Chloride/bicarbonate exchange adversely modifies cardiovascular responses to traumatic brain injury

Physical trauma, psychosocial stress, and oxidative stress increase the neuronal transcription ratio of genes encoding the sodium-potassium chloride cotransporter (Nkcc1, Slc12a2) and the potassium chloride cotransporter (Kcc2, Slc12a5), which leads to neuronal depolarization and excitability. We hypothesized that increases in the Nkcc1:Kcc2 ratio of gene transcription in these injuries would be countered with downregulation of the gene encoding the cardiac and neuronal isoform of the chloride/bicarbonate exchanger (Ae3, Slc4a3). We found a reflex decrease in cardiac and neuronal Ae3 transcription that was associated with diminished traumatic brain injury (TBI)-induced increases in systolic blood pressure and decrements in heart rate and posttraumatic stress disorder (PTSD)-induced anxiety. We also observed pronounced sex differences in Nkcc1:Kcc2 expression, with female control and Ae3 knockout mice exhibiting significantly higher brain Nkcc1:Kcc2 ratios compared with males. Administration of testosterone after injury reduced the excessive cardiovascular reactivity induced by TBI. We suggest that pharmacologic antagonism of the cardiac/neuronal isoform of Ae3, perhaps with testosterone supplementation, may prove salutary in reducing the adverse cardiovascular and behavioral sequelae of TBI or psychological stress.