Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl and water into the brain across an intact blood-brain barrier (BBB), together with astrocyte swelling as they take up the ions and water crossing the BBB. Our previous studies provided evidence that luminal BBB Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. Both NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC) are rapidly stimulated by the ischemic factors hypoxia, aglycemia and arginine vasopressin (AVP) and inhibition of these transporters by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. Here, we examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundances. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemia. We found that hypoxia, aglycemia and AVP all increase CMEC NHE activity through 5 hr and that NHE1 but not NHE2 abundance is increased by 1-5 hr exposures to these factors. Further, we found that the factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities.