recovery on reperfusion. These changes may contribute to the adverse effects of hyperglycemia in stroke. A reduction in CPV may be a useful indicator of an increased incidence of hemorrhagic infarction after thrombolytic therapy for ischemic stroke.