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TRANSLATIONAL PHYSIOLOGY

Increased tolerance to oxygen and glucose deprivation in astrocytes from Na⁺/H⁺ exchanger isoform 1 null mice

Departments of ¹Neurosurgery and ²Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53792; ³Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267; and ⁴Department of Cardiovascular Sciences, University of Leicester, Leicester LE2 7LX, United Kingdom

Submitted 10 December 2003 ; accepted in final form 4 March 2004

ABSTRACT

The ubiquitously expressed Na⁺/H⁺ exchanger isoform 1 (NHE1) functions as a major intracellular pH (pH_i) regulatory mechanism in many cell types, and in some tissues its activity may contribute to ischemic injury. In the present study, cortical astrocyte cultures from wild-type (NHE1^+/+) and NHE1-deficient (NHE1^–/–) mice were used to investigate the role of NHE1 in pH_i recovery and ischemic injury in astrocytes. In the absence of HCO₃^–, the mean resting pH_i levels were 6.86 ± 0.03 in NHE1^+/+ astrocytes and 6.53 ± 0.04 in NHE1^–/– astrocytes. Removal of extracellular Na⁺ or blocking of NHE1 activity by the potent NHE1 inhibitor HOE-642 significantly reduced the resting level of pH_i in NHE1^+/+ astrocytes. NHE1^+/+ astrocytes exhibited a rapid pH_i recovery (0.33 ± 0.08 pH unit/min) after NH₄Cl prepulse acid load. The pH_i recovery in NHE1^+/+ astrocytes was reversibly inhibited by HOE-642 or removal of extracellular Na⁺. In NHE1^–/– astrocytes, the pH_i recovery after acidification was impaired and not affected by either Na⁺-free conditions or HOE-642. Furthermore, 2 h of oxygen and glucose deprivation (OGD) led to an 80% increase in pH_i recovery rate in NHE1^+/+ astrocytes. OGD induced a 5-fold rise in intracellular [Na⁺] and 26% swelling in NHE1^+/+ astrocytes. HOE-642 or genetic ablation of NHE1 significantly reduced the Na⁺ rise and swelling after OGD. These results suggest that NHE1 is the major pH_i regulatory mechanism in cortical astrocytes and that ablation of NHE1 in astrocytes attenuates ischemia-induced disruption of ionic regulation and swelling.

intracellular pH; cortical astrocytes; sodium/calcium exchange; ischemia; intracellular sodium

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