We investigated the combined effect of increased brain topical K⁺ concentration and reduction of the nitric oxide(NO^.) level caused by nitric oxide scavenging or nitric oxide synthase (NOS) inhibition on regional cerebral blood flow and subarachnoid direct current (DC) potential. Using thiopental-anesthetized male Wistar rats with a closed cranial window preparation, brain topical superfusion of a combination of the NO^. scavenger hemoglobin(Hb; 2 mmol/L) and increased K⁺ concentration in the artificial cerebrospinal fluid ([K⁺]_ACSF) at 35 mmol/L led to sudden spontaneous transient ischemic events with a decrease of CBF to 14 ± 7% (n = 4) compared with the baseline (100%). The ischemic events lasted for 53 ± 17 minutes and were associated with a negative subarachnoid DC shift of −7.3 ± 0.6 mV of 49 ± 12 minutes' duration. The combination of the NOS inhibitor N-nitro-L-arginine(L-NA, 1 mmol/L) with [K⁺]_ACSF at 35 mmol/L caused similar spontaneous transient ischemic events in 13 rats. When cortical spreading depression was induced by KCl at a 5-mm distance, a typical cortical spreading hyperemia (CSH) and negative DC shift were measured at the closed cranial window during brain topical superfusion with either physiologic artificial CSF (n = 5), or artificial CSF containing increased [K⁺]_ACSF at 20 mmol/L (n = 4), [K⁺]_ACSF at 3 mmol/L combined with L-NA (n = 10), [K⁺]_ACSF at 10 mmol/L combined with L-NA (five of six animals) or [K⁺]_ACSF at 3 mmol/L combined with Hb (three of four animals). Cortical spreading depression induced long-lasting transient ischemia instead of CSH, when brain was superfused with either[K⁺]_ACSF at 20 mmol/L combined with Hb (CBF decrease to 20± 20% duration 25 ± 21 minutes, n = 4), or [K⁺]_ACSF at 20 mmol/L combined with L-NA (n = 19). Transient ischemia induced by NOS inhibition and [K⁺]_ACSF at 20 mmol/L propagated at a speed of 3.4 ± 0.6 mm/min, indicating cortical spreading ischemia (CSI). Although CSH did not change oxygen free radical production, as measured on-line by in vivo lucigenin-enhanced chemiluminescence, CSI resulted in the typical radical production pattern of ischemia and reperfusion suggestive of brain damage (n = 4). Nimodipine (2 μg/kg body weight/min intravenously) transformed CSI back to CSH (n = 4). Vehicle had no effect on CSI(n = 4). Our data suggest that the combination of decreased NO^. levels and increased subarachnoid K⁺ levels induces spreading depression with acute ischemic CBF response. Thus, a disturbed coupling of metabolism and CBF can cause ischemia. We speculate that CSI may be related to delayed ischemic deficits after subarachnoid hemorrhage, a clinical condition in which the release of Hb and K⁺ from erythrocytes creates a microenvironment similar to the one investigated here.