Cortical spreading depression (CSD) evokes a large cerebral blood flow (CBF) increase in normal rat brain. In contrast, in focal ischemic penumbra, CSD-like periinfarct depolarizations (PID) are mainly associated with hypoperfusion. Because PIDs electrophysiologically closely resemble CSD, we tested whether conditions present in ischemic penumbra, such as tissue hypoxia or reduced perfusion pressure, transform the CSD-induced CBF response in nonischemic rat cortex. Cerebral blood flow changes were recorded using laser Doppler flowmetry in rats subjected to hypoxia, hypotension, or both. Under normoxic normotensive conditions, CSD caused a characteristic transient CBF increase (74 +/- 7%) occasionally preceded by a small hypoperfusion (-4 +/- 2%). Both hypoxia (pO(2) 45 +/- 3mmHg) and hypotension (blood pressure 42 +/- 2mmHg) independently augmented this initial hypoperfusion (-14 +/- 2% normoxic hypotension; -16 +/- 6% hypoxic normotension; -21 +/- 5% hypoxic hypotension) and diminished the magnitude of hyperemia (44 +/- 10% normoxic hypotension; 43 +/- 9% hypoxic normotension; 27 +/- 6% hypoxic hypotension). Hypotension and, to a much lesser extent, hypoxia increased the duration of hypoperfusion and the DC shift, whereas CSD amplitude remained unchanged. These results suggest that hypoxia and/or hypotension unmask a vasoconstrictive response during CSD in the rat such that, under nonphysiologic conditions (i.e., mimicking ischemic penumbra), the hyperemic response to CSD becomes attenuated resembling the blood flow response during PIDs.