ATP-sensitive potassium channels are activated under hypoxic or ischemic conditions. The effects of ATP-sensitive potassium channel activators on cerebrovasculature and cerebral blood flow (CBF) are not well understood. We examined the effect of the ATP-sensitive potassium channel activator Y-26763 on focal cerebral ischemia in rats. In 24 spontaneously hypertensive rats, either Y-26763 (24 micrograms/kg) or vehicle was given by intracarotid infusion over 60 min, starting 30 min before photochemically induced thrombotic occlusion of the middle cerebral artery. CBF was measured by laser-Doppler flowmetry in the peri-ischemic penumbral cortex. Although Y-26763 lowered systemic blood pressure by 13 mmHg, the infarct volume assessed 3 days after the occlusion was significantly smaller in the Y-26763-treated group (n = 12, 71.2 +/- 22.0 mm3) than in the control group (n = 12, 94.7 +/- 20.4 mm3, P = 0.013). Y-26763 did not affect CBF before or after occlusion compared with CBF values of the control group. The results are consistent with the view that the activation of the ATP-sensitive potassium channel is neuroprotective in focal cerebral ischemia.